The pharmacology of a drug determines its therapeutic use and side effect profile, but also helps explain the potential adverse effects that might occur when the drug is discontinued. In this four-part series of articles, I am providing a broad overview of the potential adverse effects associated with the discontinuation of various psychotropic drugs. This second article will focus on antidepressant drugs.
Antidepressant drugs are classified according to their chemical structure or their presumed mechanism of action (Brunton, Lazo, Parker, Buxton, & Blumenthal, 2006). The main classes of antidepressant agents are tricyclic antidepressant (TCA), monoamine oxidase inhibitor (MAOI), selective serotonin reuptake inhibitor (SSRI), serotonin-norepinephrine reuptake inhibitor (SNRI), and various atypical antidepressant drugs. The primary use of these drugs is for the treatment of depressive and anxiety disorders, but other clinical uses include the treatment of insomnia, chronic pain, headache, premenstrual dysphoric disorder, eating disorders, attention-deficit/hyperactivity disorder (ADHD), and addictions. For all antidepressant drugs, when they are being used for the treatment of depression there is a small risk of developing hypomania or mania. Somewhat paradoxically, however, abruptly stopping anti-depressant drugs can sometimes result in “rebound” hypomania or mania (Andrade, 2004). This phenomenon is probably triggered by the dysregulating effects of sudden neurotransmitter changes or changes in the sensitivity of neurotransmitter receptors. When used for other clinical conditions, suddenly stopping antidepressant drugs may lead to a return of the underlying symptoms. A recent study found that the time to recurrence risk for depression or panic anxiety was significantly shorter after rapid than after gradual discontinuation of antidepressant medication (Baldessarini, Tondo, Ghiani, & Lepri, 2010).
Tricyclic Antidepressant Drugs
The TCA drugs include imipramine (Tofranil®), desipramine (Norpramin®), amitriptyline (Elavil®), nortriptyline (Pamelor®), doxepin (Sinequan®), trimipramine (Surmontil®), protriptyline (Vivactil®), clomipramine (Anafranil®), amoxapine (Asendin®), and maprotiline (Ludiomil®). The antidepressant and anti-anxiety effects of TCAs are mediated primarily by their reuptake inhibition of the neurotransmitters norepinephrine (NE), serotonin (5HT), and dopamine (DA), but their blockade of postsynaptic 5HT-2 receptors (a 5HT receptor subtype) contributes to these clinical effects (Sadock, Sadock, & Sussman, 2006). TCAs also block various neurotransmitter receptors throughout the central and peripheral nervous system, accounting for many of their common adverse effects. Dry mouth, constipation, blurred vision, urinary retention, tachycardia, and memory impairment are due to cholinergic receptor blockade (referred to as anticholinergic effects). Abrupt discontinuation of TCA drugs can lead to an anticholinergic discontinuation syndrome characterized by cholinergic rebound (Muzina, 2010). These symptoms include nausea, vomiting, abdominal cramping, sweating, headache, and muscle spasms. Dizziness, hypotension, and reflex tachycardia are caused by alpha-1 and alpha-2 receptor blockade. Similar to adrenergic drugs, abruptly stopping TCA drugs can cause rebound anxiety, restlessness, sweating, tremors, abdominal pain, heart palpitations, headache, and hypertension. Abruptly stopping these drugs can also be associated with vivid dreams and nightmares.
Monoamine Oxidase Inhibitor Drugs
The MAOI drugs include phenelzine (Nardil®), isocarboxazid (Marplan®), tranylcypromine (Parnate®), and transdermal selegiline (Emsam®). In the brain, liver, gut, and elsewhere in the body, the enzyme monoamine oxidase (MAO) metabolizes the neurotransmitters 5HT, NE, and DA. By inhibiting MAO activity, MAOI drugs increase the availability of these neurotransmitters (Brunton et al., 2006). Typical adverse effects of MAOI drugs include hypotension, dizziness, sedation, insomnia, weight gain, dry mouth, and sexual dysfunction. Significant MAO enzyme inhibition persists for several weeks even after stopping these drugs. Patients stopping MAOI drugs are at risk for dietary and drug interactions for at least 2 weeks. Although MAO inhibition explains much of the clinical properties of MAOI drugs, they also have direct effects on the neuronal release and reuptake of these neurotransmitters. Hence, abrupt discontinuation of MAOI drugs can sometimes result in flu-like symptoms, dysphoria, restlessness, tachycardia, hypertension, and a delirium-like state characterized by excitation or psychosis, although this does not seem to occur following abrupt discontinuation of transdermal selegiline (Schatzberg, Cole, & DeBattista, 2007).
Selective Serotonin Reuptake Inhibitor Drugs
The SSRI drugs include fluoxetine (Prozac®, Prozac Weekly™, Sarafem®), paroxetine (Paxil®, Paxil CR®, Pexeva®), sertraline (Zoloft®), citalopram (Celexa®), escitalopram (Lexapro®), and fluvoxamine (Luvox®). The SSRI drugs are not related chemically, but they have a similar mechanism of action, which is their potent and specific inhibition of presynaptic 5HT reuptake. The SSRIs have minimal effects on other neurotransmitters or receptors. Common adverse effects of the SSRIs include nausea, diarrhea, insomnia, nervousness, headache, sexual dysfunction, sweating, fatigue, apathy, and weight gain. Abruptly stopping SSRI drugs is sometimes associated with a distinct discontinuation syndrome characterized by dizziness, weakness, nausea, headache, lethargy, insomnia, anxiety, poor concentration, and paresthesias (unusual tactile sensations) (Haddad, 1998). Discontinuation is not dangerous but can be extremely uncomfortable. Discontinuation has been described with all SSRIs, but most commonly fluvoxamine and paroxetine.
Serotonin-Norepinephrine Reuptake Inhibitor Drugs
The primary mechanism of action of SNRI drugs—venlafaxine (Effexor®, Effexor XR®), desvenlafaxine (Pristiq®), and duloxetine (Cymbalta®)—is inhibition of the reuptake of 5HT and NE. Common adverse effects of SNRIs include nausea, headache, dizziness, dry mouth, constipation, loss of appetite, nervousness, insomnia, fatigue, sweating, sexual dysfunction, and urinary hesitancy. Abruptly stopping SNRI drugs can result in a serotonergic discontinuation syndrome similar to that described for SSRI drugs (Muzina, 2010). In addition, the abrupt loss of the NE adrenergic effects can result in urinary urgency and increased gastrointestinal (GI) motility.
Milnacipran (Savella®) is an SNRI drug indicated for fibromyalgia. European studies have shown that it is effective for treating depression, but it is not approved in the United States for this indication (Puozzo, Panconi, & Deprez, 2002). Sibutramine (Meridia®) is an SNRI drug indicated for obesity (Stock, 1997). It has antidepressant properties but is not approved for depression. Tramadol (Ultram®), structurally similar to venlafaxine, is a weak SNRI drug with weak muopioid receptor agonist effects that is used for analgesia (Markowitz & Patrick, 1998). Abrupt discontinuation of these three drugs may result in adverse effects similar to the other SNRI drugs. In addition, discontinuation of tramadol may include a mild opioid withdrawal syndrome, characterized by anxiety, runny nose, dilated pupils, elevated heart rate, increased blood pressure, sweating, nausea, abdominal pain, and diarrhea.
Atypical Antidepressant Drugs
The atypical antidepressant agents refer to various drugs that are unrelated to each other and unrelated to the TCAs, MAOIs, SSRIs, or SNRIs. Bupropion (Wellbutrin®, Wellbutrin SR®, Wellbutrin XL®, Zyban®) is an antidepressant drug whose mechanism of action is uncertain, although it seems to enhance the effects of NE and DA (Sadock et al., 2006). Bupropion has virtually no effect on other neurotransmitters or receptors. It lacks the usual adverse effects associated with the TCAs, MAOIs, SSRIs, or SNRIs and has not been associated with any type of discontinuation-related adverse effects.
Trazodone (Desyrel®) has weak effects on neurotransmitter reuptake, but it does block postsynaptic 5HT-2 receptors and alpha-1 receptors (Sadock et al., 2006). Common adverse effects include sedation, dry mouth, dizziness, headache, and nausea. Potentially serious adverse effects, related to the alpha-1 blocking effect, are priapism (in men) and orthostatic hypotension. Abrupt discontinuation can result in insomnia and, similar to the adrenergic drug prazosin (Minipress®), may cause rebound tachycardia and hypertension.
Nefazodone (Serzone®) is structurally related to trazodone. Its primary mechanism of action is blockade of postsynaptic 5HT-2 receptors (Sadock et al., 2006). It has less potent effects on blocking alpha-1 receptors and very weak NE and 5HT reuptake inhibition. Common adverse effects include sedation, dry mouth, nausea, headache, constipation, and dizziness. Hypotension may occur rarely at high dosages. Abruptly stopping nefazodone may cause rebound tachycardia and hypertension, similar to prazosin.
Mirtazapine (Remeron®) blocks presynaptic alpha-2 receptors and postsynaptic 5HT-2 and 5HT-3 receptors (Sadock et al., 2006). The net effect of these receptor effects is to increase 5HT and NE transmission in the brain. Mirtazapine potently blocks postsynaptic histamine receptors, contributing to its most prominent adverse effects (i.e., sedation and weight gain). It has moderate effects at blocking alpha-1 receptors (causing dizziness) and cholinergic receptors (causing dry mouth and constipation). Abruptly stopping mirtazapine may result in insomnia, rebound tachycardia and hypertension, and a mild anticholinergic withdrawal syndrome.
Atomoxetine (Strattera®) is a selective NE reuptake inhibitor drug (Schatzberg et al., 2007). It has relatively weak antidepressant effects and is not used or approved for depression, but it is indicated for ADHD. Common adverse effects include dry mouth, nausea, headache, dizziness, abdominal pain, constipation, decreased appetite, weight loss, insomnia, and urinary retention. The abrupt loss of the NE adrenergic effects with discontinuation may cause urinary urgency and increased GI motility.
Buspirone (Buspar®) is a partial agonist at the 5HT-1A receptor, which is associated with anti-anxiety and antidepressant effects (Schatzberg et al., 2007). It is indicated for generalized anxiety disorder. Buspirone has antidepressant effects at high dosages, but it is not ordinarily used alone for treating depression and is not approved for this indication. Possible adverse effects include headache, nausea, dizziness, and insomnia, but it has not been associated with any type of discontinuation-related adverse effects.