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Antidepressant are medications primarily used to treat clinical depression. Antidepressants have also been used to treat anxiety (including generalized anxiety, social anxiety, and panic disorder), obsessive-compulsive disorder, posttraumatic stress disorder, chronic pain, narcolepsy, alcoholism, bulimia, Parkinson’s disease, and attention-deficit hyperactivity disorder and to aid in smoking cessation.

In the first half of the 20th century, treatments for depression included stimulants (e.g., amphetamine), chemical shock, and electric shock therapy (Lieberman, 2003).

The first antidepressants were discovered inadvertently in the 1950s when a tuberculosis medication, iproniazidOpens in new window (Marsilid, Iprozid, Rivivol), was found to improve patients’ moods (Preston, O’Neal, & Talaga, 2008). It was found that iproniazid inhibited monoamine oxidase (MAO)Opens in new window, an enzyme that breaks down the neurotransmitters (chemical messengers) serotonin, dopamine, and norepinephrine in neurons.

This discovery led to the development of the first class of antidepressant medication, the monoamine oxidase inhibitors (MAOIs, e.g., Marplan, Nardil, Selegiline). ImipramineOpens in new window, developed as an antipsychotic in the 1950s, was also found to have antidepressant properties.

Imipramine (Tofranil) was followed by the development of amitriptyline (Elavil) and other cyclic antidepressants (Preston et al., 2008). The cyclic antidepressants include the tricyclic (TCA, e.g., Sinequan) and tetracyclic (e.g., Serzone, Trazodone) antidepressants.

In addition to the MAOIs and TCAs, other types of antidepressants include selective serotonin reuptake inhibitors (SSRIs, e.g., Prozac, Paxil, Zoloft), serotonin and norepinephrine reuptake inhibitors (SNRIs, e.g., Effexor), norepinephrine reuptake inhibitors (NRIs, e.g., maprotiline, reboxetine), and atypical antidepressants.

Some of the atypical include selective serotonin reuptake enhancers (SSREs, e.g., tianeprine), noradrenergic and specific serotonergic antidepressants (NaSSAs, e.g., Remeron), muscarinic antagonists (e.g., dibenzepin), reversible inhibitors of monoamine oxidase A (RIMAs, e.g., Aurorix), dopamine reuptake inhibitors (DARIs, e.g., amineptine), and norepinephrine-dopamine reuptake inhibitors (NDRIs, e.g., bupropion or Wellbutrin).

Sometimes stimulants (e.g., Ritalin) are used to treat depression. One type of antidepressant may be used to augment treatment with an antidepressant of a different type.

Some research demonstrates that alternative to pharmaceutical antidepressants such as St. John’s wort (an herb) and S-adenoysl-L-methionine (SAMe), a substance found in the body, show some efficacy in the treatment of depression.

Other complementary treatments—such as L-tryptophan (a natural antidepressant found in foods such as turkey, potatoes, and milk), 5-hydroxytryptophan (5-HT), melatonin, tyrosine, amino acids, vitamins, and minerals—have less solid research backing, and there is a great deal of controversy regarding their efficacy, side effects, and potential drug interactions.

Side effects of antidepressants vary by type of antidepressant. TCA side effects can be grouped into four categories:

  1. anticholinergic (dry mouth, dry skin, blurred vision, constipation),
  2. adrenergic (sweating, sexual dysfunction, sudden drop in blood pressure),
  3. antihistaminic (sedation, weight gain), and
  4. miscellaneous (e.g., lowered seizure threshold, cardiac arrhythmia, elevated heart rate, hepatitis, rashes, sweating, anxiety; Preston et al., 2008).

Common side effects of SSRIs, SNRIs, NRIs, and atypical antidepressants include anxiety, sedation, insomnia, nausea, and sexual dysfunction.

MAOIs are used in the treatment of major depression or panic disorder generally only after other antidepressants have failed due to potentially fatal severe hypertensive (high blood pressure) reactions that can be caused by taking decongestants or other antidepressants, or by eating foods high in tyramine (e.g., salami, chicken liver, some sausages, some types of fish, bologna, beef bouillon, sauerkraut, some types of beer or wine).

Other side effects of MAOIs may include sedation, agitation, confusion, insomnia, a sudden drop in blood pressure, and edema.

A disadvantage of most antidepressants is that side effects are often experienced before therapeutic effects. For example, someone taking an SSRI may have to endure uncomfortable side effects for six to eight weeks before seeing any therapeutic benefits (i.e., reduction of target symptoms). This can cause some people to discontinue antidepressant treatment before realizing any benefits.

Serotonin syndrome—a potentially lethal condition resulting from toxic levels of serotonin in the central nervous system—can result from combining antidepressants (SSRIs, MAOIs, TCAs, SNRIs, bupropion) with each other or with some opioids (e.g., tramadol, fentanyl), triptans (antimigraine medications), stimulants (e.g., amphetamines, cocaine), psychedelics (e.g., MDMA or Ecstasy), herbs (e.g., St. John’s wort), and various other medications and over-the-counter products.

Symptoms of Serotonin syndrome may include rapid heart rate, sweating, shivering, dilated pupils, tremor or twitching, muscular rigidity, elevated temperature, confusion, agitation, delirium, hallucinations, coma, or death. In 2002, the Toxic Exposure Surveillance SystemOpens in new window reported 26,733 incidents of toxic effects from SSRIs, resulting in 93 deaths (Boyer & Shannon, 2005). This is thought to be a conservative estimate due to underreporting and lack of physician awareness of serotonin syndrome, which occurs in 14 to 16 percent of individuals who overdose on SSRIs (Boyer & Shannon, 2005).

Combining antidepressants and alcohol is not advisable; alcohol, a depressant, can worsen clinical depression. Alcohol can also increase the toxicity of some types of antidepressants such as SSRIs.

Some antidepressants are started at a low (less than therapeutic) dose and are titrated (increased) upward until a therapeutic dosage is reached. This may be done to minimize side effects and to help gauge the most beneficial dose for an individual.

Sudden discontinuation of some types of antidepressants (SSRIs, MAOIs, some of the atypical) can result in a withdrawal syndrome. Withdrawal symptoms can vary but may include dizziness, nausea, sweating, insomnia, tremor, or confusion. A schedule for tapering off antidepressants should be discussed with a doctor.

Risks of taking antidepressants while pregnant vary by type of antidepressant. Some (e.g., TCAs and MAOIs) either show evidence of maternal harm or harm to the fetus, or risk cannot be ruled out. SSRI use during pregnancy may increase prenatal complications and adversely affect the newborn (Preston et al., 2008).

Antidepressants should only be taken as prescribed while under the care of a doctor. To avoid potentially harmful side effects and drug interactions, health care consumers should be sure that their doctors and pharmacists are aware of all medications they are taking, including over-the-counter medications, herbs and natural remedies, and dietary supplements.

The monoamine hypothesis—the main theory spurring development of earlier antidepressants such as TCAs, MAOIs, and SSRIs—holds that the antidepressant effect of these medications is achieved by inhibiting the reuptake or breakdown of monoamine neurotransmitters (such as serotonin and norepinephrine), allowing more of these neurotransmitters to be available for neurotransmission.

Recent research has shown that more complex mechanisms are at work. For example, some depressed people have been found to have elevated levels of cortisol (a stress hormone), deficiencies in brain-derived neurotrophic factor (BDNF; a substance involved in keeping neurons healthy), or atrophy in a brain structure, the hippocampus (Patterson, 2006).

While development of new antidepressant medications continues, the mechanism of action of many antidepressant medications is not clearly understood (Patterson, 2006).

See also:
  1. Agency for Healthcare Research and Quality. (2002). S-adenosyl-L-methionine for treatment of depression, osteoarthritis, and liver disease (Evidence Report/Technology Assessment No. 64, AHRQ Publication No. 02-E033).
  2. Lieberman, J.A. (2003). History of the use of antidepressants in primary care. Primary Care Companion, Journal of Clinical Psychiatry, 5 (Suppl. 7), 6 – 10.
  3. National Center for Complementary and Alternative Medicine. (2004). Get the facts: St. John’s wort (Hypericum perforatum) and the treatment of depression (NCCAM Publication No. D005).
  4. Patterson, J. (2006). Therapist’s guide to psychopharmacology: Working with patients, families, and physicians to optimize care. New York: Guilford.
  5. Preston, J.D., O’Neal, J.H., & Talaga, M.C. (2008). Handbook of clinical psychopharmacology for therapists (5th ed.). Oakland, CA: New Harbinger.