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.
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.
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
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.
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.
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.
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