Adverse Effects - Clinical Pharmacology of Antidepressants

Adverse Effects

Although some potential adverse effects are common to all antide-pressants, most of their adverse effects are specific to a subclass of agents and to their pharmacodynamic effects. An FDA warning applied to all antidepressants is the risk of increased suicidality in patients under the age 25. The warning suggests that use of antide-pressants is associated with suicidal ideation and gestures, but not completed suicides, in up to 4% of patients under 25 years who were prescribed antidepressant in clinical trials. This rate is about twice the rate seen with placebo treatment. For those over 25, there is either no increased risk or a reduced risk of suicidal thoughts and gestures on antidepressants, particularly after age 65. Although a small minority of patients may experience a treatment-emergent increase in suicidal ideation with antidepressants, the absence of treatment of a major depressive episode in all age groups is a par-ticularly important risk factor in completed suicides.

A. Selective Serotonin Reuptake Inhibitors

The adverse effects of the most commonly prescribed antidepres-sants—the SSRIs—can be predicted from their potent inhibition of SERT. SSRIs enhance serotonergic tone, not just in the brain but throughout the body. Increased serotonergic activity in the gut is commonly associated with nausea, gastrointestinal upset, diar-rhea, and other gastrointestinal symptoms. Gastrointestinal adverseeffects usually emerge early in the course of treatment and tend to improve after the first week. Increasing serotonergic tone at the level of the spinal cord and above is associated with diminished sexual function and interest. As a result, at least 30–40% of patients treated with SSRIs report loss of libido, delayed orgasm, or diminished arousal. The sexual effects often persist as long as the patient remains on the antidepressant but may diminish with time.

Other adverse effects related to the serotonergic effects of SSRIs include an increase in headaches and insomnia or hypersomnia. Some patients gain weight while taking SSRIs, particularly parox-etine. Sudden discontinuation of short half-life SSRIs such as par-oxetine and sertraline is associated with a discontinuation syndrome in some patients characterized by dizziness, paresthesias, and other symptoms beginning 1 or 2 days after stopping the drug and per-sisting for 1 week or longer.

Most antidepressants are category C agents by the FDA teratogen classification system. There is an association of par-oxetine with cardiac septal defects in first trimester exposures. Thus, paroxetine is a category D agent. Other possible associa-tions of SSRIs with post-birth complications, including pul-monary hypertension, have not been clearly established. 

B. Serotonin-Norepinephrine Reuptake Inhibitors and Tricyclic Antidepressants 

SNRIs have many of the serotonergic adverse effects associated with SSRIs. In addition, SNRIs may also have noradrenergic effects, including increased blood pressure and heart rate, and CNS activation, such as insomnia, anxiety, and agitation. The hemodynamic effects of SNRIs tend not to be problematic in most patients. A dose-related increase in blood pressure has been seen more commonly with the immediate-release form of venlafaxine than with other SNRIs. Likewise, there are more reports of cardiac toxicity with venlafaxine overdose than with either the other SNRIs or SSRIs. Duloxetine is rarely associ-ated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discon-tinuation syndrome resembling that seen with SSRI discon-tinuation.

The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects result in dry mouth, constipation, uri-nary retention, blurred vision, and confusion. They are more common with tertiary amine TCAs such as amitriptyline and imipramine than with the secondary amine TCAs desipramine and nortriptyline. The potent α-blocking property of TCAs often results in orthostatic hypotension. H₁ antagonism by the TCAs is associated with weight gain and sedation. The TCAs are class 1A antiarrhythmic agents  and are arrhythmogenic at higher doses. Sexual effects are common, particularly with highly serotonergic TCAs such as clomip-ramine. The TCAs have a prominent discontinuation syn-drome characterized by cholinergic rebound and flulike symptoms

C. 5-HT₂ Antagonists

The most common adverse effects associated with the 5-HT₂ antagonists are sedation and gastrointestinal disturbances. Sedative effects, particularly with trazodone, can be quite pronounced. Thus, it is not surprising that the treatment of insomnia is cur-rently the primary application of trazodone. The gastrointestinal effects appear to be dose-related and are less pronounced than those seen with SNRIs or SSRIs. Sexual effects are uncommon with nefazodone or trazodone treatment as a result of the relatively selective serotonergic effects of these drugs on the 5-HT₂ receptor rather than on SERT. However, trazodone has rarely been associ-ated with inducing priapism. Both nefazodone and trazodone are α-blocking agents and may result in a dose-related orthostatichypotension in some patients. Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of fulminant hepatic failure requiring transplantation. The rate of serious hepa-toxicity with nefazodone has been estimated at 1 in 250,000 to 1 in 300,000 patient-years of nefazodone treatment.

D. Tetracyclics and Unicyclics

Amoxapine is sometimes associated with a parkinsonian syndrome due to its D₂-blocking action. Mirtazapine has significant sedative effect. Maprotiline has a moderately high affinity for NET and may cause TCA-like adverse effects and, rarely, seizures. Bupropion is occasionally associated with agitation, insomnia, and anorexia.

E. Monoamine Oxidase Inhibitors

The most common adverse effects of the MAOIs leading to dis-continuation of these drugs are orthostatic hypotension and weight gain. In addition, the irreversible nonselective MAOIs are associated with the highest rates of sexual effects of all the antide-pressants. Anorgasmia is fairly common with therapeutic doses of some MAOIs. The amphetamine-like properties of some MAOIs contributes to activation, insomnia, and restlessness in some patients. Phenelzine tends to be more sedating than either selegi-line or tranylcypromine. Confusion is also sometimes associated with higher doses of MAOIs. Because they block metabolism of tyramine and similar ingested amines, MAOIs may cause danger-ous interactions with certain foods and with serotonergic drugs (see Interactions). Finally, MAOIs have been associated with a sudden discontinuation syndrome manifested in a delirium-like presentation with psychosis, excitement, and confusion.