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 associated with hepatic toxicity in patients with a history of liver damage. All the SNRIs have been associated with a discontinuation syndrome resembling that seen with SSRI discontinuation.
The primary adverse effects of TCAs have been described in the previous text. Anticholinergic effects are perhaps the most common. These effects include dry mouth, constipation, urinary 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 (see Chapter 14) and are arrhythmogenic at higher doses. Sexual effects are common, particularly with highly serotonergic TCAs such as clomipramine. The TCAs have a prominent discontinuation syndrome characterized by cholinergic rebound and flulike symptoms.
C. 5-HT Receptor Modulators
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 currently 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 associated with inducing priapism. Both nefazodone and trazodone are α-blocking agents and may result in a dose-related orthostatic hypotension in some patients. Nefazodone has been associated with hepatotoxicity, including rare fatalities and cases of fulminant hepatic failure requiring transplantation. The rate of serious hepatotoxicity with nefazodone has been estimated at 1 in 250,000 to 1 in 300,000 patient-years of nefazodone treatment.
As with the SSRIs, the most common adverse effects of vortioxetine are serotonergic and include dose-dependent gastrointestinal effects, particularly nausea, as well as sexual dysfunction. Higher doses of vortioxetine tend to increase the rate of GI and sexual side effects. The teratogenic risks of vortioxetine are not known but like most other antidepressants, it is considered a category C agent.
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. Vilazodone may have somewhat higher rates of gastrointestinal upset, including diarrhea and nausea, than the SSRIs.
E. Monoamine Oxidase Inhibitors