SIDE EFFECTS OF ANTIDEPRESSANTS
As previously mentioned the TCAs have variable effects in blocking reuptake of norepinephrine and serotonin. The other major difference between the various drugs in this therapeutic class is the variability in side effect profile.
They vary greatly in their anticholinergic potential, as can be seen from the data presented in Table 5-1. Anticholinergic effects are manifested clinically by dry mouth,blurred vision, constipation, difficulty urinating, and tachycardia. Since these drugs must enter the brain to exert their therapeutic effect, their anticholinergic actions may also be manifested centrally. Elderly persons and those with organic brain dysfunction are much more sensitive to the central anticholinergic effects of these drugs. Young healthy persons may also become quite uncomfortable as a result of anticholinergic effects. The CNS manifestations of cholinergic blockade include impaired memory and impaired concentrating ability, both of which may also be seen in untreated depressed patients. Occasionally, patients receiving antidepressants experience difficulties expressing their thoughts verbally. Speech blockage and stuttering may occur with cyclic antidepressants, particularly those which are more strongly anticholinergic, and have been reported as a rare side effect of MAOI antidepressants and alprazolam, which have minimal anticholinergic activity. Persons who are particularly sensitive to cholinergic blockade, or patients who have taken excessive dosages of antidepressants, may experience confusion, disorientation, disorganized thinking, and visual or auditory hallucinations. Toxic psychoses can occur in response to centrally acting anticholinergic drugs.In some individuals with an underlying psychotic illness or history of bipolar affective illness, antidepressants used to treat a depressive illness may produce a dramatic exacerbation of the underlying psychotic or manic condition, probably as a result of both central anticholinergic and noradrenergic effects. In choosing an antidepressant for a patient with a prior history of sensitivity to anticholinergic effects, it is preferable to utilize a drug with lower potential for cholinergic blockade such as desipramine, fluoxetine, amoxapine, maprotiline, or trazodone. This is particularly true in the elderly, especially those with organic brain dysfunction. Likewise, in a patient with cardiovascular disease, a drug with lower anticholinergic potential may be advantageous since it will be less likely to increase heart rate and affect electrical conduction within the heart. Postural hypotension is a rather common unwanted effect of tricyclic antidepressants, which is probably related to the drugs’ ability to relax vascular smooth muscle. Amoxapine, nortryptiline, and maprotiline are less likely to produce significant postural hypotension than imipramine or amitriptyline.
Sedation is another pharmacologic parameter that differentiates the various antidepressants. In a depressed patient who has difficulty sleeping it is often advantageous to utilize a more strongly sedating antidepressant in a single dose at bedtime. If the patient is not likely to have difficulty with a strongly anticholinergic agent, amitriptyline, the most sedating TCA, would be an appropriate choice. If, on the other hand, there is need to avoid cholinergic blockade and at the same time a desire for a drug with more prominent sedating qualities, doxepin, maprotiline, or trazodone in a single bedtime dose would be desirable. If the patient tends to be excessively drowsy during the day it is often preferable to utilize one of the antidepressants with lower sedative potential. Desipramine has little sedative effect, and amoxapine, whose sedative action is likewise relatively mild, are both well tolerated if given in divided doses throughout the day. Since amoxapine has some ability to inhibit serotonin reuptake as well as a primary effect on norepinephrine reuptake, it may be more effective than desipramine which only inhibits norepinephrine reuptake. Additionally, amoxapine has a mild anxiolytic effect, which may obviate the need for concurrent use of antianxiety agents if amoxapine is given in divided doses throughout the day.
Decreased libido, reduced sexual arousal, and impaired orgasmic function may all be associated with depressive illness. Unfortunately, similar symptoms of sexual dysfunction may occur in both men and women during treatment with tricyclic and heterocyclic antidepressants as well as with MAOls although the latter are somewhat more likely to impair sexual arousal,erectile function, and orgasm than are TCAs and HCAs. There is no evidence that any one of the cyclic antidepressants is dramatically more or less likely to produce sexual dysfunction. Sexual arousal and orgasmic function are rarely completely inhibited by cyclic antidepressants, and usually satisfactory sexual performance can be achieved with adequate time and effort, even in conjunction with high-dose cyclic antidepressant therapy. The pharmacologic mechanisms of impaired sexual function appear to represent a composite of the noradrenergic, serotonergic, and anticholinergic actions of antidepressant drugs. Decreased libido and impaired ejaculation may be improved by the use of neostigmine,7.5 to 15 mg approxamately 0.5 to 1.0 hour prior to intercourse. Neostigmine inhibits cholinesterase and thereby increases cholinergic activity. Bethanechol, a direct-acting cholinergic stimulant, given in a dose of 10 mg tid, may improve erectile function. Cyproheptadine, a serotonin receptor antagonist, in a dose of 4 mg daily has been shown to alleviate anorgasmia induced by cyclic as well as by monoamine oxidase inhibitor-type antidepressants.
Some clinicians have found that changing from a mixed serotonergic-noradrenergic antidepressant to a pure noradrenergic drug such as desipramine may alleviate antidepressant-induced sexual dysfunction. In contrast, the serotonergic antidepressant trazodone has been reported to increase libido and sexual arousal in women. Prolonged, painful erections, known as priapism, have been reported in a number of men during trazodone treatment. The mechanism of drug-induced priapism is unknown; it appears to be related to alphaadrenergic blockade, which is known to occur with trazodone. Priapism has also been reported as a rare complication of neuroleptic medications and MAOls, but apparently does not occur with other cyclic antidepressants or lithium.
Tricyclic and heterocyclic antidepressants have a quinidinelike effect and through this mechanism may depress intraventricular conduction and myocardial contractility, as will be discussed in chapter 10.22- 23 The electrophysiologic, noradrenergic, and anticholinergic activity of cyclic antidepressants accounts for their ability to both provoke and suppress cardiac arrhythmias, depending on the patient’s clinical condition, drug dosage, and coadministration of other medications.
Occasionally, cyclic antidepressants may interfere with sleep, produce nightmares, and hypnagogic phenomena. Sleep disturbances most commonly occur with MAOls, occur somewhat less frequently with noradrenergic-type cyclic antidepressants, and occur least often with serotonergic antidepressants. Changing the regimen from one type of antidepressant to another, or the short-term use of 1 to 2 mg of trifluoperazine at bedtime, often alleviates antidepressant-induced sleep disturbances. Appetite stimulation, carbohydrate craving, and weight gain are common side effects of cyclic antidepressants and many other psychotropic drugs, and are discussed in detail in chapter 17.
Convulsions are a rare complication of cyclic antidepressant drug therapy. Generally, if seizures do occur with these drugs, they are most likely the result of an overdose, an excessively high therapeutic dosage, or exacerbation of a dormant seizure disorder by the convulsive threshhold-lowering effect of cyclic antidepressants. All tricyclic antidepressants have, on occasion, been associated with the occurrence of seizures, and there are no good data to suggest that any of these drugs presents a greater or lesser convulsive risk. On the other hand, with careful patient, dosage, and, where indicated, plasma drug concentration monitoring, tricyclic antidepressants can be safely used even in patients with previous seizure disorders. Monoamine oxidase inhibitors appear less likely than tricyclic drugs to provoke convulsive events. Among all antidepressants, maprotiline appears most likely to lower seizure threshold and provoke convulsions at therapeutic dosage or when high doses are employed, or when the patient has a previous convulsive disorder. As the dose of maprotiline is titrated above 150 mg/day, caution should be employed and prolonged use of dosages exceeding 200 mg/day should generally be avoided. Maprotiline should not be used in the treatment of any patient with a previously known convulsive disorder and should be discontinued and not restarted in any patient who develops seizure activity during maprotiline treatment.