How Long Until It Works

• Psychotic and manic symptoms can improve within 1 week, especially with first-line use, but often takes several weeks for full effect on behavior as well as on cognition and affective stabilization, especially in treatment-resistant cases

• Classically recommended to wait at least 4–6 weeks to determine efficacy of drug, but in practice patients often require up to 16–20 weeks to show a good response, especially in treatment-resistant cases

If It Works

• As for other antipsychotics, most often reduces positive symptoms in schizophrenia but does not eliminate them

✽ However, clozapine may reduce positive symptoms in patients who do not respond to other antipsychotics, especially other conventional antipsychotics

• Can improve negative symptoms, as well as aggressive, cognitive, and affective symptoms in schizophrenia

• Most schizophrenic patients do not have a total remission of symptoms but rather a reduction of symptoms by about a third

• Many patients with bipolar disorder and other disorders with psychotic, aggressive, violent, impulsive, and other types of behavioral disturbances may respond to clozapine when other agents have failed

• Perhaps 5–15% of schizophrenic patients can experience an overall improvement of greater than 50–60%, especially when receiving stable treatment for more than a year

✽ Such patients are considered super-responders or “awakeners” since they may be well enough to be employed, live independently, and sustain long-term relationships; super-responders are anecdotally reported more often with clozapine than with some other antipsychotics

• Continue treatment until reaching a plateau of improvement

• After reaching a satisfactory plateau, continue treatment for at least a year after first episode of psychosis

• For second and subsequent episodes of psychosis, treatment may need to be indefinite

• Even for first episodes of psychosis, it may be preferable to continue treatment indefinitely to avoid subsequent episodes

• Treatment may not only reduce mania but also prevent recurrences of mania in bipolar disorder

If It Doesn’t Work

• Consider obtaining clozapine plasma levels

• Some patients may respond better if switched to a conventional antipsychotic

✽ Some patients may require augmentation with a conventional antipsychotic or with an atypical antipsychotic (especially risperidone or amisulpride), but these are the most refractory of all psychotic patients and such treatment can be expensive

✽ Consider augmentation with valproate or lamotrigine

• Consider noncompliance and switch to another antipsychotic with fewer side effects or to an antipsychotic that can be given by depot injection

• Consider initiating rehabilitation and psychotherapy such as cognitive remediation

• Consider presence of concomitant drug abuse

Best Augmenting Combos for Partial Response or Treatment Resistance

• Valproic acid (valproate, divalproex, divalproex ER)

• Lamotrigine

• Other mood stabilizing anticonvulsants (carbamazepine, oxcarbazepine)

• Conventional antipsychotics

• Benzodiazepines

• Lithium

Tests

✽ Complete blood count before treatment, weekly for 6 months of treatment, biweekly for months 6–12, and every 4 weeks thereafter

• Weekly monitoring of white blood cell count and absolute neutrophil count for a period of 12 months is required in patients who are rechallenged with clozapine after recovery from an initial episode of moderate leukopenia (white blood cell count between 2,000/mm³ and 3,000/mm³, absolute neutrophil count between 1,000/mm³ and 1,500/mm³)