The pharmacological properties that underlie the side effects of antidepressants have been better characterized than the properties responsible for the therapeutic effects. While newer antidepressants have provided little additional therapeutic efficacy compared to older drugs, they are unequivocally safer and much better tolerated. In general, side effects can be divided into those that occur early in the course of treatment and those that emerge gradually over continuous use.
Frequently Occurring Initial Side Effects (first 1 to 4 weeks). The majority of initial side effects of antidepressant and antimanic drugs relate in a dose-dependent way to muscarinic cholinergic, histamine H1 and H2, and a1 -adrenergic antagonist properties. Some initial side effects are also caused by increasing levels of 5-HT or NE (see Bolden-Watson and Richelson, 1993, for reviews). Most early side effects diminish in intensity over time, although cardiovascular side effects may not. Side effects due to receptor antagonist properties are seen almost exclusively in the older TCA and MAOI antidepressants, while side effects seen with the newer agents tend to be related to reuptake inhibition. Idiosyncratic and allergic responses also usually occur during the first 4 weeks of therapy and can occur with drugs in any of the classes.
Some of the most limiting side effects of antidepressant drugs are caused by a1-adrenergic antagonist properties and include orthostatic hypotension, sedation, and reflex tachycardia. The most common drugs to cause these effects are TCAs, MAOIs, and trazodone.
Some medications, especially the TCAs, mirtazapine, and olanzapine, have potent antihistamine H1 properties. This effect can cause sedation, weight gain, and in some instances hypotension. Most newer antidepressants such as the SSRIs, bupropion, ven-lafaxine, and duloxetine have no antihistamine effects.
Antimuscarinic cholinergic properties cause dry mouth, dental caries (due to dry mouth), blurred vision, constipation, sinus tachycardia, urinary retention, and memory loss and confusion. The most serious of these effects is the possibility of an anticholin-ergic delirium (atropine psychosis). This is usually associated with elevated plasma levels of TCA drugs but can be seen at therapeutic blood levels. Typical symptoms include impaired short-term memory, confusion, and peripheral signs of anticholiner-gic activity such as dry mouth, enlarged pupils, and dry skin. Older patients seem to be at much increased risk for this side effect and other anticholinergic side effects. The newer agents do not cause these effects. Antimuscarinic effects enhance pupillary dilatation, which can precipitate significant increases in intraocular pressure in patients with preexisting narrow-angle glaucoma.
Norepinephrine reuptake blockade can cause tremor, tachycardia, and erectile and ejaculatory dysfunction; 5-HT reuptake inhibition causes nausea and anxiety or sedation. DA reuptake inhibition causes activation and can exacerbate psychosis.
The causes of some side effects of antidepressant drugs are less understood and are probably related to combinations of pharmacological effects. These include most cardiovascular side effects, perspiration, tremor, speech blockage, sexual dysfunction, akathisia, insomnia, and seizures. Cardiovascular effects are potentially the most serious and are most often seen with TCA and MAOI antidepressants (see Roose and Glassman, 1989). These include dose-related increases in heart rate and prolongation of ventricular conduction (increased PR, QRS, and QTc), orthostatic hypotension, and quinidinelike antiarrhythmic effects. Trazodone may lead to increased ventricular irritability and ectopy.
5-HT Syndrome. Potent 5-HT reuptake inhibitors are the most likely to cause nausea, anorgasmia, and sometimes myoclonus. When these drugs are used in combination with MAOIs, a hypermetabolic syndrome can occur consisting of gastrointestinal distress, headache, agitation, hyperpyrexia, increase heart rate, increased respiratory rate, hypotension or hypertension, muscular rigidity, myoclonus, convulsions, coma, and often death (Sternbach, 1991) The hypermetabolic symptoms reported with this syndrome closely resemble the symptoms of malignant hyperthermia and neuroleptic malignant syndrome, raising questions as to whether these may be manifestations of a common mechanism. Many preclinical and clinical studies have shown that 5-HT reuptake inhibitors have effects on the DA system, and it has been suggested that changes in DA function may be a common element to these conditions (see Beasley et al., 1993, for comprehensive review).
Because of the potential lethality of this reaction, it is recommended that MAOIs be discontinued for at least 2 weeks prior to using an SSRI, and SSRIs should be discontinued for at least 2 weeks prior to initiation of a MAOI. The exception to this is fluoxetine. Because of its long half life and accumulation it should be discontinued for at least 6 weeks prior to using an MAOI.
Frequent Side Effects Occurring after Prolonged Treatment (>4 weeks).
Late occurring side effects with antidepressant and antimanic drugs include weight gain, myoclonus, and sexual dysfunction. Weight gain is most common with tertiary TCAs, MAOIs, mirtazapine, and olanzapine but can also be seen with SSRIs after long-term treatment. Myoclonus can occur with any of these medications but may be relatively more common with MAOIs, SSRIs, and lithium.
While sexual side effects can appear at any time, they are more often reported later in the course of treatment, possibly because they are not noticed until the patient has begun to resume more normal function in other spheres of life. SSRIs are the most likely to cause these side effects but TCAs, MAOIs, venlafaxine, lithium, and carbamazepine can also cause them. SSRIs, MAOIs, and venlafaxine are more prone to causing anorgasmia and decreased libido while TCAs are the most likely to cause difficulty maintaining erection.
Withdrawal Reactions. Several types of withdrawal reactions have been reported to occur within hours to days following discontinuation of antidepressant drugs. Symptoms can include gastrointestinal disturbances, sleep disturbances, behavioral activation, agitation, and/or acute depressive reactions. Black et al. (1993) reported dizzi-ness/incoordination, headaches, nausea, and irritability following acute discontinuation of SSRIs. The mechanisms underlying antidepressant withdrawal reactions are not known. Withdrawal is more likely after discontinuation of drugs with short-half lives.
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