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Pharmacotherapy
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
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
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
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
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
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
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
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
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
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
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
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
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®)
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)
Clozaril® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2014.
Clozapine (Clozaril®)
Pharmacotherapy
• 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.
.
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
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
• Wait 5min
NICOTINE NASAL SPRAY:
PATIENT EDUCATION
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
Maximum of 16 cartridges/day
Nonnicotine
cessation aid
Sustained-release
antidepressant
Wellbutrin?
Oral formulation
BUPROPION
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
Nonnicotine
cessation aid
Partial nicotinic
receptor agonist
Oral
formulation
VARENICLINE
• MOA: Binds with high affinity and selectivity at 42
neuronal nicotinic acetylcholine receptors
* 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
NicVAX Vaccine
Pharmacotherapy Abstinence Rates
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
•Review
•Mechanism of Action
•Formulations
•Adverse Effects, Precautions, Contraindications,
Black Box Warnings
•Treatment Guidelines
•Monitoring
•Patient Case
Review
Review
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
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
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
Adverse Effects
•Common
•Decreased appetite, delayed growth, insomnia,
headache, irritability
•Rare
•Hypertension, tachycardia, tics, psychosis, mania,
priapism, peripheral vasculopathy
Stimulants
Precautions
Contraindications
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)
CNS depressants
• May enhance sedative effect of alpha-2 agonists
• 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
Caregiver education
• Structured schedule
• Positive and negative reinforcement
Classroom modifications
• Individualized education plans
• Small classrooms
• Work/test modifications
Depression
• Stimulants, guanfacine, clonidine
Atomoxetine
Dosing
Guanfacine ER
Monitoring
Indices of Therapeutic Effect
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
Irritability
• Reduce dosage, assess for comorbidities
Tics
• Reduce dosage, alternative therapy
Psychiatric disorder
• Discontinue medication, alternative therapy
Follow-Up
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
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
• 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)
Hypnotic Selection
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)
• 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
• Specific phobias
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
• Presenting symptoms
• Patient preference
• Drug cost
SSRI Options
• 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
Escitalopram + 0
Paroxetine ++++ 0
Sertraline + +
Drug Interactions continued…
Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents
Venlafaxine 0/+ 0
Duloxetine +++ 0
• 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
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
• Respiratory depression
• 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?
• Presenting symptoms
• 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
Citalopram + 0
Fluoxetine ++++ ++
Fluvoxamine 0 +++
Clomipramine: another TCA Option
• 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
Relapse
severity
Response
Symptoms
Syndrome
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
• 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
• 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!
• Smokers • Hypertension
• Fatigue or sleepiness
• 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
http://brainyinfo.com/antidepressants/snri/
SNRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)
• Can become excessive and/or debilitating and may develop into a disorder when these feelings become
frequent/excessive
• Anxiety disorders are the most commonly found and the most commonly misdiagnosed mental illnesses
• Specific phobias
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
• Presenting symptoms
• Patient preference
• Drug cost
SSRI Options
• 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
Escitalopram + 0
Paroxetine ++++ 0
Sertraline + +
Drug Interactions continued…
Duloxetine 50 12 6 90 None
Drug Interactions with the SNRI Options
• Have relatively fewer CYP interactions than the SSRI agents
Venlafaxine 0/+ 0
Duloxetine +++ 0
• 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
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
• Respiratory depression
• Drugs that inhibit CYP3A4 (ketoconazole, an antifungal, is an example) can increase blood levels
of alprazolam and diazepam
• 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
• 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?
• Presenting symptoms
• 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)
Citalopram + 0
(Celexa)
Fluoxetine ++++ ++
(Prozac)
Strong 2D6 inhibitor
Fluvoxamine 0 +++
(Luvox)
Strong 3A4 inhibitor
Clomipramine (Anaframil) : another TCA Option
• 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
Relapse
severity
Response
Symptoms
Syndrome
• 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
• Trazodone and Vilazodone are substrates of CYP3A4, but does not inhibit or induce it
• Caution when combining with CYP3A4 inducers or inhibitors
• ADR:
• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold
• 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
• 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
• Smokers • Hypertension
• Fatigue or sleepiness
• Insomnia • Hyperlipidemia
• Underweight patients/low
appetite
Initial Treatment
Severity Level PHQ-9 Score Initial Treatment
Strategies
Mild 10-14 psychotherapy OR
pharmacotherapy
Escitalopram Lexapro®
Fluoxetine Prozac®
Fluvoxamine Luvox®
Paroxetine Paxil®
Sertraline Zoloft®
SSRI Agents
Generic Brand GAD Panic MDD Notes
(8-12wK) (delayed
4-12wk)
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)
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
• Presenting symptoms
• Patient preference
• Drug cost
Pharmacotherapy Options for GAD
Guidelines First Line Second Line Txt-Resistant
• 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
Escitalopram + 0
(Lexapro)
Paroxetine ++++ 0
(Paxil)
Sertraline + +
(Zooft(
Drug Interactions continued…
Venlafaxine 0/+ 0
(Effexor)
Duloxetine +++ 0
(Cymbalta)
• 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)
MOA Antihistamine
• Respiratory depression
• 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?
• Presenting symptoms
• Patient preference
• Drug cost
Pharmacokinetic Interactions: Inhibitory Potentials of CYP Liver
Enzymes
CYP Liver Enzyme
Citalopram + 0
Fluoxetine ++++ ++
Fluvoxamine 0 +++
Phenelzine (Nardil)
Relapse
severity
Response
Symptoms
Syndrome
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%
www.pharmacy-and-drugs.com
Bupropion (Wellbutrin)
• Side effects include:
• Nausea
• Vomiting
• Tremor
• Insomnia
• Dry mouth
• Lowers seizure threshold
• 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)
• Smokers • Hypertension
• Fatigue or sleepiness
dailymed.nlm.nih.gov
Mirtazapine (Remeron)
• 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)
• 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
• Smokers • Hypertension
• Fatigue or sleepiness
• 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
• 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
• ↓ 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
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
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
Hematologic tests X X
Metabolic 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
Hematologic tests X X
Metabolic tests X X
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
Hematologic tests
Metabolic 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
Hematologic tests X X
Metabolic 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!!
• 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
Hematologic tests
Metabolic 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
• 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
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
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
Hematologic tests X X
(CBC w/ diff + platelets)
Metabolic tests X X
(FBG, Lipids, weight)
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
• 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
Hematologic tests X X
Metabolic tests X X
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
Hematologic tests
Metabolic 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)
• Monitoring
• Everything except thyroid and metabolic test
Carbamazepine (Tegretol) Monitoring
Baseline Q6-12 months
Hematologic tests X X
(CBC and platelets at baseline - subsequent
monitoring is individualized )
Metabolic 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
Hematologic tests
Metabolic 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
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
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
● Vascular Dementia
● 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)
● 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
● Memantine (Namenda®)
http://glaucoma-today.blogspot.com
Memantine (Namenda ®)
NMDA Receptor Antagonist
Vitamin E No clinical benefit in dementia treatment ↑bleed risk / toxicity (fat sol)
● 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
● Vitamin D
○ Correlation b/w low serum Vit D levels and incidence of cognitive decline
● 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?
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
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
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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
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
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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
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?