- monitor clinical progress more frequently, focusing on symptoms that suggest syncope or near syncope (unexplained episodic nausea, drowsiness)
- obtain routine ECGs to identify the rare population at increased risk for arrhythmia with either severely prolonged QT (>500 msec) or a serious AV conduction delay at baseline (second-degree or greater).
Laboratory tests should include electrolytes, as hypoleukemia is compellingly associated with development of arrhythmias.
Cardiac toxicity with clozapine. Reports of myocarditis and cardiomyopathy associated with clozapine have raised concern that this agent may be associated with other forms of cardiac toxicity. In January 2002, Novartis Pharmaceuticals Corp. reported 213 cases of myocarditis, 85% of which occurred while patients were taking recommended doses of clozapine within the first 2 months of therapy.33 Eosinophilia in many of the cases indicates that an IgE-mediated hypersensitivity reaction may be involved.34
Novartis also reported 178 cases of clozapineassociated cardiomyopathy, 80% of which occurred in patients younger than 50. Almost 20% of the incidents resulted in death, an alarming figure that may reflect either delay in diagnosis and treatment or simple reporting bias.
Detecting cardiac toxicity is particularly challenging because its manifestations—tachycardia, fatigue, and orthostatic hypotension—are frequently observed in clozapine-treated patients, particularly when dosages are changed.35 The poor specificity of signs for cardiac toxicity requires that we:
- identify at baseline patients with a personal or family history of heart disease
- set our threshold for suspicion of direct cardiotoxicity particularly low when titrating clozapine.36
Hyperprolactinemia
Higher elevations with risperidone. Many antipsychotics cause hyperprolactinemia because their antidopaminergic activity prevents dopamine from inhibiting prolactin secretion. Among the atypicals, however, only risperidone significantly elevates prolactin.37 Caracci et al also demonstrated a two- to four-fold greater prolactin elevation with risperidone than with typical antipsychotics38 and noted that hyperprolactinemia with risperidone could occur at standard daily doses.
We believe that risperidone’s tendency to disperse disproportionately within the plasma space accounts for its differential effect on D2 receptors in the tubuloinfundibular system (brain/plasma ratio of about 0.02 versus approximately 20 for most other antipsychotics). Thus, the lactotrophs, which are outside the blood brain barrier, are exposed to much higher levels of risperidone than are the D2 receptors within the CSF space, resulting in seemingly paradoxical co-occurence of EPS-free hyperprolactinemia.
Table 5
INTERVENTIONS TO CONTROL ANTIPSYCHOTIC-RELATEDWEIGHT GAIN
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Clinical effects. Elevated prolactin levels do not necessarily lead to clinical symptoms. A large study comparing olanzapine and risperidone found that although more patients receiving risperidone had elevated prolactin levels, few patients in either group reported prolactin-related events such as amenorrhea, galactorrhea, gynecomastia, or sexual side effects.39 Elevated prolactin levels have not been shown to be intrinsically harmful, although they can cause hypogonadism via negative feedback and inhibition of gonadotropin-releasing hormone, leading to inadequate follicle-stimulating hormone and luteinizing hormone.
Hyperprolactinemia also reduces serum testosterone levels in men, which may lead to decreased libido, impotence, infertility, gynecomastia, and rarely galactorrhea.40 Premenopausal women may experience infertility, oligomenorrhea or amenorrhea, galactorrhea, and reduced bone mineral density.41
Treatment options. When patients develop hyperprolactinemia, switching to another antipsychotic is not the only option.42 Standard therapies for hyperprolactinemia—the prodopaminergic drugs bromocriptine and amantadine—are effective, though they may have a slight tendency to provoke or worsen psychosis.43 In our experience, most patients can be managed with judicious dosages of bromocriptine (less than 5 mg/d) or even lower dosages of cabergoline (0.25 mg weekly to twice weekly), which causes very few psychiatric side effects.
Birth control pills are a reasonable alternative for women below age 35 who are nonsmokers—a relatively small proportion of those afflicted with schizophrenia but a much higher proportion of those likely to develop endocrine toxicities.
Sexual dysfunction
Sexual dysfunction—including decreased libido, impaired arousal, and erectile orgasmic dysfunction—is common among patients receiving atypical antipsychotics.44 These effects may be caused by anticholinergic activity, alpha-1 inhibition, and hypogonadism due to hyperprolactinemia.45 Delineating one specific cause of sexual dysfunction can be difficult because:
- antipsychotics are often administered with other psychotropics that influence sexual function
- schizophrenia itself is associated with sexual dysfunction.
The asociality associated with schizophrenia’s negative symptoms may be accompanied by decreased libido, fewer sexual thoughts, and fewer sexual relationships. In surveys, patients treated with atypical antipsychotics tend to report improved sex drive and libido but more erectile dysfunction and anorgasmia.46 Untreated patients report having fewer sexual thoughts and diminished libido but better erectile function and potency.47 The atypicals’ positive effect on social behavior may facilitate a willingness to engage in sexual activity, making sexual dysfunction more apparent.48