antidepressant

antidepressant, any member of a class of drugs prescribed to relieve depression. There are several major classes of antidepressant drugs, the best known of which include the tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). Other important groups include the norepinephrine reuptake inhibitors (NRIs), the serotonin-norepinephrine reuptake inhibitors (SNRIs), and the atypical antidepressants, a disparate group of agents that possess unique structural features and mechanisms of action.

Chemically speaking, depression is apparently caused by reduced quantities or reduced activity of the monoamine neurotransmitters (e.g., serotonin, norepinephrine, and dopamine) within the brain. This etiology is supported by evidence that drugs that restore chemical imbalances in the levels of neurotransmitters in the brain effectively mitigate symptoms of depression. All antidepressants, in fact, achieve their effects by inhibiting the body’s reabsorption or inactivation of monoamine neurotransmitters, thus allowing the neurotransmitters to accumulate and remain in contact with their receptors for prolonged periods of time; these changes seem to be important in elevating mood and relieving depression.

One of the first antidepressants to demonstrate success clinically was iproniazid, a drug developed originally for the treatment of tuberculosis. In the 1950s scientists discovered that the extreme euphoria and hyperactivity experienced by some patients who were taking iproniazid was caused by the drug’s inhibition of monoamine oxidase, an enzyme in the liver and brain that normally breaks down the monoamine neurotransmitters. Drugs that were better at blocking the activity of this enzyme were even more effective in evoking euphoria. As a group, these drugs came to be known as MAOIs.

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therapeutics: Antidepressant drugs

Also in the 1950s the first tricyclic antidepressants were discovered. These agents, so called because they are composed chemically of three carbon rings, inhibit the active reuptake, to varying degrees, of norepinephrine, serotonin, and dopamine in the brain. The tricyclics include imipramine, amitriptyline, desipramine, nortriptyline, and a number of other compounds. These drugs relieve symptoms in a high proportion (more than 70 percent) of depressed patients. As with the MAOIs, the antidepressant action of tricyclic drugs may not become apparent until two to four weeks after treatment begins.

SSRIs were introduced in the 1980s, and shortly thereafter they became some of the most commonly used antidepressants, primarily because they have fewer side effects than tricyclics or MAOIs. SSRIs include fluoxetine (Prozac), paroxetine (Paxil), and sertraline (Zoloft). SSRIs are also used in the treatment of anxiety, eating disorders, panic disorder, obsessive-compulsive disorder, and borderline personality disorder.

Other antidepressants inhibit the reuptake of monoamine neurotransmitters in variable amounts. For example, the SNRI venlafaxine blocks both serotonin and norepinephrine reuptake; therapeutic doses of the drug, however, also weakly inhibit dopamine reuptake. Nefazodone, an atypical antidepressant, inhibits serotonin and norepinephrine reuptake and is an antagonist at certain serotonin receptors and at α₁-adrenoceptors.

Three to four weeks are typically required to produce significant improvement in individuals who are taking antidepressant medications. Most physicians recommend that patients continue to take antidepressants for at least six months to prevent a relapse. The type of antidepressant that a physician prescribes depends largely on symptoms and severity of the condition and on the patient’s tolerance of side effects. For instance, the MAOIs—chiefly isocarboxazid, phenelzine, and tranylcypromine—in general are used only after treatment with tricyclic drugs has proved unsatisfactory, because these drugs’ side effects are unpredictable and their complex interactions are incompletely understood. Fluoxetine often relieves cases of depression that have failed to yield to tricyclics or MAOIs.

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Side effects vary among the types of antidepressants and may include sleepiness, tremors, anxiety, loss of sexual desire, and nausea. The possible side effects of tricyclics specifically include dry mouth, blurred vision, constipation, dizziness, and difficulty in urination. Cerebral and cardiac toxicity have been observed in some individuals. In rare instances, antidepressants may cause life-threatening side effects. For instance, nefazodone is associated with a low risk of death from hepatic (liver) failure; the discovery of this risk association resulted in the drug’s discontinuation in the United States. Many antidepressants also have the potential to produce dangerous drug interactions. This is especially true of MAOIs; the interaction of these drugs with tyramine, which is found in many foods as well as in wine and certain types of beer, can cause hypertension (high blood pressure) and severe headache.