Central Nervous System Effects

The principal action of the tricyclic and tetracyclic agents in the central nervous system is to alleviate depression. In particular, they reduce the symptoms of depression rather than simply elevating mood. Nondepressed subjects given imipramine may feel sleepy, quieter, light-headed, clumsy, and tired. These effects are generally unpleasant (DiMascio et al. 1964).

The anticholinergic and antihistaminic effects of the tricyclics and tetracyclics can produce confusion or delirium. The incidence of delirium is dose-dependent and increases at blood levels above 300 ng/mL. One study reported that 67% of patients with blood levels above 450 ng/mL developed delirium when receiving the tertiary amines, particularly amitriptyline (Livingston et al. 1983; Preskorn and Simpson 1982). The clinician should be alert to the possibility of delirium in a patient whose depression is worsening during treatment. This can be especially problematic in patients with psychotic depression. Patients with concurrent dementia are particularly vulnerable to the development of delirium, and the more anticholinergic tricyclics should be avoided in these patients. Intramuscular or intravenous physostigmine can be used to reverse or reduce the symptoms of delirium. Although physostigmine may represent a useful diagnostic test, its short duration of action makes the continued use of this agent difficult.

Seizures can occur with all of the tricyclic and tetracyclic agents and are dosage- and blood level-related (Rosenstein et al. 1993). For clomipramine, the risk for seizures is reported to be 0.5% at dosages up to 250 mg/day. At dosages above 250 mg/day, the seizure risk increases to 1.67% (new drug application data on file with the FDA). For maprotiline, the overall risk of seizures is reported to be 0.4%, but, again, this risk increases at dosages above the maximum recommended dose of 225 mg/day (Dessain et al. 1986). The seizure risk for some of the older compounds was not as well established at the time of marketing. A retrospective meta-analysis of imipramine found an estimated seizure rate of 1 per 1,000 patients receiving less than 200 mg/day (Peck et al. 1983). At dosages above 200 mg/day, the rate was 0.6%. Another large review (Jick et al. 1983) found similar dose-dependent rates for amitriptyline and doxepin. Rates of 1%-4% have been reported at doses between 250 mg/day and 450 mg/day, but the samples in these studies were often small, and the confidence intervals for these rates were large. Consistent with a dose-dependent effect, the risk of seizures is substantially increased following overdose (Spiker et al. 1975). Seizure rates for the secondary amines have not been well described. Because the risk of convulsions is clearly increased in patients with predisposing factors such as a prior history of seizures, brain injury, or presence of neuroleptics; because the rates are low (e.g., 1/100); and because sample size in drug trials is often on the order of 200 patients, inclusion of a few patients who have a significant vulnerability to seizures can have a marked effect on the rate of seizures reported. The mechanism by which tricyclics produce seizures is not well understood. It has been suggested that antidepressant drugs induce convulsions by acting at the 7-aminobutyric acid (GABA) receptor chloride-ionophore complex, where they inhibit chloride conductance (Escorihuela et al. 1989; Malatynska et al. 1988).

A fine, rapid tremor can occur with use of tricyclic agents. Because this tremor is dose dependent, tends to occur at higher levels, and is not a typical depressive symptom, development of a tremor may be a clinical indicator of an elevated blood level (Nelson et al. 1984). Dose reduction will often lead to improvement in the tremor.

Because the 7-hydroxy metabolite of amoxapine has neuroleptic properties, administration of amoxapine carries the potential risk of neuroleptic malignant syndrome, which has been reported (Lesaca 1987; Madakasira 1989; Taylor and Schwartz 1988; Washington et al. 1989), and tardive dyskinesia. The occurrence of these adverse events is rare; however, the seriousness of the risk and the availability of many alternatives suggest that use of amoxapine should be reserved for patients whose clinical condition warrants the use of an agent with antipsychotic properties.

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