THERAPEUTICS

Brands

• Clozaril
• Leponex
• see index for additional brand names

Generic?

• Yes

Class

• Atypical antipsychotic (serotonin-dopamine antagonist; second generation antipsychotic; also a mood stabilizer)

Commonly Prescribed for

• (bold for FDA approved)
• Treatment-resistant schizophrenia
• Reduction in risk of recurrent suicidal behavior in patients with schizophrenia or schizoaffective disorder
• Treatment-resistant bipolar disorder
• Violent aggressive patients with psychosis and other brain disorders not responsive to other treatments

How the Drug Works

• Blocks dopamine 2 receptors, reducing positive symptoms of psychosis and stabilizing affective symptoms
• Blocks serotonin 2A receptors, causing enhancement of dopamine release in certain brain regions and thus reducing motor side effects and possibly improving cognitive and affective symptoms
• Interactions at a myriad of other neurotransmitter receptors may contribute to clozapine’s efficacy
• Specifically, interactions at 5HT2C and 5HT1A receptors may contribute to efficacy for cognitive and affective symptoms in some patients
• Mechanism of efficacy for psychotic patients who do not respond to conventional antipsychotics is unknown

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 is very 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
• 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)

Before starting an atypical antipsychotic

• Weigh all patients and track BMI during treatment

• Get baseline personal and family history of diabetes, obesity, dyslipidemia, hypertension, and cardiovascular disease

• Get waist circumference (at umbilicus), blood pressure, fasting plasma glucose, and fasting lipid profile

• Determine if the patient is
  • overweight (BMI 25.0–29.9)
  • obese (BMI ≥30)
  • has pre-diabetes (fasting plasma glucose 100–25 mg/dL)
  • has diabetes (fasting plasma glucose >126 mg/dL)
  • has hypertension (BP >140/90 mm Hg)
  • has dyslipidemia (increased total cholesterol, LDL cholesterol, and triglycerides; decreased HDL cholesterol)
• Treat or refer such patients for treatment, including nutrition and weight management, physical activity counseling, smoking cessation, and medical management

Monitoring after starting an atypical antipsychotic

• BMI monthly for 3 months, then quarterly
• Consider monitoring fasting triglycerides monthly for several months in patients at high risk for metabolic complications and when initiating or switching antipsychotics
• Blood pressure, fasting plasma glucose, fasting lipids within 3 months and then annually, but earlier and more frequently for patients with diabetes or who have gained >5% of initial weight

• Treat or refer for treatment and consider switching to another atypical antipsychotic for patients who become overweight, obese, pre-diabetic, diabetic, hypertensive, or dyslipidemic while receiving an atypical antipsychotic

• Even in patients without known diabetes, be vigilant for the rare but life-threatening onset of diabetic ketoacidosis, which always requires immediate treatment, by monitoring for the rapid onset of polyuria, polydipsia, weight loss, nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma

• Liver function testing, electrocardiogram, general physical exam, and assessment of baseline cardiac status before starting treatment
• Liver tests may be necessary during treatment in patients who develop nausea, vomiting, or anorexia

• Electrocardiograms and cardiac evaluation to rule out myocarditis may be necessary during treatment in patients who develop shortness of breath or chest pain