The medications in this category are used to treat both positive and negative symptoms of schizophrenia (Box 21-7 Seven Categories of Positive Symptoms in Patients with Schizophrenia and Box 21-8 Seven Categories of Negative Symptoms in Patients with Schizophrenia). However, they can also be used to treat psychotic symptoms of other psychiatric disorders (schizoaffective disorders, major depression with psychotic features, and bipolar disorders).
Hypotheses on Mechanisms of Action
The mechanisms of action of atypical antipsychotics are not defined. It has been hypothesized that the atypical agents are more selective than the typical ones when they interact with different types of dopamine receptors. For instance, the dopamine receptors, which are associated with movement disorders, are less affected by atypical agents such as clozapine (Clozaril) or quetiapine (Seroquel). However, the atypical agents also affect multiple neurotransmitter systems, making it difficult for their exact mechanisms of action to be understood.
Efficacy in Treating Symptoms
The positive symptoms respond faster to antipsychotics than the negative symptoms in general. Changes in negative symptoms or regaining of affect, social activities, or motivation may be observed over months and years of treatment when these agents are used along with psychosocial rehabilitation interventions.
A new long-acting agent, risperidone (Risperdal Consta), with average half-life of 2 weeks is also available in intramuscular forms. The active agent (risperidone) in white microspheres needs to be mixed gently with the water-based diluent right before the administration every 2 weeks. The vials of 25 mg, 37.5 mg, and 50 mg come with a syringe with the diluent in it. They need to be stored in a refrigerator.
Common Side Effects
The atypicals are generally less associated with EPS than the typical agents, but there are a wide range of other side effects.
Clozapine (Clozaril/FazaClo) Excessive salivation during sleep, orthostatic hypotension, sedation, tachycardia, anticholinergic effects (constipation, blurred vision, urinary retention), seizure, agranulocytosis (seen in 0.4%–1.0% of patients), myocarditis, respiratory depression, weight gain with increased appetite, urinary incontinence, diabetes mellitus type II, excessive sweating, nausea, dizziness, and low-grade fever.
Risperidone (Risperdal/Consta) Orthostatic hypotension, tachyarrhythmia, akathisia, dysmenorrhea, reduced libido, rhinitis, insomnia, headaches, weight gain, EPS, and prolactinemia.
Olanzapine (Zyprexa/Zydis) Weight gain with increased appetite, diabetes mellitus type II, tachycardia, sedation, orthostatic hypotension. EPS, akathisia.
Quetiapine (Seroquel) Sedation, weight gain with increased appetite, dry mouth, constipation, diabetes mellitus type II, orthostatic hypotension, tachyarrhythmia.
Ziprasidone (Geodon) Akathisia, EPS, orthostatic hypotension, prolonged QT interval, tachyarrhythmia
Aripiprazole (Abilify) Insomnia, nausea, akathisia, weight gain, bradyarrhythmia, tachyarrhythmia.
Related Clinical Concerns
Because of the lack of studies on long-term effects of antipsychotics in children, a drug-free period may be periodically considered. Antipsychotic medications could contribute to cognitive blunting, leading to school problems. Atypicals have been used with some success in treatment of behavioral symptoms of autism.
Side effect of weight gain often affects compliance. Long-term use of antipsychotics in the presence of a serious psychiatric disorder like schizophrenia has not been well studied.
Use of atypical antipsychotics for dementia-related psychosis may be associated with increased risk of mortality from infection, heart failure, and other medical conditions. Orthostatic hypotension side effect can be a safety concern.
Other Clinical Concerns
Management Systems for the Patient Taking Clozapine Because of the possibility of granulocytosis, clozapine has been marketed under unique systems set up by the pharmaceutical companies. All patients to be started on clozapine must be cleared through one of the systems before the treatment begins. The therapy can be initiated if the patient has:
The physician and pharmacist are responsible for obtaining weekly WBC and ANC. Only a week's supply of clozapine will be dispensed after the WBC/ANC counts are reported every week to the pharmacy. After 6 months of treatment with no hematological problems, a 2-week supply of clozapine can be dispensed as the acceptable WBC/ANC counts are reported biweekly (Table 21-9 Monitoring Granulocyte Counts During Clozapine Therapy). After 12 months of established clozapine treatment without any abnormal hematological data, monitoring of WBC/ANC and dispensing of clozapine can be done every 4 weeks.