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Second-Generation (Atypical) Antipsychotics

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Clozapine (Clozaril) has been available in the United States for about 20 years for use with patients who have treatment-resistant schizophrenia or patients who are unable to tolerate the side effects of first-generation antipsychotics. Clozapine was in many ways the best new development in the treatment of schizophrenia since chlorpromazine was discovered. The drug does have problems and dangers, it does not work for everyone, and patients who are helped substantially may still be far from well. However, it is thus far the only antipsychotic drug that has been shown in controlled studies to be clearly more effective than older antipsychotics in resistant schizophrenia. It is also thus far the only antipsychotic drug that causes essentially no pseudoparkinsonism or dystonia and that is, apparently, unlikely to cause tardive dyskinesia.

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Table Reference Number

Note. CNS = central nervous system; EPS = extrapyramidal symptoms; EtOH = ethanol; FDA = U.S. Food and Drug Administration; NMS = neuroleptic malignant syndrome.

Second-generation (dopamine-serotonin antagonist) antipsychotics: overview

Efficacy

Schizophrenia (FDA approved for all)

Treatment-resistant schizophrenia (clozapine)

Mania (FDA approved for olanzapine, quetiapine, and ziprasidone)

Bipolar depression (FDA approved for quetiapine)

Depression/anxiety/agitation (efficacy established but not FDA approved for these purposes)

Side effects

Weight gain

Gastrointestinal effects

Insulin resistance

Sedation

Akathisia

Orthostatic hypotension

Bradykinesia

Tachycardia

Dizziness

Triglycerides (except ziprasidone)

EPS, NMS (rare)

Agranulocytosis (clozapine) (rare)

Seizures (clozapine)

Safety in overdose

Seizures with clozapine in overdose. Respiratory depression in combination with other CNS depressants. QT interval changes. Lavage and vital sign support.

Dosage and administration

Clozapine: 12.5–25 mg; then increase dosage 25–50 mg per week, as needed and tolerated, to 300–600 mg/day

Risperidone: 0.5–1 mg bid to 3 mg bid by end of first week, as tolerated

Olanzapine: 2.5–5 mg hs; increase by 5 mg every week to 20 mg hs

Quetiapine: 25 mg bid; increase total daily dose by 50 mg, as needed and tolerated, to 300–600 mg/day

Ziprasidone: 20 mg qd or bid; increase by 20–40 mg per week, to a maximum dosage of 80 mg bid

Aripiprazole: 15 mg qd; increase up to 30 mg/day after 1 week

Full benefits in 4 weeks to 6 months

Discontinuation

Mild cholinergic rebound, faster relapse.

Taper as slowly as titrated up.

Drug interactions

Fluvoxamine (1A2 inhibitor): second-generation antipsychotic levels

EtOH: sedation and orthostasis

Antihypertensives: may orthostasis

Carbamazepine: serum levels of olanzapine; clozapine levels; hematological adverse events with clozapine

CNS depressants: sedation

Ciprofloxacin (Cipro) (potent 1A2 inhibitor): second-generation antipsychotic levels

Table Reference Number
Table 4–3. APA/ADA recommendations for screening patients who are taking second-generation antipsychotics
Table Reference Number
Table 4–4. Guidelines for clozapine monitoring

References

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