Serotonin-Related Side Effects

A host of medications have been nsed to treat TD including medications that block norepinephrine activity (clonidine and propranolol), dopamine-activating medications (bromocriptine), benzodiazepines, acetylcholine-activating medications, calcium channel blockers, and monoamine oxidase inhibitors. In addition, vitamin E supplementation and atypical antipsychotics including clozapine have been used to treat TD. 

Of all these treatments, the only consistent improvement is seen with the atypical antipsychotic clozapine (Clozaril). Treatment-resistant TD is in fact one generally accepted indication for nsing clozapine. However, becanse of the expense of this drug, the risk for granulocytopenia, and the reqnirement for biweekly blood draws, other measures should hrst be tried. 

Among the benzodiazepines, long-acting clonazepam (Klonopin) is sometimes effective for TD. Unfortnnately, after several months of treatment, tolerance to its beneficial effects often develops and the TD reemerges. When this occurs, clonazepam should be discontinued for a few weeks. It can then be restarted and may again lessen TD for a few more months. 

The success of clozapine makes it reasonable to try it or one of the other atypical antipsychotics. Althongh we know that the atypical agents are far less likely to cause TD, other than clozapine, we do not currently know enough about how well they treat preexisting TD. 

In snmmary, if a patient develops TD, we recommend switching to an atypical antipsychotic if this has not already been done. One can also try coadministering clonazepam and/or vitamin E. If these measures fail, a trial of clozapine is warranted, despite the risk of agranulocytosis. 

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The most serious side effect is dose-related mental depression resulting from CNS depletion of catecholamines and serotonin. This can be minimized by not exceeding 0.25 mg daily. 

Antipsychotic medications antagonize dopamine, which is believed to contribute to the antipsychotic effect of these medications. The atypical antipsychotics have other physiological properties as well, some of which appear to relate to antagonism of the serotonin type 2 (5-HT2) receptor, which may modify dopamine activity in a regionally specific manner. Dual 5-HT2 receptor-dopamine type 2 (D2) receptor antagonism is believed to account, at least in part, for the superior efficacy and more favorable side-effect profile of atypical antipsychotics. 

FIGURE 8—11. Serotonin 1A partial agonists such as buspirone may reduce anxiety by actions both at presynaptic somatodendritic autoreceptors (left) and at postsynaptic receptors (right). Presynaptic actions are more likely related to anxiolytic actions, and postsynaptic actions are perhaps more likely linked to side effects such as nausea and dizziness. 

Clozapine is considered to be the prototype of the atypical antipsychotics, as it was the first to be recognized as having few if any extrapyramidal side effects, not causing tardive dyskinesia, and not elevating prolactin. Clozapine is one of five antipsychotics with somewhat related chemical structures (Fig. 11-36). Although certainly a serotonin 2A-dopamine 2 antagonist, clozapine also has one of the most complex... 

Sibutramine (Meridia), a weight-loss drug introduced in 1998, inhibits the reuptake of the brain chemicals norepinephrine, dopamine, and serotonin, but does not promote monoamine release like the amphetamines. Yet the drug has been linked to serious side effects, including rapid heart rate, increased blood pressure, heart disease, stroke, seizure, and mental impairments. In March 2002, Italy s Health Ministry announced that it was immediately withdrawing all sibutramine products from the market due to health-related problems. Also, Meridia was the subject of a class action lawsuit filed in the United States. 

Introduced in 1988, Prozac is the oldest in the SSRI class and is still the most commonly prescribed (Morris, 1999). Prozac is a highly successful antidepressant that has revolutionized the treatment of depression because of its ability to raise serotonin levels in the brain. Increased availability of this neurochemical has been directly related to addressing effectively the symptoms prevalent in depression, and Prozac was recently approved to treat obsessive-compulsive disorder and the eating disorder bulimia. Prozac and the other SSRIs are also considered the medication of choice for working with depressed older individuals because of fewer side effects than the tricyclic medications (Haider Miller, 1993). In 1999 Prozac was endorsed by the FDA as being especially effective for geriatric depression (Hussar, 2000). 

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