Antipsychotics

Characteristics of schizophrenia
Prevalence 0.51.0% of population
Onset
Positive features in late adolescence or early adulthood
Aspects of cognitive deficits detectable earlier in life

Comorbidity
Depression: 3050%
Substance abuse: 50%
Suicide: 510%

Schizophrenia:
A Disease with Various Aspects
Positive Symptoms
Delusions
Hallucinations
Disorganized speech
Catatonia

Cognitive Deficits
Attention
Memory
Executive functions
(e.g., abstraction)

Social/Occupational
Dysfunction
Work
Interpersonal
relationships
Self-care

Negative Symptoms
Affective flattening
Alogia
Avolition
Anhedonia
Social withdrawal

Mood Symptoms
Depression
Anxiety
Aggression
Hostility
Hopelessness
Suicidality

Inter-relationship between disease factors and drug-induced adverse factors in

the burden of schizophrenia
Other effects
Anticholinergic
Prolactin elevation
QTc prolongation

Adverse effect of
antipsychotic drugs

Risk of hyperglycemia/
diabetes

Sedation

Extrapyramidal
symptoms

Weight gain

Drug-induced factors

Tardive
dyskinesia

Dysphoria

Disease factors

Positive
symptoms

Suicidality
Cognitive
symptoms

Negative
symptoms

Depression/Anxiety

Diverse symptoms
of schizophrenia
Int Clin Psychopharmacol 2005, 20:183198.

Treatment Goal of Schizophrenia

Acute Phase
Treatment
Rapid symptom control

Initiation of
therapeutically effective
dose
No need for initial dose
titration for tolerability

Stabilization
Phase Treatment
Patient relationship
Insight on medication

Minimal drug-drug
interaction
Proven efficacy and
safety

Maintenance
Phase Treatment
Relapse/recurrence
prevention
Adherence
Functional recovery

Increased tolerance to
occasional missed doses
Proven relapse
prevention effect
Improved PSP

Factors affecting antipsychotic response

Receptor pharmacology
(binding capacity)

Pharmacokinetics

Patient variables

Pharmacogenetics
(CYP450)

Comorbid condition/
polypharmacy

The Dopamine hypothesis of psychosis

Overactivity of dopamine neurons in the
mesolimbic dopamine pathway may mediate the
positive symptoms
Dopamine hypocactivity in mesocortical
dopamine pathway may mediate the negative and
cognitive symptoms
Dorsolateral prefrontal cortex negative, cognitive
symptoms
Ventromedial prefrontal cortex negative, affective
symptoms

Brain dopaminergic tracts

2
3

5 CTZ

6 Lateral hypothalamus

Simplify Neurocircuitry of Dopamine in Schizophrenia

Mesolimbic pathway
Hyperdopaminergia

DA

D2

Mesocortical pathway
Hypodopaminergia

DA

Limbic

Positive symptoms

D1

PFCx

Negative symptoms
Cognitive symptoms
Affective symptoms

SOME DEFINITIONS
Neuroleptic: synonym for antipsychotic
drug; originally indicated drug
w/antipsychotic efficacy but with
neurologic (extrapyramidal motor) side
effects
Typical neuroleptic: older agents fitting
this description
Atypical neuroleptic: newer agents:
antipsychotic efficacy with reduced or no
neurologic side effects

Antipsychotic Drugs: Development Timeline

Minimal efficacy with regard to positive

symptoms in 20-30% of patients

At least as effective as typical neuroleptics

with regard to positive symptoms

Much weaker effect on negative

symptoms than positive symptoms

More effective than typical agents with

regard to negative symptoms

Significant parkinsonian symptoms and

anticholinergic effects (poor
compliance and potentially disabling)

Much lower incidence of parkinsonian

symptoms and anticholinergic effects than
typical agents

Tardive dyskinesia in a minimum of 20%

of patients who receive chronic
neuroleptic treatment.

TD does occur but at much lower

incidence
Elevated risk of metabolic side effects

NEUROLEPTICS
TYPICAL NEUROLEPTICS:
PHENOTHIAZINES:
Chlorpromazine (Thorazine )
Thioridazine (Mellaril )
Fluphenazine (Prolixin )
THIOXANTHENE
Thiothixene (Navane )
OTHER
Haloperidol (Haldol )

NEUROLEPTICS
ATYPICAL NEUROLEPTICS:
Risperidone (Risperdal ; most
frequently prescribed in U.S.)
Clozapine (Clozaril )
Olanzapine (Zyprexa )
Quetiapine (Seroquel )

Therapeutic effects from

D2 receptor blockade
Amelioration of the positive signs,
symptoms of psychosis, manic symptoms,
aggressive behaviors
Antiemetic effect

Modified J Clin Psychiatry 1999;60(suppl 10):514.

Adverse effects from

D2 receptor blockade
Extrapyramidal symptom (EPS)
Acute; akathisia, acute dystonia, parkinsonism
Late; tardive dyskinesia

Endocrine effects: prolactin elevation

Weight gain due to increase feeding
Modified J Clin Psychiatry 1999;60(suppl 10):514.

Binding affinities of chlorpromazine and

haloperidol for various receptor

J Psychiatr Pract 2005;11:25861.

Higher potency
Higher EPS
Lower anticholinergic effect

Haloperidol
Fluphenazine
Trifluoperazine
Thioxanthine
Perphenazine
Pimozide

Lower potency
Low EPS
Higher anticholinergic effect

Chlorpromazine
Thioridazine
Mesoridazine

Rational explanations for SDA

therapeutic effects
Therapeutic effects
D2-receptor blockade in the mesolimbic pathway to reduce
positive symptoms
Enhanced dopamine release and 5-HT2A receptor blockade
in the mesocortical pathway to reduce negative symptoms

Side-effect profile
5-HT2A antagonism in the nigrostriatal pathway reduces
EPS and tardive dyskinesia
5-HT2A antagonism in the tuberoinfundibular pathway
reduces hyperprolactinemia

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Raphe

Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT

T
HT
5-

5-HT2A

DA

D1

D2

Caudate/putamen
Normal function

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Raphe

Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT

T
HT
5-

5-HT2A

DA

Haloperidol
D1

D2

Caudate/putamen

EPS

Role of 5-HT in Nigrostriatal Dopaminergic Synapse

Raphe

Sunstantia nigra
pars
compacta
Nigrostriatal tract
5-HT

T
HT
5-

5-HT2A

DA

D1

SDA
D2

Caudate/putamen

Less EPS

Receptor affinities of selected atypical

antipsychotics
Receptor
D2

HAL

CLOZ OLAN

RIS

QUET

ZIP

ARI

0.7

126

11

160

0.45

(partial)

5-HT1A

2600

875

>7100

210

>830

4.4

(partial)

5-HT2A

45

16

0.5

295

0.4

3.4

5-HT2C

1500

16

23

25

1500

15

19

0.7

10

57

360

230

87

H1

440

20

11

47

61

M1

All values are

(nM).
>1500
1.9reported
1.9as Ki
>10,000

120

Modified from Clin Ther 2004;26:649-66

>1,00 >10,000
0

GENERAL CHARACTERISTICS OF
TYPICAL NEUROLEPTICS
The older, typical neuroleptics are effective
antipsychotic agents with neurologic side
effects involving the extrapyramidal motor
system.
Typical neuroleptics block the dopamine-2
receptor.

GENERAL CHARACTERISTICS OF TYPICAL

NEUROLEPTICS
Typical neuroleptics do not produce a
general depression of the CNS, e.g.
respiratory depression

Abuse, addiction, physical dependence do

not develop to typical neuroleptics.

GENERAL CHARACTERISTICS OF
TYPICAL NEUROLEPTICS

Typical neuroleptics are generally

more effective against positive (active)
symptoms of schizophrenia than the
negative (passive) symptoms.

Positive/active symptoms include thought

disturbances, delusions, hallucinations

Negative/passive symptoms include social

withdrawal, loss of drive, diminished affect,
paucity of speech. impaired personal
hygiene

THERAPEUTIC EFFECTS OF TYPICAL

NEUROLEPTICS
All appear equally effective; choice
usually based on tolerability of side
effects
Most common are haloperidol,
chlorpromazine and thioridazine
Latency to beneficial effects; 4-6 week
delay until full response is common
70-80% of patients respond, but 30-40%
show only partial response

THERAPEUTIC EFFECTS OF TYPICAL

NEUROLEPTICS (Continued)
Relapse, recurrence of symptoms is
common ( approx. 50% within two years).
Noncompliance is common.
Adverse effects are common.

GENERAL CHARACTERISTICS OF
ATYPICAL NEUROLEPTICS
Effective antipsychotic agents with greatly
reduced or absent EPS, esp. reduced
Parkinsonism and tardive dyskinesia
All atypical neuroleptics block dopamine
and serotonin receptors; other
neurochemical effects differ
Are effective against positive and negative
symptoms of schizophrenia; and in
patients refractory to typical neuroleptics

Effects of blockade of neuroreceptors

Receptors

Effects of blockade

D2

Anipsychotic, antimanic, antiaggressive,

EPS/akathisia, tardive dyskinesia, increase
prolactin, weight gain

5-HT1A

Anxiolytic, antidepressant, anti-EPS/akathisia

5-HT2A

Anti-EPS/akathisia, possible antipsychotics,

improve REM sleep

5-HT2C

Possible increased appetite/weight

Modified from J Clin Psychiatry 2008;69[suppl4]:26-36.

Effects of blockade of neuroreceptors

Receptors
1

Effects of blockade
Postural hypotension, dizziness, syncope, nasal
congestion

Antidepressive effect, increase alertness,

increase blood pressure

H1

Anxiolytic, sedation, weight gain, potentiate CNS

depressant drug

Modified from J Clin Psychiatry 2008;69[suppl4]:26-36.

Effects of blockade of neuroreceptors

Receptors

Effects of blockade

M1

Memory dysfunction, delirium, confusion, sedation,

(central)

REM sleep disturbance , anti-EPS

M2, M3

Blurred vision, attack or exacerbation of narrow-angle

(peripheral) glaucoma, dry mouth, sinus tachycardia, constipation

urinary retention, interfere pancreatic insulin release

Modified from J Clin Psychiatry 2008;69[suppl4]:26-36.

Impact of receptor binding

affinity on clinical
responses of antipsychotics

Receptor affinities of selected atypical

antipsychotics: Potential risk
Receptor

HAL

CLOZ

OLAN

RIS

QUET

ZIP

ARI

0.7

126

11

160

0.45

(partial)

5-HT1A

2600

875

>7100

210

>830

4.4

(partial)

5-HT2A

45

16

0.5

295

0.4

3.4

5-HT2C

1500

16

23

25

1500

15

19

0.7

10

57

360

230

87

H1

440

20

11

47

61

M1

>1500

1.9

1.9

>10,000

D2

EPS risk and

hyperprolactinemia

Orthostatic
hypotension

120All values
>1,000
>10,000
are reported as Ki (nM).
Sedation, weight gain
Anticholinergics

Modified from Clin Ther 2004;26:649-66

Receptor affinities of selected atypical

antipsychotics: Potential Benefit
Receptor

HAL

CLOZ

OLAN

RIS

QUET

ZIP

ARI

0.7

126

11

160

0.45

(partial)

5-HT1A

2600

875

>7100

210

>830

4.4

(partial)

5-HT2A

45

16

0.5

295

0.4

3.4

5-HT2C

1500

16

23

25

1500

15

19

0.7

10

57

360

230

87

H1

440

20

11

47

61

M1

>1500

1.9

1.9

>10,000

D2

PD psychosis

BPSD, autism

120All values
>1,000
>10,000
are reported as Ki (nM).

Sedative action

Alleviate EPS risk

Modified from Clin Ther 2004;26:649-66

Sleep quality
improvement

Aripiprazole Activity at Cloned Human D2

Receptors
Dopamine

Maximum DA Response (%)*

100

100 nM Dopamine
+ Aripiprazole

Full
Receptor Activity

50

Aripiprazole

Partial
Receptor Activity

100 nM Dopamine
+ Haloperidol

(Modulated)

No
Receptor Activity
10-10

10-9

10-8

10-7

10-6

Drug Concentration

10-5

(Blocked)
Haloperidol

*Receptor activity measured as inhibition of forskolin-induced cAMP accumulation in CHO cells transfected with human D 2L DNA.
Adapted from Burris et al. J Pharmacol Exp Ther. 2002;302:381.

Paliperidone vs Risperidone
Paliperidone is
active metabolite
of risperidone via
metabolism by
CYP2D6.
High affinity for
D2, 5-HT2A, 1 and
2 receptors
Very low affinity
for M1 as same as
as risperidone
Expert Opin Drug Saf. 2007 ;6(6):651-62.

Pharmacokinetics differences of risperidone

and paliperidone
Risperidone

Paliperidone

Tmax

1-2 hr (risperidone)
3 hr (paliperidone in CYP2D6 EM)
17 hr (paliperidone in CYP2D6 PM)

1-2 Hr (IR form)

24 hr (ER form)

T1/2

3 hr

23 hr (IR and ER
form)

Elimination
pathway

CYP2D6 to paliperidone (major)

CYP3A4 (minor)

CYP3A4 to (minor)
inactive metabolite
and >80% found in
urine and
60%unchanged

Adverse Effect Profile

of Antipsychotics

Shift in Risk Perception

of Antipsychotics
Past Areas of
Concern

Current Medical Realities

Diabetes

Tardive
Dyskinesia

Weight
Gain

Sedation

Insulin
Resistance

CHD
Prolactin

Hyperlipidemia

Weight Gain

Prolactin

TD

Hyperlipidemia

Insulin
Resistance
Sedation

Coronary Heart
Disease

DOPAMINE-2 receptor blockade in

meso-limbic and meso-cortical systems
for antipsychotic effect.
DOPAMINE-2 receptor blockade in basal
ganglia (nigro-striatal system) for EPS
DOPAMINE-2 receptor supersensitivity
in nigrostriatal system for tardive
dyskinesia

LONG TERM EFFECTS OF D2 RECEPTOR

BLOCKADE:

Dopamine neurons reduce activity.

Postsynaptic D-2 receptor numbers
increase (compensatory response).
When D2 blockade is reduced, DA
neurons resume firing and stimulate
increased number of receptors >>
hyper-dopamine state >> tardive
dyskinesia

ADVERSE EFFECTS OF TYPICAL

NEUROLEPTICS
Anticholinergic (antimuscarinic) side
effects:
Dry mouth, blurred vision, tachycardia,
constipation, urinary retention, impotence

ADVERSE EFFECTS OF TYPICAL

NEUROLEPTICS
Antiadrenergic (Alpha-1) side effects:
Orthostatic hypotension w/ reflex
tachycardia
sedation

ADVERSE EFFECTS OF TYPICAL

NEUROLEPTICS
Antihistamine effect: sedation, weight gain

D2 Blocking-related
Side Effects

Late
onset

Acute
onset

Spectrum of EPS

Acute dystonia

Relationship between clinical effectiveness, EPS

and D2 receptor occupancy

80%

Threshold for EPS

Threshold for
antipsychotic
efficacy

Medication used to treat EPS

Am J Health-Sys Pharm 1997;54:2461-77.

Association of medication, target dose, and likelihood of

treatment-emergent EPS

J Psychiatric Pract 2007;13:1324.

Tardive dyskinesia (TD)

TD is a latent extrapyramidal effect
generally not occurring for months or
years, occur in 20% patient treated with
antipsychotic.
It is characterized by abnormal movements
that can occur in any part of the body,
including faces, tongue, shoulders, hips,
extremities, fingers, and toes

Prominent Feature of TD
Lingual-facial hyperkinesias
Chewing movements
Smacking and licking of the
lips
Sucking movements
Tongue movements within the
oral cavity
Tongue protrusion
Tongue tremor with mouth
open
Myokemic movements (wormlike movement on the surface
of the tongue)
Blinking
Grotesque grimaces and
spastic facial distortions

Neck and trunk movements

Spasmodic torticollis
Retrocollis
Torsion movements of the trunk
Axial hyperkinesia (hip-rocking)

Choreoathetoid movements of the

extremities

Neuroleptic malignant syndrome

NMS is an uncommon but serious and potentially fatal
complication of therapy
It is a syndrome of EPS, hyperthermia, altered
consciousness, and autonomic changes (tachycardia,
unstable BP, incontinence)
Management
Discontinuation of the antipsychotic agents
Supportive therapy
Bromocriptine may be benificial

The onset is sudden and recovery may take 5-10 days

after discontinuation of the agent

Simplified Pathophysiology of
Neuroleptic Malignant Syndrome (NMS)

Am J Psychiatry 2007;164:870-876.

Spectrum-based concept of NMS

J Am Acad Child Adolesc Psychiatry 1992;31:11614.

Proposed Treatment Algorithm for NMS

Spectrum-Related Symptoms

Am J Psychiatry 2007;164:870-876.

Hyperprolactinemia: possible signs and

symptoms

Osteoporosis

J Clin Psychopharmacol 2007;27:639661.

Mean Plasma Prolactin Level Changes Over 24 Hours in 18 Patients After Taking
Clozapine, Olanzapine, or Risperidone and in Five of the Same Patients After Not
Taking the Drugs

Am J Psychiatry 2002; 159:133135

Effects of Antipsychotics on Prolactin Levels

J Clin Psychopharmacol 2007;27:639661.

Sedation

Receptor blocking properties that affect

arousal and sleep stages
Blocking of H1 sedation
Blocking of M1 sedation, REM sleep
interference
Blocking of 1, 2, 5-HT2A promote cholinergic
pedunculopontine (PPT) and laterodorsal
tegmental nuclei (LDT) firing REM sleep
improvement

Receptor affinities of selected atypical

antipsychotics
Receptor

HAL

CLOZ

RIS

OLAN

QUET

ZIP

ARI

D1

210

85

460

31

455

525

265

D2

0.7

126

11

160

0.45

D3

473

10

49

340

0.8

D4

35

27

1600

32

44

5-HT1A

2600

875

210

>7100

>830

4.4

5-HT2A

45

16

0.5

295

0.4

3.4

5-HT2C

1500

16

25

23

1500

15

0.7

19

10

57

360

230

87

H1

440

20

11

47

61

M1

>1500

1.9 Ther>10,000
1.9
Clin
2004;26:649-66

120

All values are reported as Ki (nM).

>1,00 >10,000

(partial)

(partial)

Sedation

J Clin Psychiatry 2008;69 Suppl 1:18-31.

Obesity and
metabolic syndromes

Clinical issues of weight gain and

antipsychotics
Not everyone gains weight
Difficult to predict who will have weight
gain
Multifactorial etiology
Not dose related ADR.
Start in first few weeks
Reach plateau between 3 months to 1 year

Mean weight gain during treatment with

antipsychotic drugs.

CNS Drugs 2005; 19 (Suppl. 1): 193.

Mechanisms of antipsychotic-induced weight

gain and metabolic abnormalities
Interfere feeding behavior by blocking many
neuroreceptor
Feeding center
Lateral hypothalamus (DA D2)
Ventromedial hypothalamus (5-HT 5-HT2A, 5-HT2C)

Satiety center
Paraventricular nuclei (NE 1, , Histamine H1)

Interfere pancreatic insulin release

Pancreas (ACh M3 )

Atropine

Olanzapine

Ziprasidone

Risperidone

Diabetes 2005; 54:15521558.

Clozapine

Haloperidol

Receptor affinities of selected atypical

antipsychotics
Receptor

HAL

CLOZ

RIS

OLAN

QUET

ZIP

ARI

D1

210

85

460

31

455

525

265

D2

0.7

126

11

160

0.45

D3

473

10

49

340

0.8

D4

35

27

1600

32

44

5-HT1A

2600

875

210

>7100

>830

4.4

5-HT2A

45

16

0.5

295

0.4

3.4

5-HT2C

1500

16

25

23

1500

15

0.7

19

10

57

360

230

87

H1

440

20

11

47

61

M1

>1500

1.9 Ther>10,000
1.9
Clin
2004;26:649-66

120

All values are reported as Ki (nM).

>1,00 >10,000

(partial)

(partial)

Olanzapine-Associated Weight Gain

Plateaus After First 39 Weeks of Treatment
LOCF; Median = 2.5 Years
Mean Weight Change (kg)
up to 3 years

8
6
4
2
0
-2
-4

OLZ (N=573)

-6

HAL (N=103)

-8

0
20
40
60
80
100
Patients Observed for 39 Weeks or More; Week
Double-blind and open-label olanzapine.

120

140

160

Kinon BJ, et al. J Clin Psychiatry 2001;62:92-100

Weight gain by
olanzapine is not
dose dependent
(5-20 mg dose
range).

Why Less weight gain in quetiapine,

ziprasidone and aripiprazole?
Quetiapine
Norquetiapine inhibit
norepinephrine reuptake
transporter

Aripiprazole
Low affinity H1, 5-HT2C
Partial D2 agonist

Ziprasidone
Moderate affinity for 1
Low affinity H1
Full 5-HT1A agonist
Inhibit 5-HT/NA reuptake
transporter

Metabolic Abnormalities

Clin Psy 2007;68(Suppl 7):27-33.

Monitoring protocol for patients on SDAs

Baseline

4 weeks

8 weeks

12 weeks

Personal/
family history

Weight
(BMI)

Waist
circumference

() ()

Blood
pressure

() ()

Fasting
plasma
glucose

() ()

Fasting lipid
profile

()

Quarterly

Annually

Every
5 years

()

() ()

()

()

()

()

()

()

()

() ()

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

Other Adverse effects

QTC interval prolongation
Thioridazine, ziprasidone

Agranulocytosis
Clozapine

Epileptogenic
Clozapine

Retinitis pigmentosa
Thioridazine > 800 mg/day

Incidence of categorical increases in QTc (Bazett

correction)

There is a consensus that a QTc interval of >500ms, or an absolute in-crease of 60ms compared with drug-free
baseline, puts a patient at significant risk of torsade depointes, ventricular fibrillation and sudden death

Clozapine safety issues

Clozapine is one of the atypical agents
that is EPS/TD free, as same as quetiapine
However, clozapine is still reserved as
last-line therapy because of its increased
incidence of agranulocytosis,
myocarditis/cardiomyopathy, and convulsion
and the need for frequent monitoring

Clozapine safety issues

Seizure risk
1-2% and increase to 3-5% if dose is greater than 600
mg/day.

Agranulocytosis
1% in general
95% cases in first 6 m,
peak in 4-18 week
CBC weekly

Management of clozapine-induced
agranulocytosis
US
New patients: weekly blood
counts

UK
New patients: weekly blood
counts

Twice weekly monitoring: WBC

Weekly monitoring: WBC 3000-

3000-3500 and ANC >1500

3500 and/or ANC1500-2000

Temporary discontinuation: WBC

2000-3000 and/or ANC 10001500
Permanent discontinuation: WBC
<2000 and/or ANC <1000
> 6 months: monitor once every
two weeks

Discontinue: WBC <3000 and/or

ANC 1500
Weeks 19-52: at least every 2
weeks
> 52 weeks: monitor at least
monthly thereafter

Contribution of CYP450 in atypical

antipsychotic drug metabolism
Drug

1A2

Aripiprazole
Clozapine
Olanzapine
Paliperidon
e
Quetiapine
Risperidone
Ziprasidone

CYP450
2C9/2C19 2D6

3A4

//

Enzyme
CYP1A2

Substrate
Clozapine,
olanzapine

CYP2C19

Inhibitor

Inducer

Fluvoxamine,
ciprofloxacin

Carbamazepine,
smoking

Fluoxetine, fluvoxamine

Carbamazepine,
phenytoin

CYP2D6

Aripiprazole,
clozapine,
olanzapine,
risperidone,
conventional
antipsychotics

Bupropion, fluoxetine,
paroxetine, duloxetine

CYP3A4

Aripiprazole,
clozapine,,
quetiapine,
ziprasidone

Azole antifungal
Carbamazepine,
Most of macrolide except
phenytoin,
azitromycin
rifampin,
ARVs; indinavir, nelfinavir,
phenobarbita
ritonavir
l

Dose-response curve for

seizure risk with clozapine

Dose-response curve for

extrapyramidal adverse
effects with risperidone

J Psychiatric Pract 2005;11:116-122.

Acute treatment of psychotic

patients
Injectable, conventional agents are typically used
such as haloperidol 5-10 mg IM or zuclopenthixol
acetate 50150mg
It may be given every hour until
Acute symptoms are controlled
Side effects occur
Patient falls asleep

Once control has been obtained, the patient can

be converted to oral therapy

Selection of antipsychotic agents

Based on the patients history and safety
profile of the available agents
Newly diagnosed patients, the APA suggest
initiating therapy with atypical agent (SGAs)
because of these agentsimprove safety profile

Monitoring of first episode

Less disturbed sleep patterns and decreased anger and
anxiety should be observed within the first day or two of
treatment, with gradual improvement in other symptoms
in the first week and near-maximal effects in six to eight
weeks
Lack of improvement in the first one to four weeks should
prompt an increase in the dose, followed by a change to
another drug, usually clozapine or another secondgeneration drug after an additional four to six weeks, if
the response remains inadequate

N Eng J Med 2003;349:1738-49.

Monitoring of early adverse effects

It appears within days to weeks of starting
the antipsychotic dose
It maybe transient and time limited (it will
be disappear after the first month of
treatment)

J Clin Psy 2007;68(Suppl 7):34-43.

Initial dose and titration

schedule for a first episode

J Clin Psy 2007;68(Suppl 7):3443.

Strategies for managing side effects in

stable patients

J Clin Psy 2007;68(Suppl 7):34-43.

Medical Issues in Schizophrenia

Factor

Prevalence in
Schizophrenia

Prevalence in
General
Population

Smoking

75%

25%

Obesity

50%

33%

13-14%

7%

HIV

3%

0.3%

Hepatitis C

20%

1.8%

Diabetes Mellitus

Other:
-inactivity, poor nutrition
-substance use

Meyer JM and Nasrallah H eds. Medical Illness and Schizophrenia. APPI 2003
Regenold WT, et al. Increased prevalence of type 2 diabetes mellitus among psychiatric inpatients with bipolar I affective and
schizoaffective disorders independent of psychotropic drug use. Journal of Affective Disorders. 2002 Jun;70(1):19-26

Medical conditions that may influence

antipsychotic treatment dicisions

Antipsychotics switching
Avoid if possible
Consider in
Not responing patient with adequate trial
Not able to tolerate
Non-compliance (switch to depot preparation)
Significant long term risk with current medication
Obesity, TD, persistent cognitive deficit, CVS problems,
DDI

Patient / family member request

Switching Techniques for Antipsychotics

CNS Drugs 2005; 19 (1): 27-42

Dopaminergic considerations
Cross switching of 2 high potency D2
antagonist may increase EPS risk.

J Clin Psy 2007;68(Suppl 7):109.

Dopaminergic considerations
Prolong exposure of high potency D2 antagonist
results in D2 supersensitivity
Switching D2 antagonist from higher potency to
lower potency or D2 partial agonist
May lead to switch-emergent dopamine psychosis.
Improvement in prolactin-related side effects such as
galactorrhea, amenorrhea and sexual dysfunction and EPS

Muscarinic considerations
There is a potential that patient who have
been maintained on anticholinergic
antipsychotics to develop cholinergic
supersensitivity.
Nausea, vomiting and insomnia may occur
when anticholinergic drugs is withdrawn or
switched to less potent anticholinergic
drugs.

Muscarinic considerations
If patient is being changed because of EPS in
which an anticholinergic agents was initiated, the
patient can remain on the anticholinergic agent
until the cross taper and titrated is completed
Exception in the case of clozapine being added
as the new therapy, the anticholinergic drugs
should be discontinued when the cross taper and
titration begins

Estimated side effects after switching

J Clin Psy 2008;69(Suppl 1):4-17.

PHARMACOLOGY OF ATYPICAL
ANTIPSYCHOTIC

PHARMACOLOGY OF CLOZAPINE
FDA-approved for patients not
responding to other agents or with
severe tardive dyskinesia
Effective against negative symptoms
Also effective in bipolar disorder
Little or no parkinsonism,
tardive dyskinesia,
PRL elevation,
neuro-malignant syndrome;
some akathisia

Blockade of alpha-1 adrenergic receptors

Blockade of muscarinic cholinergic
receptors
Blockade of histamine-1 receptors

PHARMACOLOGY OF CLOZAPINE
(Continued )
Other adverse effects;
Weight gain
Increased salivation
Increased risk of seizures
Risk of agranulocytosis requires continual
monitoring

PHARMACOLOGY OF OLANZAPINE

Olanzapine is clozapine without the

agranulocytosis.
Same therapeutic effectiveness
Same side effect profile

PHARMACOLOGY OF QUETIAPINE
(SEROQUEL )

Quetiapine is olanzapine without the

anticholinergic effects.
Same therapeutic effectiveness
Same side effect profile

PHARMACOLOGY OF RISPERIDONE
Highly effective against positive and
negative symptoms
Adverse effects:
EPS incidence is dose-related
Alpha-1 receptor blockade
Little or no anticholinergic or antihistamine
effects
Weight gain, PRL elevation

General Therapeutic Principles for Use of

Neuroleptics in Schizophrenia
(NIH Consensus Statement, 1999)
Use atypical for:
1st acute episode w/ + or +/- symptoms
Switch to atypical if:
Breakthrough after Rx w/ typical
Use typical (depot prep) when:
Patient is noncompliant

General Therapeutic Principles for Use of

Neuroleptics in Schizophrenia

If response is inadequate to:

Typical; switch to Atypical
Atypical; raise dose or switch to another
Atypical
Typical and Atypical; switch to Clozaril
For maintenance, lifetime Rx is required.

Conclusions
Antipsychotics are not uniform drug class which
different in their pharmacological profile, efficacy
and ADRs.

Adherence of treatment should be enhanced by

various strategies e.g.
Counseling
Awareness of DDI
ADR monitoring and management