Antidepressant Medications

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Medications effective in reducing the symptoms of major depression are called antidepressants. The Food and Drug Administration requires controlled, double-blind studies showing safety and efficacy before approving an antidepres-sant medication to be available in the United States.

Major Depressive Disorder is characterized by sadness and an inability to experience pleasure. Associated symptoms include decreased self-esteem, feelings of hopelessness and worthlessness, excessive guilt, and difficulty with concentration, memory, and decision making. Anxiety manifested as fear, nervousness, or excessive worry is also common in depression. Agreater focus on bodily sensations can result in somatic symptoms. Sleep difficulties marked by reduced or excessive sleep, and a change in appetite with consequent weight loss or gain, are also present. Suicidal ideas can lead to suicidal attempts with the potential to succeed. The diagnosis of major depression requires these symptoms to be present fairly continuously for a minimum of 2 weeks and to be associated with significant distress or impairment in role function.

There are different forms of major depression, including one seen in bipolar disorder in which individuals have episodes of not only depression but also forms of mania; melancholia, characterized by symptoms like a distinct quality of sadness, inability to experience pleasure, and early morning awakening; and atypical depression, which is more responsive to environmental events and associated with an increase in appetite and need for sleep. The presence of depressive symptoms that fall below the threshold of criteria for major depression is called by various names: dysthymia (which is a chronic lower-grade depression and still impairing), depressive symptoms in response to negative life events, and minor depression.

Depression is believed to arise from a combination of genetic vulnerabilities and environmental factors. Traumatic experiences, particularly if they occur in childhood, are a potential environmental risk factor for the development of depression.

Medications to treat depression are classified based on their chemical structure and pharmacological effect. Three major classes of antidepressants are available in the United States. These are the tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs). The initial effects of these medications in the brain are primarily on two chemical messengers called neurotransmitters—norepinephrine and serotonin. The TCAs have a prominent effect in blocking the recycling of norepinephrine. Commonly used TCAs included imipramine (trade name Tofranil), amitryptaline (Elavil), doxepin (Sinequan), desipramine (Norpramin), and nortriptyline (Pamelor and Aventyl). One TCA, clomipramine (Anafranil), also powerfully blocks the recycling of serotonin. The MAOIs inhibit an enzyme, monoamine oxidase, that is important in the physiological breakdown of norep-

inephrine and serotonin. Commonly used MAOIs include phenelzine (Nardil) and tranylcypramine (Parnate). The SSRIs selectively block the recycling of serotonin. These include fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), and citalopram (Celexa).

Some antidepressant medications do not fall easily into the above groups. Buproprion (Wellbutrin) is believed to block the recycling of norepinephrine as well as another neurotransmitter, dopamine. Venlafaxine (Effexor) blocks the recycling of both serotonin and norepinephrine. Nefa-zodone (Serzone) blocks the recycling of serotonin and additionally a specific serotonin receptor. Mirtazapine (Re-meron) impacts a specific norepinephrine receptor on the serotonin cell, increasing its firing rate while simultaneously blocking some serotonin receptors.

The benefits of antidepressant medications are rarely immediate but accrue gradually over several weeks. They appear to modulate primary negative emotional responses like anxiety in structures like the amygdala, such that cognitive and executive choices are more available to drive behavioral responses. The maximum benefit may not plateau until several months. The initial effect of antidepressants begins a cascade of events in critical neurons that are ultimately believed to alter the expression of specific genes. Recent studies suggest that antidepressants enhance the activity of neurotropic agents that impact neurogenesis. This process is gradual, thus the delay in obtaining the full benefits of antidepressant medications.

In addition to their therapeutic benefits, antidepressant medications also have unwanted effects. These side effects can be explained by their pharmacological effects in areas other than the sites involved in their beneficial effects, or by their effects on other receptors. The TCAs appear to have the largest number of such unwanted effects, including potential effects on the electrical conduction system in the heart. This effect makes them particularly dangerous if taken in overdose. The TCAs'effects on the cholinergic, his-taminergic, and alpha-1 adrenergic receptors mediate the majority of their adverse effects. MAOIs indiscriminately inhibit the monoamine oxidase enzyme, and as a result they have the potential to interact with other specific medications or with food substances like cheese. Such an interaction may increase blood pressure, which, if high enough, can cause strokes and even death. The newer antidepres-sants like the SSRIs, because of their greater selectivity in their pharmacological actions, are less likely to cause serious side effects. However, with the exception of buproprion, nefazodone, and mirtazapine, their potential for causing sexual side effects seems to be greater.

Antidepressants have been increasingly recognized as being effective in a variety of other conditions other than major depression. These include dysthymia and the anxiety disorders like Generalized Anxiety Disorder, Panic Disorder, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, and Social Anxiety Disorder.

In a general group of patients with major depression, roughly 10-20% are intolerant to the first antidepressant tried. Of the remaining, roughly half are able to tolerate the medications without any significant side effects. Side effects, when they occur, may fade as the individual gets used to the medication. Occasionally, side effects develop gradually over time.

An adequate trial of an antidepressant requires a minimum of a month or two on an adequate dose. Roughly two thirds of the individuals will obtain at least a 50% reduction in the severity of their depressive symptoms. One quarter to one third may achieve remission, which is considered a full or close to a full level of response. Those who fail to respond might respond to either switching the medication to another class of antidepressants or augmenting the first antidepressant with one of several choices. Individuals who fail to respond to antidepressant medications may respond to electroconvulsive therapy, believed to be the most powerful treatment available for major depression.

Philip T. Ninan

Emory University School of Medicine

See also: Anxiety Disorders; MAO Inhibitors; Tricyclic Antidepressants

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