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Antipsychotic Drugs 

Compliance

• 30-50% of schizophrenics do not take their medication as prescribed

• Carefully assess and manage side effects

• Monitor blood levels

• Switch to depot preparations

Optimizing the Antipsychotic Dose

• Conventional neuroleptics need 60-75% dopamine (D2) occupancy to be effective

• Dose-response curve plateau

• Parkinsonian symptoms associated with 80% D2 blockade

• Titrate up/downward

• Side effects determine dose

• Consider differences in metabolism antipsychotic drug, schizophrenia treatment, neuroleptic

After First Antipsychotic Drug Fails

• Switch Neuroleptics (all conventional agents with comparable therapeutic effects)

• At least two trials from different classes

• Each trial at least four weeks duration at moderate to high doses as tolerated

• Add adjuvant agents

• Trial of an atypical neuroleptic (risperidone or clozapine)

Adjuvant Agents

• Lithium: particularly if affective sxs, blood level of 0.8-1.2 for 3-5 wk trial May improve positive and negative symptoms

• Consider drug interactions with Anti-hypertensive agents, NSAIDs

• Anticonvulsants: decrease tension, suspiciousness, manic symptoms, EEG abnormalities

• Carbamazepine increases P450 activity- may lower neuroleptic blood levels

• Benzodiazepines: 2-3 wk trial, monitor for disinhibition and abuse

• Can decrease agitation, psychotic symptoms, social withdrawal

• Buspirone: helpful with agitation at 15-40 mg/d

• ECT: catatonia, affective sxs, short duration of illness (long-term effectiveness unclear)

• Beta blockers: decrease agitation, violence, impulsivity (may require high doses)

• Antidepressants: TCAs may delay response of acute psychosis, SSRIs may increase neuroleptic blood level, improve depressive and negative symptoms

• Anticholinergics: for dystonia, EPS, may worsen tardive dyskinesia

Risperidone

Clinical Indications

• Relatively expensive

• Has not been tested adequately in treatment resistant patients or against clozapine

• Appropriate step before clozapine in treatment resistant or intolerant patients

• May be effective in mood disorders, but report of precipitation of mania

Pharmacology

• 5HT₂ and D2 antagonist "S₂D₂"

• Also antagonist at D4, noradrenergic and histaminergic receptors

• Rapid onset; half-life of 24 hours

• Metabolized by P450 2D6

• Optimal dose for most (not all) patients: 6 mg/day

Efficacy (compared to haloperidol 20 mg in 8-week trial)

• Fewer EPS (increase with increasing dose above 10 mg)

• More effective for negative symptoms

• More effective for psychotic symptoms

• Less tardive dyskinesia

Side effects

• Dizziness/hypotension (particularly after first dose)

• Headache

• Nausea/vomiting

• Anxiety

• Rhinitis/coughing

• Weight gain

• Hyperprolactinemia-persistent

Clozapine

Indications for Clozapine

• Treatment failure despite adequate doses of two neuroleptic trials lasting >6 wks

• Treatment intolerance: severe EPS or tardive dyskinesia

• Aggression

• Mood instability

• Polydipsia/hyponatremia

• Psychosis in Parkinson's disease

Atypical Properties

• Minimal EPS

• More effective than conventional agents in some patients

Pharmacology: Dopamine Systems

• Weak D₂ antagonist

• Relatively greaterD₁ antagonism

• Possible specificity for mesolimbic and mesocortical tracts (D₄)

• Minimal effect on prolactin levels

• Does not cause dopamine supersensitivity or depolarization blockade in nigrostriatal dopamine neurons

Pharmacology: Other Transmitter Systems

• Strongly anticholinergic

• Alpha adrenergic

• Histaminergic (HI) antagonist

• Serotonin ($HT2) antagonist

Clinical Efficacy

• Effective in 30% of treatment-resistant patients at 6 wks (60% at 6 mos?)

• Improvement in all items of BPRS

• Compared to CPZ (plus benztropine):

• Earlier onset

• More effective

• Less EPS

• Greater suppression of T.D.

• Dose range 25-900 mg/d; average dose 400-500 mg/d

Adverse Effects

• Sedation 39% (Tolerance)

• Tachycardia 25% (can give atenolol)

• 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% (<300 mg/d: 1-2%, 300-600 mg/d:3-4%, >600 mg/d:5-6%) Weight gain 30% associated with good response?

Clozapine-Induced Agranulocytosis

• Cumulative incidence of 1.6% when taken over 52 wks

• Risk factor: Ashkenazi Jews (HLA-B38, DR4, DQw3)

• Maximum risk: 4-18 weeks (77%)

• Recovery usually within 14 days if drug stopped

• No cross-reactivity; but avoid carbamazepine, captopril, sulfonamides and PTU

• Sensitization: Do not rechallenge

Olanzapine (Zyprexa)

Pharmacology

• Most closely resembles clozapine

• High 5HT₂/D₂ ratio

• High D₄/D₂ ratio

• Anticholinergic, antihistaminergic, alpha adrenergic antagonist

• Metabolized by CYP 1A2 and 3A4, 2D6

Efficacy

• Comparable antipsychotic efficacy to haloperidol

• More effective for negative symptoms

• Linear dose response relationship (10-17.5 mg/d)

• Dose range- 2.5-30 mg/d

• Most treatment resistant patients who responded to clozapine probably not good olanzapine candidate

Side effects

• EPS <placebo at all doses

• Somnolence

• Dizziness

• Constipation

• Dry mouth

• Elevation of SGPT (no evidence of hepatotoxicity)

• Weight gain- significant

• Withdrawal dyskinesia possible

• May have emergent obsessive-compulsive symptoms

Sertindole (Serlect)

Pharmacology

• High 5HT₂/D₂ ratio

• Higher D₁, D₂, 5-HT₂A, 5-HT₂C and alpha₁ affinities compared to clozapine

• Lower anticholinergic, histaminergic

• Alpha adrenergic antagonist

• Metabolized by CYP 2D₆ and 3A

Efficacy

• Comparable antipsychotic efficacy to haloperidol

• More effective for negative symptoms- trend as compared to haloperidol

• May exhibit curvilinear dose response relationship (mean optimal dose 20 mg/d)

• Initial dose 4 mg, titrate to 12-24 mg/d

• Half-life approximately 73 hours

Side effects

• EPS <placebo at all doses

• Nasal congestion

• Decreased ejaculatory volume

• Prolonged QT/QTc

• Weight gain

Ziprasidone

Pharmacology

• Highest affinity for 5HT₂

• High affinity for dopamine D₂, 5HT 1A, 5HT2c, and 5HT 1D

• Little anticholinergic effect

• Moderate Alpha-1 adrenergic antagonist and histaminic H 1

• Doses: 40-160 mg

Efficacy

• Comparable antipsychotic efficacy to haloperidol

• Doses of 120-160 mg/d superior to placebo and comparable to haloperidol

• More effective for negative symptoms- compared to placebo

• No difference between high and low doses

Side effects

• Dizziness

• Nausea

•No sustained elevation of prolactin

• Weight gain-less compared to clozapine

Quetiapine

Pharmacology

• High affinity for 5HT₂, alpha 1 and 2 adrenergic, antihistaminic H₁

• Moderate affinity for dopamine D₂

• Low affinity for dopamine D₁

• Not anticholinergic

• 5HT₂ versus D₂ affinity ratio similar to clozapine

Efficacy

• Comparable antipsychotic efficacy to haloperidol and chlorpromazine

• More effective for negative symptoms but modest results

• Dose range 150-800 mg/d

• Optimum dose probably greater than 250 mg/d

Side effects

• EPS <placebo at all doses

• Somnolence

• Agitation

• Constipation

• Dry mouth

• Mild elevation of ALT and AST levels

• Postural hypotension, tachycardia

• Dizziness

• Weight gain

• No sustained elevation of