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Antipsychotic

Pharmacotherapy

Nicole Romstadt, PharmD


Psychiatric Clinical Pharmacy Specialist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Learning Objectives

• Describe the mechanisms of action for first and second generation


antipsychotics. Then, explain how activity at these receptors contributes to
both desirable and undesirable antipsychotic effects.
• Discuss the common and serious adverse effects associated with first and
second generation antipsychotics.
• Describe the role of long-acting injectable antipsychotics in the treatment of
schizophrenia and related disorders.
• Identify monitoring parameters and adverse effects associated with the use
of clozapine.
Common Antipsychotic Target Symptoms

Positive Symptoms Mania Symptoms


• Delusions • Grossly elevated mood
• Hallucinations • Increased energy/decreased sleep
• Auditory, visual, tactile • Racing thoughts
• Disorganized thinking • Grandiosity
• Irritability/agitation
• Example: Schizophrenia, • Impulsivity/risky behaviors
schizoaffective disorder, etc.
• Example: Bipolar disorder
Common Off-Label Uses

Potentially Inappropriate Indications


• Avoid routine use for these indications:
• Insomnia
• Anxiety disorders
• Post-traumatic stress disorder
• Behavioral and psychological symptoms of dementia
• Delirium
• Acute agitation
• If used, must frequently review the appropriateness, safety and need for
continuation
Brief Review of Pathophysiology

Schizophrenia Spectrum and Other Psychotic Disorders


• Exact mechanism is unknown
• Dopamine (DA) hypothesis
• Most recognized theory
• DA hyperfunction in limbic system leads to positive symptoms
• DA hypofunction in prefrontal cortex leads to negative symptoms
• Other implicated neurotransmitters
• Serotonin, glutamate, GABA, acetylcholine
Antipsychotic Mechanism of Action

Class Commonality
• Dopamine antagonism
• Prevents dopamine from
acting at post-synaptic D2
receptors
• Action in mesolimbic pathway
treats positive symptoms
• Requires approximately
60-70% dopamine blockade
• Higher blockade increases risk
for adverse effects
Dopamine Pathways
Dopamine Pathways

Mesolimbic pathway Nigrostriatal pathway


• Controls movement
• Emotional center related to arousal,
• D2-antagonism leads to extrapyramidal
memory, motivation, reward symptoms (EPS)
• Excess DA contributes to psychosis
• D2-antagonism relieves positive Mesocortical pathway
symptoms
• Controls cognition, communication,
executive functioning
Tuberoinfundibular pathway • Decreased DA levels contributes to
negative symptoms
• Innervates pituitary gland • D2-antagonism may worsen negative
• D2-antagonism leads to elevated symptoms
prolactin
Mechanism of Action

Class Variability
• Other receptor involvement
• 5HT2A antagonism is the commonality with SGAs
• May also act as antagonists at ⍺1, H1, M1
• Receptor affinity and activity varies between agents
• May account for either desirable or adverse effects

Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.


Mechanism of Action – Key Receptors

Receptor Mechanism Clinical Effects


D2 Antagonist • Decrease in positive symptoms, mania
• EPS, hyperprolactinemia, cognitive impairment
5HT2A Antagonist • Antidepressant, improvement in negative symptoms
• Reduced EPS
⍺1 Antagonist • Decrease in adrenergic outflow (hyperarousal)
• Orthostasis, reflex tachycardia
H1 Antagonist • Sedation, confusion, falls, weight gain
M1 Antagonist • Decrease in EPS
• Anticholinergic effects (dry eyes, mouth, constipation,
confusion, falls, urinary retention, delirium, etc.)
Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.
Pharmacotherapy Overview

Considerations when selecting medications


• Goals of treatment
• Barriers to adherence
• Consequences of non-adherence
• Individual medication properties
• Adverse effect profiles
• Cost and availability
Goals of Treatment

Phase 1 - Acute Stabilization Phase 3- Maintenance and Relapse


• Reduce threat to self and others Prevention
• Reduce acute psychotic symptoms • Achieve symptom control and
• Improve functioning remission
• Improve social and occupational
Phase 2- Stabilization functioning
• Reduce remaining positive, negative • Continue to promote adherence
and cognitive symptoms and address potential barriers to
• Promote adherence adherence
• Minimize and treat adverse effects
Practice Guidelines for the Treatment of Patients With Schizophrenia. American Psychiatric Association, 2004.
Barriers to Adherence

Patient Factors Environmental Factors


• Medication beliefs and biases • Social stigma
• Education regarding mental • Unstable living environment
illness and medication role • Complex healthcare system
• Lack of perceived efficacy • Medication cost and availability
• Intolerable side effects
• Severe symptoms,
disorganization, poor insight
• Forgetfulness
Consequences of Non-Adherence

• Suboptimal response to treatment


• Functional decline and increased risk for relapse
• Develop treatment resistance
• Kindling effect
• Increased hospitalizations and healthcare burden
• Polypharmacy and complex medication regimens
Schizophrenia Treatment Algorithm

DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014


Schizophrenia Treatment Algorithm

DiPiro JT et al. Pharmacotherapy: A Pathophysiologic Approach, 9e; 2014


First Generation Antipsychotics

First Generation – “Typical” Class Characteristics


• Chlorpromazine (Thorazine®) • Increased incidence of EPS
• Fluphenazine (Prolixin®) • More potent D2 antagonism
• Haloperidol (Haldol®) • Lower incidence of metabolic ADEs
• Loxapine (Loxitane®) • May worsen negative symptoms
• Perphenazine (Trilafon®) • Result of D2 antagonism in
mesocortical pathway
• Thioridazine (Mellaril®)
• Lack of 5HT2A antagonism
• Thiothixene (Navane®)
• Trifluoperazine (Stelazine®)
FGA D2 Potency Comparison

Low Potency Mild Potency High Potency


Chlorpromazine Loxapine Haloperidol
Thioridazine Perphenazine Fluphenazine
Thiothixene
Trifluoperazine

• Higher doses needed • Lower doses needed for


for antipsychotic effect antipsychotic effect
• Higher incidence of • Higher incidence of
anticholinergic effects, movement-related side
sedation, orthostasis effects
FGA Dosing
Medication Average Typical Max. Daily Special Considerations
Daily Dose Dosing Dose
Chlorpromazine 200-600 mg BID-QID 1000 mg Sedation, anticholinergic, orthostasis
Fluphenazine <20 mg TID-QID 40 mg High incidence EPS
Haloperidol <30 mg BID-TID 100 mg High incidence EPS
Loxapine 20-100 mg BID-QID 250 mg
Perphenazine 8-64 mg BID-QID 64 mg
Thioridazine 50-800 mg BID-QID 800 mg BBW for QTc prolongation
Thiothixene 20-30 mg BID-TID 60 mg
Trifluoperazine 15-20 mg BID 40 mg CI in liver disease
FGA Dosing Considerations

Initiation
• Initiate at low dose and titrate slowly
• Doses are often given 2-4 times per day to improve tolerability
• Less frequent dosing can be trialed once patient is tolerating
• Treatment-naïve patients are at increased risk for adverse effects/EPS

Discontinuation
• Taper over weeks to months to reduce risk for withdrawal and relapse
Black Box Warning

All Antipsychotics
• “Elderly patients with dementia-related psychosis treated with antipsychotic
drugs are at an increased risk of death. [Drug] is not approved for the
treatment of patients with dementia-related psychosis”
Adverse Effects

Extrapyramidal Symptoms (EPS)


• Akathisia
• Dystonia
• Pseudoparkinsonism
• Tardive Dyskinesia
Adverse Effects - EPS

Akathisia
Clinical Presentation • Inability to be still
• Internal restlessness
Mechanism • Unknown
• Related to dopaminergic effects of antipsychotics
Prevention • Initiate at low dose
Management • Discontinue or reduce dose
• Propranolol 30-120 mg/day in divided doses
Adverse Effects - EPS

Acute Dystonic Reaction


Clinical Presentation • Involuntary contraction of skeletal muscle
• Buccal spasms, oculogyric crisis, facial grimacing, trismus
• Onset within days of initiation
Mechanism • Rapid antagonism of D2 receptors in basal ganglia
Prevention • Initiate at low dose
• Prophylactically initiate anticholinergic or antihistamine
• Avoid IM injections
Management • Discontinue or reduce dose
• Benztropine 1-2 mg IM
• Diphenhydramine 25-50 mg
Adverse Effects - EPS

Pseudoparkinsonism
Clinical Presentation • Slowing of voluntary muscle movements (bradykinesia)
• Muscle rigidity (cogwheel)
• Tremor at rest (pill-rolling)
• Shuffling gait, stooped posture
Mechanism • D2-antagonism in nigrostriatal pathway
Prevention • Initiate at low dose
Management • Discontinue or reduce dose
• Benztropine 1-5 mg/day
• Trihexyphenidyl 5-15 mg/day
• Diphenhydramine 25-150 mg/day
Adverse Effects - EPS

Tardive Dyskinesia (TD)


Clinical Presentation • Stereotypical, irreversible involuntary movements
• Includes lip smacking, lateral jaw, tongue movements
• Purposeless movements of neck, trunk and/or extremities
• Later symptom onset; may be months-years after initiation
Mechanism • Possible result of DA hypersensitivity
• Secondary to prolonged D2-antagonism
• Thought to be worsened with prolonged anticholinergic use
Prevention • Minimize antipsychotic exposure
• Attempt periodic gradual dose reductions
• Avoid prolonged anticholinergic use
Adverse Effects - EPS

Tardive Dyskinesia (TD)


Management • Discontinue the suspected antipsychotic
• Consider switching to clozapine
• Attempt to reduce anticholinergic
• Provide supportive treatments
• Valbenazine (Ingrezza®) recently approved by FDA
Monitoring • Abnormal Involuntary Movement Scale (AIMS)
• Every 3-6 months with FGA
• Every 6-12 months with SGA
Adverse Effects

Neuroleptic Malignant Syndrome


Clinical Presentation • Muscle rigidity (Elevated CK)
• Autonomic instability (Elevated HR, BP, Temp)
• Altered mental status
• Onset days to weeks after initiation
Prevention • Use minimum dose of antipsychotic
• Avoid neuroleptic polypharmacy
• Minimize use of IM injections (higher risk)
Management • Discontinue all antipsychotics
• Provide supportive care
• Dopamine agonist – bromocriptine, amantadine
• Skeletal muscle relaxant - dantrolene
Adverse Effects

Cardiovascular
• Clinical presentation
• Orthostatic hypotension (⍺1 antagonism)
• Higher incidence with clozapine,
iloperidone, risperidone, quetiapine
• Initiate at low doses, titrate slowly
• QTc interval prolongation
• Torsades de Pointes (TdP)
• Thioridazine has BBW
• Dose-dependent increase
Nielsen J, et al. CNS Drugs. 2011;25:473–490.
Adverse Effects

Cardiovascular
• Monitoring
• ECG at baseline, then annually
• Consider ECG with addition of
QTc-prolonging medications,
dose increases, etc.
• Serum K+, Mg2+ at baseline and
as clinically indicated

Nielsen J, et al. CNS Drugs. 2011;25:473–490.


Adverse Effects

Hyperprolactinemia
• Clinical presentation
• Men: Ejaculatory/erectile dysfunction, galactorrhea, decreased libido
• Women: Amenorrhea, galactorrhea, decreased libido
• Decreased BMD (osteopenia, osteoporosis)
• Increased risk with higher D2 affinity (Includes SGA risperidone)
• Monitoring
• Prolactin level, if clinically indicated
• Not routinely monitored, as prolactin level does not correlate with symptoms
Adverse Effects

Anticholinergic
• Clinical presentation
• Dry mouth, eyes, throat, urinary retention, constipation
• Blurred vision, worsening of glaucoma
• Confusion, delirium, falls (particularly in geriatrics)
Others
• Incidence generally rare and varies between agents
• Transient elevation in LFTs
• Hematologic, Ophthalmologic, Dermatologic reactions
• Lower seizure threshold
FGA Adverse Effect Comparison
Medication Sedation Anticholinergic EPS Hypotension
Chlorpromazine High High Low Moderate
Fluphenazine Low Low Very high Low
Haloperidol Very low Very low Very high Very low
Loxapine Moderate Low Moderate Moderate
Perphenazine Low Low High Low
Thioridazine High High Low High
Thiothixene Low Low High Low
Trifluoperazine Low Low High Low
Second Generation Antipsychotics

Second Generation – “Atypical”


• Aripiprazole (Abilify®) • Paliperidone (Invega®)
• Asenapine (Saphris®) • Quetiapine (Seroquel®)
• Brexpiprazole (Rexulti®) • Risperidone (Risperdal®)
• Cariprazine (Vraylar®) • Ziprasidone (Geodon®)
• Clozapine (Clozaril®)
• Iloperidone (Fanapt®)
• Lurasidone (Latuda®)
• Olanzapine (Zyprexa®)
Second Generation Antipsychotics

Class Characteristics
• Less potent D2 antagonism, shorter duration of receptor occupancy
• Lower incidence of EPS
• 5HT2A antagonism is common mechanism in this class
• Potentially improves negative symptoms (Controversial results)
• Increased incidence of metabolic effects
• Newer agents exhibit D2 partial agonism
• Aripiprazole, brexpiprazole, cariprazine
• Reduces DA neurotransmission, without complete antagonism
• Allows for minimal DA transmission in nigrostriatal, which reduces EPS
SGA Dosing
Medication Average Typical Max. Daily Special Considerations
Daily Dose Dosing Dose
Aripiprazole 20-30 mg Daily 30 mg Partial D2 agonism
Higher incidence of akathisia
BBW for SI in children-adolescents
Asenapine 10-20 mg BID 20 mg Do not eat or drink within 10 mins
Only available as SL
Brexpiprazole 1-4 mg daily 4 mg Partial D2 agonism
BBW for SI in children-adolescents
Cariprazine 1.5-6 mg daily 6 mg Partial D2 agonism

Clozapine 300 – 450 mg daily 900 mg REMS program

Iloperidone 12 – 24 mg BID 24 mg Cardiovascular effects


SGA Dosing
Medication Average Typical Max. Daily Special Considerations
Daily Dose Dosing Dose

Lurasidone 20-120 mg Daily 160 mg Take with 350 calories


BBW for SI in children-adolescents
Olanzapine 10-15 mg Daily 20 mg BBW for post-injection delirium/
sedation syndrome (PDSS) with LAI
Paliperidone 3-6 mg Daily 12 mg Metabolite of risperidone

Quetiapine 400-800 mg Daily-BID 800 mg BBW for SI in children-adolescents

Risperidone 4-6 mg Daily 16 mg Orthostasis, hyperprolactinemia

Ziprasidone 80-160 mg BID 160 mg Take with 500 calories


Adverse Effects

Overlap with FGAs


• Many FGA adverse effects also occur with SGAs
• Overall less EPS and more metabolic adverse effects with SGAs

Metabolic Effects
• Clinical presentation
• Hyperlipidemia
• Weight gain
• Glucose intolerance, DM2
• Hypertension
Adverse Effects

Metabolic Effects
• Monitoring
• Consensus guidelines from the American Diabetes Association, the American
Psychiatric Association, the American Association of Clinical Endocrinologists,
and the North American Association for the Study of Obesity

American Diabetes Association. Diabetes Care. 2004;27(2):596-601.


Adverse Effect Comparison
Medication Sedation Anticholinergic EPS Weight Glucose Lipid
Gain Intolerance Elevation
Aripiprazole Low Low Low Very low Low Very low
Clozapine High High Very low Very high High High
Lurasidone Low Low Low Very low Low Low
Olanzapine Moderate Moderate Low High High High
Paliperidone Low Low High Moderate Moderate Low
Queitapine High Moderate Very low High High High
Risperidone Low Low High Moderate Moderate Low
Ziprasidone Low Low Low Very low Low Very low
Drug Interactions

Pharmacodynamic
• Additive properties of 2+ medications
• Anticholinergic (cognitive impairment, delirium, constipation, etc.)
• Over-sedation (falls, drowsiness)
• QTc prolongation, etc.
Drug Interactions

Pharmacokinetic
• CYP Interactions (both generations)
• APs are primarily metabolized via CYP1A2, 2D6 and 3A4
• Dose reductions may be required with concomitant CYP inhibitors
• May also be required if patient is known poor metabolizer
• Ex. Aripiprazole, brexpiprazole, iloperidone recommend 50% dose
reduction when combined with CYP2D6 and/or 3A4 inhibitors
• Hydrocarbons produced from smoking cigarettes induce CYP1A2
• May reduce levels of clozapine and olanzapine, requiring dose adjustments
if smoking status changes
Antipsychotic Conversion

Oral Conversion Strategies


• Discontinue old medication and initiate the new one (no-overlap)
• Increased risk for withdrawal symptoms
• Cannot be done with clozapine
• Initiate new medication at full dose, then taper off old medication
• Increased risk for adverse effects while on two treatment doses
• Slowly cross taper by initiating new medication at low dose, while decreasing
old medication
• Reduces risk for withdrawal or adverse effect symptoms
• Taper length (usually 1-2 weeks) varies based on treatment location (inpatient
vs. outpatient), patient tolerability and response
Long-Acting Injectable Antipsychotics (LAIs)

Goals of Treatment
• Improve adherence to antipsychotics
• It’s estimated that 40-50% of patients are non-adherent to antipsychotics,
which may lead to negative outcomes, including:
• Functional decline
• Relapse and treatment resistance
• Psychiatric hospitalizations
• Increased healthcare costs
Long-Acting Injectable Antipsychotics (LAIs)

Role in Treatment
• Chronic mental illness in patients with history of relapse following oral
antipsychotic non-adherence
• Particularly if patient manages medications independently
• Typically not first-line in antipsychotic naïve patients
• Oral formulations more easily titrated and less expensive
• Patients preferring injectable agent versus oral agent

Bartolomeis A, et al. Neuropsychiatr Dis Treat. 2016;12:99-108.


Long-Acting Injectable Antipsychotics (LAIs)

Available Agents
• First Generation Antipsychotics
• Fluphenazine decanoate
• Haloperidol decanoate
• Second Generation Antipsychotics
• Risperidone (Risperdal Consta®)
• Paliperidone (Invega Sustenna®, Invega Trinza®)
• Olanzapine (Zyprexa Relprevv®)
• Aripiprazole (Abilify Maintena®, Aristada®)
First Generation LAIs

Medication Dosing Oral Overlap Considerations


Fluphenazine • Starting dose = 1.25x PO • Continue • Deltoid or gluteal
decanoate dose until 2nd LAI IM injection
• Maintenance = 12.5-100 dose • Z-track technique
mg IM every 2-4 weeks

Haloperidol • Starting dose = 10-15x PO • Continue • Deltoid or gluteal


decanoate dose until 2nd LAI IM injection
• 50-200 mg IM every 4 dose • Z-track technique
weeks • Give as two
injections for doses
>100 mg
Second Generation LAIs

Medication Dosing Oral Overlap Considerations


Aripiprazole lauroxil • Starting dose based on oral • 21-day oral • Adjust dose for
(Aristada®) • 441 mg, 662 mg, or 882 mg aripiprazole CYP2D6 and/or 3A4
IM q4-6 weeks interactions
• Deltoid or gluteal
Aripiprazole • Standard dose is 400 mg; • 14-day oral • Adjust dose for
monohydrate dose reduced if DDIs aripiprazole CYP2D6 and/or 3A4
(Abilify Maintena®) • 200 mg, 300 mg, 400 mg or other AP interactions
IM qmonth
• Deltoid or gluteal
Second Generation LAIs

Medication Dosing Oral Overlap Considerations


Olanzapine pamoate • Starting dose based on oral • None • REMS program
(Zyprexa Relprevv®) • 210 mg, 300 mg, 405 mg • Provider, patient
IM q2-4weeks and facility must be
• Gluteal registered

Paliperidone • Loading sequence of • None • Detailed directions


palmitate 234 mg, then 156 mg in package insert
(Invega Sustenna®) • 39 mg, 78 mg, 117 mg, regarding
156 mg, 234 mg IM requirements for
qmonth missed doses
• Deltoid (initial) then either
deltoid or gluteal
Second Generation LAIs

Medication Dosing Oral Overlap Considerations


Paliperidone • Starting dose based on • N/A • Must be stable on
palmitate current Invega Sustenna® monthly LAI
(Invega Trinza®) maintenance dose formulation for at
• 273 mg, 410 mg, 546 mg, least 4 months,
819 mg IM q3months then transition
• Deltoid or gluteal directly to Trinza®
Risperidone • Starting dose 12.5-25 mg • 21-day oral • Microsphere
microspheres • 12.5 mg, 25 mg, 37.5 mg, risperidone release is delayed
(Risperdal Consta®) 50 mg IM q2weeks or other AP 3-weeks post
• Deltoid or gluteal injection
Clozapine (Clozaril®)

Treatment Resistant Schizophrenia


• Lack of significant symptom improvement despite adequate trials (dose, duration,
adherence) of at least two antipsychotics (at least one SGA)

Clozapine
• Guidelines recommend clozapine for “patient who has had no response or partial
and suboptimal response to two trials of antipsychotic medication or for a patient
with persistent suicidal ideation or behavior that has not responded to other
treatments”
• Evidence has consistently shown clozapine to be superior to other antipsychotics in
this patient population

Practice Guidelines for the Treatment of Patients With Schizophrenia. American Psychiatric Association, 2004.
Clozapine (Clozaril®)

Mechanism of Action
• Low potency at D2 receptor and high affinity for 5HT2A
• Very low EPS and may improve TD
• Antagonism at ⍺1, H1 and M1 contributes to significant side effect profile
Receptor Mechanism Clinical Effects
⍺1 Antagonist • Decrease in adrenergic outflow (hyperarousal)
• Orthostasis, reflex tachycardia
H1 Antagonist • Sedation, confusion, falls, weight gain
M1 Antagonist • Decrease in EPS
• Anticholinergic effects (dry eyes, mouth, constipation,
confusion, falls, urinary retention, delirium, etc.)
Miyamoto S et al. Molecular Psychiatry. 2012;17:1206-1227.
Clozapine (Clozaril®)

Black Box Warnings


• Dementia-related mortality
• Severe neutropenia
• Orthostatic hypotension
• Myocarditis
• Seizures

Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)

Mitigating Severe Adverse Effects


• Dose-related effects
• Neutropenia, orthostatic hypotension, bradycardia, syncope, seizures
• Initiating at low doses and slow titration reduces risk
• Titration
• Initial dose of 12.5 mg 1-2 times per day
• Increase total daily dose (TDD) by 25-50 mg per day, as tolerated
• Goal of 300-450 mg divided 2-3 times per day
• Must restart dose titration if interruption in therapy ≥ 2 days

Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)

Risk Evaluation and Mitigation Strategy (REMS) Program


• Patient, prescriber and pharmacy must be registered
• Outlines absolute neutrophil count (ANC) monitoring requirements
• Once weekly for first 6 months
• Every-other-week after 6-12 months
• Once monthly after 12 months

Clozapine REMS Program website (www.clozapinerems.com)


Clozapine (Clozaril®)

Clozapine REMS Program website (www.clozapinerems.com)


Clozapine (Clozaril®)

Clozapine REMS Program website (www.clozapinerems.com)


Clozapine (Clozaril®)

Other Adverse Effects


• High incidence of metabolic effects and lowest incidence of EPS
• Constipation
• Consider prophylactic bowel regimen
• Sialorrhea
• May require pharmacotherapy if bothersome to patient
• Sublingual anticholinergic - ipratropium nasal spray or atropine eye drops
• Oral anticholinergic - benztropine or oxybutynin
Cost Considerations
Medication Generic Example Average Wholesale
Dosing Price for 30DS

Chlorpromazine Yes 100 mg BID $892

Fluphenazine Yes 5 mg BID $72

Haloperidol Yes 10 mg BID $107


Cost Considerations
Medication Generic Example Average Wholesale
Dosing Price for 30DS

Aripiprazole Yes 20 mg daily $1362

Asenapine No 10 mg BID $1316

Brexpiprazole No 3 mg daily $1211

Cariprazine No 4.5 mg daily $1316

Clozapine Yes 100 mg BID $205

Iloperidone No 10 mg BID $2364


Cost Considerations
Medication Generic Example Average Wholesale
Dosing Price for 30DS

Lurasidone No 80 mg daily $1336

Olanzapine Yes 10 mg daily $596

Paliperidone Yes 6 mg daily $916

Quetiapine Yes 400 mg BID $1195

Risperidone Yes 4 mg daily $456

Ziprasidone Yes 60 mg BID $645


Antipsychotic DementiaDementia

Pharmacotherapy

Nicole Romstadt, PharmD


Psychiatric Clinical Pharmacy Specialist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Substance Abuse Disorders:
Alcohol,Tobacco, Opiates

Gretchen L. Johnson, Pharm.D., BCPS


Substance Abuse Pharm:
Alcohol
Acute Alcohol Withdrawal
• BZDs are first-line due to cross-tolerance with alcohol
• Symptom triggered BZD treatment is the standard of care to
minimize sx and avoid progression to more severe stages of
withdrawal (seizures, delirium)
– Results in shorter treatment duration and less risk of
oversedation
• All BZDs equally efficacious, but Lorazepam (Ativan) is preferred
due to multiple routes of administration (PO, SL,IV, IM) with
predictable results
– Lorazepam 2mg PO/IM/IV q 1 hour PRN withdrawal sx.
– Sx. assessed via a validated rating scale- Clinical Institute
Withdrawal Alcohol-Revised
• Anticonvulsants are not required to treat alcohol withdrawal sz.
unless progresses to status epilepticus
• Supportive care with IV fluids, thiamine, MVI, electrolytes
– Watch for low K, Mg, PO4
Chronic Alcohol Abuse
• Pharmacologic Management of Alcohol Dependence
– Disulfiram (Antabuse)- Deterrent
– Naltrexone (ReVia)- Anticraving
– Naltrexone IM depot (Vivitrol)- Anticraving
– Acamprosate (Campral)- Anticraving
Chronic EtOH Abuse: Disulfiram (Antabuse)
• Deters a pt. from drinking by producing a negative reaction when alcohol is consumed

• MOA:
– Inhibits aldehyde dehydrogenase (EtOH Metabolism) → ↑[acetlyaldehyde] → disulfiram reaction
• N/V
• Flushing
• throbbing HA
• Palpitations, tachycardia, hypotension
• CP
• Weakness
• blurred vision
• confusion
– Can occur up to 7-14 days after the last dose
– The intensity and duration of symptoms are related to the dose, the amount of ETOH consumed
and individual sensitivity
– Can occur with as little as “ml” of ETOH and last 30 min - 2 hrs.

• Fallen out of favor


– Data is mixed as to effectiveness
– Poorly tolerated
Chronic EtOH Abuse: Disulfiram (Antabuse)
• Contraindications:
– CAD, severe cardiac disease
– hepatic disease, cirrhosis
– seizure disorders
– schizophrenia
– Hypersensitivity to rubber (thiuram) derivatives
– concomitant use of ETOH or ETOH-containing products
– Metronidazole- causes acute psychosis and confusion
• Side Effects (Usually transient/dose-related)
– GI upset, sedation, rash, garlicky or metallic taste, flushing
– Hepatotoxic- monitor LFTs
• Drug Interactions: Inhibitor of CYP3A4
– May increase and prolong effects of :warfarin, phenytoin, isoniazid, rifampin.
Metronidazole, theophylline
• Pt education:
– Abstain from EtOH at least 12 hours before use
– Avoid OTC meds alcohol content, including topicals
– Medical alert ID bracelet
Chronic EtOH Abuse: Naltrexone (ReVia)
• MOA:
– Opiate antagonist → ↓cravings/”buzz” from EtOH (reinforcing effects) of a
• Efficacy
– More effective than acamprosate in reducing risk of heavy drinking in nonabstinent
pts.
• Pt. must be opiate-free for 7-10 days
– Verify with urine drug screen
• Contraindications: hepatitis/liver failure; lactation; current opioid use
• ADR: nausea (10%), vomiting, cramps, headache (7%),dizziness, fatigue,
constipation, dose-related reversible hepatotoxicity
• Hepatotoxic- monitor LFTs
• Pregnancy Category C
• Patient Education:
– Medical alert ID bracelet
– DC 24-48 hr prior to procedures where opioids are needed (otherwise they wont
work)
Naltrexone IM (Vivitrol)
• Once monthly IM naltrexone formulation
• ↑compliance/adherence
• Watch for injection site reactions
– Cellulitis, hematoma, abscess
Chronic EtOH Abuse: Acamprosate (Campral)
• MOA:
– glutamate modulator at the NMDA receptor → ↓craving
• Efficacy:
– More effective than naltrexone in maintaining abstinence
– Combination of acamprosate + naltrexone appears to be more
efficacious than acamprosate alone
• ADRs: >10% = diarrhea, flatulence, syncope, dizziness,
edema, insomnia, anxiety, headache, nausea
• Precautions:
– Moderate renal impairment
• Dec. dose in renal impariment; Not rec. if Clcr < 30ml/min
– Depression/suicidality
– Pregnancy- Category C
Other Off-label Anticraving Agents
• Topiramate (Topamax)
• Baclofen (Lioresal)
• Varenicline (Chantix)
Substance Abuse Pharm: Tobacco

.
Slides adapted and used with permission from Erin Adams PharmD
What ever happened to Joe Camel?

1991
NONPHARMACOLOGIC METHODS
• Cold turkey: Just do it!  Aversion therapy
• Unassisted tapering (fading)  Acupuncture
– Reduced frequency of use therapy
– Lower nicotine cigarettes
– Special filters or holders  Hypnotherapy
• Assisted tapering  Massage therapy
 Apps
PHARMACOLOGIC METHODS:
FIRST-LINE THERAPIES
Three general classes of FDA-approved
drugs for smoking cessation:
 Nicotine replacement therapy (NRT)
 Nicotine gum, patch, lozenge (OTC)
 nasal spray or inhaler (Rx)
 Psychotropics
 Sustained-release Buproprion (Zyban) (Rx)
 Partial nicotinic receptor agonist
 Varenicline (Chantix) (Rx)
NRT: RATIONALE for USE

↓ physical withdrawal from nicotine


Allows patient to focus on behavioral and
psychological aspects of tobacco cessation

NRT APPROXIMATELY DOUBLES QUIT RATES.


NRT: PRECAUTIONS
Patients with underlying cardiovascular
disease
– MI within past 2 weeks
– Serious arrhythmias
– Serious or worsening angina
NICOTINE GUM
Nicorette (GlaxoSmithKline); generics

• Sugar-free chewing gum base


• Contains buffering agents to enhance buccal
absorption of nicotine
• Available: 2 mg, 4 mg; regular, FreshMint,
Fruit Chill, Orange & Cinnamon Surge
NICOTINE GUM: DOSING
Dosage based on current smoking
patterns:

NOTE: dosing difference


NICOTINE GUM:
CHEWING TECHNIQUE SUMMARY
NICOTINE GUM: ADDITIONAL PATIENT EDUCATION

To improve chances of quitting, use at


least nine pieces of gum daily
The effectiveness of nicotine gum may
be reduced by some foods and
beverages:
 Coffee  Juices
 Wine  Soft drinks

Do NOT eat or drink for 15 minutes BEFORE or while


using nicotine gum.
NICOTINE GUM:
ADD’L PATIENT EDUCATION (cont’d)

Chewing gum too rapidly can Side effects of nicotine


cause excessive release of gum include
nicotine, resulting in
– Mouth soreness
– Lightheadedness
– Hiccups
– Nausea/vomiting
– Dyspepsia
– Irritation of throat and mouth
– Jaw muscle ache
– Hiccups
Caution:
– Indigestion
Dental work/aids
TMJ
NICOTINE LOZENGE
Commit (GlaxoSmithKline); generics

 Nicotine polacrilex
formulation
– Delivers ~25% more nicotine
than equivalent gum dose
 Sugar-free, mint or cherry
flavor or MINI sized
 Contains buffering agents
to enhance buccal
absorption of nicotine
 Available: 2 mg, 4 mg
– Dissolves
NICOTINE LOZENGE: DOSING
Dosage is based on the “time to first cigarette”
(TTFC) as an indicator of nicotine addiction
NICOTINE LOZENGE:
DOSING (CONT’D)
Recommended Usage Schedule for
Commit Lozenge
Weeks 1–6 Weeks 7–9 Weeks 10–12
1 lozenge 1 lozenge 1 lozenge
q 1–2 h q 2–4 h q 4–8 h
DO NOT USE MORE THAN 24/day
Rotate lozenge
NICOTINE LOZENGE: ADDITIONAL PATIENT EDUCATION

• The effectiveness of the nicotine lozenge


may be reduced by some foods and
beverages:
 Coffee  Juices
Wine  Soft drinks

Do NOT eat or drink for 15 minutes BEFORE or while


using the nicotine lozenge.
NICOTINE LOZENGE:
ADD’L PATIENT EDUCATION (cont’d)

Side effects of the nicotine lozenge


include
– Nausea
– Hiccups
– Cough
– Heartburn
– Headache
– Flatulence
– Insomnia
TRANSDERMAL NICOTINE PATCH
Nicoderm CQ (GlaxoSmithKline); generic

 Avoids hepatic first-pass metabolism


 Plasma nicotine levels are lower and
fluctuate less than with smoking
TRANSDERMAL NICOTINE PATCH:
PREPARATION COMPARISON

Product Nicoderm CQ/Generic


Nicotine
24 hours
delivery
Availability OTC
Strengths 7-mg patch
14-mg patch
21-mg patch
TRANSDERMAL NICOTINE PATCH: DOSING

Product Light Smoker Heavy Smoker


Nicoderm CQ 10 cigarettes/day >10 cigarettes/day
Step 2 (14 mg x 6 Step 1 (21 mg x 6
weeks) weeks)
Step 3 (7 mg x 2 Step 2 (14 mg x 2
weeks) weeks)
Step 3 (7 mg x 2 weeks)
Generic 10 cigarettes/day >10 cigarettes/day
(formerly Step 2 (14 mg x 6 Step 1 (21 mg x 4
Habitrol) weeks) weeks)
Step 3 (7 mg x 2 Step 2 (14 mg x 2
weeks) weeks)
Step 3 (7 mg x 2 weeks)
TRANSDERMAL NICOTINE PATCH:
DIRECTIONS for USE
 Apply adhesive side
– Clean, dry, hairless
and not irritated
– Location
 Rotate
– Press firmly x10 sec
 Wash hands
 Other info:
– OK to shower with patch on
– Do not cut patches
– No more than 24 hours/patch
– Adhesive remaining on skin
– Disposal of used patch
TRANSDERMAL NICOTINE PATCH:
DIRECTIONS for USE (cont’d)
• Side effects to expect in first hour:
– Mild itching
– Burning
– Tingling
• Additional possible side effects:
– Headache
– Vivid dreams or sleep disturbances
• Avoid use in dermatological issues
NICOTINE NASAL SPRAY
Nicotrol NS (Pfizer)
 Aqueous solution of
nicotine in a 10-ml
spray bottle
 Each metered dose
actuation delivers 0.5
mg nicotine
 ~100 doses/bottle
NICOTINE NASAL SPRAY:
DOSING & ADMINISTRATION

• Dose: 1 spray in each nostril


• Start with 1–2 doses per hour
– Maximum : 5 doses/hr or 40 mg daily
• For best results, patients should use at
least 8 doses daily for the first 6–8 weeks
• Termination:
– Gradual tapering over an additional 4–6
weeks
NICOTINE NASAL SPRAY:
DIRECTIONS FOR USE

• Blow nose (if not clear)


• Prime
– If pump is not used for 24 hours, prime the
pump 1–2 times

• Do not sniff or inhale while spraying


– If nose runs

• Wait 5min
NICOTINE NASAL SPRAY:
PATIENT EDUCATION

What to expect (first week):


 Hot peppery feeling in back of throat or nose
 Sneezing
 Coughing
 Watery eyes
 Runny nose

Caution
 If side effects do not decrease after a week, contact health care
provider
 Patients with chronic nasal disorders or severe reactive airway
disease should not use the spray
NICOTINE INHALER
Nicotrol Inhaler (Pfizer)

Nicotine inhalation
system consists of
 Mouthpiece
 Cartridge with porous plug
containing 10 mg nicotine
Delivers 4 mg nicotine
vapor
May satisfy hand-to-
mouth ritual of smoking
NICOTINE INHALER
Nicotrol Inhaler (Pfizer)

Nicotine inhalation
system consists of
 Mouthpiece
 Cartridge with porous plug
containing 10 mg nicotine
Delivers 4 mg nicotine
vapor
May satisfy hand-to-
mouth ritual of smoking
NICOTINE INHALER: DOSING

 Start with 6 cartridges/day

 Maximum of 16 cartridges/day

 Use for minimum of 3 weeks, maximum of 12 weeks

 Gradual dosage reduction: if needed over additional 6–12


weeks
NICOTINE INHALER:
NICOTINE INHALER:
DIRECTIONS FOR USE (CONT’D)
• Inhale into back of throat or puff in
short breaths
– Frequent puffing
• Depletion of plug
– Cartridge does not have to be used all at once
– Open cartridge retains potency for 24 hours
NICOTINE INHALER:
ADDITIONAL PATIENT EDUCATION
• Side Effects
– Mild irritation
– Unpleasant taste or cough when first using
the inhaler
• Other (less common) side effects include
– Rhinitis
– Dyspepsia
– Hiccups
– Headache
• Precautions
– Underlying bronchospastic conditions
– Storage
NICOTINE INHALER:
ADD’L PATIENT EDUCATION (cont’d)

• Effectiveness of the nicotine inhaler


may be reduced by some foods and
beverages
 Coffee  Juices
 Wine  Soft drinks

Do NOT eat or drink for 15 minutes BEFORE or while


using the nicotine inhaler.
BUPROPION
Zyban (GlaxoSmithKline); Buproban ER

Nonnicotine
cessation aid
Sustained-release
antidepressant
Wellbutrin?
Oral formulation
BUPROPION

• MOA: Atypical antidepressant


thought to affect levels of various
brain neurotransmitters
– Dopamine
– Norepinephrine
• Clinical effects
–  craving for cigarettes
–  nicotine withdrawal
BUPROPION:
CONTRAINDICATIONS & WARNINGS
• Contraindications: • Precautions:
– Patients with a seizure – History of seizure/
disorder meds that lower
– Patients taking seizure threshold
• Wellbutrin, Wellbutrin (antipsychotics,
SR, Wellbutrin XL antidep, theophylline,
• MAO inhibitors in systemic steroids
preceding 14 days – Bipolar patients
– Anorexia or bulimia – History of cranial
nervosa trauma
– Abrupt d/c of alcohol or – severe hepatic
sedatives cirrhosis
BUPROPION SR: DOSING

Patients should begin therapy 1 to 2 weeks PRIOR


to their quit date to ensure that therapeutic plasma levels of the
drug are achieved.

Initial treatment
 150 mg po q AM x 3 days

Then…
 150 mg po bid
 Duration, 7–12 weeks
BUPROPION:
ADVERSE EFFECTS
Common side effects:
– Insomnia (avoid bedtime dosing)
– Dry mouth
WARNING: neuropsychiatric symptoms

Less common but reported effects:


– Tremor
– Skin rash
– Suicidal Ideations
VARENICLINE
Chantix (Pfizer)

Nonnicotine
cessation aid
Partial nicotinic
receptor agonist
Oral
formulation
VARENICLINE
• MOA: Binds with high affinity and selectivity at 42
neuronal nicotinic acetylcholine receptors

– Competitively inhibits binding of nicotine


• Clinical effects

–  symptoms of nicotine withdrawal


– Blocks dopaminergic stimulation responsible for
reinforcement & reward associated with smoking
• T1/2 24 hours
VARENICLINE: DOSING

Patients should begin therapy 1 week PRIOR to their


quit date. Can also begin therapy and taper cigarettes in first 12
weeks
Treatment Day Dose
0.5 mg
Day 1 to day 3
Initial qd
dose
0.5 mg
titration Day 4 to day 7
bid
Day 8 to end of treatment* 1 mg bid

* Up to 12 weeks
VARENICLINE:
ADVERSE EFFECTS
• Common: • Post-marketing
– Nausea – Dizziness/falls/loss
– Sleep disturbances (insomnia, of consciousness
abnormal dreams) – Cardiac rhythm
– Constipation disturbances
– Flatulence – Acute MI
– Vomiting – Severe skin
reactions
• Neuropsychiatric symptoms
– Seizures
• Cardiovascular effects – Diabetes
– Spasms
PHARMACOLOGIC METHODS:
Second-line and Future Therapies

Clonidine (Catapres transdermal or


oral)
Nortriptyline (Pamelor oral)

NicVAX Vaccine
Pharmacotherapy Abstinence Rates

Evidence suggests that rates of smoking abstinence


may increase from
• approximately 10% in control groups (placebo or
no pharmacotherapy) to 17% in persons using any
form of NRT
• approximately 11% in control groups (placebo or
no bupropion SR) to 19% in those using bupropion
SR
• approximately 12% in control groups (placebo) to
28% in those using varenicline
COMBINATION PHARMACOTHERAPY
Combination NRT- moderately better than
one NRT product alone
Long-acting formulation (patch)
PLUS
Short-acting formulation (gum, lozenge, inhaler, nasal spray)

Bupropion + NRT- may be better than


Bupropion alone
 Monitor BP
Varenicline + NRT
Varenicline + Bupropion
USE in PREGNANCY

NRT
Category D
Bupropion and
varenicline
Category C
Attempt nondrug
treatment first
Substance Abuse Pharm: Opiates
Methadone Prescribing Laws
• In the treatment of detoxification or maintenance,
methadone can only be used by Opiate Treatment
Programs (OTP) that are accredited by Center for
Substance Abuse Treatment.
• Above is waived if patients are admitted for a life
threatening condition that requires methadone to
stabilize their opioid dependence while in the
hospital
– May prescribe to opioid dependent pt up to 72 hr as
bridge to treatment entry
Office-based opioid treatment
• Evolved after passage of the Drug Addiction Treatment
Act of 2000 (DATA 2000)- Updated with Comprehensive
Addiction and Recovery Act of 2016 (CARA 2016)
• CARA 2016 expanded prescribing for buprenorphine to
PAs and NPs
– Can apply to become waivered to prescribe
buprenorphine for opiate addiction
– Obtain 24 hr training course
– Can treat up to 30 patients in first year with option to
increase to up to 100 patients after 1 year if certain
conditions met
– Defers to state law as to if PA/NP must work with a
physician in a supervisory or collaborative manner
Buprenorphine Pharmacology
• A mu receptor partial-agonist and an antagonist at kappa
receptor
• High affinity for the mu receptor but low efficacy; thus
producing a dose-related response with a ceiling effect
• High affinity for mu may displace other opioids from the
receptor and cause withdrawal sx
– Start in office AFTER pt shows signs of withdrawal
• Partial agonism:
– Does not activate the mu receptor fully, therefore has a ceiling
effect
– Larger doses do NOT lead to greater agonist effect
– 16mg buprenorphine = 60mg methadone
– Methadone is a full agonist and has no ceiling effect
• Greater margin of safety, less respiratory depression
Buprenorphine
• Subutex (buprenorphine): CIII
– Use at beginning of tx to dec. risk of withdrawal
– Available as SL tabs
• Suboxone(buprenorpine/naloxone): CIII
– Use in maintenance management
– Naloxone: added to guard against IV abuse of
buprenorphine
– No effect of naloxone orally or SL - poorly absorbed
– Available as SL tabs and SL film
• Dosed once daily
– Do not chew or swallow- dec. absorption
– Dosage adjustment needed in hepatic impairment
Buprenorphine
• Buprenorphine implant (Probuphine) Schedule III
– New dosage form- 4 subdural rods that are implanted in the inside of
the upper arm every 6 months
• Treatment duration is 12 months
– May address problems with diversion and compliance
– Only for stable patients on <8mg SL buprenorphine daily
– Prescribers must complete a training course in order to prescribe and
implant
– Expensive
Buprenorphine
• Drug interactions:
– Benzodiazepines: potentially fatal interaction- resp
depression
• Avoid use
– Increase effects of buprenorphine (3A4 substrate)
• Antiretrovirals, BZD, fluvoxamine, ketoconzaole, ETOH
– Decrease effects of buprenorphine (3A4 substrate)
• CBZ, phenobarbital, rifampin, phenytoin
• Patient education
– Caution with driving care or operating heavy machinery
– Avoid concomitant alcohol
– Store in a secure area out of reach of children and pets
and avoid theft
Buprenorphine Adverse Effects
• Constipation
• Headache
• N/V
• Sedation
• Hepatotoxicity- get baseline and periodic LFTs
• Precipitate withdrawal

• Pregnancy category C
• Avoid during breastfeeding- passes in to breast milk
Induction, Stabilization, Maintenance
• Generally start with Subutex and give a small supply to pt (usually 2
days)
– If > 1 prescriber with Rx, assume diversion
• Suboxone is preferred for long-term tx
• Determine min amount of buprenorphine required to prevent
withdrawal sx, cravings
• Stabilization lasts 2-3 months at lowest dose
• Length of treatment (maintenance) = at least 6 months but can last
up to 2 yrs.
– Length depends on past instability
– Previous response to tx
Reversal Agents
• Naloxone (Narcan)
– MOA: Opiate receptor antagonist
– Used to reverse opiate effects/overdose
– CARA 2016 expanded use to law enforcement and other first responders
– Some states are now allowing prescribing to third parties to administer in the case of
overdose
– Public health emergency declared in VA- Anyone can get naloxone at a pharmacy for either
themselves or someone else of concern through a standing order from the State Health
Commisioner
– Consider for patients at high risk- on large doses of opiates, opiate plus BZDs, prior h/o
overdose
• Flumazenil (Romazicon)
– MOA: BZD receptor antagonist
– Used to reverse BZD effects/overdose
Attention Deficit/
Hyperactivity
Disorder
Molly Rincavage, PharmD
Objectives

1. Recognize the pharmacology of medications


used to manage ADHD
2. Select a treatment plan for ADHD that
considers patient and agent related
variables
3. Identify an appropriate monitoring plan for
a patient with ADHD, including how to
mitigate adverse effects
Outline

•Review
•Mechanism of Action
•Formulations
•Adverse Effects, Precautions, Contraindications,
Black Box Warnings
•Treatment Guidelines
•Monitoring
•Patient Case
Review
Review

Which of the following is not a core symptom of


ADHD?
A.Inattention
B. Hyperactivity
C. Defiance
D.Impulsivity
Review

True or False: ADHD occurs predominantly


in young, female individuals
Review

Which of the following is not a common comorbidity


in patients with ADHD?
A.Disruptive behavior disorder
B. Hyperthyroidism
C. Mood disorder
D.Anxiety disorder
Mechanism
of
Action
Pharmacologic Classes

Stimulants
• Methylphenidates
• Methylphenidate
• Dexmethylphenidate
• Amphetamines
• Dextroamphetamine
• Levoamphetamine
• Lisdexamfetamine

Non-stimulants
• Selective norepinephrine reuptake inhibitors
• Atomoxetine
• Alpha-2 agonists
• Guanfacine
• Clonidine
Stimulants

• Amphetamines and
methylphenidates
• Block the reuptake of
norepinephrine and
dopamine into the
presynaptic neuron, thus
increasing the
concentrations of these
monoamines in the
extraneural space
Non-stimulants

• Atomoxetine
• Selective norepinephrine
reuptake inhibitor
• Inhibits reuptake of
norepinephrine, thus
increasing concentration in
synaptic cleft
Non-stimulants

• Guanfacine and clonidine


• Alpha 2-adrenergic
receptor agonists
• Increase noradrenergic tone
in prefrontal cortex by
stimulating postsynaptic
alpha-2A receptors
Formulations
Medication Administration at School

ADHD affects a largely pediatric population, which often requires


coverage throughout the school day

There is a stigma associated with taking medication at school

Medication Authorization Form


• Completed by the parent which authorizes the school nurse to
give child medication
• Completed by the practitioner to provide information on the
diagnosis, medication, time, dosage to be dispensed, and
possible side effects
Plasma Concentration Time Profile
Amphetamine Formulations
Formulation Brand Name Duration of Frequency
Action (hours)
Mixed Immediate- Adderall 4-6 1-3 times daily
release (IR) salts

Amphetamine Evekeo 4-6 1-3 times daily


sulfate IR
Dextroamphetamine Dexedrine 4-6 1-3 times daily
IR
Dextroamphetamine ProCentra 4-6 1-3 times daily
IR liquid
Amphetamine Formulations

Formulation Brand Name Available Dosage Forms Duration of Frequency


Action (hours)
Dextroamphetamine Extended- Dexedrine 5, 10, 15 mg capsules 6-8 Daily
release (ER) Spansule
Lisdexamfetamine Vyvanse 20, 30, 40, 50, 60, 70 mg 10-12 Daily
capsules
Mixed Extended-release (XR) Adderall XR 5, 10, 15, 20, 25, 30 mg 10-12 Daily
salts capsules
Amphetamine sulfate XR orally Adzenys-XR- ODT 3.1, 6.3, 9.4, 12.5, 15.7, 12 Daily
disintegrating tablet 18.8 mg tablets

Amphetamine sulfate XR Dyanavel XR 2.5 mg/ml 12 Daily


suspension
Mixed Extended-release (XR) Mydayis 12.5, 25, 37.5, 50 mg 16 Daily
salts capsules
Methylphenidate Formulations

Formulation Brand Name Duration of Frequency


Action
(hours)
Immediate-release (IR) Methylin 3-6 1-3 times daily
Ritalin
Dexmethylphenidate IR Focalin 3-6 1-3 times daily
Extended release (ER) Metadate ER 6-8 Daily
Sustained release (SR) Ritalin SR 6-8 Daily
Long-acting (LA) Ritalin LA 6-8 Daily
Controlled delivery (CD) Metadate CD 6-8 Daily
Methylphenidate Formulations
Formulation Brand Name Duration of Frequency
Action (hours)
Dexmethylphenidate XR Focalin XR 8-12 Daily

Transdermal patch Daytrana 8-10 Daily

Osmotic release oral system Concerta 10-12 Daily


(OROS)
Methylphenidate XR orally Contempa-XR- ODT 12 Daily
disintegrating tablet
Extended release multilayer Aptensio XR 12 Daily
bead (MLR)
Extended-release (XR) Quillivant XR 12 Daily
suspension
Extended-release (ER) Quillichew ER 12 Daily
chewable tablet
Non-stimulants

Medication Brand Frequency Notes


Name

Atomoxetine Strattera 1-2 times Dosed by weight


daily Takes 4-6 weeks
to see response

Clonidine extended- Kapvay 1-2 times Takes 2-4 weeks


release daily to see response
Guanfacine Intuniv Daily Dosed by weight
extended-release Takes 2-4 weeks
to see response
Wax Matrix

Formulations:
● Metadate ER
● Ritalin SR
Multilayer Extended Release Bead

Formulations:
● Aptensio
XR
DiffuCaps and SODAS

Formulations:
● Ritalin LA
● Focalin XR
● Adderall XR
● Metadate CD
● Mydayis
Osmotic Release Oral System (OROS)

Formulations:
● Concerta
Prodrug

Formulations:
● Vyvanse
LiquiXR

Formulations:
● Dyanavel
XR-ODT

Formulations:
● Adzenys
● Contempla
Administration Instructions

Immediate release tablets


• May crush

Extended release tablets


• Do not crush or chew

Extended release capsules


• Do not crush or chew. Capsules may be opened and contents
sprinkled on food (ex: applesauce).
Administration Instructions

Patch
• Apply to hip 2 hours before effect is needed and remove up to
9 hours after application. Effects persists for 1-3 hours after
removal.
Suspension
• Shake vigorously for 10 seconds before administration

Orally disintegrating tablet


• Place tablet on top of tongue and allow to dissolve
Adverse Effects,
Precautions,
Contraindications,
Black Box Warnings
Stimulants

Adverse Effects
•Common
•Decreased appetite, delayed growth, insomnia,
headache, irritability
•Rare
•Hypertension, tachycardia, tics, psychosis, mania,
priapism, peripheral vasculopathy
Stimulants

Precautions

•Bipolar disorder, anxiety, seizure disorder

Contraindications

• History of substance abuse, hyperthyroidism,


cardiovascular disease, circulatory disorders,
uncontrolled hypertension, glaucoma, tics, MAOI use
within 14 days
Stimulants

Black Box Warnings


•Use has been associated with serious cardiovascular
events including sudden death in patients with
preexisting structural cardiac abnormalities or other
serious heart problems
•Stimulants have high potential for abuse and
dependence. Administration for prolonged periods may
lead to drug dependence and must be avoided. Assess
the risk of abuse prior to prescribing and monitor for
signs of abuse and dependence while on therapy
Atomoxetine

Adverse effects
• Common
•Headache, nausea, vomiting, dry mouth, insomnia,
somnolence
• Rare
•Tachycardia, hypertension, priapism, hepatotoxicity,
psychosis, mania
Atomoxetine

Precautions
• Bipolar disorder, uncontrolled hypertension, hepatic
impairment
Contraindications
•Severe cardiovascular disease, glaucoma,
pheochromocytoma, MAOI use within 14 days
Black Box Warning
•Atomoxetine increases the risk of suicidal ideation in
studies in children and adolescents with ADHD
Guanfacine (Intuniv) and Clonidine (Kapvay)

Adverse Effects
• Somnolence, hypotension, bradycardia
• Taper when discontinuing to prevent rebound
hypertension

Precautions
• Hypotension, bradycardia, heart block
• Operating heavy machinery
Drug/Food and Drug/Drug Interactions
Guanfacine (Intuniv) & Clonodine (Kapvay)

High fat meals


• Delay time to peak concentration of extended release
stimulants
Acidic foods
• Decrease absorption and increase excretion of immediate
release stimulants
Acid suppressing medications (PPIs, H2RAs, antacids)
• Increase absorption and decrease excretion of immediate
release stimulants
Guanfacine (Intuniv) and Clonodine (Kapvay) DDIs

Monoamine oxidase inhibitors


• Concurrent use with stimulants or atomoxetine can result in
hypertensive crisis

CNS depressants
• May enhance sedative effect of alpha-2 agonists

CYP2D6 inhibitors (paroxetine, fluoxetine, bupropion, quinidine)


• May require decreased dose of atomoxetine
Treatment
Guidelines
AAP Treatment Guidelines

Preschool-aged children (4 –5 years of age)


• 1st line
• Behavior therapy

• 2nd line
• Methylphenidate IR
• Off label, but evidence to support its use in
moderate to severe dysfunction if patient fails
behavior therapy
AAP Treatment Guidelines

Elementary school-aged children (6-11 years of age)


• 1st line
• Methylphenidate or amphetamine +/- behavior
therapy
• 2nd line
• Atomoxetine, guanfacine ER, or clonidine ER
+/- behavior therapy
AAP Treatment Guidelines

Adolescents (12-18 years of age)


• 1st line
• Methylphenidate or amphetamine +/- behavior
therapy
• 2nd line
• Atomoxetine, guanfacine ER, or clonidine ER
+/- behavior therapy
ADHD Treatment in Adults

• Stimulants and atomoxetine are FDA approved


for use in adults
• Weak evidence for guanfacine ER and clonidine
ER
Non-pharmacologic Therapy

Caregiver education
• Structured schedule
• Positive and negative reinforcement

Classroom modifications
• Individualized education plans
• Small classrooms
• Work/test modifications

Social skills training


• Learn teamwork
Medication Selection

Patient related variables


• Patient preferences
• Age
• Comorbidities
• Risk of abuse
• Patient ability to swallow pills

Agent related variables


• Onset, peak, duration
• Frequency of dosing
• Adverse effects
• Expense
Medication Selection

Personal or family history of substance abuse


• Vyvanse (prodrug), Concerta (OROS), Daytrana
(patch), atomoxetine, guanfacine, clonidine

Uncontrolled hypertension, structural cardiac


abnormality, cardiomyopathy, heart murmur,
arrhythmia
• Guanfacine, clonidine
Medication Selection

Depression
• Stimulants, guanfacine, clonidine

Bipolar disorder, tics


• Guanfacine, clonidine
Medication Selection

Difficulty swallowing pills


• Daytrana (patch), Dyanavel (liquid),
Quillichew (chewable), Quillivant (liquid),
Procentra (liquid), Adzenys (ODT), Contempla
(ODT), crush immediate release

Difficulty affording medications


• Immediate release, generics
Dosing

• Start at lowest dose and titrate on a 7-day basis


• Young children have slower metabolism so should
be started at a lower dose that is increased in smaller
increments
• When converting from one formulation to another,
not a 1:1 conversion
Dosing

Atomoxetine
Dosing

Guanfacine ER
Monitoring
Indices of Therapeutic Effect

• Improvement in core symptoms


• Improvement in family and peer relationships
Rating Scales

Conners’ Rating Scale


•Used clinically and in clinical trials
•Parent-rated version (full length 110 items, abbreviated 43 items)
and teacher-rated version (full length 115 items, abbreviated 39
items)
•Items scored 0 (never) to 3 (very often)
•Raw score converted to percentile indicative of ADHD
•Scales for inattentive, hyperactive-impulsive, and combined
subtypes of ADHD
•Screens for oppositional defiant disorder and conduct disorder
Monitoring

Efficacy Safety
• Rating scales • HR • Appetite
• School • BP • Mood
performance • Height • EKG if
• Weight history of
• Sleep cardiac
disease
Managing Adverse Effects

Insomnia
• Take earlier in day, switch to shorter duration, use
medication for sleep

Reduced appetite
• High calorie meals at lowest effect of medication
(early morning, late evening)

Nausea/vomiting
• Take with food, reduce dosage
Managing Adverse Effects

Rebound symptoms
• Add dose in afternoon,
change time of second dose,
change to longer
formulation

Delayed growth (crosses two


major percentile lines)
• Reduce dosage, drug
holiday, alternative therapy
Managing Adverse Effects

Cardiovascular (change in BP ≥15 mmHg or HR ≥20 bpm)


• Reduce dosage, alternative therapy

Irritability
• Reduce dosage, assess for comorbidities

Tics
• Reduce dosage, alternative therapy

Psychiatric disorder
• Discontinue medication, alternative therapy
Follow-Up

• A follow-up visit is recommended 1 month after initiation to monitor for


safety and efficacy
• Visits can then occur on a monthly basis until there is a consistent
optimal response, and then every 3 months
• Need for continued use should be assessed every 12 months
•Continue as long as symptoms are present and cause functional
impairment
•If patient is on a stimulant, consider drug holidays during vacations,
weekends, summer
Response

Maximum
Dose?
Titrate to No Yes
maximum Response?
dose

Partial None

Switch to other
Add non-stimulant
stimulant class

If still no
response,
switch to non-
stimulant
Patient Case
Patient Case

Peter is an 8 year old male who was recently


diagnosed with ADHD, with a predominantly
hyperactive-impulsive presentation. His personal
history is unremarkable. He has a family history
of diabetes, MI, and colon cancer. What class of
medications would you recommend as initial
therapy?
Patient Case

Peter arrives to school at 8:00AM. His teachers report his symptoms


affect his ability to complete his work at school. Peter’s parents
state that the symptoms then persist when he does homework after
school, which takes until 4:00PM. Peter’s parents are worried
about being able to afford his medication. Which of the following
therapies would you recommend for Peter?

A. Ritalin (methylphenidate) LA 20 mg every morning


B. Amphetamine salts IR 5 mg in the morning and at lunch
C. Vyvanse (lisdexamphetamine) 20 mg every morning
D. Daytrana (methylphenidate) 10 mg patch daily
Patient Case

Peter is initiated on the recommended


therapy. He returns for a follow up visit in
one month. What pertinent information
would you want to assess as part of your
monitoring plan?
Patient Case

Over the course of 6 months, Peter is titrated to the maximum dose


of Adderall. Peter’s score on the Conners Scale has improved by
25%. His parents feel that Peter’s symptoms have improved, but
still interfere with his ability to complete his schoolwork. What
changes, if any, would you recommend to his regimen?

A. Switch to a methylphenidate product


B. Switch to clonidine ER 0.1 mg daily
C. Add guanfacine ER 1 mg daily
D. No changes are necessary at this time
Questions?
mrincava@su.edu
References

1. Attention-Deficit / Hyperactivity Disorder (ADHD) [Internet]. Centers for Disease Control and Prevention; [updated
18 July 2017; cited 5 Sept 2017]. Available from: https://www.cdc.gov/ncbddd/adhd/index.html
2. Diagnostic and statistical manual of mental disorders: DSM-5. 5th edition. Washington, DC: American Psychiatric
Association; 2013.
3. About ADHD [Internet]. CHADD-The National Resource on ADHD; [cited 7 Sept 2017]. Available from:
http//www.chadd.org
4. DiPiro J.T., Talbert R.L., Yee G.C., Matzke G.R., Wells B.G., Posey L. Attention Deficit/Hyperactivity Disorder.
Pharmacotherapy: A Pathophysiologic Approach. 9 ed. McGraw-Hill; 2014.
5. Conners CK. Conners 3rd Edition. Toronto, Multi-Health Systems, Inc., 2008.
6. AACAP Workgroup on Quality Issues. Practice Parameter for the Assessment and Treatment of Children and
Adolescents With AttentionDeficit/Hyperactivity Disorder. Journal of the American Academy of Child and Adolescent
Psychiatry. 2007;46(7):894-921.
7. Harstad EB, Weaver AL, Katusic SK, Colligan RC, Kumar S, Chan E, Voigt RG, Barbaresi WJ. ADHD, stimulant
treatment, and growth: a longitudinal study. Pediatrics. 2014;134(4):e935.
8. Cooper WO, Habel LA, Sox CM, Chan KA, Arbogast PG, Cheetham TC, Murray KT, Quinn VP, Stein CM, Callahan ST,
Fireman BH, Fish FA, Kirshner HS, O'Duffy A, Connell FA, Ray WA. ADHD drugs and serious cardiovascular events in
children and young adults.N Engl J Med. 2011;365(20):1896.
9. American Academy of Pediatrics. ADHD: clinical practice guidelines for the diagnosis, evaluation, and treatment of
Attention-Deficit/Hyperactivity Disorder in children and adolescents. Pediatrics. 2011;128(5):1007-22.
Pharmacotherapy of Insomnia

Gretchen L. Johnson, PharmD, BCPS


Insomnia
• Defined as difficulty falling asleep, difficulty maintaining sleep
or experiencing nonrestorative sleep.
• Most common complaint in general medical practice
• 40% of pts with chronic insomnia have a psych diagnosis
(depression, anxiety, substance abuse)
• 10-20% self-medicate with OTC meds or alcohol
Insomnia
• Three types of Insomnia
– Transient- lasting 2-3 nights (Ex. jetlag)
– Short-term- lasting < 3 months (Ex. situational)
– Chronic- lasting > 3 months
Common Causes of Insomnia
• Situational
– Work or financial stress, major life events, interpersonal conflicts, jet lag or
shift work
• Medical
– Cardiac: angina, arrhythmias, HF
– Respiratory: asthma, sleep apnea
– Chronic pain
– Endocrine: DM, hyperthyroidism
– GI: GERD, ulcers
– Neurologic: delirium, Parkinson’s, Seizures, RLS
– Pregnancy
Common Causes of Insomnia
• Psychiatric
– Mood disorders: depression, mania
– Anxiety disorders: GAD, OCD
– Substance abuse: alcohol, sedative-hypnotic withdrawal
• Drug-induced Insomnia
– Anticonvulsants
– Central adrenergic blockers
– Stimulants
– SSRIs, Bupropion
– Steroids
– Diuretics
Determining Management
• Determine if transient, short-term, or chronic
• Assess onset, duration and frequency of sx
• Assess effect on daytime functioning
• Assess for underlying causes
• Assess sleep hygiene
• Assess stress
Nonpharmacologic Treatment
• Cognitive behavioral therapy
– May be more effective than drugs in > 55yo
– Stimulus control, good sleep hygiene, cognitive therapy, relaxation
therapy
• Table 72-2 Stimulus Control and Sleep
Hygienehttp://accesspharmacy.mhmedical.com.suproxy.su.ed
u/ViewLarge.aspx?figid=134128156&gbosContainerID=0&gbos
id=0
OTC options
• Antihistamines
– Diphenhydramine (Tylenol PM, Sominex)
– Doxylamine (Unisom)
• Herbal meds
– Melatonin
– Valerian
– Kava Kava
Nonprescription Treatments
• Antihistamines
– Watch for anticholinergic side effects- esp. problematic
in elderly
– Tolerance develops to sedative effects after 1 week
– Diphenhydramine- Pregnancy Category B; Lactation-
may dry up milk
• Herbals
– Little if any evidence of efficacy
• Melatonin may be helpful in jet lag
• Hepatotoxicity reported with Kava Kava and Valerian root
Prescription Treatments
• Benzodiapezines (BZDs)
– Temazepam (Restoril)
– Flurazepam (Dalmane)
– Triazolam (Halcion)
– Estazolam(Prosom)
– Quazepam (Doral)
• Non-BZD GABA-A agonists- “Z- hypnotics”
– Zolpidem (Ambien)
– Zaleplon (Sonata)
– Eszopiclone (Lunesta)
Prescription Treatments (cont’d)
• Melatonin receptor agonist
– Ramelteon (Rozerem)
• Sedating antidepresants
– Amitriptyline (Elavil)
– Doxepin (Silenor)
– Trazodone (Deseryl)
– Mirtazepine (Remeron)
Benzodiazepines
• MOA: GABA-A receptor agonists
• Controlled subtance
Drug Onset Duration T 1/2

Triazolam 30 min 2-4 hrs 2-5 hrs

Temazepam 60-120 min 8-10 hrs 9-12 hrs

Estazolam 60-120 min 8-10 hrs 10-20 hrs

Quazepam 30-60 min 8-10 hrs 40 hrs

Flurazepam 30-60 min 8-20 hrs 40-150 hrs

• Effective in dec. time to fall asleep and inc. total sleep time
Benzodiazepines
• Do not use in:
– Pregnancy
– Substance abuse
– Untreated sleep apnea
• Avoid use with alcohol and other CNS depressants
• Caution with driving or operating heavy machinery
Benzodiazepines
• ADRs: daytime sedation, psychomotor incoordination, decreased
concentration and mental alertness, cognitive deficits,
respiratory depression
• ADRs are dose-related- use lowest effective dose
• Tolerance can develop
• Scheduled substance
– Can be habit forming
• Rebound insomnia can occur with abrupt DC
• Anterograde amnesia, an impairment of memory and recall of
events occurring after the dose is taken, can occur
• Can accumulate in the elderly
– Avoid BZDs with long t1/2- flurazepam and quazepam
– Inc. risk of falls and hip fracture
• Pregnancy Category X- cleft pallette, resp. depression
• Breastfeeding- not recommended
Non-BZD GABA-A agonists
• Zolpidem (Ambien)
• Zaleplon (Sonata)
• Eszopiclone (Lunesta)

• MOA: selective GABA-A receptor agonist subtype 1


• Controlled substance
Non-BZD GABA-A agonists
• Zolpidem
– Formulations available: IR (Ambien), CR (Ambien CR), lingual spray
(Zolpimist), SL (Edular, Intermezzo)
– Both zolpidem CR and eszopiclone are FDA approved for
chronic insomnia and effective for up to 6 months.
Product Onset Duration

Zolpidem IR,Edular SL, Zolpimist 30 min 6 hours

Zolpidem CR 30 min >6 hours

Intermezzo SL 30 min 4-6 hours

– Useful to initiate and maintain sleep; some residual effects


• Intermezzo for middle of the night wakenings- Need 4 hours of sleep left
Non-BZD GABA-A agonists
• Zaleplon (Sonata)
– Onset: 30 min Duration: 2 hours
– Useful to initiate sleep; Can take in middle of night but need 4 hr left in bed; Not for
maintaining sleep unless redosed
– Least likely to cause next-day impairment or anterograde amnesia
• Eszopiclone (Lunesta)
– Onset: 45 min Duration = 5-8 hr
– Useful to initiate sleep and maintain sleep
– No evidence of tolerance after 6 months of use
– ADR: unpleasant/metallic taste (20-33% incidence)
Zolpidem Dosing Change 2013
• FDA Recommends Lower Dose
• Reason:
– Morning blood levels in some pt (females) may be high enough to
impair activities requiring alertness – driving
– Highest risk with ER forms and women eliminate the drug more
slowly than men
• Use 5mg vs. 10mg for IR; Use 6.25mg vs. 12.5mg for CR
• Intermezzo (no change) already at a lower dosage (11/2011)
Eszopiclone Dosing Change 2014
• FDA recommended lower dose
• Reason
– 3mg dose can impair driving ability, coordination, and memory for
over 11 hours
• Start with 1mg for all pts
– Do not exceed 2mg for elderly and 3mg for young pts
Non-BZD GABA-A agonists
• High fat/heavy meal can delay absorption – delays onset
• CYP3A4 inhibitors can increase plasma levels
• Hepatic impairment may require lower doses
• Side effects:
– Headache
– Dizziness
– GI: nausea, dyspepsia
– Anterograde amnesia (high dose zolpidem)
• Withdrawal reactions uncommon but reported
• Pregnancy Category C; Breastfeeding: zolpidem compatible
BZD and Non-BZD GABA-A agonists
• FDA Labeling Changes
• Caution
– Anaphylaxis, facial angioedema
– Complex sleep behaviors- engaging in these activites while not fully awake and
with no recollection afterwards
• Sleep driving
• Sleep eating
• Phone calls
• Risk increased with concurrent alcohol use and doses above maximum recommended
Ramelteon (Rozerem)
• Selective MT1 and MT2 receptor agonist
• Onset: 30 min T1/2= 1-2.6 hours
• Effective for dec. time to fall asleep
• Not effective for maintaining sleep
• ADRs: HA, dizziness, somnolence
• Not a controlled substance
– May be an option in substance abuse pts
• Pregnancy Category C; Breastfeeding- unknown
Sedating Antidepressants
• Alternatives for pt who cannot take BZD or if concommitant
depression
• Improve sleep in depression with stimulating SSRI or bupropion
– Mostly see Trazodone used
• Doses used for insomnia are not effective for treating depression
• Amitriptyline 10-50mg Qhs; Doxepin (Silenor®) 3-6mg Qhs
– Disadvantages
• Anticholinergic side effects, adrenergic blockade
(orthostatic hypotension), cardiac conduction problems,
daytime sedation
• Trazodone 25-150mg QHS
– Watch for orthostatic hypotension, priapism
• Mirtazapine 7.5 – 30mg QHS
– Watch for daytime sedation, weight gain
Suvorexant(Belsomra)
• New class of sleep agent
• MOA: orexin receptor antagonist
– Orexins are involved with promoting wakefulness so antagonising
their effect would cause sedation
• Schedule IV
• Same precautions about combining with alcohol and other
sedating drugs and risk for impairment in driving and other
activities the next day
Treatment of Insomnia
• Stepwise approach to select hypnotic
– ? Type of insomnia
• Difficulty initiating sleep
• Difficulty maintaining sleep/early morning awakening
– ? Duration
– ? Etiologies
• Sleep apnea, psychiatric/medical issues
– ? Sleep habits
– Substance abuse history
 Select agents based on symptoms, kinetic and ADR profile
Clinical Practice Guideline
General Treatment Approach
1. Short-intermediate acting BZD, Non-BZD RA or ramelteon
Ex. Zolpidem, eszoplicone, zaleplon, temazepam
2. Alternate short-intermediate acting BZD, Non-BZD RA or
ramelteon
3. Sedating antidepressant
Ex. Amitriptyline, trazodone, doxepin, mirtazepine
4. Combined BzRA or ramelteon + sedating antidepressant
5. Other sedating agents- with appropriate comorbid
conditions
Ex. Quetiapine, gabapentin

Journal of Clinical Sleep Medicine, Vol. 4, No. 5, 2008


Algorithm
Adapted and Used With Permission from Mitsi Lizer, Pharm.D.

Hypnotic Selection

DFA DMS MNA

Ramelteon, Zolpidem, Zaleplon


triazolam, zaleplon, Eszopiclone,
zolpidem Temazepam Intermezzo

DFA: Difficulty falling asleep; DMS: maintaining sleep: MNA: middle of the night awakening
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP


Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
Objectives
• At the end of the presentation, each student should be able to:
• Explain the pharmacology of anti-anxiety agents and antidepressants
• Identify appropriate, guideline-based pharmacological treatment options for anxiety
and depression
• Distinguish the drug properties of the different pharmacological treatment options
• Create a pharmacological treatment plan for a sample patient case
Introducing Our Patient: MG
Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for
acute complaints of rapid onset episodes of palpitations, shortness of breath, sweats,
trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the
belief that she was having a heart attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology
screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes
occurring at work, at home, and while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the
resolution of the symptoms of each acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
ANXIETY DISORDERS AND
THEIR TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Overview of anxiety
• Anxiety is an emotional state commonly caused by the perception of real or perceived
danger that threatens the security of an individual

• Anxiety may become excessive and/or debilitating

• May present with both physiological and psychological features


• Physiological: tachycardia, diaphoresis, shortness of breath
• Psychological: worry, anticipation of threats

• Individuals may develop an anxiety disorder when feelings of fear and anxiety become
frequent and excessive
Overview continued…
• Anxiety disorders are the most frequent mental illnesses found in clinical practice and are
also the most commonly misdiagnosed

• Anxiety disorders generally develop before the age of 30 years old

• Common risk factors include:


• Sex
• Social issues
• Family history of anxiety or depression
Types of anxiety disorders (not inclusive!)
• Generalized anxiety disorder (GAD)

• Panic disorder (PD)

• Social anxiety disorder (aka social phobia)

• Specific phobias

• Obsessive-compulsive disorder (OCD)

• Posttraumatic stress disorder (PTSD)


Managing anxiety disorders
• GOAL: remission of symptoms ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into two phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into maintenance phase
• Time range: minimum of 4 weeks, up to 12 weeks
• Maintenance phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: minimum of 1 year at adequate dose, up to lifelong therapy
Anxiety Pharmacotherapy:
The Meds (pharmacology
first)!
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD and PD
• Mechanism of action (MOA):
• Inhibit the reuptake of serotonin back into the presynaptic neuron by inhibiting the activity of the serotonin transporter (SERT)
• This, in turn, keeps the serotonin in the synapse and allows it to exert its actions of regulating mood, emotions, sleep and
appetite
Brief Animation of how SSRIs work
• https://www.youtube.com/watch?v=ocSptPUBbuo
Available SSRI Agents
Generic Name Brand Name
Citalopram Celexa®

Escitalopram Lexapro®

Fluoxetine Prozac®

Fluvoxamine Luvox®

Paroxetine Paxil®

Sertraline Zoloft®
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• Some of these agents are first line options for GAD and PD
• MOA:
• Inhibit the activity of SERT (like the SSRIs)
• In addition to inhibiting SERT, the SNRIs also inhibit the norepinephrine transporter (NET)
• These mechanisms allow serotonin and norepinephrine to stay in the synapse and exert their actions on postsynaptic receptors

http://brainyinfo.com/antidepressants/snri/
Available SNRI Agents
Generic Name Brand Name

Venlafaxine Effexor®

Desvenlafaxine Pristiq®
(enantiomer of venlafaxine)

Duloxetine Cymbalta®

Milnacipran Savella®

Levomilnacipran ER Fetzima®
(enantiomer of milnacipran)
Benzodiazepines
• Primary site of action: GABA A receptor (a chloride ion channel)
Available Benzodiazepines
Generic Name Brand Name
Alprazolam Xanax®

Chlordiazepoxide Librium®

Clonazepam Klonopin®

Clorazepate Tranxene®

Diazepam Valium®

Estazolam Prosom®

Flurazepam Dalmane®

Lorazepam Ativan®

Midazolam Versed®

Oxazepam Serax®

Quazepam Doral®

Temazepam Restoril®

Triazolam Halcion®
Tricyclic Antidepressants (TCAs)
• MOA:
• Similar to SNRis (inhibit reuptake of serotonin and norepinephrine by inhibiting activity of SERT and NET)
• Within this class, these is variability in affinity for SERT vs. NET
• Antagonize postsynaptic receptors, such as H 1 and α, that leads to increased side effects

quizlet.com
Available TCA Agents
Generic Name Brand Name
Amitriptyline Elavil®

Clomipramine Anafranil®

Desipramine Norpramin®

Doxepin Sinequan®

Imipramine Tofranil®

Nortriptyline Pamelor®

Trimipramine Surmontil®

Amoxapine Asendin®

Protriptyline Vivactil®
Monoamine Oxidase inhibitors (MAOis)
• Found to be a treatment option for treatment-resistant PD
• Mechanism of action:
• Inhibits the activity of monoamine oxidase (degradation of neurotransmitters) in the neuron and increases neurotransmitters
• Some are irreversible, while are others are reversible; some are selective to one form of MAO, while others are nonselective

http://www.neurosoup.com/maoi
s/
Available MAOi Agents
Generic Name Brand Name

Phenelzine Nardil®

Selegiline Emsam®

Tranylcypromine Parnate®

Isocarboxazid Marplan®

Moclobemide Manerix®
Pregabalin (Lyrica®)
• Could be a second line option for GAD
• MOA:
• Reduces calcium influx by binding to the presynaptic α2-δ subunit of voltage-gated calcium channels
• In trials, it has been shown to produce anxiolytic effects similar to certain benzodiazepines
(lorazepam and alprazolam) and venlafaxine

http://www.apiapollo.com/Pregabalin.html
Buspirone (Buspar®)
• A second line option for GAD
• MOA:
• Does not interact directly with GABA systems
• 5-HT1A agonist on presynaptic neurons (reduces the firing of serotonergic neurons) and acts as a
partial agonist at these receptors on postsynaptic neurons
• Increases the release of norepinephrine and dopamine

google.com
Hydroxyzine (Vistaril®)
• An alternative option for GAD
• MOA:
• Chemical classification: an antihistamine
• In clinical trials, it has been shown to reduce anxiety symptoms

http://www.answers.com/topic/hydroxyzine
Second Generation Antipsychotics (SGAs)

• Some guidelines state that three of these agents (risperidone, olanzapine, and
quetiapine) can be used as augmentation with first and second line therapies for
treatment resistant GAD
Anxiety Pharmacotherapy:
Treatment Guidelines second!
GENERALIZED ANXIETY
DISORDER (TREATMENT
GUIDELINES AND DRUG
PROPERTIES)
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines Escitalopram* Imipramine Augmentation with:


Paroxetine* Buspirone* Alprazolam
Sertraline Hydroxyzine Diazepam
Venlafaxine XR* Risperidone
Duloxetine* Olanzapine
Pregabalin

IPAP2 Review and SSRI Partial or no response: Assess for co-morbidities


Algorithm SNRI -Increase dose
-Switch to another
Addition of a antidepressant
benzodiazepine if rapid -Augment
response

1World Federation of Societies of Biological Psychiatry *FDA-approved for GAD


2The International Psychopharmacology Algorithm Project
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options

Escitalopram Paroxetine Sertraline


Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%
Initial Dosing 10 mg/day 20 mg/day 50 mg/day
Dosing Range 10-20 mg/day 20-50 mg/day 50-200 mg/day

Black Box Suicidal ideation in children, adolescents, and


Warning young adults

Side Effects Insomnia, jitteriness, headache,


nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Escitalopram 80 27-32 5 56 None

Paroxetine 50 24-31 5-7 95 None

Sertraline 36 (increases by 30-40% 27 6-8 99 None


when taken with food)
Why do we care about pharmacokinetics?
• Helps us to understand what the body does to the drug

• Half-life  agents with a long half-life may be beneficial in instances when doses are
missed, for example
• Fluoxetine is the SSRI agent with the longest half-life (4-6 days)

• Active metabolites  if an agent has an active metabolite, this needs to be taken into
consideration because the drug will be acting for a longer period of time in the body
• Fluoxetine is the only SSRI that has an active metabolite
Drug Interactions with the SSRI Options
• Two types of drug-drug interactions:
1. Pharmacokinetic – most common interactions for SSRIs
• **REMEMBER: what the body does to the drug**
• Includes liver enzyme interactions (cannot be inclusive of all drug interactions)
• Example  Paroxetine is a strong CYP2D6 inhibitor; TCAs are CYP2D6 substrates; co-
administration of these agents may lead to elevated drug concentrations of the TCAs
• Citalopram and escitalopram are the two SSRI agents with the least potential of pharmacokinetic
interactions
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Escitalopram + 0

Paroxetine ++++ 0

Sertraline + +
Drug Interactions continued…

2. Pharmacodynamic – what the drug does to the body


• An example – the concomitant administration of two or more
serotonergic agents, leading to serotonin syndrome
• This interaction leads to physiological changes
SNRI Options
Venlafaxine XR Duloxetine
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%

Initial Dosing 37.5 or 75 mg/day 30 or 60 mg/day


Dosing Range 75-225 mg/day 60-120 mg/day

Black Box Suicidal ideation in children, adolescents, and


Warning young adults

Side Effects Jitteriness, nausea/vomiting, diarrhea,


headache, sexual dysfunction, elevated blood
pressure, insomnia
Pharmacokinetic Properties of SNRI Options
Agent Bioavailability Half-life Time to Peak Protein Active
(%) (hours) (hours) Binding Metabolites
(%)
Venlafaxine XR 45 5 2 27 Yes (O-
desmethylvenlafaxine
)

Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents

• Venlafaxine is a substrate, but not an inhibitor, of CYP2D6 and


other CYP enzymes

• Inhibitory Potentials of CYP Liver Enzymes


CYP Liver Enzyme
SNRI Agent 2D6 3A4

Venlafaxine 0/+ 0

Duloxetine +++ 0

• Pharmacodynamic interactions also exist (same instance as SSRIs)


Pregabalin

Mechanism of action Reduces calcium influx by


binding to the alpha2-delta
subunit of the voltage-gated
calcium channels
Initial Dosing 50 mg three times a day
Dosing Range 150-600 mg/day

Side Effects Dizziness, somnolence,


peripheral edema, weight gain
Imipramine: a TCA Option

Mechanism of action Tricyclic antidepressant

Initial Dosing 50 mg/day


Dosing Range 75-200 mg/day

Side Effects Jitteriness, anticholinergic


effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Imipramine

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Imipramine 22-77 6-34 1.5-3 63-96 Yes (desipramine)
Drug Interactions with Imipramine
• As stated earlier, TCAs are CYP2D6 substrates
• Combination of CYP2D6 inhibitor and imipramine may result in an increase of imipramine drug
concentration (pharmacokinetic interaction)

• TCAs generally do not induce or inhibit CYP enzymes


• Imipramine has the potential to inhibit CYP2C19, however

• Due to the multiple receptor binding affinities of TCAs, there is an increased risk of side
effects with this class of medications
• Examples of pharmacodynamic interactions:
• Imipramine + Benadryl® = increased risk of antihistamine and anticholinergic side effects
• Imipramine + antihypertensive agents = increased risk of orthostatic hypotension
Buspirone

Initial Dosing 7.5 mg twice daily


Dosing Range 15-60 mg/day

Side Effects Nausea/vomiting, abdominal


pain, drowsiness, dizziness
Pharmacokinetic Properties of Buspirone

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Buspirone 4 2.5 (needs to <1 86 Yes
be dosed 2-3
times a day)
Drug Interactions with Buspirone
• Drugs that inhibit CYP3A4 can increase buspirone levels since buspirone is a CYP3A4
substrate

• Likewise, drugs that induce CYP3A4 can decrease buspirone levels

• Both are pharmacokinetic interactions


Hydroxyzine

Mechanism of action Antihistamine

Initial Dosing 25 or 50 mg four times a day


Dosing Range 200-400 mg/day

Side Effects Dry mouth, headache,


somnolence
Benzodiazepines
Alprazolam Chlordiazepoxide Clonazepam

Initial IR: 0.75 mg daily 25 mg daily 0.25 mg 1-2


Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 25-400 mg/day 1-4 mg/day


Range XR: 1-10 mg/day
Benzodiazepines continued…
Clorazepate Diazepam Lorazepam Oxazepam

Initial IR: 0.75 mg daily 0.25 mg 1-2 25 mg daily 30 mg daily


Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 1-4 mg/day 25-400 mg/day 30-120 mg/day
Range XR: 1-10 mg/day

**only these 7 benzodiazepines have FDA


approval for GAD
Common side effects of benzodiazepines
• Drowsiness, fatigue

• Memory impairment and amnesia

• Respiratory depression

• Potential for dependence

• Withdrawal symptoms may occur


Pharmacokinetic Properties of Benzodiazepine Options
Drug Half-life (hours) Time to Peak (hours) Protein Binding (%) Active Metabolites

Alprazolam 12-15 1-2 80 None

Chlordiazepoxide 5-30 1-4 96 Yes, multiple

Clonazepam 30-40 1-4 85 None

Clorazepate Prodrug 1-2 97 Yes

Diazepam 20-80 0.5-2 98 Yes (oxazepam is


one of them)

Lorazepam 10-20 2-4 85 None

Oxazepam 5-20 2-4 97 None


Drug Interactions with the benzodiazepines:
IMPORTANT interactions to know!
• IMPORTANT: Benzodiazepines may cause CNS depression**

• Simultaneous use of another CNS depressant, such as alcohol, with a


benzodiazepine may result in additive CNS depressant effects

• Other CNS depressants include antihistamines, antipsychotics, and opioids


More drug interactions with benzodiazepines
• Pharmacokinetic interactions

• Drugs that inhibit CYP3A4 (ketoconazole, an antifungal, is an example) can increase blood levels of
alprazolam and diazepam

• Drugs that induce CYP3A4 (carbamazepine is an example) can decrease benzodiazepine blood levels
Tolerance and dependence

• What is tolerance?

• What is dependence?
Benzodiazepine Withdrawal Syndrome
• Need to properly taper down dose
• Frequent withdrawal symptoms:
• Anxiety
• Insomnia
• Irritability
• Muscle aches and tension
• Nausea
• Blurred vision
• Palpitations
• Severe withdrawal symptoms:
• Seizures
• Psychosis
• Delirium and confusion
• Can occur within one day and extend to > 2 weeks, depending on dose
and agent patient was on
Drug properties to consider when predicting a withdrawal
syndrome

• The higher the dose, the more serious the abrupt withdrawal is

• The longer the half-life, the slower the elimination, the fewer and less severe withdrawal
symptoms occur

• The longer the half-life, the later the withdrawal symptoms will occur
Serotonin Syndrome (SS)
• Any antidepressant that increases serotonergic neurotransmission can increase the risk of
developing SS

• Symptoms:
• Mental status changes (agitation)
• Autonomic instability (temperature > 38°C, diaphoresis)
• Neuromuscular abnormalities (tremor, hyperreflexia, spontaneous clonus, muscle rigidity)

• Treatments:
• Lower the dose of the medication and discontinue it
• Benzodiazepines to control agitation and seizures that may occur
• Serotonin-production blocking agents (cyproheptadine is an antihistamine that reduce the
production of serotonin)
How long do we treat for?

• Monitor efficacy every 2 weeks, initially

• Adequate trial of SSRI or SNRI = 4-6 weeks with


adequate dose

• Continue treatment for at least a year once patient


has responded to pharmacotherapy
PANIC DISORDER
(TREATMENT GUIDELINES
AND DRUG PROPERTIES)
Pharmacotherapy Options for PD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines SSRI


Venlafaxine XR*

APA2 Guidelines SSRI Partial or no response: MAOi


SNRI -Increase dose
TCA -Switch to another
Benzodiazepine medication
CBT -Augment

1World Federation of Societies of Biological Psychiatry


2 American Psychiatric Association *FDA-approved for PD
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options
Citalopram Fluoxetine Fluvoxamine
Efficacy 60-80% response rate
Antipanic effect of SSRIs is delayed for at least 4
weeks (some patients do not respond for 8-12
weeks)
Initial Dosing 10 mg/day 5 mg/day 25 mg/day
Dosing Range 20-40 mg/day 10-80 mg/day 100-300
mg/day
Black Box Suicidal ideation in children, adolescents, and
Warning young adults

Side Effects Insomnia, jitteriness, headache,


nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Citalopram >/= 80 33 2-4 80 None

Fluoxetine 95 4-6 days 4-8 94 Yes


(norfluoxetine)

Fluvoxamine 53 15-26 2-8 77 None


Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Citalopram + 0

Fluoxetine ++++ ++

Fluvoxamine 0 +++
Clomipramine: another TCA Option

Mechanism of action Tricyclic antidepressant

Initial Dosing 25 mg/day


Dosing Range 25-250 mg/day

Side Effects Jitteriness, anticholinergic


effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Clomipramine

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Clomipramine 50 12-36 2-6 98 Yes
Phenelzine

Mechanism of action Monoamine oxidase inhibitor


(nonselective)
Initial Dosing 15 mg/day
Dosing Range 30-90 mg/day

Side Effects Jitteriness, hypertensive crisis


in overdose, orthostatic
hypotension
Pharmacokinetic Properties of Phenelzine

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Phenelzine Unknown 11 Unknown Unknown None
Drug Interactions with MAOis
• Significant interaction to note:
• When MAOis are taken with certain foods, especially those high in tyramine
• Examples of foods high in tyramine include aged cheeses, sour cream, yogurt, cottage cheese, American
cheese, wine, beer, sardines, canned or processed meats, raisins, liver, soy sauce, coffee, chocolate, licorice
• Result: hypertensive crisis
• Symptoms include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood
pressure

• MAOis can also interact with buspirone and other antidepressants


• Increased risk of developing serotonin syndrome
How long do we treat for?
• Monitor efficacy every 1-2 weeks for the first 1-3 months
of pharmacotherapy, and then every 2-4 weeks
• After dose is stabilized and symptoms have decreased,
monitor patient every 2 months

• SSRIs and SNRIs should work within 4-8 weeks, but


could be up to 12 weeks

• Benzodiazepines – effective for acute treatment


• Use short-term for only 2-4 weeks

• Continue treatment for 12-24 months


MAJOR DEPRESSIVE
DISORDER AND ITS
TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Video: What people with depression want you
to know

• https://www.youtube.com/watch?v=IQr1G1OOEEQ
An easy acronym
“SIGE CAPS”
• Sleep increased or depressed
• Interest and/or mood is diminished **
• Guilt or worthless feelings
• Energy is diminished

• Concentration is impaired
• Appetite increased or decreased
• Psychomotor retardation or agitation
• Suicidal thoughts, attempts, or plans

**essential features (must have at least one to hold diagnosis of


MDD)
Assessing Depression: PHQ-9 Scale
Managing MDD
• Euthymia: a patient’s baseline state, no depressive symptoms
• GOAL: remission of symptoms; patient returns to euthymic state ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into three phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into continuation phase
• Time range: 6 – 12 weeks
• Continuation phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: 4 – 9 months
• Maintenance phase
• The time after continuation phase where management involves “watchful waiting” or
treatment is continued at dose that achieved remission of symptoms
• Time range: years – lifelong
Managing MDD continued…

• Relapse – return of depressive symptoms during the acute or


continuation phase

• Recurrence – return of depressive symptoms during the


maintenance phase
Managing MDD:
A depiction
Remission
Relapse Recurrence
Euthymia
Increased

Relapse
severity

Response
Symptoms

Syndrome

Treatment phases Acute Continuation Maintenance


(6 to 12 wk) (4 to 9 mo) (1 y)
Time
Depression Pharmacotherapy:
The Meds (pharmacology
first)!
Mixed Serotonergic Agents
• All these agents are treatment options for MDD
• 3 agents in this class, all with slightly different mechanisms of action
• Trazodone (Desyrel®)

the-medical-dictionary.com

• Nefazodone (Serzone®)

medlibrary.org

• Vilazodone (Viibryd®)

www.medicinescomplete.com
Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• Also involved with the presynaptic release of NE (norepinephrine) and DA (dopamine) into the
synaptic cleft

www.pharmacy-and-drugs.com
Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist that, in turn, enhances the presynaptic release of NE and
serotonin
• Antagonizes 5-HT2 and 5-HT3 receptors  leads to lower anxiety levels and GI side effects
• H1 antagonist

dailymed.nlm.nih.gov
Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of MDD

• MOA:
• Inhibits the reuptake of serotonin
• 5-HT1A receptor agonist
• Partial 5-HT1B receptor agonist
• 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist
Depression Pharmacotherapy:
Treatment Guidelines second!
How to pick an antidepressant?
• Since the effectiveness of antidepressants is generally comparable between classes and
within classes of medications, the APA (American Psychiatric Association) guidelines state
to:
• Pick an antidepressant based on:
• Side effect profile
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
• Patient preference
SNRIs not discussed earlier
• Desvenlafaxine (Pristiq®)
• Initial and usual doses are 50 mg/day, with no additional benefit seen with higher doses
• Extended release tablets  dosed once a day
• Half-life is 11 hours and there are no active metabolites
• Relatively new SNRI compared to the others in its class
TCAs not discussed earlier
• Amitriptyline
• Initial dose: 25 mg/day; dose range is 100-300 mg/day

• Nortriptyline
• Amitriptyline’s metabolite
• Initial dose: 25 mg/day; dose range is 50-150 mg/day
• Half-life can reach up to 88 hours, while amitriptyline’s half-life can reach 46 hours
MAOis not discussed earlier
• Selegiline
• A transdermal patch
• Initial dose is 6 mg/24 hours and the maximum dose is 12 mg/24 hours
• Dose may be increased by 3 mg/day increments every 2 weeks

• Tranylcypromine
• Initial dose: 10 mg/day; dose range is 20-60 mg/day

• Pharmacokinetic properties are not determined


Mixed Serotonergic Agents
Nefazodone Trazodone Vilazodone

Initial Dosing 100 mg/day 50 mg/day 10 mg/day


Dosing Range 300-600 150-g00 10-40 mg/day
mg/day mg/day
Note Carries a BBW Place in
for liver failure therapy has
not been
determined yet
Side Effects Orthostatic Orthostatic Diarrhea,
hypotension, hypotension, nausea,
dizziness, sedation, vomiting,
somnolence, dizziness trouble
dry mouth, sleeping
nausea,
Pharmacokinetics of mixed serotonergic agents
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Nefazodone 20 2-4 1 99 Yes

Trazodone Unknown 6-11 1-2 92 Yes

Vilazodone 72 25 4-5 > 95 Not determined


Drug Interactions with the mixed serotonergic agents
• Nefazodone is an inhibitor of CYP3A4
• Example: nefazodone can increase triazolam levels, so reduce triazolam dose by 75%

• Trazodone is a substrate of CYP3A4, but does not inhibit or induce it


• Caution when combining with CYP3A4 inducers or inhibitors

• Vilazodone is also a substrate of CYP3A4

• Caution when using with other serotonergic agents due to risk of SS


Bupropion
• Initial dose: 150 mg/day; dose range is 150-450 mg/day

• Side effects include:


• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold

• Interesting fact: bupropion is actually used as a smoking cessation agent

• Another interesting fact: bupropion could be used to mitigate sexual dysfunction side effects of
SSRI agents
Bupropion continued…
• Pharmacokinetic properties
• Half-life is 10-21 hours
• 3 active metabolites exist for bupropion, so take into consideration when using this medication

• Drug Interactions
• Use with MAOis may increase the risk of hypertensive crisis
• Medications that also lower the seizure threshold (examples: antipsychotics, antihistamines)
• One of bupropion’s metabolites inhibits CYP2D6 (like fluoxetine and paroxetine)
Mirtazapine
• Initial dose is 15 mg/day; dose range is 15-45 mg/day

• Side effects include:


• Somnolence and sedation
• Dry mouth
• Weight gain
• Constipation

• Interesting fact: in clinical practice, mirtazapine is used as an appetite stimulant


Mirtazapine continued…
• Pharmacokinetic properties
• Half-life is 20-40 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• Sedating effects of mirtazapine may be enhanced when given with CNS depressants such as alcohol
or benzodiazepines
• Mirtazapine is a substrate of CYP2D6, CYP3A4, and CYP1A2
• Inhibitors may increase mirtazapine blood levels and inducers may decrease mirtazapine levels
Vortioxetine
• Initial dose: 5 or 10 mg/day; dosing range = 5-20 mg/day

• Side effects:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
Vortioxetine continued…
• Pharmacokinetic properties
• Half-life is ~ 66 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• Vortioxetine is metabolized by CYP2D6
• Inhibitors of CYP2D6 will increase concentration of vortioxetine, while inducers will decrease concentration of
vortioxetine
Consider this for the SSRI Agents!

Consider for… Avoid or use caution in…

• Paroxetine for underweight • Paroxetine for overweight or


patients obese patients
• Paroxetine for insomnia • Citalopram and escitalopram
• Fluoxetine and sertraline for in QTc prolongation or
psychomotor retardation torsades risk
• Fluoxetine for overweight or • Fluoxetine and sertraline in
obese patients agitation or insomnia
• Paroxetine in pregnancy
Consider this for the SNRI Agents!

Consider for… Avoid or use caution in…

• Psychomotor retardation • Hypertension

• Chronic pain • Agitation or insomnia


Consider this for Bupropion!

Consider for… Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients


Consider this for Mirtazapine!

Consider for… Avoid or use caution in…

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 10-14 Evidence-based
monotherapy:
psychotherapy or
pharmacotherapy

Moderate 15-19 Evidence-based


monotherapy:
psychotherapy or
pharmacotherapy

Severe >/= 20 Combination of


psychotherapy and
pharmacotherapy
STAR*D Trial
• STAR*D Trial
• Sequenced Treatment Alternatives to Relieve Depression
• Funded by the National Institute of Mental Health
• Largest and longest study ever conducted to evaluate
depression treatment
• Goal: to assess the effectiveness of depression treatments in
patients diagnosed with MDD
• 4 levels in the study
• Those participants who did not reach remission in one level could
proceed to the next level of treatment
STAR*D Trial continued…
• Who participated?
• 7-year period, study enrolled 4,041 outpatients
• Ages 18-75 years old
• 1,165 excluded, so 2,876 participants were actually evaluated
• Treatment Levels
• Level 1: Citalopram was given to participants for 12-14 weeks
• Level 2: Switch to sertraline, bupropion SR, venlafaxine XR or psychotherapy, or
add bupropion SR, buspirone, or psychotherapy to citalopram from level 1
• Level 3: Switch to mirtazapine or nortriptyline, or add lithium or triiodothyronine
(T3) to their current regimen
• Level 4: Switch to tranylcypromine or combination of venlafaxine XR with
mirtazapine
STAR*D Trial continued…
• Results
• Outcome measure in this trial was remission of symptoms, not response
• In level 1, ~33% reached remission and another 10-15% responded
• It took approximately 7 weeks to reach remission
• In level 2, in the switch group, ~25% reached remission, and in the add-on
group, ~33% reached remission
• In level 3, in the switch group, 12-20% reached remission, and in the add-on
group, ~20% reached remission
• In level 4, 7-10% reached remission
• Investigators conclude: ~50% of participants reached remission after 2
treatment levels, and over the course of all 4 levels, almost 70% of those
who did not withdraw reached remission
STAR*D Trial continued…
• What can we take away from this trial?
• If a patient fails one SSRI, it does not mean that he/she will fail another
• Monoamine oxidase inhibitors are limited because of their tolerability
profiles
• Patients with difficult-to-treat depression can get well after trying different
treatment strategies, but the odds of reaching remission lessen with every
additional treatment strategy needed
• Those who reach remission have a better chance of remaining symptom-
free compared with those who just experience symptom response
• Provide medications at optimal doses, maintain diligent monitoring, and try
different treatment choices
Assessing the Adequacy of Antidepressant Interventions
• APA Guidelines
• 4-6 weeks of treatment at target dose is needed before
concluding that a patient is unresponsive or partially
responsive to a specific therapy
• If patient has not reached remission, may consider
switching a patient to an agent within the same class or
to an agent from a different class
• Augmenting the first therapy with a non-MAOi
antidepressant from a different class or augmenting with
a non-antidepressant therapy (lithium, T3, second-
generation antipsychotic) are also second-line options
Assessing the Adequacy of Therapeutic Interventions
continued…
• After 7-10 days
• Improved sleep
• Reduced anxiety
• After 7-21 days
• Improved self-care
• Improved thinking, concentration
• Increased energy, activity level
• Appetite impairments resolve
• After 2-4 weeks
• Improved mood
• Reduced suicidal ideation (SI)
Back to our patient: MG
Recap of Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for acute complaints of rapid onset
episodes of palpitations, shortness of breath, sweats, trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the belief that she was having a heart
attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes occurring at work, at home, and
while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the resolution of the symptoms of each
acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
In Conclusion
• Anxiety is a normal human emotion, that when excessive, may result in an
anxiety disorder
• Anxiety disorders are frequently misdiagnosed
• Major depressive disorder is a DSM-5 diagnosable condition Treatment
guidelines help healthcare professionals make treatment recommendations
and choices
• There is overlap between the agents that can be used to treat anxiety disorders
(especially the two discussed in this presentation) and MDD
Valuable MDD Resources
• VA/DoD Clinical Practice Guidelines for the Management
of Major Depressive Disorder (2016):
https://www.healthquality.va.gov/guidelines/MH/mdd/VA
DoDMDDCPGFINAL82916.pdf

• APA Practice Guideline for the Treatment of Patients


With Major Depressive Disorder (2010):
http://psychiatryonline.org/pb/assets/raw/sitewide/practic
e_guidelines/guidelines/mdd.pdf
Questions??
Thank you for your time and attention!
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP


Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP


Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
Objectives
• At the end of the presentation, each student should be able to:
• Explain the pharmacology of anti-anxiety agents and antidepressants
• Identify appropriate, guideline-based pharmacological treatment options for anxiety
and depression
• Distinguish the drug properties of the different pharmacological treatment options
• Create a pharmacological treatment plan for a sample patient case
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD and PD
• MOA
• ↓ serotonin transporter (SERT) reuptake @ presynaptic neuron → ↑serotonin in the synapse
• Serotonin – regulates mesolimbic system (mood, emotions, sleep and appetite)
• Black Box warning : Suicidal ideation in pt <25 y/o
• ADR
• Insomnia
• Weight gain
• Sexual dysfunction
• Jitteriness
• HA, N/V/D
• DI
• CYP interactions >SNRIz
• Serotonin Syndrome
SSRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)

Citalopram Celexa ✅ ↓potential for PK interactions


Avoid in Qtc prolongation/torsades (≤40mg)
High bioavailability
Escitalopram Lexapro ✅ Highest bioavailability
↓potential for PK interactions
Avoid in Qtc prolongation/torsades
Fluoxetine Prozac® ✅ Longest t1/2 (4-6d)
Active metabolite (norfluxitine) (16d - need
washout period)
Strong 2D6 inhibitor (↑[TCAs})
Good for psychomotor retardation
Good for overweight/obese pt
Avoid if agitation/insomnia
Fluvoxamine Luvox ✅ Strong 3A4 inhibitor

Paroxetine Paxil ✅ Highly protein bound


Strong 2D6 inhibitor (↑[TCAs})
Good for underweight pts (avoid if obese)
Good for insomnia pt
CI in pregnancy
Sertraline Zoloft Not FDA Highly protein bound
Take with food!
Good for psychomotor retardation
Avoid if agitation/insomnia
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• MOA
• ↓ serotonin transporter (SERT) reuptake @ presynaptic neuron → ↑serotonin in the synapse
• ↓norepinephrine transporter (NET) @ presynaptic neuron → ↑NE in the synapse
• ↑NE → ↑ energy, reaction time, arousal, attention
• Black Box warning : Suicidal ideation in pt <25 y/o
• ADR
• Jitteriness
• Sexual dysfunction
• ↑BP
• Insomnia
• HA, N/V/D
• DI
• Fewer CYP interactions than SSRIs
• Serotonin Syndrome
• MDD
• Good for psychomotor retardation/chronic pain
• Avoid if HTN, agitation or insomnia

http://brainyinfo.com/antidepressants/snri/
SNRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)

Venlafaxine XR Effexor ✅ Lowest protein binding


Desmethylvenlafaxine
active metabolite
Substrate of 2D6
Desvenlafaxine Pristiq Enantiomer of
venlafaxine

Duloxetine Cymbalta ✅ Strong inhibitor of 2D6


XR Initial and maintenance
dose = 50mg (no
↑benefit)
Milnacipran Savella for fibromyalgia NOT
psych

Levomilnacipra Fetzima Enantiomer of


n ER Minacipran
(enantiomer of For depression only
milnacipran)
Benzodiazepines
• MOA
• Bind to GABAA receptor → ↑ chloride ion influx to ↑inhibitory effects of GABA
• ADR
• Drowsiness/fatigue (block H1 receptors → ↑ sedation when added to antipsychotics)
• Memory impairment/amnesia
• Respiratory depression
• Dependence
• Withdrawal symptoms if taking for extended period of time (need to taper off slowly)
• GAD
• 7 agents for short term tx for resistant pt (2-4wks)
• MDD
• Avoid in pt who have high suicide potential/substance use disorder (CNS depression)
Benzodiazepines
Generic Brand GAD Panic MDD Notes
Alprazolam Xanax ✅ Pregabalin (Lyrica) is as effective
Metab by 3A4 (↑by ketoconazole; ↓Tegretol)
Chlordiazepoxid Librium ✅ Protein bound ; metabolites
e
Clonazepam Klonopin ✅
Clorazepate Tranxen ✅ Protein bound; metabolites
e Prodrug
Diazepam Valium ✅ Metab by 3A4 (↑by ketoconazole; ↓Tegretol)
Longest t1/2 (80 hr) + metabolites (oxazepam
Protein bound
Estazolam Prosom
Flurazepam Dalmane
Lorazepam Ativan ✅ Pregabalin (Lyrica) is as effective
Not CYP metabolized
Midazolam Versed
Oxazepam Serax ✅ Not CYP metabolized
Protein bound
Quazepam Doral
Temazepam Restoril
Triazolam Halcion
ANXIETY DISORDERS AND
THEIR TREATMENT AGENTS
Overview of Anxiety
• emotional state caused by the perception of real or perceived danger that threatens the security of an individual

• Can become excessive and/or debilitating and may develop into a disorder when these feelings become
frequent/excessive

• May present with physiological and psychological features


• Physiological: tachycardia, diaphoresis, shortness of breath
• Psychological: worry, anticipation of threats

• Anxiety disorders are the most commonly found and the most commonly misdiagnosed mental illnesses

• Generally develop <30 years old

• Common risk factors include:


• Sex (Female)
• Social issues
• Family history of anxiety or depression
Types of anxiety disorders (not inclusive!)
• Generalized anxiety disorder (GAD)

• Panic disorder (PD)

• Social anxiety disorder (aka social phobia)

• Specific phobias

• Obsessive-compulsive disorder (OCD)

• Posttraumatic stress disorder (PTSD)


Managing anxiety disorders
• GOAL: remission of symptoms ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into two phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into maintenance phase
• Time range: minimum of 4 weeks, up to 12 weeks
• Maintenance phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: minimum of 1 year at adequate dose, up to lifelong therapy
Tricyclic Antidepressants (TCAs)
• MOA:
• Similar to SNRis (inhibit reuptake of serotonin and norepinephrine by inhibiting activity of SERT and NET)
• Within this class, these is variability in affinity for SERT vs. NET
• Antagonize postsynaptic receptors, such as H 1 and α, that leads to increased side effects

quizlet.com
TCA Agents
Generic Brand GAD Panic MDD
Amitriptyline Elavil®

Clomipramine Anafranil® ✅

Desipramine Norpramin®

Doxepin Sinequan®

Imipramine Tofranil®

Nortriptyline Pamelor®

Trimipramine Surmontil®

Amoxapine Asendin®

Protriptyline Vivactil®
Monoamine Oxidase inhibitors (MAOis)
• Found to be a treatment option for treatment-resistant PD
• Mechanism of action:
• Inhibits the activity of monoamine oxidase (degradation of neurotransmitters) in the neuron and increases neurotransmitters
• Some are irreversible, while are others are reversible; some are selective to one form of MAO, while others are nonselective

http://www.neurosoup.com/maoi
s/
MAOi Agents
Generic Brand Panic

Phenelzine Nardil ✅

Selegiline Emsam

Tranylcypromine Parnate

Isocarboxazid Marplan

Moclobemide Manerix
Pregabalin (Lyrica®)
• Could be a second line option for GAD
• MOA:
• Reduces calcium influx by binding to the presynaptic α2-δ subunit of voltage-gated calcium channels
• In trials, it has been shown to produce anxiolytic effects similar to certain benzodiazepines
(lorazepam and alprazolam) and venlafaxine

http://www.apiapollo.com/Pregabalin.html
Buspirone (Buspar®)
• A second line option for GAD
• MOA:
• Does not interact directly with GABA systems
• 5-HT1A agonist on presynaptic neurons (reduces the firing of serotonergic neurons) and acts as a
partial agonist at these receptors on postsynaptic neurons
• Increases the release of norepinephrine and dopamine

google.com
Hydroxyzine (Vistaril®)
• An alternative option for GAD
• MOA:
• Chemical classification: an antihistamine
• In clinical trials, it has been shown to reduce anxiety symptoms

http://www.answers.com/topic/hydroxyzine
Second Generation Antipsychotics (SGAs)

• Some guidelines state that three of these agents (risperidone, olanzapine, and
quetiapine) can be used as augmentation with first and second line therapies for
treatment resistant GAD
Anxiety Pharmacotherapy:
Treatment Guidelines second!
GENERALIZED ANXIETY
DISORDER (TREATMENT
GUIDELINES AND DRUG
PROPERTIES)
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines Escitalopram* Imipramine Augmentation with:


Paroxetine* Buspirone* Alprazolam
Sertraline Hydroxyzine Diazepam
Venlafaxine XR* Risperidone
Duloxetine* Olanzapine
Pregabalin

IPAP2 Review and SSRI Partial or no response: Assess for co-morbidities


Algorithm SNRI -Increase dose
-Switch to another
Addition of a antidepressant
benzodiazepine if rapid -Augment
response

1World Federation of Societies of Biological Psychiatry *FDA-approved for GAD


2The International Psychopharmacology Algorithm Project
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options

Escitalopram Paroxetine Sertraline


Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%
Initial Dosing 10 mg/day 20 mg/day 50 mg/day
Dosing Range 10-20 mg/day 20-50 mg/day 50-200 mg/day

Black Box Suicidal ideation in children, adolescents, and


Warning young adults

Side Effects Insomnia, jitteriness, headache,


nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Escitalopram 80 27-32 5 56 None

Paroxetine 50 24-31 5-7 95 None

Sertraline 36 (increases by 30-40% 27 6-8 99 None


when taken with food)
Why do we care about pharmacokinetics?
• Helps us to understand what the body does to the drug

• Half-life  agents with a long half-life may be beneficial in instances when doses are
missed, for example
• Fluoxetine is the SSRI agent with the longest half-life (4-6 days)

• Active metabolites  if an agent has an active metabolite, this needs to be taken into
consideration because the drug will be acting for a longer period of time in the body
• Fluoxetine is the only SSRI that has an active metabolite
Drug Interactions with the SSRI Options
• Two types of drug-drug interactions:
1. Pharmacokinetic – most common interactions for SSRIs
• **REMEMBER: what the body does to the drug**
• Includes liver enzyme interactions (cannot be inclusive of all drug interactions)
• Example  Paroxetine is a strong CYP2D6 inhibitor; TCAs are CYP2D6 substrates; co-
administration of these agents may lead to elevated drug concentrations of the TCAs
• Citalopram and escitalopram are the two SSRI agents with the least potential of pharmacokinetic
interactions
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Escitalopram + 0

Paroxetine ++++ 0

Sertraline + +
Drug Interactions continued…

2. Pharmacodynamic – what the drug does to the body


• An example – the concomitant administration of two or more
serotonergic agents, leading to serotonin syndrome
• This interaction leads to physiological changes
SNRI Options
Venlafaxine XR Duloxetine
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%

Initial Dosing 37.5 or 75 mg/day 30 or 60 mg/day


Dosing Range 75-225 mg/day 60-120 mg/day

Black Box Suicidal ideation in children, adolescents, and


Warning young adults

Side Effects Jitteriness, nausea/vomiting, diarrhea,


headache, sexual dysfunction, elevated blood
pressure, insomnia
Pharmacokinetic Properties of SNRI Options
Agent Bioavailability Half-life Time to Peak Protein Active
(%) (hours) (hours) Binding Metabolites
(%)
Venlafaxine XR 45 5 2 27 Yes (O-
desmethylvenlafaxine
)

Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents

• Venlafaxine is a substrate, but not an inhibitor, of CYP2D6 and


other CYP enzymes

• Inhibitory Potentials of CYP Liver Enzymes


CYP Liver Enzyme
SNRI Agent 2D6 3A4

Venlafaxine 0/+ 0

Duloxetine +++ 0

• Pharmacodynamic interactions also exist (same instance as SSRIs)


Pregabalin

Mechanism of action Reduces calcium influx by


binding to the alpha2-delta
subunit of the voltage-gated
calcium channels
Initial Dosing 50 mg three times a day
Dosing Range 150-600 mg/day

Side Effects Dizziness, somnolence,


peripheral edema, weight gain
Imipramine: a TCA Option

Mechanism of action Tricyclic antidepressant

Initial Dosing 50 mg/day


Dosing Range 75-200 mg/day

Side Effects Jitteriness, anticholinergic


effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Imipramine

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Imipramine 22-77 6-34 1.5-3 63-96 Yes (desipramine)
Drug Interactions with Imipramine
• As stated earlier, TCAs are CYP2D6 substrates
• Combination of CYP2D6 inhibitor and imipramine may result in an increase of imipramine drug
concentration (pharmacokinetic interaction)

• TCAs generally do not induce or inhibit CYP enzymes


• Imipramine has the potential to inhibit CYP2C19, however

• Due to the multiple receptor binding affinities of TCAs, there is an increased risk of side
effects with this class of medications
• Examples of pharmacodynamic interactions:
• Imipramine + Benadryl® = increased risk of antihistamine and anticholinergic side effects
• Imipramine + antihypertensive agents = increased risk of orthostatic hypotension
Buspirone

Initial Dosing 7.5 mg twice daily


Dosing Range 15-60 mg/day

Side Effects Nausea/vomiting, abdominal


pain, drowsiness, dizziness
Pharmacokinetic Properties of Buspirone

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Buspirone 4 2.5 (needs to <1 86 Yes
be dosed 2-3
times a day)
Drug Interactions with Buspirone
• Drugs that inhibit CYP3A4 can increase buspirone levels since buspirone is a CYP3A4
substrate

• Likewise, drugs that induce CYP3A4 can decrease buspirone levels

• Both are pharmacokinetic interactions


Hydroxyzine

Mechanism of action Antihistamine

Initial Dosing 25 or 50 mg four times a day


Dosing Range 200-400 mg/day

Side Effects Dry mouth, headache,


somnolence
Benzodiazepines
Alprazolam Chlordiazepoxide Clonazepam

Initial IR: 0.75 mg daily 25 mg daily 0.25 mg 1-2


Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 25-400 mg/day 1-4 mg/day


Range XR: 1-10 mg/day
Benzodiazepines continued…
Clorazepate Diazepam Lorazepam Oxazepam

Initial IR: 0.75 mg daily 0.25 mg 1-2 25 mg daily 30 mg daily


Dosing XR: 1 mg daily times a day

Dosing IR: 0.75-4 mg/day 1-4 mg/day 25-400 mg/day 30-120 mg/day
Range XR: 1-10 mg/day

**only these 7 benzodiazepines have FDA


approval for GAD
Common side effects of benzodiazepines
• Drowsiness, fatigue

• Memory impairment and amnesia

• Respiratory depression

• Potential for dependence

• Withdrawal symptoms may occur


Pharmacokinetic Properties of Benzodiazepine Options
Drug Half-life (hours) Time to Peak (hours) Protein Binding (%) Active Metabolites

Alprazolam 12-15 1-2 80 None

Chlordiazepoxide 5-30 1-4 96 Yes, multiple

Clonazepam 30-40 1-4 85 None

Clorazepate Prodrug 1-2 97 Yes

Diazepam 20-80 0.5-2 98 Yes (oxazepam is


one of them)

Lorazepam 10-20 2-4 85 None

Oxazepam 5-20 2-4 97 None


Drug Interactions with the benzodiazepines:
IMPORTANT interactions to know!
• IMPORTANT: Benzodiazepines may cause CNS depression **

• Simultaneous use of another CNS depressant, such as alcohol, with a benzodiazepine


may result in additive CNS depressant effects

• Other CNS depressants include antihistamines, antipsychotics, and opioids


More drug interactions with benzodiazepines
• Pharmacokinetic interactions

• Drugs that inhibit CYP3A4 (ketoconazole, an antifungal, is an example) can increase blood levels
of alprazolam and diazepam

• Drugs that induce CYP3A4 (carbamazepine is an example) can decrease benzodiazepine


blood levels
Tolerance and dependence

• What is tolerance?

• What is dependence?
Benzodiazepine Withdrawal Syndrome
• Need to properly taper down dose
• Frequent withdrawal symptoms:
• Anxiety
• Insomnia
• Irritability
• Muscle aches and tension
• Nausea
• Blurred vision
• Palpitations
• Severe withdrawal symptoms:
• Seizures
• Psychosis
• Delirium and confusion
• Can occur within one day and extend to > 2 weeks , depending
on dose and agent patient was on
Drug properties to consider when predicting a withdrawal
syndrome

• The higher the dose, the more serious the abrupt withdrawal is

• The longer t1/2, the slower the elimination, the fewer and less severe withdrawal
symptoms occur

• The longer t1/2 , the later the withdrawal symptoms will occur
Serotonin Syndrome (SS)
• Any antidepressant that increases serotonergic neurotransmission can increase the risk of
developing SS

• Symptoms – Serotonin Syndrome Triad:


• Mental status changes (agitation)
• Autonomic instability (temperature > 38°C, diaphoresis)
• Neuromuscular abnormalities (tremor, hyperreflexia, spontaneous clonus, muscle rigidity)

• Treatments:
• Lower the dose of the medication and discontinue it
• Benzodiazepines to control agitation and seizures that may occur
• Serotonin-production blocking agents (cyproheptadine is an antihistamine that reduce the
production of serotonin)
How long do we treat for?

• Monitor efficacy every 2 weeks, initially

• Adequate trial of SSRI or SNRI = 4-6 weeks with


adequate dose

• Continue treatment for at least a year once


patient has responded to pharmacotherapy
PANIC DISORDER
(TREATMENT GUIDELINES
AND DRUG PROPERTIES)
Pharmacotherapy Options for PD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines SSRI


Venlafaxine XR*
(Effexor)

APA2 Guidelines SSRI - any Partial or no response: MAOi


SNRI - any -Increase dose • Phenelzine (Nardil)
TCA -Switch to another
• Clomipramine medication
(Anafranil) -Augment
Benzodiazepine
CBT

1World Federation of Societies of Biological Psychiatry


2 American Psychiatric Association *FDA-approved for PD
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
SSRI Options (Any SSRI can be used)
Citalopram Fluoxetine Fluvoxamine
(Celexa) (Prozac) (Luvox)
Efficacy 60-80% response rate
Antipanic effect of SSRIs is delayed for at least 4
weeks (some patients do not respond for 8-12
weeks)
Initial Dosing 10 mg/day 5 mg/day 25 mg/day
Dosing Range 20-40 mg/day 10-80 mg/day 100-300
(MDD 40mg dt mg/day
↑risk QT
prolongation)
Black Box Suicidal ideation in children, adolescents, and
Warning young adults (pt <25 y/o)

Side Effects Insomnia, jitteriness, headache,


Pharmacokinetic Properties of SSRI Options
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Citalopram >/= 80 33 2-4 80 None
(Celexa)

Fluoxetine 95 4-6 days 4-8 94 Yes


(Prozac) (norfluoxetine –
t1/2 16 days)

Fluvoxamine 53 15-26 2-8 77 None


(Luvox)

• Celexa & Prozac – Highest Bioavailability


• Prozac – longest T1/2 (4-6d) and metabolite
(16d) need long washout period before
trying a new med
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Citalopram + 0
(Celexa)

Fluoxetine ++++ ++
(Prozac)
Strong 2D6 inhibitor

Fluvoxamine 0 +++
(Luvox)
Strong 3A4 inhibitor
Clomipramine (Anaframil) : another TCA Option

MOA TCA – inhibits SERT and NERT to ↓seritonin


and NE reuptake
Acts on other receptors (H1, muscarinic,
α)→↑ADR
Initial Dosing 25 mg/day
Dosing Range 25-250 mg/day

Side Effects Jitteriness, anticholinergic effects


(constipation, dry mouth, blurred vision,
difficulty urinating, drowsiness), weight gain,
sedation, cardiac arrhythmias, orthostatic
hypotension
Pharmacokinetic Properties of Clomipramine (Anaframil)

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Clomipramine 50 12-36 2-6 98 Yes
(Anaframil)
Phenelzine (Nardil) For tx resistant PD

MOA Monoamine oxidase inhibitor


(nonselective)
- MAO-A – NE, Epi, Seritonin
- MAO-B –dopamine, tyramine
- ↓degredation of these n-trans by the
neuron to ↑them in the synaptic cleft
Initial Dosing 15 mg/day
Dosing Range 30-90 mg/day

Side Effects Jitteriness, hypertensive crisis in overdose,


orthostatic hypotension
Pharmacokinetic Properties of Phenelzine (Nardil)

Bioavailability Half-life Time to Peak Protein Active


(%) (hours) (hours) Binding Metabolites
(%)
Phenelzine Unknown 11 Unknown Unknown None
(Nardil)
Drug-Food Interaction with MAOis
• MAOis + tyramine → hypertensive crisis
• aged cheeses, sour cream, yogurt, cottage cheese, American cheese
• wine, beer, coffee
• sardines, canned or processed meats, liver
• soy sauce,, chocolate, licorice, raisins

• Symptoms of HTN crisis


• occipital HA
• Neck stiffness
• N/V
• Sweating
• Sharp ↑ in BP

• MAOis + buspirone/antidepressants →↑risk serotonin syndrome


How long do we treat for?
• Monitor efficacy
• Q1-2 weeks for the first 1-3 months
• Q2-4 weeks after first 3 mo
• After dose is stabilized and symptoms ↓monitor Q2 mo

• SSRIs and SNRIs should work within 4-8 weeks, but


could be up to 12 weeks

• Continue treatment for 12-24 months

• Benzodiazepines –for acute treatment (2-4wk)


MAJOR DEPRESSIVE
DISORDER AND ITS
TREATMENT AGENTS
Go to: pollev.com/anneschempp781
Video: What people with depression want you
to know

• https://www.youtube.com/watch?v=IQr1G1OOEEQ
An easy acronym
“SIGE CAPS”
• Sleep increased or depressed
• Interest and/or mood is diminished **
• Guilt or worthless feelings
• Energy is diminished

• Concentration is impaired
• Appetite increased or decreased
• Psychomotor retardation or agitation
• Suicidal thoughts, attempts, or plans

**essential features (must have at least one to hold diagnosis of


MDD)
Assessing Depression: PHQ-9 Scale
Managing MDD
• Euthymia: a patient’s baseline state, no depressive symptoms
• GOAL: remission of symptoms; patient returns to euthymic state
***
• Response: improvement of symptoms after a therapy has been
initiated
• Management is divided into three phases:
• Acute phase (6-12 weeks)
• Phase where the dose of the medication is being titrated
• Continuation phase (4-9 months)
• Phase where the dose that achieved remission SS in acute phase is continued
• Maintenance phase (years-lifelong)
• “watchful waiting” or continued tx at dose that achieved remission of
symptoms
Managing MDD continued…

• Relapse – return of depressive symptoms during the acute or


continuation phase

• Recurrence – return of depressive symptoms during the


maintenance phase
Managing MDD:
A depiction
Remission
Relapse Recurrence
Euthymia
Increased

Relapse
severity

Response
Symptoms

Syndrome

Treatment phases Acute Continuation Maintenance


(6 to 12 wk) (4 to 9 mo) (1 y)
Time
Depression Pharmacotherapy:
The Meds (pharmacology
first)!
Mixed Serotonergic Agents (End in –ZODONE)
• All these agents are treatment options for MDD (different MOAs)
• Trazodone (Desyrel®)
• Inhibits serotonin reuptake at 5HT2A, 5HT adrenoreceptors, H1 and α-1 receptors
• Inhibit serotonin reuptake

• Nefazodone (Serzone®)
• Blocks 5HT2A, and α-1 receptors
• Inhibits serotonin and NE reuptake

• Vilazodone (Viibryd®)
• Inhibits reuptake of serotonin
• Selective 5HT1A partial agonist
Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• ↑presynaptic release of NE (norepinephrine) and DA (dopamine) into the synapse (like
sympathomimetic – ADHD medications)

www.pharmacy-and-drugs.com
Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist (blocking)→ ↑ presynaptic release of NE and serotonin
• Antagonizes 5-HT2 (↑ dopamine) and 5-HT3 (GI) receptors  ↓ anxiety + ↓N/V
• H1 antagonist → ↑sedation

dailymed.nlm.nih.gov
SSRI - Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of MDD
• Don’t know what some of the benefits of the MOA are

• MOA:
• Inhibits the reuptake of serotonin
• agonist (stimulant) 5-HT1A
• Partial agonist 5-HT1B
• antagonist 5-HT1D, 5-HT3 → ↓ N/V and 5-HT7
Depression Pharmacotherapy:
Treatment Guidelines second!
How to pick an antidepressant?
• effectiveness of antidepressants is comparable between and within classes
• Start with SSRI, SNRI, Mertazapine or Buproprion
• Pick an antidepressant based on:
• Side effect profile
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
• Patient preference
SNRIs
• Desvenlafaxine (Pristiq®)
• Initial and maintenance doses are the same → 50 mg/day
• no additional benefit seen with higher doses
• Extended release tablets  dosed QD
• T1/2 = 11 hours; no active metabolites
• Relatively new SNRI compared to the others in its class
• Often used for neuropathic pain
TCAs
• Amitriptyline (Elavil)
• Higher affinity for SERT
• Tertiary amine → breaks down and nortriptyline
• Initial dose: 25 mg/day
• dose range is 100-300 mg/day
• T1/2 = 46hr

• Nortriptyline (Pamelor)
• Higher affinity for NET
• Amitriptyline (Elavil) metabolite
• Initial dose: 25 mg/day
• dose range is 50-150 mg/day
• T1/2 =88 hr
MAO-I
• Selegiline (Emsam)
• A transdermal patch
• Initial dose is 6 mg/24 hours
• Max dose is 12 mg/24 hours
• Dose may be increased by 3 mg/day Q2 weeks

• Tranylcypromine (Parnate)
• Initial dose: 10 mg/day
• dose range is 20-60 mg/day

• Pharmacokinetic properties are not determined


Mixed Serotonergic Agents (End in –ZODONE)
Nefazodone Trazodone Vilazodone
(Desyrel) (Serzone) (Viibyrd)
Initial Dosing 100 mg/day 50 mg/day 10 mg/day
Dosing Range 300-600 150-600 10-40 mg/day
mg/day mg/day
Note BBW for liver Place in
failure therapy has
not been
determined yet
ADR Orthostatic Orthostatic Diarrhea,
hypotension, hypotension, nausea,
dizziness, sedation vomiting,
somnolence, (used for sleep trouble
dry mouth, at lower sleeping
nausea, doses)
Pharmacokinetics of mixed serotonergic agents
Agent Bioavailability Half-life Time to Protein Active
(%) (hours) Peak Binding Metabolite
(hours) (%) s
Nefazodone 20 2-4 1 99 Yes
(Desyrel)
3A4 inhibitor

Trazodone Unknown 6-11 1-2 92 Yes


(Serzone)
3A4 inhibitor

Vilazodone 72 25 4-5 > 95 Not determined


(Viibyrd)
3A4 inhibitor
Drug Interactions with the mixed serotonergic agents
• Nefazodone (Desyrel) is an inhibitor of CYP3A4
• Example: nefazodone can increase triazolam levels, so reduce triazolam dose by 75%

• Trazodone and Vilazodone are substrates of CYP3A4, but does not inhibit or induce it
• Caution when combining with CYP3A4 inducers or inhibitors

• Caution when using with other serotonergic agents due to risk of SS


Bupropion (Welbutrin)
• Initial dose: 150 mg/day;
• dose range is 150-450 mg/day
• T1/2 = 10-21hr; 3 active metabolites

• ADR:
• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold

• Bupropion is actually used as a smoking cessation agent

• Buproprion + SSRI → ↓ sexual dysfunction ADR of SSRI agents

• DI
• Wellbutrin + MAOis → ↑ risk HTN crisis
• Caution if combined with other meds that ↓ seizure threshold
• Metabolite inhibits 2D6 (like fluoxetine and paroxetine)
Mirtazapine (Remeron)
• Initial dose is 15 mg/day; dose range is 15-45 mg/day

• Side effects include:


• Somnolence and sedation
• Dry mouth
• Weight gain
• Constipation

• Interesting fact: in clinical practice, mirtazapine is used as an appetite stimulant


Mirtazapine continued…
• Pharmacokinetic properties
• T1/2 = 20-40 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• ↑Sedation if combined with CNS depressants (EtOH, benzodiazepines
• Mirtazapine is a substrate of CYP2D6, 3A4, and 1A2
• Hydrocarbon in smoke are strong 1A2 inhibitors
• Inhibitors may increase mirtazapine blood levels and inducers may decrease mirtazapine levels
Vortioxetine (Trintellix)
• Initial dose: 5 or 10 mg/day; dosing range = 5-20 mg/day

• Side effects:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
Vortioxetine continued…
• Pharmacokinetic properties
• Half-life is ~ 66 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents as the risk of SS is increased
• Vortioxetine is metabolized by CYP2D6
• Inhibitors of CYP2D6 will increase concentration of vortioxetine, while inducers will decrease concentration of
vortioxetine
SSRI Agents for MDD

Good options BAD OPTIONS

• Paroxetine (Paxil) • Paroxetine (Paxil)


• underweight • Overweight/obese
• insomnia patients
• Fluoxetine (Prozac) • Pregnancy
• psychomotor retardation • Citalopram (Celexa) or
• Overweight/obese escitalopram
patients • ↑QTc prolongationt or
• Sertraline (Zoloft) torsades risk
• psychomotor retardation • Fluoxetine (Prozac) or
sertraline (Zoloft)
• Agitation/insomnia
SNRI Agents

Good option for: Avoid in:


• Psychomotor retardation • Hypertension

• Chronic pain • Agitation or insomnia


Bupropion (Welbutrin)

Good option for: Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients


Mirtazapine (Remeron)

Good option for: Avoid in:

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 10-14 psychotherapy OR
pharmacotherapy

Moderate 15-19 psychotherapy OR


pharmacotherapy

Severe >/= 20 psychotherapy AND


pharmacotherapy
STAR*D Trial
• STAR*D Trial
• Sequenced Treatment Alternatives to Relieve Depression
• Funded by the National Institute of Mental Health
• Largest and longest study ever conducted to evaluate
depression treatment
• Goal: to assess the effectiveness of depression treatments in
patients diagnosed with MDD
• 4 levels in the study
• Those participants who did not reach remission in one level could
proceed to the next level of treatment
STAR*D Trial continued…
• Who participated?
• 7-year period, study enrolled 4,041 outpatients
• Ages 18-75 years old
• 1,165 excluded, so 2,876 participants were actually evaluated
• Treatment Levels
• Level 1: Citalopram was given to participants for 12-14 weeks
• Level 2: Switch to sertraline, bupropion SR, venlafaxine XR or psychotherapy, or
add bupropion SR, buspirone, or psychotherapy to citalopram from level 1
• Level 3: Switch to mirtazapine or nortriptyline, or add lithium or triiodothyronine
(T3) to their current regimen
• Level 4: Switch to tranylcypromine or combination of venlafaxine XR with
mirtazapine
STAR*D Trial continued…
• Results
• Outcome measure in this trial was remission of symptoms, not response
• In level 1, ~33% reached remission and another 10-15% responded
• It took approximately 7 weeks to reach remission
• In level 2, in the switch group, ~25% reached remission, and in the add-on
group, ~33% reached remission
• In level 3, in the switch group, 12-20% reached remission, and in the add-on
group, ~20% reached remission
• In level 4, 7-10% reached remission
• Investigators conclude: ~50% of participants reached remission after 2
treatment levels, and over the course of all 4 levels, almost 70% of those
who did not withdraw reached remission
STAR*D Trial continued…
• What can we take away from this trial?
• If a patient fails one SSRI, it does not mean that he/she will fail another
• Monoamine oxidase inhibitors are limited because of their tolerability
profiles
• Patients with difficult-to-treat depression can get well after trying different
treatment strategies, but the odds of reaching remission lessen with every
additional treatment strategy needed
• Those who reach remission have a better chance of remaining symptom-
free compared with those who just experience symptom response
• Provide medications at optimal doses, maintain diligent monitoring, and try
different treatment choices
Assessing the Adequacy of Antidepressant Interventions
• APA Guidelines
• 4-6 weeks of treatment at target dose is needed before
concluding that a patient is unresponsive or partially
responsive to a specific therapy
• If patient has not reached remission, may consider
switching a patient to an agent within the same class or
to an agent from a different class
• Augmenting the first therapy with a non-MAOi
antidepressant from a different class or augmenting with
a non-antidepressant therapy (lithium, T3, second-
generation antipsychotic) are also second-line options
Assessing the Adequacy of Therapeutic Interventions
continued…
• 7-10 days
• Improved sleep
• Reduced anxiety
• 7-21 days
• Improved self-care
• Improved thinking, concentration
• Increased energy, activity level
• Appetite impairments resolve
• 2-4 weeks (longest to remit)
• Improved mood
• Reduced suicidal ideation (SI)
Back to our patient: MG
Recap of Patient case: MG
• CC: “I am tired of this.”
• HPI:
• MG is a 23-year-old WF who was referred for a psychiatric evaluation by her cardiologist
• In the past two months, MG has presented to the Emergency Department four times for acute complaints of rapid onset
episodes of palpitations, shortness of breath, sweats, trembling, and fears that she was going to die
• The symptoms seemed to peak within minutes, leaving her scared, worried, and with the belief that she was having a heart
attack
• Medical exams have found normal physical examinations, vital signs, lab results, toxicology screens, and EKGs
• MG reported a total of five of these episodes in the past three months, with the episodes occurring at work, at home, and
while walking her dog
• She has developed a fear of having other episodes, which has led her to miss days of work
• Her sleep quality has declined and so has her mood
• MG believes that her medical evaluations were inaccurate since they were done after the resolution of the symptoms of each
acute episode
• She continues to suspect that something is wrong with her heart
Patient case continued…
• PMH:
• Psoriasis (increased itchiness and flakiness in the past three months)
• Medications:
• Topical steroid for psoriasis
• Acetaminophen 500 mg 1-2 tablets by mouth every 4-6 hours as needed for menstrual cramps and headaches
• Multivitamin 1 tablet daily
• Allergies:
• None
• SH:
• Single, lives alone
• Works as a marketing consultant
• (+) 1 glass of wine 2-3 nights per week
• (-) Smoking
• (-) Illicit drug use
• FH:
• Mother had major depressive disorder (MDD); committed suicide by overdose four years earlier
• Father –healthy
• Two brothers are healthy
In Conclusion
• Anxiety is a normal human emotion, that when excessive, may result in an
anxiety disorder
• Anxiety disorders are frequently misdiagnosed
• Major depressive disorder is a DSM-5 diagnosable condition Treatment
guidelines help healthcare professionals make treatment recommendations
and choices
• There is overlap between the agents that can be used to treat anxiety disorders
(especially the two discussed in this presentation) and MDD
Valuable MDD Resources
• VA/DoD Clinical Practice Guidelines for the Management
of Major Depressive Disorder (2016):
https://www.healthquality.va.gov/guidelines/MH/mdd/VA
DoDMDDCPGFINAL82916.pdf

• APA Practice Guideline for the Treatment of Patients


With Major Depressive Disorder (2010):
http://psychiatryonline.org/pb/assets/raw/sitewide/practic
e_guidelines/guidelines/mdd.pdf
Questions??
Thank you for your time and attention!
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
October 3, 2017 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D., BCPP


Clinical Psychiatric Pharmacist
Assistant Professor of Pharmacy Practice
Bernard J. Dunn School of Pharmacy
Shenandoah University
ANXIETY/PANIC/DEPRESSION
AGENTS
PA Pharmacotherapeutics Course
November 8, 2016 (1:30 – 3:30 pm)

Lecturer: Teresa Elsobky, Pharm.D


Clinical Psychiatric Pharmacist
Assistant Professor of Clinical Sciences
Bernard J. Dunn School of Pharmacy
Shenandoah University
ANXIETY DISORDERS AND
THEIR TREATMENT AGENTS
Managing anxiety disorders
• GOAL: remission of symptoms ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into two phases:
• Acute phase (4-12 weeks)
• Dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into maintenance phase
• Maintenance phase (1 year – lifelong)
• Dose that achieved remission of symptoms is continued
Anxiety Pharmacotherapy:
The Meds (pharmacology
first)!
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD
and PD
• MOA:
• Inhibit serotonin reuptake by inhibiting activity of the
presynaptic serotonin transporter (SERT) → ↑ serotonin
in synapse to regulate mood, emotions, sleep and
appetite
Selective Serotonin Reuptake Inhibitors (SSRIs)
• Some of these agents are first line options for GAD and PD
• MOA
• ↓ serotonin transporter (SERT) reuptake @ presynaptic neuron → ↑serotonin in the synapse
• Serotonin – regulates mesolimbic system (mood, emotions, sleep and appetite)
• Black Box warning : Suicidal ideation in pt <25 y/o
• ADR
• Insomnia
• Weight gain
• Sexual dysfunction
• Jitteriness
• HA, N/V/D
• DI
• CYP interactions >SNRIs
• Serotonin Syndrome
SSRI Agents
Generic Name Brand Name
Citalopram Celexa®

Escitalopram Lexapro®

Fluoxetine Prozac®

Fluvoxamine Luvox®

Paroxetine Paxil®

Sertraline Zoloft®
SSRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)

Citalopram Celexa ✅ ↓potential for PK interactions


Avoid in Qtc prolongation/torsades (≤40mg)
High bioavailability
Escitalopram Lexapro ✅ Highest bioavailability
↓potential for PK interactions
Avoid in Qtc prolongation/torsades
Fluoxetine Prozac® ✅ Longest t1/2 (4-6d)
Active metabolite (norfluxitine) (16d - need
washout period)
Strong 2D6 inhibitor (↑[TCAs})
Good for psychomotor retardation
Good for overweight/obese pt
Avoid if agitation/insomnia
Fluvoxamine Luvox ✅ Strong 3A4 inhibitor

Paroxetine Paxil ✅ Highly protein bound


Strong 2D6 inhibitor (↑[TCAs})
Good for underweight pts (avoid if obese)
Good for insomnia pt
CI in pregnancy
Sertraline Zoloft Not FDA Highly protein bound
Take with food!
Good for psychomotor retardation
Avoid if agitation/insomnia
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• Some of these agents are first line options for GAD and PD
• MOA:
• Inhibit the activity of SERT (like the SSRIs) and the NE transporter (NET) → ↑ serotonin and NE in the synapse

http://brainyinfo.com/antidepressants/snri/
Serotonin Norepinephrine Reuptake Inhibitors (SNRIs)
• MOA
• ↓ serotonin transporter (SERT) reuptake @ presynaptic neuron → ↑serotonin in the synapse
• ↓norepinephrine transporter (NET) @ presynaptic neuron → ↑NE in the synapse
• ↑NE → ↑ energy, reaction time, arousal, attention
• Black Box warning : Suicidal ideation in pt <25 y/o
• ADR
• Jitteriness
• Sexual dysfunction
• ↑BP
• Insomnia
• HA, N/V/D
• DI
• Fewer CYP interactions than SSRIs
• Serotonin Syndrome
• MDD
• Good for psychomotor retardation/chronic pain
• Avoid if HTN, agitation or insomnia
SNRI Agents
Generic Name Brand Name

Venlafaxine Effexor®

Desvenlafaxine Pristiq®
(enantiomer of venlafaxine)

Duloxetine Cymbalta®

Milnacipran Savella®

Levomilnacipran ER Fetzima®
(enantiomer of milnacipran)
SNRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)

Venlafaxine XR Effexor ✅ Lowest protein binding


Desmethylvenlafaxine
active metabolite
Substrate of 2D6
Desvenlafaxine Pristiq Enantiomer of
venlafaxine

Duloxetine Cymbalta ✅ Strong inhibitor of 2D6


XR Initial and maintenance
dose = 50mg (no
↑benefit)
Milnacipran Savella for fibromyalgia NOT
psych

Levomilnacipra Fetzima Enantiomer of


n ER Minacipran
(enantiomer of For depression only
milnacipran)
Benzodiazepines
• Primary site of action: GABAA receptor (a chloride ion channel)
Benzodiazepines
• MOA
• Bind to GABAA receptor → ↑ chloride ion influx to ↑inhibitory effects of GABA
• ADR
• Drowsiness/fatigue (block H1 receptors → ↑ sedation when added to antipsychotics)
• Memory impairment/amnesia
• Respiratory depression
• Dependence
• Withdrawal symptoms if taking for extended period of time (need to taper off slowly)
• GAD
• 7 agents for short term tx for resistant pt (2-4wks)
• MDD
• Avoid in pt who have high suicide potential/substance use disorder (CNS depression)
Benzodiazepine Agents
Generic Name Brand Name
Alprazolam Xanax®

Chlordiazepoxide Librium®

Clonazepam Klonopin®

Clorazepate Tranxene®

Diazepam Valium®

Estazolam Prosom®

Flurazepam Dalmane®

Lorazepam Ativan®

Midazolam Versed®

Oxazepam Serax®

Quazepam Doral®

Temazepam Restoril®

Triazolam Halcion®
Benzodiazepines
Generic Brand GAD Panic MDD Notes
Alprazolam Xanax ✅ Pregabalin (Lyrica) is as effective
Metab by 3A4 (↑by ketoconazole; ↓Tegretol)
Chlordiazepoxid Librium ✅ Protein bound ; metabolites
e
Clonazepam Klonopin ✅
Clorazepate Tranxen ✅ Protein bound; metabolites
e Prodrug
Diazepam Valium ✅ Metab by 3A4 (↑by ketoconazole; ↓Tegretol)
Longest t1/2 (80 hr) + metabolites (oxazepam
Protein bound
Estazolam Prosom
Flurazepam Dalmane
Lorazepam Ativan ✅ Pregabalin (Lyrica) is as effective
Not CYP metabolized
Midazolam Versed
Oxazepam Serax ✅ Not CYP metabolized
Protein bound
Quazepam Doral
Temazepam Restoril
Triazolam Halcion
Tricyclic Antidepressants (TCAs)
• MOA:
• Similar to SNRis (inhibit reuptake of serotonin and norepinephrine by inhibiting activity of SERT and NET)
• Within this class, these is variability in affinity for SERT vs. NET
• Antagonize postsynaptic receptors, such as H1 and α, that leads to increased side effects (compared to SNRIs)

quizlet.com
TCA Agents
Generic Name Brand Name
Amitriptyline Elavil®

Clomipramine Anafranil®

Desipramine Norpramin®

Doxepin Sinequan®

Imipramine Tofranil®

Nortriptyline Pamelor®

Trimipramine Surmontil®

Amoxapine Asendin®

Protriptyline Vivactil®
TCA Agents
Generic Brand GAD Panic MDD
Amitriptyline Elavil®

Clomipramine Anafranil® ✅

Desipramine Norpramin®

Doxepin Sinequan®

Imipramine Tofranil®

Nortriptyline Pamelor®

Trimipramine Surmontil®

Amoxapine Asendin®

Protriptyline Vivactil®
Monoamine Oxidase inhibitors (MAOis)
• Found to be a treatment option for treatment-resistant PD
• MOA
• Inhibits the activity of monoamine oxidase (degradation of neurotransmitters) in the neuron and ↑neurotransmitters
• Some are irreversible, while are others are reversible; some are selective to one form of MAO, while others are nonselective

http://www.neurosoup.com/maoi
s/
MAOi Agents
Generic Name Brand Name

Phenelzine Nardil®

Selegiline Emsam®

Tranylcypromine Parnate®

Isocarboxazid Marplan®

Moclobemide Manerix®
MAOi Agents
Generic Brand Panic

Phenelzine Nardil ✅

Selegiline Emsam

Tranylcypromine Parnate

Isocarboxazid Marplan

Moclobemide Manerix
Pregabalin (Lyrica®)
• Could be a first line option for GAD
• MOA:
• Reduces calcium influx by binding to the presynaptic α2-δ subunit of voltage-gated calcium channels
• In trials, it has been shown to produce anxiolytic effects similar to certain benzodiazepines
(lorazepam and alprazolam) and venlafaxine

http://www.apiapollo.com/Pregabalin.html
Buspirone (Buspar®)
• A second line option for GAD
• MOA:
• Does not interact directly with GABA systems
• 5-HT1A agonist on presynaptic neurons (reduces the firing of serotonergic neurons) and acts as a
partial agonist at these receptors on postsynaptic neurons
• ↑NE and DA release

google.com
Hydroxyzine (Vistaril®)
• An alternative option for GAD
• MOA:
• Chemical classification: an antihistamine
• In clinical trials, it has been shown to reduce anxiety symptoms

http://www.answers.com/topic/hydroxyzine
Second Generation Antipsychotics (SGAs)

• Some guidelines state that three of these agents (risperidone, olanzapine, and
quetiapine) can be used as augmentation with first and second line therapies for
treatment resistant GAD
Anxiety Pharmacotherapy:
Treatment Guidelines second!
GENERALIZED ANXIETY
DISORDER (TREATMENT
GUIDELINES AND DRUG
PROPERTIES)
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines Escitalopram* Imipramine Augmentation with:


Paroxetine* Buspirone* Alprazolam
Sertraline Hydroxyzine Diazepam
Venlafaxine XR* Risperidone
Duloxetine* Olanzapine
Pregabalin

IPAP2 Review and SSRI Partial or no response: Assess for co-morbidities


Algorithm SNRI -Increase dose
-Switch to another
Addition of a antidepressant
benzodiazepine if rapid -Augment
response

1World Federation of Societies of Biological Psychiatry *FDA-approved for GAD


2The International Psychopharmacology Algorithm Project
GAD - SSRI Options
Escitalopram Paroxetine Sertraline
(Lexapro) (Paxil) (Zoloft)
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%
Black Box Suicidal ideation in children, adolescents, and
Warning young adults (<25y/o)

Side Effects Insomnia, jitteriness, headache,


nausea/vomiting, diarrhea, weight gain, sexual
dysfunction
Why do we care about pharmacokinetics?
• Helps us to understand what the body does to the drug

• Half-life  agents with a long half-life may be beneficial in instances when doses are
missed, for example
• Fluoxetine is the SSRI agent with the longest half-life (4-6 days)

• Active metabolites  if an agent has an active metabolite, this needs to be taken into
consideration because the drug will be acting for a longer period of time in the body
• Fluoxetine is the only SSRI that has an active metabolite
Drug Interactions with the SSRI Options
• Two types of drug-drug interactions:
1. Pharmacokinetic – most common interactions for SSRIs
• **REMEMBER: what the body does to the drug**
• Includes liver enzyme interactions (cannot be inclusive of all drug interactions)
• Example  Paroxetine is a strong CYP2D6 inhibitor; TCAs are CYP2D6 substrates; co-
administration of these agents may lead to elevated drug concentrations of the TCAs
• Citalopram and escitalopram are the two SSRI agents with the least potential of
pharmacokinetic interactions
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Escitalopram + 0
(Lexapro)

Paroxetine ++++ 0
(Paxil)

Sertraline + +
(Zooft(
Drug Interactions continued…

2. Pharmacodynamic – what the drug does to the body


• An example – the concomitant administration of two or more
serotonergic agents, leading to serotonin syndrome
• This interaction leads to physiological changes
SNRI Options
Venlafaxine XR Duloxetine
(Effexor) (Cymbalta)
Efficacy Acute therapy (8-12 weeks): 60-68% response
rates
Remission rates: 30%

Black Box Suicidal ideation in children, adolescents, and


Warning young adults (<25 y/o)

Side Effects Jitteriness, nausea/vomiting, diarrhea,


headache, sexual dysfunction, ↑BP , insomnia
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents

• Venlafaxine is a substrate, but not an inhibitor, of CYP2D6 and


other CYP enzymes

• Inhibitory Potentials of CYP Liver Enzymes


CYP Liver Enzyme
SNRI Agent 2D6 3A4

Venlafaxine 0/+ 0
(Effexor)

Duloxetine +++ 0
(Cymbalta)

• Pharmacodynamic interactions also exist (same instance as SSRIs)


Pregabalin (Lyrica)

MOA ↓Ca influx by binding to the


alpha 2-delta subunit of the
voltage-gated calcium channels

Side Effects Dizziness, somnolence,


peripheral edema, weight gain
Imipramine (Tofranil)

MOA TCA – inhibits SERT, NET, H1 and


alpha1 receptors
Side Effects Jitteriness, anticholinergic
effects (constipation, dry
mouth, blurred vision, difficulty
urinating, drowsiness), weight
gain, sedation, cardiac
arrhythmias, orthostatic
hypotension
Imipramine (Tofranil) DDIs
• As stated earlier, TCAs are CYP2D6 substrates
• Combination of CYP2D6 inhibitor and imipramine may result in an increase of imipramine drug
concentration (pharmacokinetic interaction)
• Duloxetine (Cymbalta) or Paroxetine (Paxil)

• TCAs generally do not induce or inhibit CYP enzymes


• Imipramine has the potential to inhibit CYP2C19, however

• Due to the multiple receptor binding affinities of TCAs, there is an increased risk of side
effects with this class of medications
• Examples of pharmacodynamic interactions:
• Imipramine + Benadryl® = increased risk of antihistamine and anticholinergic side effects
• Imipramine + antihypertensive agents = increased risk of orthostatic hypotension
Buspirone (Buspar)

Side Effects Nausea/vomiting, abdominal


pain, drowsiness, dizziness
Drug Interactions with Buspirone
• Drugs that inhibit CYP3A4 can ↑ buspirone levels since buspirone is a CYP3A4 substrate

• Likewise, drugs that induce CYP3A4 can decrease buspirone levels

• Both are pharmacokinetic interactions


Hydroxyzine (Vistaril)

MOA Antihistamine

Side Effects Dry mouth, headache,


somnolence
Common ADR of benzodiazepines
• Drowsiness, fatigue

• Memory impairment and amnesia

• Respiratory depression

• Potential for dependence

• Withdrawal symptoms may occur


Pharmacokinetic Properties of Benzodiazepine Options
Drug Half-life (hours) Time to Peak (hours) Protein Binding (%) Active Metabolites

Alprazolam 12-15 1-2 80 None

Chlordiazepoxide 5-30 1-4 96 Yes, multiple

Clonazepam 30-40 1-4 85 None

Clorazepate Prodrug 1-2 97 Yes

Diazepam 20-80 0.5-2 98 Yes (oxazepam is


one of them)

Lorazepam 10-20 2-4 85 None

Oxazepam 5-20 2-4 97 None


Drug Interactions with the benzodiazepines:
IMPORTANT interactions to know!
• IMPORTANT: Benzodiazepines may cause CNS depression**

• Simultaneous use of another CNS depressant, such as alcohol, with a


benzodiazepine may result in additive CNS depressant effects

• Other CNS depressants include antihistamines, antipsychotics, and opioids


Benzodiazepine Withdrawal Syndrome
• Need to properly taper down dose
• Frequent withdrawal symptoms:
• Anxiety
• Insomnia
• Irritability
• Muscle aches and tension
• Nausea
• Blurred vision
• Palpitations
• Severe withdrawal symptoms:
• Seizures
• Psychosis
• Delirium and confusion
• Can occur within one day and extend to > 2 weeks, depending on dose
and agent patient was on
Drug properties to consider when predicting a withdrawal
syndrome

• The higher the dose, the more serious the abrupt withdrawal is

• The longer the half-life, the slower the elimination, the fewer and less severe withdrawal
symptoms occur

• The longer the half-life, the later the withdrawal symptoms will occur
Serotonin Syndrome (SS)
• Any antidepressant that increases serotonergic neurotransmission can increase the risk of
developing SS

• Symptoms:
• Mental status changes (agitation)
• Autonomic instability (temperature > 38°C, diaphoresis)
• Neuromuscular abnormalities (tremor, hyperreflexia, spontaneous clonus, muscle rigidity)

• Treatments:
• ↓dose of the medication (taper down) and discontinue it
• Benzodiazepines to control agitation and seizures that may occur
• Serotonin-production blocking agents (cyproheptadine is an antihistamine that reduce the
production of serotonin)
How long do we treat for?

• Monitor efficacy every 2 weeks, initially

• Adequate trial of SSRI or SNRI = 4-6 weeks with


adequate dose

• Continue treatment for at least a year


PANIC DISORDER
(TREATMENT GUIDELINES
AND DRUG PROPERTIES)
Pharmacotherapy Options for PD
Guidelines First Line Second Line Txt-Resistant

WFSBP1 Guidelines SSRI


Venlafaxine XR*

APA2 Guidelines SSRI Partial or no response: MAOi


SNRI -Increase dose
TCA -Switch to another
Benzodiazepine medication
CBT -Augment

1World Federation of Societies of Biological Psychiatry


2 American Psychiatric Association *FDA-approved for PD
Factors to consider when choosing an agent
• Patient’s history of response

• History of familial response

• Patient’s concurrent medical illnesses and medications

• Presenting symptoms

• Potential for drug-drug interactions

• Side effect profile

• Patient preference

• Drug cost
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme

SSRI Agent 2D6 3A4

Citalopram + 0

Fluoxetine ++++ ++

Fluvoxamine 0 +++
Phenelzine (Nardil)

MOA Monoamine oxidase inhibitor


(nonselective)
Side Effects Jitteriness, hypertensive crisis
in overdose, orthostatic
hypotension
Drug Interactions with MAOis
• Significant interaction to note:
• When MAOis are taken with certain foods, especially those high in tyramine
• Examples of foods high in tyramine include aged cheeses, sour cream, yogurt, cottage cheese, American
cheese, wine, beer, sardines, canned or processed meats, raisins, liver, soy sauce, coffee, chocolate, licorice
• Result: hypertensive crisis
• Symptoms include occipital headache, stiff neck, nausea, vomiting, sweating, and sharply elevated blood
pressure

• MAOis can also interact with buspirone and other antidepressants


• Increased risk of developing serotonin syndrome
How long do we treat for?
• Monitor efficacy every 2 weeks, initially, and then
every 2 months

• SSRIs and SNRIs should work within 4-8 weeks,


but could be up to 12 weeks

• Benzodiazepines – effective for acute treatment


• Use short-term for only 2-4 weeks

• Continue treatment for 12-24 months


MAJOR DEPRESSIVE
DISORDER AND ITS
TREATMENT AGENTS
Managing MDD
• Euthymia: a patient’s baseline state, no depressive symptoms
• GOAL: remission of symptoms; patient returns to euthymic state ***
• Response: improvement of symptoms after a therapy has been initiated
• Management is divided into three phases:
• Acute phase
• Phase where the dose of the medication is being titrated
• When full response is reached (remission of symptoms), move into continuation phase
• Time range: 6 – 12 weeks
• Continuation phase
• Phase where the dose that achieved remission of symptoms is continued
• Time range: 4 – 9 months
• Maintenance phase
• The time after continuation phase where management involves “watchful waiting” or
treatment is continued at dose that achieved remission of symptoms
• Time range: years – lifelong
Managing MDD continued…

• Relapse – return of depressive symptoms during the acute or


continuation phase

• Recurrence – return of depressive symptoms during the


maintenance phase
Managing MDD:
A depiction
Remission
Relapse Recurrence
Euthymia
Increased

Relapse
severity

Response
Symptoms

Syndrome

Treatment phases Acute Continuation Maintenance


(6 to 12 wk) (4 to 9 mo) (1 y)
Time
Depression Pharmacotherapy:
The Meds (pharmacology
first)!
Mixed Serotonergic Agents
• All these agents are treatment options for MDD
• 3 agents in this class, all with slightly different mechanisms of action
• Trazodone (Desyrel®)

the-medical-dictionary.com

• Nefazodone (Serzone®)

medlibrary.org

• Vilazodone (Viibryd®)

www.medicinescomplete.com
Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• Also involved with the presynaptic release of NE (norepinephrine) and DA (dopamine) into the
synaptic cleft

www.pharmacy-and-drugs.com
Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist that, in turn, enhances the presynaptic release of NE and
serotonin
• Antagonizes 5-HT2 and 5-HT3 receptors  leads to lower anxiety levels and GI side effects
• H1 antagonist

dailymed.nlm.nih.gov
Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of MDD

• MOA:
• Inhibits the reuptake of serotonin
• 5-HT1A receptor agonist
• Partial 5-HT1B receptor agonist
• 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist
Depression Pharmacotherapy:
Treatment Guidelines second!
How to pick an antidepressant?
• Since the effectiveness of antidepressants is generally comparable between classes and
within classes of medications, the APA (American Psychiatric Association) guidelines state
to:
• Pick an antidepressant based on:
• Side effect profile
• Safety and tolerability
• Pharmacological properties (half-life, drug interactions)
• Historical response to medications
• Cost
• Patient preference
SNRIs not discussed earlier
• Desvenlafaxine (Pristiq®)
• Initial and usual doses are 50 mg/day, with no additional benefit seen with higher doses
• Extended release tablets  dosed once a day
• Half-life is 11 hours and there are no active metabolites
• Relatively new SNRI compared to the others in its class
TCAs not discussed earlier
• Amitriptyline
• Initial dose: 25 mg/day; dose range is 100-300 mg/day

• Nortriptyline
• Amitriptyline’s metabolite
• Initial dose: 25 mg/day; dose range is 50-150 mg/day
• Half-life can reach up to 88 hours, while amitriptyline’s half-life can reach 46 hours
Mixed Serotonergic Agents
Trazodone Nefazodone Vilazodone
(Desyrel) (Serzone) (Viibyrd)
Note BBW for liver Place in therapy
failure has not been
determined yet
Side Effects Orthostatic Orthostatic Diarrhea, nausea,
hypotension, hypotension, vomiting, trouble
sedation, dizziness, sleeping
dizziness somnolence, dry
mouth, nausea,
asthenia
CYP interactions 3A4 substrate 3A4 inhibitor 3A4 substrate
Drug Interactions with the mixed serotonergic agents
• Nefazodone is an inhibitor of CYP3A4
• Example: nefazodone can ↑ Benzo triazolam (Halicon) levels, so reduce triazolam dose by 75%

• Trazodone is a substrate of CYP3A4, but does not inhibit or induce it


• Caution when combining with CYP3A4 inducers or inhibitors

• Vilazodone is also a substrate of CYP3A4

• Caution when using with other serotonergic agents due to risk of SS


Bupropion (Wellbutrin®)
• Unique agent as it has no effect on serotonin
• MOA:
• Classically known as a NDRI (norepinephrine dopamine reuptake inhibitor)
• Also involved with the presynaptic release of NE (norepinephrine) and DA (dopamine) into the
synaptic cleft

www.pharmacy-and-drugs.com
Bupropion (Wellbutrin)
• Side effects include:
• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold

• Interesting fact: bupropion is actually used as a smoking cessation agent

• Another interesting fact: bupropion could be used to mitigate sexual dysfunction side
effects of SSRI agents
Bupropion (Wellbutrin)
• Pharmacokinetic properties
• Half-life is 10-21 hours
• 3 active metabolites exist for bupropion, so take into consideration when using this medication

• Drug Interactions
• Buproprion + MAOis → ↑risk of hypertensive crisis
• Buproprion + antipsychotics/antihistamines → ↑seizure risk
• All lower seizure threshold
• One of bupropion’s metabolites inhibits CYP2D6 (like fluoxetine and paroxetine)
Bupropion (Welbutrin)

Good option for: Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients


Mirtazapine (Remeron®)
• Another unique agent that is an option for MDD
• MOA:
• Presynaptic α2 receptor antagonist that, in turn, enhances the presynaptic release of NE and
serotonin
• Antagonizes 5-HT2 and 5-HT3 receptors  leads to lower anxiety levels and GI side effects
• H1 antagonist

dailymed.nlm.nih.gov
Mirtazapine (Remeron)

• Side effects include:


• Somnolence and sedation
• Dry mouth
• Weight gain
• Constipation

• Interesting fact: in clinical practice, mirtazapine is used as an appetite stimulant


Mirtazapine (Remeron)
• Pharmacokinetic properties
• Half-life is 20-40 hours
• No active metabolites

• Drug Interactions
• Other serotonergic agents →↑ risk serotonin syndrome
• Sedating effects of mirtazapine may be enhanced when given with CNS depressants such as alcohol
or benzodiazepines
• Mirtazapine is a substrate of CYP2D6, CYP3A4, and CYP1A2
• 2D6 - Inhibitors like Fluoxetine, Paroxetine, Duloxetine and Bupropion will ↑ levels of Mertaxapine
• Inhibitors may increase mirtazapine blood levels and inducers may decrease mirtazapine levels
Mirtazapine (Remeron)

Good option for: Avoid in:

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Vortioxetine (Trintellix®)
• New medication approved by the FDA in 2013 for the treatment of MDD

• MOA:
• Inhibits the reuptake of serotonin
• 5-HT1A receptor agonist
• Partial 5-HT1B receptor agonist
• 5-HT1D, 5-HT3, and 5-HT7 receptor antagonist
Vortioxetine (Trintellix)

• Side effects:
• Sexual dysfunction
• Nausea/vomiting
• Dizziness
• Dry mouth
• Diarrhea/constipation
SSRI Agents for MDD

Good options BAD OPTIONS

• Paroxetine (Paxil) • Paroxetine (Paxil)


• underweight • Overweight/obese
• insomnia patients
• Fluoxetine (Prozac) • Pregnancy
• psychomotor retardation • Citalopram (Celexa) or
• Overweight/obese escitalopram
patients • ↑QTc prolongationt or
• Sertraline (Zoloft) torsades risk
• psychomotor retardation • Fluoxetine (Prozac) or
sertraline (Zoloft)
• Agitation/insomnia
SNRI Agents for MDD

Good option for: Avoid in:


• Psychomotor retardation • Hypertension

• Chronic pain • Agitation or insomnia


Consider this for Bupropion!

Consider for… Avoid or use caution in…

• Sexual dysfunction concern • Seizure disorders

• Smokers • Hypertension

• Psychomotor retardation • Agitation or insomnia

• Fatigue or sleepiness

• Overweight or obese patients


Consider this for Mirtazapine!

Consider for… Avoid or use caution in…

• Agitation • Overweight or obese patients

• Insomnia • Hyperlipidemia

• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 5-14 • Supportive counseling for 1
mo
• Pharm or psychoterapy

Moderate 15-19 • Start with monotherapy


• Pharm or psychoterapy

Severe >/= 20 Start with pharm AND


psychotherapy
STAR*D Trial
• What can we take away from this trial?
• If a patient fails one SSRI, it does not mean that he/she will fail another
• Monoamine oxidase inhibitors are limited because of their tolerability
profiles
• Patients with difficult-to-treat depression can get well after trying different
treatment strategies, but the odds of reaching remission lessen with every
additional treatment strategy needed
• Those who reach remission have a better chance of remaining symptom-
free compared with those who just experience symptom response
• Provide medications at optimal doses, maintain diligent monitoring, and try
different treatment choices
Assessing Adequacy of Antidepressant Interventions in MDD

• APA Guidelines
• 4-6 weeks of treatment are needed before concluding that a
patient is unresponsive or partially responsive to a specific
therapy
• If patient has not reached remission, may consider switching a
patient to an agent within the same class or to an agent from
a different class
• Augmenting the first therapy with a non-MAOi antidepressant
from a different class or augmenting with a non-
antidepressant therapy (lithium, T3, second-generation
antipsychotic) are also second-line options
Assessing the Adequacy of Therapeutic Interventions for MDD
• 7-10 days tx (1st things to improve)
• ↑ sleep
• ↓ anxiety
• 7-21 days tx
• Improved self-care
• Improved thinking, concentration
• Increased energy, activity level
• Improved Appetite
• 2-4 weeks tx (LAST things to improve
• Improved mood
• ↓ suicidal ideation (SI)
BPD PHARMACOTHERAPY:
THE MEDS (PHARMACOLOGY
FIRST)!
“MOOD STABILIZERS”
• Term used to describe the class of medications used in the treatment of BPD
• Different medications work better in different episodes of BPD, so use of term is inaccurate
• Medications that fall into this category:
• Lithium
• 1st line agent for acute mania, acute bipolar depression, and maintenance treatment for bipolar I and II
disorders
• DOC for mania
• Anticonvulsants
• Divalproex sodium/Valproic acid (VPA)
• DOC mixed states
• Lamotrigine (Lamictal)
• Prevention/treatment bipolar depression
• Maintenance
• Carbamazepine (Tegretol)
• 1st line for hypomania
• Oxcarbazepine (Trileptal)
• Less data supporting use
• Antipsychotics (both typical and atypical)
LITHIUM (LI)
• One of the first line options for BPD; drug of choice for manic states
of BPD
• Mechanism of action (MOA):
• Lithium is a monovalent cation, sharing similar properties to sodium
(Na+)
• Hypotheses (first one):
• Li directly inhibits inositol signaling

• Inhibition of the inositol signaling pathway leads to a depletion of


free inositol

• Depletion of free inositol leads to the depletion of other enzymes

• In turn, this pathway modulates energy metabolism, provide


neuroprotection, and increase neuroplasticity
Lithium (Li; Lithobid®)
• First line options for BPD
• DOC for manic state
• MOA - UNKNOWN
• monovalent cation (similar to Na+- body cannot tell the differences
between them
• Hypothesis 1
• Li directly inhibits 1p2 to Ip1 to inositol pathway→ ↓ free
inositol → ↓other enzymes
• Modulate energy metabolism
• Provide neuroprotection
• ↑ neuroplasticity
• Hypothesis 2
• Li inhibits glycogen synthase kinase-3 (GSK-3) s  same effect as
above
• Hypothesis 3
• LI ↓ generation of action potentials by gradually replacing Na+
• Hypothesis 4
• Li inhibits NE sensitive adenylyl cyclase  antidepressant and anti-
manic effects
WHAT DOES LI DO TO NEUROTRANSMITTERS?
• ↑ serotonin release
• ↑ GABA activity

• ↓ NE & DA release
• ↓ glutamate neurotransmission
• ↓ DA synthesis
DIVALPROEX SODIUM/VALPROIC ACID (VPA)
• DOC for mixed states of BPD
• MOA:
• May indirectly reduce GSK-3 activity (like Li)
• Also inhibits inositol signaling through inositol depletion
• Increases GABA effects
• May inhibit glutamate/NMDA receptor-mediated neuronal excitation
LAMOTRIGINE
• Prevent/treat bipolar depression
• maintenance treatment of bipolar I disorder
• MOA:
• Blocks voltage-sensitive Na+ channels
• Decreases glutamate release
CARBAMAZEPINE
• Could be a first line option for hypomanic episodes/states
• MOA:
• No evidence of GSK-3 inhibition
• Inhibits inositol pathway signaling  depletes inositol (similar to Li and VPA)
• Enhances GABA activity
OXCARBAZEPINE
• Currently, there is less data supporting the use of oxcarbazepine in the treatment of BPD
• MOA:
• Blocks voltage-sensitive Na+ channels
• Modulates voltage-activated Ca2+ currents
• Increases K+ conductance
ANTIPSYCHOTICS
• Two groups in this class: typical (1st generation) and atypical (2nd
generation) agents
• Classically, all antipsychotics are D2 receptor antagonists
• Restructure neuronal networks by inducing neuroplastic changes
• Typical antipsychotics (older drugs) have a greater affinity for D2
receptors
• Atypical antipsychotics (newer) bind to different receptors, in
addition to blocking D2 receptors
• Block 5-HT2A receptors
• 3 are partial D2 agonists
• Some can also block 5-HT6 and 5-HT7 receptors
• Can also act as a 5-HT1A partial agonist
BPD PHARMACOTHERAPY:
THE MEDS (GUIDELINES
SECOND)!
TREATMENT RECOMMENDATIONS
• General recommendations for manic/mixed/hypomanic episodes
• Assess for secondary causes of episode (alcohol or drug use, for example)
• Discontinue antidepressants
• Taper off stimulants and caffeine, if possible
• Treatment substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial
therapy (nonpharmacological treatments)
TREATMENT RECOMMENDATIONS CONTINUED…
Hypomania

1ST - Initiate mood-stabilizing medication: lithium, valproate,


carbamazepine, or an atypical antipsychotic
Benzodiazepine?
Alternative option: OXC

2nd – If response is inadequate after 10-14 days of first-line


treatment(s) at optimized dose(s), consider a 2-medication combo:

a) Lithium + anticonvulsant or an atypical antipsychotic


b) Anticonvulsant + another anticonvulsant or an atypical
antipsychotic
TREATMENT RECOMMENDATIONS CONTINUED…
Mania

1st – Initiate 2- or 3-medication combination:


(Lithium, valproate, or an atypical antipsychotic) plus a
benzodiazepine and/or a typical antipsychotic
Do not combine antipsychotics
3rd – If response is inadequate
Alternative option: CBZ; if no response, consider OXC
after 10-14 days of second-line
treatments at optimized doses,
consider:
a) ECT or
b) Add clozapine
2nd – If response is inadequate after 10-14 days of first-
line treatments at optimized doses, consider a 3-
medication combo:

a) Li + an anticonvulsant + an antipsychotic
b) Anticonvulsant + another anticonvulsant + an
antipsychotic
TREATMENT RECOMMENDATIONS
• General recommendations for acute depressive episodes
• Assess for secondary causes of depression (alcohol or drug use, for example)
• Taper off antipsychotics, benzodiazepines, or sedative-hypnotics, if possible
• Treatment substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial
therapy (nonpharmacological treatments)
TREATMENT RECOMMENDATIONS CONTINUED…
Mild or Moderate Depressive Episode

1ST - Initiate or optimize mood-stabilizing medication: lithium,


quetiapine, or lurasidone
Alternative options:
a) Lamotrigine
b) Valproate
c) Fluoxetine/olanzapine combination (Symbyax®)
TREATMENT RECOMMENDATIONS CONTINUED…
Severe Depressive Episode
1st – Initiate or optimize mood-stabilizing medication:
lithium or quetiapine or lurasidone
Alternative options: Symbyax®, lamotrigine, valproate
If psychotic, add an antipsychotic (however, do not
combine antipsychotics) 4th – If response is
inadequate,
consider ECT

2nd – If response is
inadequate, consider CBZ or 3rd – If response is
adding an antidepressant inadequate, consider a 3-
medication combo:

a) Lithium + lamotrigine + an
antidepressant
b) Lithium + quetiapine + an
antidepressant
LITHIUM
• It is a monovalent cation
• Therefore, it is rapidly absorbed, is not protein bound, is not
metabolized, and is excreted unchanged
• 1st line agent for acute mania, acute bipolar depression, and
maintenance treatment for bipolar I and II disorders
LITHIUM CONTINUED…
• Efficacy:
• 78% response rate when aborting an acute manic or hypomanic
episode
• More recently, slower onset of action has been discovered
• In bipolar depression, there is a 6- to 8-week delay in its
antidepressant properties
• Maintenance treatment with Li is more effective in patients with fewer
prior episodes, with a history of good functioning between episodes,
and with a family history of response to Li
• Li has been shown to reduce suicide risk by 8- to 10-fold
• Augmenting Li with CBZ, lamotrigine, or VPA has been shown to
improve treatment response in BPD I
LITHIUM CONTINUED…
• Dosing and administration:
• Initial dosing: 300 mg by mouth twice daily
• Dosing range: 900 – 2400 mg daily in divided doses
• Administer lower dose in renal impairment
• Dosing titration will depend on patient’s response to Li and tolerance to side effects
• Immediate-release and extended-release preparations exist
• Usually would still administer > 1 time per day
• Why?
LITHIUM CONTINUED…
Monitoring parameters for Lithium
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests X X

Liver function tests

Renal function tests X X

Thyroid function tests X X

Serum Electrolytes X X

Dermatological tests X X
LITHIUM CONTINUED…
• Serum drug monitoring:
• ***NEED TO OBTAIN DRUG BLOOD LEVELS WHEN ON LI***
• Li levels should be considered to be at steady state at day 5
• Blood sample should be obtained about 8-12 hours after the last dose
(around the 5th day of therapy)
• If level is therapeutic and there is a positive response, draw another level
in 2 weeks and then every 3-6 months thereafter
• If level is not therapeutic, there is a partial response, dose has been
changed (increased or decreased), and/or interacting medication(s) have
been initiated, obtain another level in 5 days of stable dose
• Target blood levels/concentrations:
• Maintenance: 0.6 – 1.2 mEq/L
• Acutely manic: may need to go up to 1.5 mEq/L
LITHIUM CONTINUED…
• Lithium toxicity:
• Lithium has a narrow therapeutic index…what does this mean?
• It is an extremely toxic drug
• Risk factors that may predispose a patient to Li toxicity:
• Na+ restriction
• Dehydration
• Vomiting, diarrhea
• Elderly patients
• Drug-drug interactions with those drugs that decrease lithium
clearance
• 3 degrees of Li toxicity and their associated symptoms:
• Mild (1.5-2.0 mEq/L) – nausea, diarrhea, polyuria, blurred vision,
fine resting tremor, confusion, drowsiness
• Moderate (2.0-2.5 mEq/L) – increasing confusion, increased deep
tendon reflexes, myoclonic twitches, increasing restlessness
• Severe (> 2.5 mEq/L) – coma, convulsions, cardiac dysrhythmias,
renal failure
LITHIUM CONTINUED…
• Initial, dose-related side effects:
• GI distress (nausea, vomiting, diarrhea, dyspepsia)
• Muscle weakness and lethargy (develops in about 30% of patients)
• Polydipsia and polyuria
• Fine hand tremor

• Not dose-related (more common with long-term therapy):


• Formation changes in the kidneys (glomerular sclerosis, tubular
atrophy)
• Thyroid changes (hypothyroidism usually occurs after 6-18 months of
therapy)
• Benign and reversible cardiac changes
• Reversible leukocytosis
• Dermatologic changes (acne, exacerbation of psoriasis)
• Weight gain
• Neurologic disturbances (EPS, slurred speech, myasthenia gravis)
LITHIUM CONTINUED…
• Drug-Drug Interactions:
• Thiazide diuretics, NSAIDs, COX-2 inhibitors, and ACEi’s can all
elevate lithium levels
• Elimination of lithium is decreased
• Examples: lithium + ibuprofen; lithium + lisinopril; lithium +
naproxen

• Neurotoxicity can also occur when lithium is combined with Ca2+


channel blockers and carbamazepine
DIVALPROEX SODIUM/ VALPROIC ACID
• FDA-approved for the treatment of acute mania and mixed episodes
• Many different formulations
• Efficacy:
• Has been shown to be as effective as lithium and olanzapine in
patients with pure mania
• More effective than lithium in mixed states and rapid cycling
• Lithium + valproate = added positive effect for treatment-refractory
rapid cycling and mixed states; combo is also efficacious in
maintenance therapy for BPD I
• Combining valproate with other BPD agents (carbamazepine,
lamotrigine, atypical antipsychotics) can be effective
• MONITORING IS KEY!
VPA CONTINUED…
Monitoring parameters for VPA
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests X X

Liver function tests X X

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
VPA CONTINUED…
• Serum drug monitoring:
• ***NEED TO OBTAIN DRUG BLOOD LEVELS WHEN ON VPA***
• Therapeutic serum level: 50 – 125 mcg/mL
• Take blood level ~ 12 hours after last dose on the 5th day of
treatment
• Obtain a blood level after each change in dose
VPA TOXICITY
• Usually benign, but may serious
• Potential signs and symptoms of toxicity:
• Hyperthermia/hypothermia
• Tachycardia
• Hypotension
• Confusion and somnolence
• Dizziness
• Nausea and vomiting
• Renal failure
• Tremors
• How to treat?
• Support the airway
• May need to administer charcoal to decontaminate the patient
• Hemodialysis may be warranted
VPA CONTINUED…
• Side effects:
• Most frequent, dose-related: GI complaints (nausea, vomiting,
indigestion, anorexia, diarrhea, and flatulence)*
• Mild tremor
• Lethargy
• Prolonged bleeding because of inhibition of platelet aggregation
• Transient increases in liver enzymes (this is why we monitor liver
enzymes)
• Weight gain
• Thrombocytopenia (monitor bleeding and bruising)
VPA CONTINUED…
BLACK BOX WARNINGS!!

• HEPATOTOXICITY

• PANCREATITIS
VPA CONTINUED…
• Drug-Drug Interactions:
• VPA is highly protein bound (other highly protein bound drugs can displace VPA)
• VPA can inhibit CYP450 enzymes  expect other medications’ metabolism to be affected
• VPA may decrease the clearance of phenobarbital
• Oral contraceptives may increase the clearance of VPA and lower serum levels
• Lamotrigine + VPA = severe dermatologic rash (half the lamotrigine dose)
LAMOTRIGINE
• FDA-approved for the maintenance treatment of BPD; not approved
for bipolar depression, but very effective for the prevention and
treatment of bipolar depression
• Efficacy:
• Possesses both antidepressant and mood-stabilizing effects
• Has a low rate of switching patients to mania
LAMOTRIGINE CONTINUED…
• Dosing and administration:
• Initial dose: 25 mg daily
• Dosing range: 50-400 mg by mouth in divided dose
• Slowly increase dose!!!!!! Slow titration!!!!!
• Example: 25 mg daily for 2 weeks, then 50 mg daily for 2 weeks,
and then increase by 50 mg increments weekly
• Doses of 400 mg daily have shown no advantages
• Need to adjust dose in hepatic and renal impairment
LAMOTRIGINE CONTINUED…
Monitoring parameters for Lamotrigine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
LAMOTRIGINE CONTINUED…
• Side effects:
• Common -
• Headache
• Nausea
• Dizziness and drowsiness
• Ataxia
• Tremor
• Rash (self-limiting and resolves eventually)  may progress to life-
threatening conditions!
LAMOTRIGINE CONTINUED…
BLACK BOX WARNING!!

• Serious rash
• Usually accompanied by a fever or sore throat
• May require hospitalization
• Discontinue treatment
• Includes Stevens-Johnson syndrome, toxic epidermal necrolysis (both life
threatening)
• How to avoid?
LAMOTRIGINE CONTINUED…
• Drug-Drug Interactions:
• Lamotrigine + VPA = severe dermatologic rash (half the lamotrigine
dose)
• Lamotrigine + oral contraceptives = reduction in the serum
concentration of lamotrigine
• Lamotrigine + carbamazepine = increase in CNS side effects
• Lamotrigine does not inhibit CYP enzymes and has a low potential for
pharmacokinetic interactions with other drugs
CARBAMAZEPINE
• FDA-approved for the treatment of acute mania and mixed episodes
associated with BPD I
• Many formulations: immediate release and extended release
• Not first line for mania, but its acute antimanic effects are
comparable to lithium
• Combo of carbamazepine with Li, VPA, or antipsychotics is often
used for treatment-resistant patients experiencing a manic episode
• Also reserved for patients who are unable to tolerate or who have an
inadequate response from Li or VPA
CARBAMAZEPINE CONTINUED…
Monitoring parameters for Carbamazepine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests X X

Metabolic tests

Liver function tests X X

Renal function tests X

Thyroid function tests

Serum Electrolytes X X

Dermatological tests X X
CARBAMAZEPINE CONTINUED…
• Serum drug monitoring:
• Obtain drug blood levels to guide toxicity!
• Obtain every 1-2 weeks during the first 2 months, and then every 3-6
months during maintenance therapy
• After changing dose (if initial therapy), obtain a new drug level in at
least 4-7 days
• After changing dose (if not initial therapy), obtain a new drug level in
2-3 days
• Draw levels 10-12 hours after the last dose
• Goal serum level: 6-10 mcg/mL; could go as low as 4 mcg/mL
(patients may be responsive at this level) and as high as 14 mcg/mL
(for treatment resistant patients)
CARBAMAZEPINE CONTINUED…
• Side effects:
• Neurosensory side effects are common (headache, fibromyalgia)
• Nausea
• Hyponatremia (increases with age; need to monitor serum
electrolytes; risk of causing seizures)
• Transient leukopenia
• Bone marrow suppression
CARBAMAZEPINE CONTINUED…
• Symptoms of acute overdose:
• Ataxia
• Diplopia and nystagmus
• Cardiac conduction changes
• Seizures
• Coma
CARBAMAZEPINE CONTINUED…
BLACK BOX WARNINGS!!

• Serious dermatologic reactions and HLA-B*1502 allele

• Aplastic anemia/agranulocytosis
CARBAMAZEPINE CONTINUED…
• Drug-Drug Interactions:
• Carbamazepine is an auto-inducer
• What does this mean?
• Induces CYP3A4, and to a lesser degree, 1A2, 2C9/2C10, and 2D6
• Increases the metabolism of many medications, including oral
contraceptives
• Carbamazepine + valproate = displacement from proteins, resulting in
more free CBZ; reduce CBZ dose
• Carbamazepine + clozapine = increased risk of bone marrow
suppression from both agents
• Medications the inhibit CYP enzymes may inhibit the metabolism of
carbamazepine, leading to carbamazepine toxicity
• Examples: diltiazem, verapamil, fluoxetine, fluvoxamine
OXCARBAZEPINE
• Not FDA-approved for BPD
• Currently, there is less data supporting the use of oxcarbazepine over carbamazepine in the
treatment of BPD
• Administer oxcarbazepine if patients have failed other treatments or have experienced
intolerable side effects
• Advantages over CBZ: milder side effects, no autoinduction of liver enzymes, and fewer drug
interactions
OXCARBAZEPINE CONTINUED…
Monitoring parameters for Oxcarbazepine
Baseline Q6-12 months

Physical Exam and General X


Chemistry

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes X X

Dermatological tests
OXCARBAZEPINE CONTINUED…
• Side effects:
• Dose-related side effects:
• Dizziness and sedation
• Headache
• Ataxia and fatigue
• Vertigo
• Abnormal vision and diplopia
• Vomiting and abdominal pain
• Hyponatremia!
• Occurs more frequently with oxcarbazepine compared to CBZ
• Can be severe (less than 125 mEq/L)
• Occurs more frequently during the first 3 months
• Symptoms: confusion, headache, lethargy, and malaise
• Hypersensitivity reactions
• May occur, especially in patients with a history of CBZ
hypersensitivity
OXCARBAZEPINE CONTINUED…
• Drug-Drug Interactions:
• Inhibits CYP2C19, and induces CYP3A3 and CYP3A4
• Induces the metabolism of oral contraceptives as an example
• May decrease the metabolism of phenytoin (due to CYP2C19
inhibition)
• Oxcarbazepine + diuretics = increase risk of hyponatremia
ANTIPSYCHOTICS
• 4 FDA Indications:
• Treatment of acute mania in BPD
• Quetiapine
• Treatment of manic/mixed states of BPD
• Aripiprazole Asenapine
• Olanzapine Risperidone
• Ziprasidone Cariprazine
• Maintenance treatment of BPD
• Aripiprazole Quetiapine
• Risperidone (IM) Ziprasidone
• Bipolar Depression
• Quetiapine Lurasidone
• Olanzapine/Fluoxetine combo
Mood Stabilizers
Objectives
• At the end of the presentation, each student should be
able to:
• Explain the pharmacology of the treatment agents for bipolar
disorder
• Identify appropriate, guideline-based pharmacological
treatment options for bipolar disorder
• Explain the drug properties of the different pharmacological
treatment agents, including specific monitoring parameters
for certain agents and specific black box warnings
• Create a pharmacological treatment plan for a sample patient
case
What is Bipolar Disorder?
• Bipolar disorder (BPD) is a chronic, cyclic mental illness that is
characterized by recurrent fluctuations in mood, energy, and
behavior
• BPD is characterized as a mood disorder, similar to depression
• BPD is a lifelong illness with a variable course
• The symptoms, course, severity, and response to treatment differ
among individuals
• Overall prevalence of bipolar disorder is 4.5%
• There are various types of BPD
Symptoms of mania and hypomania
• DIGFAST
• Distractible
• Increased activity/psychomotor agitation
• Grandiosity/superhero mentality
• Flight of ideas or racing thoughts
• Activities that are dangerous or hypersexual
• Sleep decreased
• Talkative or pressured speech
Symptoms of Depression

• Let’s review!
• Acronym? What does each letter stand for?
• What are the essential features?
• How many symptoms to be considered a MDE (Major Depressive Episode)?
• For how long?
Types of Bipolar Disorder Defined By Episodes

Disorder Type Episode


Bipolar I disorder Manic episode +/- major
depressive episode or mixed
episode
Bipolar II disorder Major depressive episode +
hypomanic episode

Cyclothymic disorder Chronic fluctuations between


subsyndromal depressive and
hypomanic episodes
Other Types of BPD
• Substance/Medication-Induced Bipolar and Related Disorder
• Bipolar and Related Disorder Due to Another Medical Condition
• Other Specified Bipolar and Related Disorder
• Symptoms characteristic of bipolar and related disorder that
cause clinically significant distress but do not meet full criteria for
any of the disorders
• Examples: short-duration hypomanic episodes, short-duration
cyclothymia
• Unspecified Bipolar and Related Disorder
• Same as ‘other specified bipolar and related disorder,’ but the
clinician chooses not to specify the reason why the criteria isn’t
met
“Mood Stabilizers”
• Lithium (Lithobid)
• Anticonvulsants
• Divalproex sodium/Valproic acid (VPA, Depakote)
• Lamotrigine (Lamictal)
• Carbamazepine (Tegretol)
• Oxcarbazepine (Trileptal)
• Antipsychotics (both typical and atypical)
Li Inhibition of Inositol Signaling
What Does Li do to Neurotransmitters?

• It has been discovered that Li:


• ↑Serotonin release (inhibitory)
• ↑ GABA activity (inhibitory)
• ↓ release of NE and DA (ecitatory)
• ↓ glutamate (excitatory)
• ↓ DA synthesis (excitatory)
Divalproex Sodium/Valproic Acid
(VPA; Depakote®)
• DOC mixed states of BPD
• MOA:
• indirectly ↓GSK-3 activity (like Li)
• ↓inositol
• ↑GABA effects
• Inhibits glutamate/NMDA receptors
Lamotrigine (Lamictal®)

• Prevention/treatment of bipolar depression not first line


• Maintenance treatment of bipolar I disorder
• MOA:
• Blocks voltage-gated Na+ channels →↓APs
• ↓glutamate release
Carbamazepine (Tegretol®)

• First line option for hypomanic episodes/states


• Bipolar depression
• MOA:
• Blocks voltage-gated Na+ channels
• Presynaptically ↓transmissions
Oxcarbazepine (Trileptal®)

• Currently, there is less data supporting the use of oxcarbazepine in the treatment of BPD
• Not as effective as other mood stabilizers
• MOA:
• Blocks voltage-sensitive Na+ channels
• Presynaptically, it acts to decrease synaptic transmission
Antipsychotics
• Two groups in this class: typical (1st generation) and atypical (2nd
generation) agents
• Classically, all antipsychotics are D2 receptor antagonists
• Typical antipsychotics (older drugs) have a greater affinity for D2
receptors
• Atypical antipsychotics (newer) bind to different receptors, in addition
to blocking D2 receptors:
• Block 5-HT2A receptors
• 3 are partial D2 agonists
• Some can also block 5-HT6 and 5-HT7 receptors
• Can also act as a 5-HT1A partial agonist
BPD Pharmacotherapy:
The Meds (Guidelines Second)!
Guidelines and Algorithms (Some of them)
• American Psychiatric Association (APA) guidelines
• Veterans Affairs/Department of Defense (VA/DoD) Clinical Practice
guidelines
• Canadian Network for Mood and Anxiety Treatments (CANMAT)
guidelines
• Updates to CANMAT guidelines by CANMAT and the International
Society for Bipolar Disorders (ISBD)
• World Federation of Societies of Biological Psychiatry (WFSBP)
guidelines
• British Association for Psychopharmacology guidelines
• Texas Implementation of Medication Algorithms (TIMA) project
Goals of Treatment for ALL BPD
• Resolve acute manic, hypomanic, and depressive episodes
• Complete remission of symptoms
• Prevent further episodes
• Maintain good functioning
• Promote treatment adherence
• Minimize medication side effects
General recommendations for manic/mixed/hypomanic
episodes
• Assess for secondary causes of episode (alcohol or drug use, for example)
• DC antidepressants (can induce a manic switch)
• Taper off stimulants and caffeine, if possible
• Treat substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial
therapy (nonpharmacological treatments)
Hypomania
1ST - Initiate mood-stabilizing medication: lithium, valproate,
carbamazepine, or an atypical antipsychotic
Benzodiazepine?
Alternative option: OXC

2nd – If response is inadequate after 10-14 days of first-line


treatment(s) at optimized dose(s), consider a 2-medication combo:
a) Lithium + anticonvulsant or an atypical antipsychotic
b) Anticonvulsant + another anticonvulsant or an atypical
antipsychotic
Mania
ia 1st – Initiate 2- or 3-medication combination:
(Lithium, valproate, or an atypical antipsychotic) plus a
benzodiazepine and/or a typical antipsychotic
Do not combine antipsychotics 3rd – If response is inadequate
Alternative option: CBZ; if no response, consider OXC after 10-14 days of second-line
treatments at optimized doses,
consider:
a) ECT or
b) Add clozapine to 2nd line
2nd – If response is inadequate after 10-14 days of first-line therapy
treatments at optimized doses, consider a 3-medication
combo:

a) Li + an anticonvulsant + an antipsychotic
b) Anticonvulsant + another anticonvulsant + an
antipsychotic
Acute Depressive Episode

• General recommendations
• Assess for secondary causes of depression (EtOH or drug use
• Taper off antipsychotics, benzodiazepines, sedative-hypnotics, if possible
• Treat substance abuse, if applicable
• Encourage good nutrition, exercise, adequate sleep, stress reduction, and psychosocial therapy
(nonpharmacological treatments)
Mild/Moderate Depressive Episode

1ST - Initiate or optimize mood-stabilizing medication: lithium,


quetiapine, or lurasidone
Alternative options:
a) Lamotrigine
b) Valproate
c) Fluoxetine/olanzapine combination (Symbyax®)
Severe Depressive Episode
1st – Initiate or optimize mood-stabilizing medication:
lithium or quetiapine or lurasidone
Alternative options: Symbyax®, lamotrigine, valproate
If psychotic, add an antipsychotic (however, do not
combine antipsychotics) 4th – If response is
inadequate,
consider ECT

2nd – If response is inadequate,


consider CBZ or adding an 3rd – If response is inadequate,
antidepressant consider a 3-medication
combo:

a) Lithium + lamotrigine + an
antidepressant
b) Lithium + quetiapine + an
antidepressant
Lithium (Li; Lithobid®)
• First line options for BPD
• DOC for manic state
• MOA - UNKNOWN
• monovalent cation (similar to Na+- body cannot tell the differences
between them
• Hypothesis 1
• Li directly inhibits 1p2 to Ip1 to inositol pathway→ ↓ free
inositol → ↓other enzymes
• Modulate energy metabolism
• Provide neuroprotection
• ↑ neuroplasticity
• Hypothesis 2
• Li inhibits glycogen synthase kinase-3 (GSK-3) s  same effect as
above
• Hypothesis 3
• LI ↓ generation of action potentials by gradually replacing Na+
• Hypothesis 4
• Li inhibits NE sensitive adenylyl cyclase  antidepressant and anti-
manic effects
• Properties
Lithium
• It is a monovalent cation
• rapidly absorbed
• not protein bound
• not metabolized
• excreted unchanged
• Indications
• 1st line agent for acute mania, acute bipolar depression, and maintenance treatment for
bipolar I and II disorders
• Efficacy
• 78% effective to stop acute manic/hypomanic episode
• More recently, slower onset of action has been discovered
• 6-8 weeks for treatment of depression
• More effective for maintenance tx in pt w/
• fewer prior episodes
• Hx of good functioning btwn episodes
• FHx of response to Li
• ↓suicide risk by 8-10 fold
• Efficacy:
Lithium Continued…
• Augment w/ the following to improve response to tx
• CBZ
• Lamotrigine
• VPA
• Dosing and administration:
• Initial dosing: 300 mg by mouth twice daily
• Dosing range: 900 – 2400 mg daily in divided doses
• Administer lower dose in renal impairment
• Dosing titration will depend on patient’s response to Li and
tolerance to side effects
• Immediate-release and extended-release preparations exist
• Usually would still administer > 1 time per day
• Why is it dosed > 1 time/day?
• Li is linked to a lot of GI ADR (Nausea) – helps ↓this
• When titrating ↑Bedtime dose first not AM dose
• Monitoring
• Everything except LFTs
Lithium: Monitoring

Baseline Q6-12 months


Physical Exam and General Chemistry X

Hematologic tests X X
(CBC w/ diff + platelets)

Metabolic tests X X
(FBG, Lipids, weight)

Liver function tests

Renal function tests X X

Thyroid function tests X X

Serum Electrolytes X X

Dermatological tests X X
Lithium Serum Drug Monitoring
• ***NEED TO OBTAIN DRUG BLOOD LEVELS WHEN ON LI***
• Levels at steady state by day 5
• Sample obtained 8-12 hours after the last dose on day 5 of tx
(before AM dose)
• Level is in therapeutic range + positive response
• Recheck 2 weeks later (week 7)
• Monitor Q3-6 months
• If level is not therapeutic, partial response, any dose change,
suspected medication interactions obtain another level in 5 days
of stable dose

• Target blood levels/concentrations:


• Maintenance: 0.6 – 1.2 mEq/L
• Acutely manic: up to 1.5 mEq/L
Lithium Toxicity
• Narrow therapeutic index – very toxic!
• Risk factors for Li toxicity:
• Na+ restriction (if Na is low H2O is low and [Li] ↑)
• Dehydration
• Vomiting, diarrhea (deplete vol status)
• Elderly
• DDI w/ drugs that ↓Li clearance
• 3 Levels of Li toxicity
• Mild (1.5-2.0 mEq/L)
• N/D
• Polyuria
• blurred vision
• fine resting tremor
• Confusion
• drowsiness
• Moderate (2.0-2.5 mEq/L)
• ↑confusion
• ↑ DTR
• myoclonic twitches
• ↑ restlessness
• Severe (> 2.5 mEq/L)
• Coma
• Convulsions
• cardiac dysrhythmias
• Renal failure
How to Treat Li Toxicity
• Transfer patient to emergency room depending on degree of toxicity
• Discontinue lithium (hold doses until levels ↓ to therapeutic range)
• If consciousness is impaired, oral airway needs to be protected
• Gastric lavage and IV (to remove unabsorbed lithium from GI tract )
• Indications for hemodialysis:
• Coma
• Convulsions
• respiratory failure
• deteriorating mental status
• renal failure
Li ADR

• 93% of patients experience side effects • Non dose-related (more common w/ LT Tx)
• Structural changes in the kidneys (glomerular
• 2 categories: sclerosis, tubular atrophy)
• Impaired H2O resorption and ↑SCr
• Initial, dose-related • Thyroid changes (hypothyroidism usually
• GI distress (nausea, vomiting, diarrhea, occurs after 6-18 months of therapy)
dyspepsia) • Li sits in thyroid gland →interferes with
• Give with food TSH production and ↑formation of
thyroid antibodies
• Give bigger dose at bed time
• ↑TSH↓T3 & 4
• Give entire dose at badtime
• Benign and reversible cardiac changes
• Muscle weakness and lethargy (develops in • Cardiac dysrhythmias and heart block if
about 30% of patients) OD
• Give dose at bedtime • Reversible leukocytosis
• Polydipsia and polyuria • Dermatologic changes (acne, exacerbation of
• Fine hand tremor psoriasis)
• Weight gain
• ↓dose
• Neurologic disturbances (EPS, slurred speech,
• Add propanolol myasthenia gravis)
• Alopecia (MV with zinc and selenium can
help)
Li DDI’s
• ↓Li Elimination →↑Li Levels
• TZD
• Removes H20 and Na+ from body → ↑[Li]
• Reabsorbs Li → ↑ [Li]
• NSAIDs (naproxen, ibuprofen) & COX-2 inhibitors (Celecoxib)
• ↓PG synthesis → ↓renal blood flow → ↓Li elimination
• ↑Na retention → ↑[Li]
• ACEi’s (Lisinopril)
• Inhibit Angiotensin I to II → ↑vasodilation → ↓aldosterone → Na retention → ↑[Li]

• Neurotoxicity
• CCB’s
• Carbamazepine (Tegretol)
Divalproex Sodium/ Valproic acid (Depakote)
• FDA-approved for the treatment of acute mania and mixed episodes
• More effective Tx than Li for mixed states!
• Many different formulations
• Efficacy:
• Has been shown to be as effective as lithium and olanzapine in
patients with pure mania
• More effective than lithium in mixed states and rapid cycling (4
episodes in a 12mo time period)
• Lithium + valproate = added positive effect for treatment-refractory
rapid cycling and mixed states; combo is also efficacious in
maintenance therapy for BPD I
• Combining valproate with other BPD agents (carbamazepine,
lamotrigine, atypical antipsychotics) can be effective
• MONITORING IS KEY!
VPA/Depakote Dosing
• Weight based dosing
• Pt with acute mania need higher doses than those with
Hypomania
• Acute mania – 20 mg/kg/day in divided doses (approximately,
250 – 500 mg by mouth twice daily)
• Hypomania, elderly patients – 5-10 mg/kg/day in divided
doses
• Maximum recommended dosage – 60 mg/kg/day
• Immediate release and extended-release products exist

• Monitoring
• Everything except renal, thyroid and electrolytes
VPA Continued…
• Monitoring parameters for VPA
Baseline Q6-12 months

Physical Exam and General Chemistry X

Hematologic tests X X

Metabolic tests X X

Liver function tests X X

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
Serum drug levels VPA/Depakote
• ***NEED TO OBTAIN DRUG BLOOD LEVELS WHEN ON VPA
(like Li but larger therapeutic range) ***
• Therapeutic level: 50 – 125 mcg/mL (for bipolar)
• Take blood level ~ 12 hours after last dose on the 5th day
of treatment
• Obtain a blood level after each change in dose
VPA/Depakote Toxicity
• Unlike Li Toxicity - Usually benign, but may serious, very rare
• SSx of toxicity:
• Hyperthermia/hypothermia
• Tachycardia
• Hypotension
• Confusion and somnolence
• Dizziness
• Nausea and vomiting
• Renal failure
• Tremors
• Treatment
• Support the airway
• May need to administer activated charcoal to decontaminate
• Hemodialysis may be warranted
VPA/Depakote ADR
• Most common are dose-related GI complaints (nausea, vomiting,
indigestion, anorexia, diarrhea, and flatulence)*
• Give with food
• Lower dose
• Give at bedtime
• Switch to XR
• Mild tremor & Weight gain (like Li)
• Lethargy
• Prolonged bleeding (dt inhibition of platelet aggregation and
thrombocytopenia)
• Monitor bleeding and bruising
• Transient ↑in Liver enzymes (monitor liver enzymes)
• ****BBW for HEPATOTOXICITY AND PANCREATITIS!!!****
VPA/Depakote DDI’s
• Highly protein bound → can be displaced by other protein bound
drugs when combined (i.e. phenytoin, carbamazapine) → ↑
[free VPA ]
• CYP450 enzyme inhibitor
• VPA + Phenobarbital  ↓ phenobarbital clearance → ↑
[phenobarbital]
• Oral contraceptives → ↑VPA clearance → ↓ [VPA]
• Same effect in Lamotrigine (Lamictal)
• Lamotrigine (lamictal) + VPA → SJS/TENs
• Use ½ dose of Lamotrigine when combined with VPA to ↓ SJS/TENs
risk
• VPA ↓ UDP enzymes (glucoronidation) → ↓Lamotrigine metabolism
→ ↑ [Lamotrigine]
Lamotrigine (Lamictal)
• FDA-approved for the maintenance treatment of BPD;
• not FDA approved for but very effective alternative to 1st line therapy to
prevent/treat bipolar depression
• Not 1st line bc requires slow dose increases therefore not good for acute issues
• Efficacy:
• Possesses both antidepressant and mood-stabilizing effects
• Low rate of manic switch
• Dosing and administration:
• Initial : 25 mg daily
• Range: 50-400 mg PO (divided doses)
• Slowly increase dose!!!!!! Slow titration!!!!! To ↓risk of SJS/TENS
• Example: 25 mg QD x 2 weeks →50mg QD x2 weeks → ↑50mg
increments weekly
• Doses of 400 mg daily have shown no advantages
• Need to adjust dose in hepatic and renal impairment

• Monitoring
• Only Derm for SJS/TENs
Lamotrigine (Lamictal) Monitoring

Baseline Q6-12 months

Physical Exam and General Chemistry X

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes

Dermatological tests X X
(dt risk of SJS/TENS)
Lamotrigine (Lamictal) ADR
• Common
• HA
• Nausea
• Dizziness and drowsiness
• Ataxia
• Tremor
• Rash (self-limiting and resolves eventually)  may progress to
life-threatening conditions!
• ***BBW for SJS/TENS***
• Serious rash + fever/sore throat
• May require hospitalization
• DC Tx
• Titrate doses SLOWLY and use ½ dose when combined with VPA to
↓risk
Stevens-Johnson Syndrome (SJS)
• Prodrome of Flu-like symptoms → painful red/purple rash that
spreads/blisters
• Symptoms:
• Fever, sore throat, fatigue, cough, and burning eyes (flu-like
symptoms prior to rash)
• Facial and tongue swelling
• Hives
• Skin pain
Lamotrigine (Lamictal) DDI’s
• Lamotrigine + VPA → SJS/TENs (1/2 the lamotrigine dose)
• VPA inhibits UDP (glucoronidation) enzymes → ↓ metabolism of
Lamotrigine → ↑ [Lamotrigine]
• Lamotrigine + oral contraceptives → ↑Lamotrigine clearance
→ ↓[Lamotrigine]
• Same as VPA/Depakote
• Lamotrigine + Carbamazepine (Tegretol) = ↑CNS ADR
• Low CYP PK interactions – mostly metabolized by
glucoronidation
Carbamazepine (Tegretol)
• FDA-approved for the treatment of acute mania (2nd line) and mixed
episodes associated with BPD I
• Many formulations: immediate release and extended release
• Acute anti-manic effects are comparable to lithium
• Carbamazepine + Li, VPA, or antipsychotics used for treatment-resistant
patients experiencing a manic episode
• Also reserved for patients who are unable to tolerate or who have an
inadequate response from Li or VPA
• Dosing and administration:
• Initial: 200mg PO BID
• Range: 200-1800mg/day BID-QID (↑by 200 mg/day every 2-4 days)

• Dose adjustment necessary in hepatic disease, but not in renal


impairment

• Monitoring
• Everything except thyroid and metabolic test
Carbamazepine (Tegretol) Monitoring
Baseline Q6-12 months

Physical Exam and General Chemistry X

Hematologic tests X X
(CBC and platelets at baseline - subsequent
monitoring is individualized )
Metabolic tests

Liver function tests X X

Renal function tests X

Thyroid function tests

Serum Electrolytes X X

Dermatological tests X X
Carbamazepine (Tegretol) Serum Monitoring
• Only obtained to guide toxicity!
• )Not the same as monitoring with Li or VPA where you are looking for
efficacy and therapeutic range ∴ not drawn as often)
• Draw levels 12 hours after the last dose
• Initial therapy - Q1-2 weeks during the first 2 months
• Maintenance therapy - Q3-6 months after first two months
• Auto-induces it’s own metabolism (both substrate and inducer of
3A4)→ ↓t1/2 of medication over time (medication reaches steady
state faster when dose is adjusted in pt when it is not initial tx)
• One week after changing dose (during first two months)
• 2-3 days after changing dose (after first two months)
• Goal level: 6-10 mcg/mL
• Can use 4 mcg/mL if pt is responsive
• Max 14 mcg/mL if tx resistant
Carbamazepine (Tegretol) ADR
• Neurosensory side effects are common (HA, fibromyalgia)
• Nausea
• Hyponatremia
• Risk↑with age
• Monitor serum electrolytes at baseline and Q6-12mo
• risk of causing seizures
• Transient leukopenia
• Bone marrow suppression
• Carbamazepine + Clozapine (Clozaril) → ↑ risk
• Clozapine (Clozaril) 2nd gen antipsychotic
• SSx of acute overdose:
• Ataxia
• Diplopia and nystagmus
• Cardiac conduction changes
• In Severe cases – Seizures & Coma

• **BBW**
• SJS/TENs
• HLA-B*1502 allele (MC in Asian pt – 10x ↑ risk) → SJS/TENs
• Need to test Asian pt for this allele and Carbamazepine is CI if present
• Aplastic anemia/agranulocytosis
Carbamazepine (Tegretol) DDI’s
• Auto-induces its own metabolism – both substrate and inducer of 3A4
• Induces CYP3A4 and other CYP enzymes to a lesser degree (1A2,
2C9/2C10, and 2D6)
• ↑metabolism → ↓ [of many medications] including oral
contraceptives
• Carbamazepine + VPA/Depakote → displacement from proteins → ↑ [free
Carbamazapine]
• Carbamazapine and VPA are both highly protein bound
• ↓Carbamazapine dose when combined with VPA to ↓risk of toxicity
• Carbamazepine + Clozapine (Clozaril) →↑risk bone marrow suppression
from both agents
• CYP Inhibitors → ↓ metabolism→ carbamazepine toxicity
• Non DHP CCBs - diltiazem, verapamil
• SSRIs - Fluoxetine (Prozac), Fluvoxamine (Luvox)
Oxcarbazepine (Trileptal)
• Not FDA-approved for BPD
• Currently, there is less data supporting use of oxcarbazepine over
carbamazepine in the treatment of BPD
• Administer oxcarbazepine if patients have failed other treatments or
have experienced intolerable side effects
• Advantages over CBZ:
• milder ADR
• no autoinduction of CYP enzymes (3A4)
• fewer DDIs
• Dosing and administration:
• Initial : 150-300mg PO BID
• ↑ dosing 300-600 mg Q3-6 days
• Range: 300-1200mg/day BID dosing
• Adjust dose in renal impairment

• Monitoring – Only Electrolytes


• (↑Hyponatremia risk > Carbamazepine)
Oxcarbazepine (Trileptal) Monitoring
Baseline Q6-12 months

Physical Exam and General Chemistry X

Hematologic tests

Metabolic tests

Liver function tests

Renal function tests

Thyroid function tests

Serum Electrolytes X X
(HIGHER RISK OF HYPONATREMIA THAN
CARBAMAZEPINE)
Dermatological tests
Oxcarbazepine (Trileptal) ADR
• Dose-related ADR:
• Dizziness and sedation
• HA
• Ataxia and fatigue
• Vertigo
• Abnormal vision and diplopia
• Vomiting and abdominal pain
• Hyponatremia!
• MC w/Oxcarbazepine than Carbamazepine
• Can be severe (<125 mEq/L →↑RISK OF SEIZURE)
• MC in first 3 months
• Symptoms: confusion, HA, lethargy, malaise
• Hypersensitivity reactions
• Cross-reativity with Carbamazepine hypersensitivity
Oxcarbazepine (Trileptal) DDI’s
• Inhibits 2C19 → ↓metabolism of phenytoin
• Induces 3A3 and 3A4
• ↑metabolism of oral contraceptives → ↓[oral
contraceptives]
• Like Carbamazepine (Tegretol)
• Oxcarbazepine + diuretics → ↑risk of hyponatremia (∴↑RISK
OF SEIZURE)
2nd Generation Antipsychotics
• Treatment of acute mania in BPD
• Quetiapine (Seroquel)
• Treatment of manic/mixed states of BPD
• Aripiprazole (Abilify)
• Asenapine (Saphris)
• Olanzapine (Zyprexa)
• Risperidone (Risperdal)
• Ziprasidone (Geodon)
• Cariprazine (Vraylar)
• Maintenance treatment of BPD
• Aripiprazole (Abilify)
• Quetiapine (Seroquel)
• Risperidone IM (Risperdal)
• Ziprasidone (Geodon)
• Bipolar Depression
• Quetiapine (Seroquel)
• Lurasidone (Latuda)
• Olanzapine/Fluoxetine combo
How To Assess Severity of Symptoms?
• Depression
• PSQ-9 – can use to measure severity at baseline and response to treatment
• Mania
• Young Mania Rating Scale (YMRS)*
• GOLD STANDSRD
• 11 items clinician rated scale of symptoms in past 48hr
• 0-4
• elevated mood
• energy levels
• sexual interest
• sleep
• language-thought disorder
• Appearance
• Insight
• O-8
• irritability
• rate and amount of speech
• content of speech
• behavior
• Goal ≤12 → remission of symptoms
• Higher the score = more manic
• 10 = some elevation but not full manic episode
Back To Our Patient: ah
Recap of •Our Patient: AH
CC: “There are hundreds of vampires in this city, and I have documents to
prove it.”
• HPI:
• AH is a 25 year-old male seen today in the Crisis Center.
• According to his neighbors who called the police, the patient has been
acting increasingly strange. The lights in the house are left on all night long,
and spiritual music is played at all hours.
• Last evening, he dug a trench around his front yard with an electric lawn
edger and filled it with garlic cloves
• This evening, he painted crosses on the front of the house and threw
furniture into his front yard and the street. When approached by neighbors,
he apparently began screaming and preaching at them. When the police
arrived, they found the patient standing naked on the dining room table in
his front yard preaching. When the police approached him, he began
throwing garlic tablets at them and screaming, “Become naked in the eyes of
the Lord and you will be saved.” He became increasingly hostile during the
arrest shouting, “Don’t hate me because I’m beautiful.” He then tried to bite
one of the officers.
Patient Case Continued…
• PMHx:
• Manic episodes first occurred while he was in college, leading to psychiatric
admissions at ages 21 and 23 for acute mania
• Patient was treated with haloperidol 5 mg by mouth once daily, and lithium 600
mg by mouth each morning and 900 mg by mouth at bedtime, with adequate
response and discharged on both occasions after about one month
• Medical problems include migraine headaches
• FHx:
• Father has a history of depression
• Paternal grandmother was placed in an “asylum” for hysteria secondary to
childbirth
• Mother and brother have Type II diabetes
• SHx:
• Recently fired from his job as a nurse at a hospital
• Patient is a single homosexual
• Religious upbringing as a Southern Baptist
• Smokes 1 ppd for 5 years
• Medications:
• Ibuprofen PRN for migraine headaches
• (interaction with Li – tell pt to use APAP)
• Allergies: None
Question #1
Question #2
Question #3
Pain Management

Patient FT is started on lithium and is undergoing an orthopedic consultation for ankle pain. Ankle
fracture is ruled out with an x-ray and physician asks for a pharmacologic option for pain control.
What medication would be best recommendation?
a. Duloxetine 60 mg by mouth once daily (neuropathic pain)
b. Ibuprofen 800 mg by mouth 3 times a day as needed for pain (NSAID)
c. Naproxen 500 mg by mouth 2 times daily until pain is gone (NSAID)
d. Acetaminophen 1000 mg by mouth 3 times a day as needed for pain (3000mg MDD)
Study Pointers from Gretchen

• Know MOA for Antidepressants, Anxiety and Panic Agents


• Know Therapeutic Class for mood stabilizers (only know MOA for Li)
• No dosing on ANY drugs for this module!
• Know which agents are most likely to have DDIs (not specific Dis)
• Know Drug –food interaction with MAOIs and tyramine containing foods
• Know first line options highlighted in attached slides
VPA Monitoring Parameter

Baseline laboratory screening before starting valproate should include which of the following?
a. Ammonia (not standard baseline screening)
b. Liver function tests (CYP enzyme inhibition)
c. HLA-B*1502 variant (Asian pt for Carbamazepine (Tegretol))
d. Thyroid function tests (Li)
In Conclusion
• Bipolar disorder (BPD) is a chronic, cyclic mental illness that is
characterized by recurrent fluctuations in mood, energy, and
behavior
• There are many different types of BPD
• The healthcare team must accurately diagnosis the patient and
determine the appropriate therapy/therapies
• For the pharmacological treatment options for BPD, there is a high risk
of toxicity, especially with those medications that have a narrow
therapeutic index
• Be aware of the therapeutic serum drug levels, drug-drug
interactions, the symptoms of toxicity, and how to properly treat
toxicities!
Neurocognitive Disorders
Kimberly Hayashi, PharmD
khayashi@su.edu
Objectives
1. Describe the differences in dementia and delirium
2. Identify common medication causes of delirium
3. Identify the MOA, doses, and common side effects of
dementia medications
4. Given a patient case, determine the reversible causes of
dementia and identify a treatment plan
5. Given a patient case, recognize non-cognitive symptoms
of dementia and identify appropriate treatment options
Case
An 95 yo male Aemon Targaryen was Medication List:
admitted to the hospital after a fall. He has a
Lisinopril/HCTZ 12.5/25 1 tab daily
past medical history of HTN, anxiety, Amlodipine 5 mg 1 tab daily
dementia, hypercholesterolemia, and type 2 Atorvastatin 40 mg 1 tab daily
diabetes mellitus. Alprazolam 1 mg 1 tab prn
Zolpidem 5 mg 1 tab nightly
Metformin 1000 mg 1 tab BID
Neurocognitive Disorders
DSM V
● Delirium ● Dementia
○ Causes ○ Minor vs Major

○ Presentation ○ Presentation

○ Management ○ Treatment

Fong TG. Nat Rev Neurol. 2009 5(4):210-20


APA Delirium Clinical Practice Guidelines 2010.
Neurocognitive Disorders
DSM V
Delirium
● Presentation
○ Hypoactive
○ Hyperactive
○ Mixed
● Duration
○ Acute
○ Persistent
Fong TG. Nat Rev Neurol. 2009 5(4):210-20
APA Delirium Clinical Practice Guidelines 2010.
Delirium
Common Causes
Potentially Modifiable Non modifiable
Medications
● Sensory Impairment ● Dementia (2/3) (especially in
● Medications ● Age (>65) elderly
● Infection ● Hx of delirium
Anticholinergic
● Metabolic (dehydration) ● Multimorbidity Benzodiazepines
● Surgery ● Chronic renal, hepatic Hypnotics
● Pain disease (Metab Opioids
● Sleep disturbances) Corticosteroids
● EtOH or illicit drug Herbals
withdrawal
Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
Delirium
Medications Hypnotics
Anticholinergic ● Zolpidem (Ambien),
● TCA’s ● Eszopiclone (Lunesta),
○ Amitriptyline (Elavil) ● Zaleplon (Sonata)
● Diphenhydramine (Benadryl) Opioids
● Oxybutynin (Ditropan, Oxytrol) ● Tramadol (Ultram),
Benzodiazepines ● Hydrocodone, Oxycodone
● Alprazolam (Xanax), Herbals/OTC
● Diazepam (Valium), ● St. John’s Wort
● Lorazepam (Ativan), ● Valerian root
● Temazepam (Restoril) ● Loperamide (Imodium)
Delirium
Presentation
Characteristic Delirium
Onset Sudden

Course Fluctuating

Cognition Disordered

Attention Disordered

Consciousness Reduced

Delusions Fleeting
Arnold E. Nursing. 2004:34(6);36-42
Fong TG et al. Nat Rev Neurol. 2009 5(4):210-20
Speech Often Incoherent Inouye et al. Ann intern Med.1990;113:941
http://nursing.advanceweb.com/
Delirium
Management
● Prevention Is Key!
○ 30-40% of delirium cases are preventable
● Non-pharmacologic strategies are First Line
○ Reorientation, appropriate environment (sleep, no restraints,
family)
● Pharmacologic treatment only if delirium might compromise
safety
○ Can cloud pt mental status and should be avoided if possible
○ ID cause of Delirium and treat that instead is better
Treatment
Pharmacologic (all equivalent)
1st Generation Antipsychotics (Typical)
● Haloperidol (Haldol) – used the longest and MC but not
FDA for Delerium
● ADR: EKG, sedation, pseudoparkinsonism, prolactin levels
2nd Generation Antipsychotics (Atypical)
● Quetiapine (Seroquel), Olanzapine (Zyprexa), Risperidone
(Risperdal), Ziprasidone (Geodon)
○ ADR: ↑anticholinergic SE, Orthostatic hypotension, weight gain
Case
An 95 yo male Aemon Targaryen was admitted to Medication List:
the hospital after a fall. He has a past medical
history of HTN, anxiety, dementia, Lisinopril/HCTZ 12.5/25 1 tab daily
hypercholesterolemia, and type 2 diabetes Amlodipine 5 mg 1 tab daily
mellitus. He has been admitted for 4 days, and at Atorvastatin 40 mg 1 tab daily
morning rounds he is withdrawn and slow to Alprazolam 1 mg 1 tab prn
respond. Later in the afternoon when the nurse Zolpidem 5 mg 1 tab nightly
comes to bring medications, Aemon was very
Metformin 1000 mg 1 tab BID
agitated, restless and had difficulty following
conversations with his nurse.
Case
1. How would you characterize Aemon’s delirium?

1. Mixed delirium

2. What are his nonmodifiable risk factors for developing delirium?

3. What are his modifiable risk factors?

4. How would you manage these causes?


Neurocognitive Disorders
DSM V
Dementia
● Minor Neurocognitive Disorder

○ Alzheimer’s Dementia, Lewy Body Dementia, Vascular Dementia, Frontotemporal


Dementia

○ With or without behavioral disturbances

● Major Neurocognitive Disorder

○ Alzheimer’s Dementia, Lewy Body Dementia, Vascular Dementia, Frontotemporal


Dementia

○ Severity: Mild, Moderate, Severe

○ With or without behavioral disturbances


Dementia
Types of Dementia
● Alzheimer’s Dementia
○ Most Common - 50-60% of diagnosed dementias

● Vascular Dementia

● Lewy Body Dementia

● Frontotemporal Dementia (Pick’s Disease)

● Reversible causes of Dementia


Reversible Causes
Diagnosis of Exclusion
● Drugs
Drugs
● Emotional illness (depression)
Anticholinergic
● Metabolic/endocrine disorders Benzodiazepines
Hypnotics
Opioids
● Eye (visual problems)/Ear (hearing) Antipsychotics
Anticonvulsants
● Nutrition/neurologic problems

● Tumors; trauma; toxins


Dementia
Medications
Anticholinergic Antipsychotics
● Haloperidol (Haldol),
Benzodiazepines ● Risperidone (Risperdal),
● Olanzapine (Zyprexa),
● Ziprasidone (Geodon)
Hypnotics Anticonvulsants
● Phenytoin (Dilantin),
Opioids ● Valproate (Valproic Acid),
● Carbamazepine (Tegretol)
Herbals ● Levetiracetam (Keppra)
● Monitor for drug interactions
Dementia
Presentation
Characteristic Dementia Delirium

Onset Gradual Sudden

Course Stable Fluctuating


Cognition Impaired Disordered

Attention Usually normal Disordered


Consciousness Clear Reduced
Speech Word finding difficulties and Often incoherent
perseveration
Arnold E. Nursing. 2004:34(6);36-42
Dementia
Prevention
● Cognitive Stimulation

● Diet

● Exercise

● Smoking cessation

Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
Alzheimer's Disease
Neurotransmitter Dysfunction
● Pathology ● Neurotransmitter depletion
○ Neurofibrillary tangles (NFTs) ○ Acetylcholine (40-80%↓)
and β-amyloid plaques ○ Norepinephrine
○ Degeneration of neurons ○ Serotonin
○ Cortical atrophy ○ Dopamine→ metabolized to
MAO-B

● Dysregulation
○ Glutamate
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Treatment
Goals
● Support quality of life for both patient and caregiver
● Preserve function for as long as possible -
↓worsening of ADLs
● Minimize psychiatric/ behavioral symptoms
● Palliative care approach
Cannot cure or reverse disease process
Slattum PW, Peron EP, Hill A. Chapter 38. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 9e. 2014
Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
Treatment
Non-Pharmacologic
● Setting schedules
● Reduce environmental triggers
○ Noises, insecure space, light
● Caregiver support programs
● Adequate sleep, hydration, nutrition
○ Exercise, relaxation techniques
● Occupational therapy
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Seeley WW, Miller Bl. Chapter 371. Dementia. In: Harrison’s Principles of Internal Medicine, 18e. 2012.
Treatment
Pharmacologic
● Acetylcholinesterase Inhibitors
○ Donepezil (Aricept)
○ Rivastigmine (Exelon)
○ Galantamine (Razadyne)

● N-Methyl D-Aspartate Receptor Antagonist


○ Memantine (Namenda)
Treatment
AChE Inhibitors
● MOA: Reversibly
inhibits AChE to prevent
the degradation of ACh

● AChE Inhibitor
○ Donepezil (Aricept®)
○ Rivastigmine (Exelon®)
○ Galantamine (Razadyne®)
http://peaknootropics.com/acetylcholinesterase-memory-problems/
Donepezil (Aricept®)
AChE Inhibitor
Indication Mild- Severe Alzheimer's Dementia
SLOW Titration
Dosing Mild/Mod- 5 mg once daily → dt GI ADR
Recommended 10 mg once daily
Mod/Sev- 5mg once daily → Max 23mg 5mg→ 10mg
once daily after 4-6 weeks

Dosage Tablets/ODT- 5 mg, 10 mg 10mg→ 23 mg


Form Film coated tabs- 23mg After ≥ 3 mos

Adjustments No Adjustments necessary


Donepezil (Aricept®)
AChE Inhibitor
Adverse Dose related:N/V/D, Anorexia, weight loss
Effects Non-Dose related: insomnia, abnormal
dreams, accidental injury,bradycardia,
dizziness, syncope, QTc prolongation Benefit:
3-6 Months
New Warning Rhabdomyolysis, Neuroleptic Malignant
Syndrome (NMS) (Very uncommon)
Drug Anticholinergics, Antipsychotics (EPS),
Interaction Succinylcholine, QTc Prolonging
Monitoring Mood, Behavior, Cognition, Functional Ability,
Bowel/Bladder Function, Pulse, QTc
Rivastigmine (Exelon®)
AChE Inhibitor
Indication Mild- Mod Alzheimer’s Dementia (PO) SLOW
Mild- Severe Alzheimer’s Dementia (Patch) Titration!
Mild-Mod Parkinson’s related Dementia
(Both) PO: Q 2
weeks
Dosing Mild/Mod: PO- 1.5 mg BID → Max 6 mg BID
*with meals Patch- 4.6 mg/24 hr→ 9.5mg/24 hrs Patch: Q 4
Mod/Severe: PO- Same as above Weeks
Patch - Increase to 13.3 mg/24hr
Adjustments Weight <50 kg: consider lower maintenance
dose
Rivastigmine (Exelon®)
AChE Inhibitor
***
Adverse GI (dose): N/V/D, anorexia, weight loss
Diarrhea
Effects CNS: Dizziness, HA, agitation, falling
Other: tremor, site reaction (patch) Urination
Miosis
Drug Nicotine, Anticholinergics,
Bronchospasm/
Interaction Antipsychotics (EPS), Succinylcholine
Bradycardia
Monitoring Cognition, Cholinergic Crisis*, CBC Excitability
(GI bleed risk), GI Tolerance, Pulse
Lacrimation
Salivation/
If therapy is interrupted, restart titration at lowest
dose Sweating
Rivastigmine (Exelon®)
AChE Inhibitor
Galantamine (Razadyne®)
AChE Inhibitor
Indication Mild- Mod Alzheimer's Dementia
Dosing IR/Solution: 4 mg BID (range: 16-24 mg SLOW
*with meals divided) Titration!
ER: 8 mg once daily (range: 16-24 mg daily)
Must wait at
Adjustments Renal Impairment: least 4 weeks
Mod (CrCl 9-59): Max dose 16 mg/day to increase
Sev (CrCl < 9 ml/min) Do not use
Hepatic Impairment:
Mod (Class B): Max dose 16 mg/day
Sev(Class C): Do not use
Galantamine (Razadyne®)
AChE Inhibitor
Adverse GI: Nausea(25%), Vomiting(13%), diarrhea, anorexia,
Effects weight loss
CNS:Dizziness, HA, depression, fatigue, insomnia,
Other: UTI (8%), Bradycardia, Rash
Drug Anticholinergics, Antipsychotics (EPS), Succinylcholine,
Interaction QTc Prolonging agents
Monitoring Cognition, Cholinergic Crisis*, Weight, GI tolerance, Pulse

If therapy is interrupted, restart titration at lowest dose


Treatment
NMDA Receptor Antagonist
● MOA: Uncompetitive binding to Mg2+ site on the
NMDA receptors → blocks excessive stimulation

● Memantine (Namenda®)

http://glaucoma-today.blogspot.com
Memantine (Namenda ®)
NMDA Receptor Antagonist

Indication Mod- Severe Alzheimer's Dementia


Dosing IR Soln: (10mg/5mL) 5 mg daily → target dose 10 mg BID
ER cap: 7 mg daily → Max: 28 mg daily
--Can titrate weekly--
Adjustments Renal Impairment = CrCl 5-29 mL/min:
IR:Max 5 mg BID; ER: 14 mg daily
ER has NO added benefit
Memantine (Namenda ®)
NMDA Receptor Antagonist
Adverse CV: hypertension, hypotension
effects CNS: dizziness, confusion (↑ when starting but should
clear in 2-3 wks) HA, anxiety, depression,
GI: constipation, diarrhea Other: cataract
Drug Bupropion, Trimethoprim
Interaction
Monitoring Cognition, hypertension, constipation, CNS changes, rash
Clinical Pearls
Acetylcholinesterase Inhibitors
● Benefit in 3-6 months
● Donepezil best tolerated oral AChE Inh
● Transdermal rivastigmine has least GI ADEs
● Remember goals of therapy-
○ DC medications if no benefit
○ Taper Cholinesterase Inhibitors
■ Ex. Donepezil 10 mg → 5 mg for one month→ Then
discontinue
Clinical Pearls
NMDA Receptor Antagonists
● Over all well tolerated

● No clinical difference between XR and IR

● When added to Acetylcholinesterase Inhibitors


likely no clinically significant benefit
Alternative Treatments have no
benefits
Treatment Evidence Concerns

Vitamin E No clinical benefit in dementia treatment ↑bleed risk / toxicity (fat sol)

Ginkgo biloba RCT show no protection in developing Interaction: anticoagulants,


dementia antiplatelet

Omega-3 Fatty Acids No clinical benefit in Alzheimer's Antiplatelet activity

Huperzine A Limited clinical benefit GI, insomnia

Prevagen No peer-review research in humans or HA, Dizziness, confusion


animals
Noncognitive Symptoms

● Psychotic symptoms

● Disruptive/inappropriate behavior

● Depression

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Non-Cognitive Sx
Management
● Nonpharmacologic treatment (do this 1st!)
○ Redirection, animal therapy, multisensory stimulation, emotion
oriented therapy
○ Occupational Therapy
● Pharmacologic
○ Initiate when symptoms pose a risk to patient or caregiver
○ Patient in severe distress
Risk vs Benefits
VA-ESP Project #50-225, 2011
American Association for Geriatric Psychiatry Position Statement, 2006
Noncognitive Symptoms
Psychosis
Antipsychotics - haloperidol, risperidone, olanzapine,
quetiapine
● May help with aggression and agitation
● BBW- Elderly patients with dementia → ↑risk of death
● ADE- somnolence, EPS, worsening cognition, hypotension,
abnormal gait, metabolic effects, cerebrovascular events
● Do no use > 12 weeks
● Drug Interactions!!
Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Noncognitive Symptoms
Disruptive/Inappropriate Behavior
● AChE Inh - may reduce use of antipsychotics
● Antipsychotics - agitation with psychosis, sexual
aggression, impulse control in men
● Benzodiazepines- PRN for infrequent agitation
○ ADEs- impaired cognition, worsening of breathing
disorders, increased fall risk
● Mood stabilizers- Carbamazepine, valproic acid
○ Evidence conflicting

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Noncognitive Symptoms
Depression
SSRIs
● Citalopram (Celexa) or sertraline (Zoloft) - 1st line
○ ADEs- Nausea, agitation, insomnia, sexual
dysfunction, less withdrawal ssx
○ May help with behavior symptoms
○ Zoloft – more GI ADR
○ Celexa – more CV ADR

Slattum PW, Peron EP, Hill A. Chapter 54. Alzheimer’s Disease. In: Pharmacotherapy: A Pathophysiologic Approach, 10e. 2017
Noncognitive Symptoms
Clinical Pearls
● Consider the symptoms you are treating and if the benefits outweigh the risks

● Use lowest effective dose

● Offer oral before parenteral

○ If IM use single drug: lorazepam, haloperidol, or olanzapine

● Regularly monitor vital signs, efficacy, ADEs


Future Directions
● Citalopram

○ Reduction in amyloid-β in healthy patients and AD mice

● Vitamin D

○ Correlation b/w low serum Vit D levels and incidence of cognitive decline

● Amyloid-β monoclonal Antibodies

● Inflammation studies

○ TNF-ɑ inhibitors

● Insulin resistance

○ GLP-1 agonists
Patient Case
An 95 yo male Aemon is following up with Medication list:
his primary care provider, as winter is
Lisinopril/HCTZ 12.5/25 1 tab daily
coming. He has a past medical history of Amlodipine 5 mg 1 tab daily
HTN, moderate dementia, anxiety, Atorvastatin 40 mg 1 tab daily
hypercholesterolemia, and type 2 diabetes Metformin 1000 mg 1 tab BID
mellitus. The PCP would like your input on
what to start for this patient’s dementia.
Case
1. What would you like to start this patient on (drug/dose/frequency) and why?

• Donepazil PO 5mg QD – titrate up slowly to 10mg to avoid GI ADR;


well tolerated agent

• If GI ADR can try patch but might be better to switch to Namenda

2. What are the common side effects you would monitor for with your treatment
regimen?
Take Aways
Delirium Dementia
● Hypoactive vs Hyperactive vs Mixed ● Screen for reversible causes
(medications)
● Medical Emergency ● Treatment goals
○ Palliative in nature
● Modifiable and non-modifiable ○ QOL of patient and caretaker
causes ● Acetylcholinesterase Inhibitors
● NMDA Receptor Antagonists
● Prevention is key! ● Noncognitive Symptom
management
● Antipsychotics are used only if safety ○ Leading cause of nursing
is compromised. home placement
Neurocognitive Disorders
Kimberly Hayashi, PharmD
khayashi@su.edu
Neuromuscular Blockade (Paralytics)
in the ICU

Marcia Brackbill, Pharm.D., BCPS


Professor of Pharmacy
BJD School of Pharmacy
Shenandoah University
Objectives
Explain the mechanism of action of neuromuscular
blocking agents used in the ICU/ED
Discuss the indications and clinical effects of
neuromuscular blockade
Identify concomitant medication(s) which are necessary
when a patient is on a neuromuscular blocker
Contrast the medications within each pharmacologic class
with regards to MOA, indication, pharmacokinetic
parameters (type of elimination), adverse effects and
precautions and/or contraindications
Identify appropriate therapeutic options to reverse
neuromuscular blockade
Normal Neuromuscular
Transmission

Image source: http://www.frca.co.uk/images/acetylcholine.jpg


Normal Neuromuscular
Transmission

Image source:
http://archive.ispub.com/journal/the-internet-journal-of-orthopedic-surgery/volume-7-number-2/orthopaedic-surgery-implications-of-a-
novel-encapsulation-process-that-improves-neuromuscular-blockade-and-reversal.html#sthash.uVggnUzg.dpbs
MOA
Work on skeletal muscles postsynaptic nicotinic acetylcholine
(ACh) receptor
Two categories (same clinical result – Paralysis)
Depolarizing – works by binding to Ach receptors and
causes persistent depolarization of the neuromuscular
endplate, causing sustained contraction
Succinylcholine is structurally similar to acetylcholine (2 ACh
molecules bonded together)
Non-depolarizing – bind to alpha subunits of intra-junctional
ACh receptor on the postsynaptic membrane leading to
inhibition of current through receptor

What do you need to be sure the patient is receiving when


you administer a NMBA?
Inhibited Transmission

Image source:
http://archive.ispub.com/journal/the-internet-journal-of-orthopedic-surgery/volume-7-number-2/orthopaedic-surgery-implications-of-a-
novel-encapsulation-process-that-improves-neuromuscular-blockade-and-reversal.html#sthash.uVggnUzg.dpbs
NMBA’s
Depolarizing – Just one agent!
Succinylcholine (Anectin)
Very quick onset and short duration of action
Onset < 1 min
Duration: 5-10 min
Produces initial muscle fasciculation followed by
a flaccid paralysis
Frequently use for intubations
Not indicated for prolonged (i.e. continuous
infusion) use b/c of SE’s: release of histamine,
rising potassium levels, risk of malignant
hyperthermia, elevated intragastric and
elevated intraocular pressures
NMBA’s
Non-Depolarizing
Chemical class: benzylisoquinoline
Atracurium (Tracrium)
Cisatracurium (Nimbex)
Chemical class: aminosteroid
Pancuronium (Pavulon)
Rocuronium (Zemuron)
Vecuronium (Norcuron)
Indications for NMBA’s
Facilitate endotracheal intubation

Assist with mechanical ventilation (after sedation and


analgesia have been optimized)
ARDS (PaO2/FiO2 is < 150)

Immobilization for selected procedures

Increased intracranial pressures


Traumatic Brain Injury (TBI)

Prevention of shivering during implementation of cardiac


hypothermia protocols

Treat life threatening agitation refractory to aggressive


sedation and analgesic therapy
Contraindications of
NMBA’s
Inability to obtain a secure airway
Patient not on analgesia and sedation
Unstable bone fractures
Relative contraindications include burns,
hemiplegia, hemiparesis, and peripheral
neuropathy
Receptors may be resistant to NMBAs and lead
to excessive doses
Factors to Consider When Selecting
a NMBA
Duration of procedure - (duration of action)
Need for quick endotracheal intubation (onset of action)
Adverse effect profile (hemodynamic instability,
histamine release)
PK/route of elimination (especially in patients with renal
or hepatic insufficiency)
Concurrent medications/drug interaction
Cost/Availability/Formulary Agents
Comparison of NMBAs
Agent Onset of Action DOA Metab Comments
atracurium 2-4 min 30-40 Hoffman can be used in MOF;

causes MCD
cisatracurium 2-3 min 40-60 Hoffman can be used in MOF
pancuronium 4-6 min 120-180 renal causes MCD
vagolytic  HR , BP
rocuronium 1-2 min 30-40 hepatic facilitates intubation
 HR
vecuronium 2-4 min 30-40 hepatic no MCD/ histamine
MOF = multiple organ failure
release
MCD = mast cell degranulation and histamine release
Factors Which May Prolong
the Action of NMBA
Paralysis
Medications
Antibiotics (aminoglycosides, clindamycin, tetracycline,
polymyxin B, vancomycin), beta blockers, Ca channel
blockers, corticosteroids, local anesthetics, lidocaine

Clinical Conditions
Acidosis, renal/ hepatic failure, severe electrolyte toxicity
(i.e. hypermagnesemia), hypothermia, neuromuscular
disease (Myasthenia Gravis, Muscular Dystrophy), renal
failure
Factors Which May Prevent
Desired Levels of Paralysis
Medications
Anticholinesterase agents, carbamazepine
(Tegretol), phenytoin (Dilantin), ranitidine
(Zantac)
Clinical Conditions
Alkalosis, demyelinating lesions, diabetes,
peripheral neuropathies
Reversal

Image source:
http://archive.ispub.com/journal/the-internet-journal-of-orthopedic-surgery/volume-7-number-2/orthopaedic-surgery-implications-of-a-
novel-encapsulation-process-that-improves-neuromuscular-blockade-and-reversal.html#sthash.uVggnUzg.dpbs
Reversal Agents
MOA: acetylcholinesterase inhibitors
Prevent breakdown of acetylcholine in synaptic
cleft to overcome the NMBA
Neostigmine (Bloxiverz)
0.03mg/kg for rocuronium & shorter duration
agents
0.07mg/kg for vecuronium and pancuronium due to
longer duration of action
Edrophonium (Enlon) -less commonly used
10mg may repeat every 5-10min up to 40mg
Reversal Agents (cont.)
MOA: Selective Relaxant Binding Agent (SRBA)
Selectively forms a tight complex with aminosteroid
NMBAs and removes them from the NMJ into the
plasma for removal
Sugammadex (Bridion)
Approved by the FDA December 2015
Potential advantage: provide more rapid reversal
of aminosteroid NMBAs
May allow for use of aminosteroids NMBA agents for
emergency intubations in patients where succinylcholine is
contraindicated

ADRs: Watch for bradycardia & hypersensitivity reactions


Complications With
Difficulty in clinical
NMBAs
DVT
assessment of certain
pathologies Pressure ulcers
Acute abdomen, angina,
neurologic alterations
Corneal ulcers

Increased protein Prolonged paralysis


catabolism may be due to
1. accumulation of the
Tachyphylaxis drug
2. acute myopathy (AKA
Myositis ossificans acute quadraplegic
(calcification of the myopathy syndrome –
muscle) most serious side effect
and may occur with
Peripheral nerve damage infusions of 1-2 days)
Monitoring NMBAs

Critical: Always verify patient is receiving Image source:


http://www.bge.com.b
r/img%20banner/01x.j
sedation/analgesia !! pg

Train-of-Four (TOF)
Peripheral nerve stimulator –used to intermittently
monitor neuromuscular transmission during long-
term administration of muscle relaxants in the ICU
TOF – Electrode Placement
TOF – Procedure and Goals
Electrical stimuli (4) used to evoke a
"twitch" responses from the patient which may be
observed (tactile and visual observation) by the clinician
Goal - 1 twitch (out of 4 ) - which correlates to 90%
blockade
Decreases likelihood of prolonged paralysis/myopathy
When do you perform TOF monitoring?
Baseline
15 minutes after bolus dose (or change in infusion rate) titrate
to clinical endpoint every 15 minutes
When patient is clinical stable (at clinical endpoint), monitor
every 4 hours
Questions?