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Antipsychotic Drugs 


Conventional (typical) antipsychotics or "neuroleptics":

Dopamine D2 blockers,

Produce extrapyramidal symptoms (EPS)

Elevate prolactin (PRL) levels

All conventional agents are equally effective but differ in potency and side effects

Atypical Antipsychotics ("second generation" antipsychotics or dopamine-serotonin antagonists)

Share D2 and 5HT2 antagonism in common 

Reduced (or absent) EPS

Minimal (or no) elevation of prolactin

Generally more effective for negative symptoms

Clozapine is the only agent clearly more effective for psychotic symptoms

Risperidone is "partially atypical"--may produce EPS at higher doses and 

Atypical Partially Atypical
Clozapine (Clozaril)

Olanzapine (Zyprexa)

Quetiapine (Seroquel)

Risperidone (Risperdal)

High-Potency Conventional Mid-Potency Conventional Low-Potency Conventional
Haloperidol (Haldol) Perphenazine (Trilafon) Chlorpromazine (Thorazine)
Fluphenazine (Prolixin) Loxapine (Loxitane) Thioridazine (Mellaril)
Trifluoperazine (Stelazine) Molindone (Moban) Mesoridazine (Serentil)
Thiothixene (Navane)

Target Symptoms

Psychosis (hallucinations, delusions, disorganization)

Negative symptoms (apathy, flat affect, social withdrawal, poverty of speech)

Agitation (hyperkinesis, tension, distractibility)

Cognitive impairment (attention, memory, judgment, insight)

Basic Pharmacology of Antipsychotic Agents 1

Acute effects on dopamine systems

Conventional agents block 75-90% of D2 receptors, clozapine 40-60%

Blockade of 

Delayed effects

Conventional agents increase density of post-synaptic D2 receptors (supersensitivity)

Conventional agents produce depolarization blockade in A9 (substantia nigra) and A 10

(ventral tegmental) dopamine neurons.

Atypical agents produce depolarization blockade in 

All agents increase c-fos in nucleus accumbens; conventionals increase c-fos in striatum 3

Dopamine Neurons/Pathways

A9/Nigrostriatal (midbrain to neostriatum), responsible for EPS

A 10/Mesolimbic (midbrain to limbic structures) possibly associated with psychosis?

A 10/Mesocortical (midbrain to frontal and temporal cerebral cortex) negative symptoms?

Side effects with conventional agents 4-7

Side effects associated with high-potency conventional agents CEPS)




Side effects associated with low potency agents



Weight gain (molindone may produce weight loss 8)

Anticholinergic symptoms (dry mouth, urinary retention, constipation, blurred vision)

Side effects unrelated to neuroleptic potency--may occur with all D2 antagonists 

Hyperprolactinemia (amenorrhea, galactorrhea, sexual dysfunction)

Tardive dyskinesia

Neuroleptic malignant syndrome

Other side effects

Impaired heat regulation (hyper- or hypothermia)

Pigmentary retinopathy (thioridazine >800 mgd)

EKG changes (pimozide, chlorpromazine, thioridazine)

Drug interactions (most metabolized by cytochrome P450 2D6)

Anticonvulsants (except valproate)                                        lower antipsychotic blood levels

Tobacco                                                                               lowers antipsychotic blood levels

Erythromycin                                                                         increases clozapine levels

Fluvoxamine                                                                          increases clozapine levels 12

Fluoxetine (most SSRIs)                                                        increase neuroleptic levels

Tricyclic antidepressants levels                                               increased by some neuroleptics

Extrapyramidal Side Effects (EPS)


Involuntary muscle contraction--may involve tongue, neck, back, eyes 

Extremely uncomfortable, jeopardizes future compliance 

Occurs within first four days of neuroleptic treatment 

Risk factors: youth and high-potency neuroleptics

All patients under age 30 started on high potency neuroleptics should receive prophylaxis: benztropine 2 mg bid x 10 days--then taper

Treatment of acute dystonia: 

benztropine 1-2 mg IM or PO 

benadry125-50 mg IM or PO 

diazepam 5 mg slow IV push

"Tardive dystonia" is a variant of tardive dyskinesia


Sensation of motor restlessness, most prominent in lower extremities

Most common with high-potency agents--dose related

Often mistaken for agitation

If present:

Switch to atypical agent or:

Lower neuroleptic dose

Beta blocker (propranolo120 mg qid)

Anticholinergic agent (benztropine 1 mg bid)

Benzodiazepine (lorazepam 0.5 mg tid)

"Tardive akathisia" variant of tardive dyskinesia


Syndrome of rigidity, tremor, bradykinesia 

Bimodal age distribution (youth and old age) 

Associated with high potency agents---dose related 

If present:

Switch to atypical agent or:

Lower neuroleptic dose

Anticholinergic agent (benztropine 1-2 mg bid, in the elderly start with 0.25 mg) 

Amantadine 100-200 mg bid 

Dopaminergic agonists not recommended

Tardive dyskinesia

Late-developing choreiform movements, most commonly oral-buccal muscles

Tardive dystonia (variant)---chronic dystonic posturing

Risk factors

Old age

More than 6 months of neuroleptic exposure (5% cumulative incidence per year)

History of parkinsonian side effects


Affective disorders and high dose identified as risk factors in some studies (not all)

Not associated with clozapine

Reduced risk with olanzapine and risperidone?


Symptoms may worsen when neuroleptic dose is decreased or with switch to atypical agent 

"Withdrawal dyskinesia" usually resolves within six weeks

May worsen with anticholinergics (reversible)

Usually does not worsen with continued neuroleptic exposure


Do not use neuroleptics if no clear benefit

Use the lowest effective dose

Monitor for TD (AIMS testing) twice-yearly 22

Warn and educate all patients who will require neuroleptics for more than 6 months 

Increasingly difficult to justify use of conventional agents on this basis


Discontinue or reduce dose of neuroleptic

Clozapine associated with increased rate of remission (especially tardive dystonia)

Vitamin E 800-1200 IU/d if duration <5 yrs (evidence for efficacy is inconsistent

Benefit of atypicals is promising but not established

Neuroleptic Malignant Syndrome (NMS)

Presentation may gradually evolve, usually in the following order:

Confusion and fluctuating levels of consciousness




Autonomic instability


Elevated CPK

Atypicals may cause non-rigid NMS (controversial)


Discontinue antipsychotic

Supportive care: hydration and temperature control

Bromocriptine 5-30 mg/day (controversial)

Wait at least 2 weeks before resuming antipsychotic

Antipsychotic Dosing

General Principles

Use a moderate, fixed dose (haloperidol 5-15 mg/d, risperidone 3-6 mg/d, olanzapine 10-15mg/d) 

An adequate trial should last 4-6 wks

Use benzodiazepines prn for agitation IM or PO (eg lorazepam 1-2 mg qid) 31, 32

Blood levels

Should not substitute for clinical titration

Inconsistent evidence for haloperidol "therapeutic window" (5-15 ng/mL)

Approx 5% of patients are poor metabolizers (low P450 2D6)---may develop toxic levels

Levels useful in cases of nonresponse, noncompliance, or drug interactions

Therapeutic Ranges

Haloperidol 5-15 ng/mL

Chlorpromazine 30-100 ng/mL

Fluphenazine 0.2-2.0 ng/mL

Perphenazine 0.8-2.4 ng/mL

Clozapine >350 ng/m

First-Break Patients

Response of first-break patients:

Respond better than chronic patients

74% full remission; 12% partial response

Respond to lower doses

Haloperidol 3-10 mg/d

Risperidone 2-4 mg/d

Early treatment associated with better outcome

Treating first-break patients:

Avoid side effects (drug selection and dosing)

Prophylaxis for dystonia if using conventional neuroleptic

Develop alliance

Educate patient and family about illness and treatment

Maintenance Treatment

Relapse rates in schizophrenia
Medication (n) Placebo (n)
Relapse in first year 41% (814) 68% (189)
Second year post discharge 15% (500) 65% (448)

Depot Neuroleptics
Time to peak (days) Half-life (days) Dosing Interval (days)
Fluphenazine Decanoate 0.3-1.5 6-9 14
Haloperidol Decanoate 3-9 21 28


Fluphenazine decanoate:                 conventional dose: 25 mg q 2wks

                                                      low dose: 5-6.25 mg q 2 wks

Low-dose versus conventional dose maintenance treatment 39, 40

Low and conventional doses approx, equal efficacy against relapse in first year

Low dose produces significantly less EPS and dysphoria

Conventional dose may be superior during second year for preventing relapse

Conversion to depot neuroleptic:

Requires approx 4 dosing intervals to achieve steady state

Should start with loading dose or supplement with oral medication

Always establish tolerability with oral preparation first

Haloperidol decanoate loading protocol 41.

20x daily oral dose in divided doses during first week, then decrease next two injections by 25% maintenance dose approx. 10x daily oral dose q 4 wks

Haloperidol decanoate supplementation protocol:

Administer maintenance dosing (10x daily oral dose q 4wks)

Continue 50% oral daily dose x 2 mos, 25% x 2 mos (titrate as necessary)


Clozapine (Clozaril)

Atypical properties

Minimal EPS

More effective than conventional agents for treatment-resistant patients

Does not elevate prolactin

Pharmacology: Dopamine systems

Weak D2 antagonist

Relatively greater D1 and D4 antagonism

Does not cause D2 receptor supersensitivity or depolarization block in A9 neurons Releases dopamine in frontal cortex

Pharmacology: Other transmitter systems

Strongly anticholinergic

Alpha adrenergic antagonist

Histaminergic (H1) antagonist

Serotonin (5HT2) antagonist

Blocks ketamine behavioral effects (NMDA receptor)

Clinical Pharmacology

Usual daily dose 300-600 mg/d (900 mg/d maximum)

Half life: 16 hrs

Metabolized by cytochromes 1A2 and 3A4


Effective in 30% of treatment-resistant patients at six weeks (50% at 6 mos?)

Prevents relapse

Stabilizes mood

Improves negative symptoms

Improves polydipsia & hyponatremia

Reduces hostility & aggression

May reduce suicide

Reduces cigarette smoking and substance abuse?

Adverse Effects

Sedation 39% (tolerance) Tachycardia 25%

Hypersalivation 31% (may impair swallowing)

Dizziness 19%

Constipation 14%

Nausea 11%

Headache 11%

Hypotension 9% (tolerance)

Fever 5% (usually within first 3 wks, lasting a few days)

Seizures 1-6% (related to absolute dose and rate of increase)

Weight gain 30% (diabetes)

Agranulocytosis (Granulocytes <500/mm3)

Cumulative incidence of 1.6% when taken over 52 weeks

Risk factors: Ashkenazi Jews (HLA B38, DR4, DQw3), Finns

Preservation of other cell lines (platelets and RBCs)

Maximum risk: 4-18 weeks (77% of cases)

Recovery usually within 14 days if drug stopped

No cross-sensitivity with other drugs, but avoid carbamazepine, captopril, sulfonamides and PTU

Sensitization: Do not rechallenge!

Monitoring for agranulocytosis

Weekly WBC for six months "No blood, no drug" 

Pretreatment WBC should be >3500 

Repeat CBC if:


WBC drops by 3000 from previous test

3 consecutive weekly drops 

If WBC=3000-3500 & granulocytes >1500, proceed with twice-weekly WBCs 

Hold drug if WBC <3000 or granulocytes <1500

Discontinue if WBC <2000 or granulocytes <1000--Do not rechallenge

After six months may monitor every 2 wks if no episodes of leukopenia

Starting clozapine

Start at 12.5 mg/d

Increase by 25 mg/d as tolerated over first week

May be added to previous antipsychotic--taper when clozapine dose >100 mg/d

BID schedule, larger dose at hs if sedation is a problem

Increase by 50 mg/d every 2-3 days during second week

Stop at 600 mg/d or when side effects develop

Risperidone (Risperdal)


5HT2 and D2 antagonist

Also antagonism at D4, noradrenergic and histaminergic receptors

Half life: 24 hours (can be given once daily)

Metabolized by P450 2D6

Mean optimal dose 4-6 mg/d in chronic patients

2-4 mg/d in treatment naive patients

0.5-2 mg/d in elderly

Dose must be titrated up (start at 1-2 mg/d in non-elderly)

Efficacy (compared to haloperidol 20 mg/d in 8 wk trial)

Fewer EPS (increase with increasing dose above 6 mg/d)

More effective for negative symptoms (partly result of less EPS)

More effective for psychotic symptoms (in some treatment-resistant patients)

Side effects

Dizziness/hypotension (particularly after first dose)



Anxiety Rhinitis/coughing


Weight gain

QT delay (usually clinically insignificant)

Olanzapine (Zyprexa)


High 5HT2/D2 ratio

Anticholinergic activity in vitro, minimal effects in vivo

Histaminergic & alpha adrenergic antagonism

Metabolized by CYP 1A2 & 3A4: Half life approx. 20 hrs

Can start with 10 mg/d at hs in non-elderly

Optimal dose 10-20 mg/d (2.5-5 mg/d in elderly)


Antipsychotic efficacy comparable to haloperidol

More effective for negative symptoms

Substantial antidepressant effect

Antimanic efficacy compared to placebo

Side effects

Low incidence of EPS


Dizziness (without hypotension)


Dry mouth

Elevation of SGPT (no evidence of hepatotoxicity)

Weight gain

Quetiapine (Seroquel)


High D2/5HT2 ratio (may be effective with <60% D2 blockade) Not anticholinergic

Alpha adrenergic antagonist

Metabolized by CYP 2D6: Half life approx. 6 hrs (multiple dosing) Must titrate due to hypotension


Comparable antipsychotic efficacy to CPZ

More effective for negative symptoms? (not well established)


Start at 25 mg bid (in non-elderly)

Titrate: 50 mg bid 100 mg bid 100 mg qAM & 200 mg qhs

Optimal dose: 300-750 mg/d

Side effects

Very low incidence of EPS

Postural hypotension


Elevation of LFTs (reversible)


Weight gain

Decreased serum T3 & T4 levels

Cataracts (in beagles--risk in humans not established, eye exams q 6 mos)

Treatment Resistance

Reassess diagnosis

Substance abuse (alcohol, PCP, stimulants) 

Neurological disorders (partial complex seizures) 

Psychotic depression (ECT, neuroleptic + antidepressant)

Drug toxicity/delirium (steroid psychosis, anticholinergic delirium) 


Identify psychosocial stressors

Adjust neuroleptic dose

Assess compliance

Time-limited trial of higher dose, particularly if:

No or mild EPS

On drugs which induce hepatic enzymes (carbamazepine)

Olanzapine to 30 mg/d, clozapine as high as tolerated (up to 900 mg/d)

Reduce dose, particularly if:

On dose >CPZ 1 gm/day (haloperidol 20 mg/d)

Moderate or severe EPS

Haloperidol blood level

Switch neuroleptics

If failure on adequate dose of conventional agent, switch to atypicals

Atypicals differ in patterns of efficacy---each is worth consideration

Clozapine remains most effective agent

Adjunctive agents

Add risperidone (or olanzapine?) to clozapine

Add lithium (particularly if affective sxs, blood level of 0.9-1.2 for 3-5 wk trial)

ECT (catatonia, affective sxs, most effective early in course of illness)

Antidepressants (SSRIs for negative sxs; TCAs may delay response of psychosis) 

Buspirone (15-30 mg/d for agitation, anxiety)

Psychosocial Interventions

Family interventions: education, realistic expectations, coping skills

Dual diagnosis treatment

Assertive community treatment (ACT)--outreach, compliance monitoring

Social skills training

Supported employment

Cognitive behavioral therapy


Medication noncompliance

Side effects (EPS, sexual side effects, weight gain)

Lack of insight

Complexity of dosing (single hs dose, no titration, depot injections)


Expressed emotion in family members--critical, affective arousal, enmeshed 

Stressful life events

Substance abuse

Alcohol, marijuana, stimulants, PCP & ketamine

Comparisons of Atypicals

Interpreting drug trials

Last observation carried forward (LOCF)---impact of dropouts

Effect size, (clinical significance vs statistical significance)

"No difference"--difficult to interpret

Primary vs. Secondary negative symptoms

"Tran study"

Olanzapine vs risperidone 28 wk double-blind trial

Clinician adjusted dose: risperidone 7 mg/d; olanzapine 17 mg/d mean doses

Higher dropout rate with risperidone (42% vs 53%)

Comparable antipsychotic effect

Olanzapine superior efficacy for negative symptoms and depression

More EPS and hyperprolactinemia with risperidone

More weight gain with olanzapine (2.3 kg vs 4.l kg)

Efficacy for positive symptoms

Clozapine often effective in treatment-resistant patients

Risperidone more effective than haloperidol in some patients

Olanzapine not effective in rigorously defined treatment-resistant patients

Risperidone & olanzapine "comparable" to clozapine in several European studies

Quetiapine has not demonstrated superior efficacy

Clozapine still "Gold Standard"

Efficacy for negative symptoms

Conventional agents modestly improve negative symptoms but EPS result in "secondary" negative symptoms

Clozapine more effective than chlorpromazine but clozapine may not be effective in "Deficit Syndrome" patients

Deficit Syndrome: prominent, continuous primary negative symptoms

Risperidone & olanzapine more effective than haloperidol

Path analysis indicates "primary" negative symptoms improved

Weight gain


Olanzapine-associated weight gain:

No wt gain 25%

>10 kg/yr 20%

Not dose related; tends to plateau at six months


Increased appetite

Good clinical response

Low baseline weight


Male gender

Start nutritional education & counseling early

Monitor serum glucose


Risperidone>conventional agents>atypicals

Amenorrhea, galactorrhea, sexual dysfunction

Osteoporosis (due to secondary hypoestrogen)

Warn patients (may not volunteer symptoms)

Consider estrogen replacement (BCPs) ifamenorrhea develops


High 5HT2/D2 ratio

Half life: 10 hrs

Usual dose: 80-160 mg/d (administered bid)

Compared to haloperidol 15 mg/d

Comparable efficacy

Less EPS

Less prolactin elevation

Minimal weight gain

IM preparation (not depot)

Glutamate in Schizophrenia

Glutamate and aspartate are endogenous agonist at all glutamate receptor subtypes

Glutamate receptors are the primary excitatory receptors in the brain (GABA are inhibitory)

Glutamate receptors are involved in memory and connecting pathways relevant to models of schizophrenia Glutamate receptors also modulate dopamine activity

NMDA Receptor Antagonists (Phencylcidine & Ketamine)

Produce impressive negative symptoms and cognitive deficits in normals

Produce psychotic relapse in stable schizophrenia patients--may be blocked by clozapine

Therapeutic agents acting at the NMDA receptor complex:

Direct agonists are neurotoxic

Agonists at the glycine recognition site safely enhance NMDA receptor activity

Glycine: full agonist

D-cycloserine: partial agonist with 60% activity

Glycine and D-cycloserine both improve negative symptoms

D-cycloserine may worsen negative symptoms when added to clozapine

Some evidence suggests that antipsychotics may act in part via glycine site--relative activity may distinguish clozapine and certain atypicals

AMPA receptors

Evidence for abnormalities in schizophrenia is stronger

"Ampakines"--positive allosteric modulators

Improve memory in elderly rats

Synergistic effect with antipsychotics in methamphetamine-induced rearing model 

Improves memory in normal elderly human subjects

Preliminary evidence of improved cognitive function in