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Chapter: Basic & Clinical Pharmacology : Antidepressant Agents

Clinical Indications - Clinical Pharmacology of Antidepressants

The FDA indication for the use of the antidepressants in the treat-ment of major depression is fairly broad.


Clinical Indications

A. Depression

The FDA indication for the use of the antidepressants in the treat-ment of major depression is fairly broad. Most antidepressants are approved for both acute and long-term treatment of major depres-sion. Acute episodes of MDD tend to last about 6–14 months untreated, but at least 20% of episodes last 2 years or longer.

The goal of acute treatment of MDD is remission of all symp-toms. Since antidepressants may not achieve their maximum benefit for 1–2 months or longer, it is not unusual for a trial of therapy to last 8–12 weeks at therapeutic doses. The antidepres-sants are successful in achieving remission in about 30–40% of patients within a single trial of 8–12 weeks. If an inadequate response is obtained, therapy is often switched to another agent or augmented by addition of another drug. For example, bupropion, an atypical antipsychotic, or mirtazapine might be added to an SSRI or SNRI to augment antidepressant benefit if monotherapy is unsuccessful. Seventy to eighty percent of patients are able to achieve remission with sequenced augmentation or switching strategies. Once an adequate response is achieved, continuation therapy is recommended for a minimum of 6–12 months to reduce the substantial risk of relapse.

Approximately 85% of patients who have a single episode of MDD will have at least one recurrence in a lifetime. Many patients have multiple recurrences, and these recurrences may progress to more serious, chronic, and treatment-resistant episodes. Thus, it is not unusual for patients to require maintenance treatment to pre-vent recurrences. Although maintenance treatment studies of more than 5 years are uncommon, long-term studies with TCAs, SNRIs, and SSRIs suggest a significant protective benefit when given chronically. Thus, it is commonly recommended that patients be considered for long-term maintenance treatment if they have had two or more serious MDD episodes in the previous 5 years or three or more serious episodes in a lifetime.

It is not clear whether antidepressants are useful for all sub-types of depression. For example, patients with bipolar depression may not benefit much from antidepressants even when added to mood stabilizers. In fact, the antidepressants are sometimes asso-ciated with switches into mania or more rapid cycling. There has also been some debate about the overall efficacy of antidepres-sants in unipolar depression, with some meta-analyses showing large effects and others showing more modest effects. Although this debate is not likely to be settled immediately, there is little debate that antidepressants have important benefits for most patients.

Psychotherapeutic interventions such as cognitive behavior therapy appear to be as effective as antidepressant treatment for mild to moderate forms of depression. However, cognitive behav-ior therapy tends to take longer to be effective and is generally more expensive than antidepressant treatment. Psychotherapy is often combined with antidepressant treatment, and the combina-tion appears more effective than either strategy alone.

B. Anxiety Disorders

After major depression, anxiety disorders represent the most com-mon application of antidepressants. A number of SSRIs and SNRIs have been approved for all the major anxiety disorders, including PTSD, OCD, social anxiety disorder, GAD, and panic disorder. Panic disorder is characterized by recurrent episodes of brief overwhelming anxiety, which often occur without precipi-tant. Patients may begin to fear having an attack, or they avoid situations in which they might have an attack. In contrast, GAD is characterized by a chronic, free-floating anxiety and undue worry that tends to be chronic in nature. Although older antide-pressants and drugs of the sedative-hypnotic class are still occa-sionally used for the treatment of anxiety disorders, SSRIs and SNRIs have largely replaced them.

The benzodiazepines  provide much more rapid relief of both generalized anxiety and panic than do any of the antidepressants. However, the antidepressants appear to be at least as effective and perhaps more effective than benzodiazepines in the long-term treatment of these anxiety disorders. Furthermore, antidepressants do not carry the risks of dependence and tolerance that may occur with the benzodiazepines.

OCD is known to respond to serotonergic antidepressants. It is characterized by repetitive anxiety-provoking thoughts (obses-sions) or repetitive behaviors aimed at reducing anxiety (compul-sions). Clomipramine and several of the SSRIs are approved for the treatment of OCD, and they are moderately effective. Behavior therapy is usually combined with the antidepressant for additional benefits.

Social anxiety disorder is an uncommonly diagnosed but a fairly comon condition in which the patient experiences severe anxiety in social interactions. This anxiety may limit their ability to function adequately in their jobs or interpersonal relationships. Several SSRIs and venlafaxine are approved for the treatment of social anxiety. The efficacy of the SSRIs in the treatment of social anxiety is greater in some studies than their efficacy in the treat-ment of MDD.

PTSD is manifested when a traumatic or life-threatening event results in intrusive anxiety-provoking thoughts or imagery, hyper-vigilance, nightmares, and avoidance of situations that remind the patient of the trauma. SSRIs are considered first-line treatment for PTSD and can benefit a number of symptoms including anxious thoughts and hypervigilance. Other treatments, including psycho-therapeutic interventions, are usually required in addition to antidepressants.

C. Pain Disorders

It has been known for over 40 years that antidepressants possess analgesic properties independent of their mood effects. TCAs have been used in the treatment of neuropathic and other pain conditions since the 1960s. Medications that possess both nor-epinephrine and 5-HT reuptake blocking properties are often useful in treating pain disorders. Ascending corticospinal mono-amine pathways appear to be important in the endogenous anal-gesic system. In addition, chronic pain conditions are commonly associated with major depression. TCAs continue to be com-monly used for some of these conditions, and SNRIs are increas-ingly used. In 2010, duloxetine was approved for the treatment of chronic joint and muscle pain. As mentioned earlier, milnaci-pran has been approved for the treatment of fibromyalgia. Other SNRIs, eg, desvenlafaxine, are being investigated for a variety of pain conditions from postherpetic neuralgia to chronic back pain.

D. Premenstrual Dysphoric Disorder

Approximately 5% of women in the child-bearing years will have prominent mood and physical symptoms during the late luteal phase of almost every cycle; these may include anxiety, depressed mood, irritability, insomnia, fatigue, and a variety of other physi-cal symptoms. These symptoms are more severe than those typi-cally seen in premenstrual syndrome (PMS) and can be quite disruptive to vocational and interpersonal activities. The SSRIs are known to be beneficial to many women with PMDD, and fluox-etine and sertraline have been approved for this indication. Treating for 2 weeks out of the month in the luteal phase may be as effective as continuous treatment. The rapid effects of SSRIs in PMDD may be associated with rapid increases in pregnenolone levels.

E. Smoking Cessation

Bupropion was approved in 1997 as a treatment for smoking ces-sation. Approximately twice as many people treated with bupro-pion as with placebo have a reduced urge to smoke. In addition, patients taking bupropion appear to experience fewer mood symp-toms and possibly less weight gain while withdrawing from nico-tine dependence. Bupropion appears to be about as effective as nicotine patches in smoking cessation. The mechanism by which bupropion is helpful in this application is unknown, but the drug may mimic nicotine’s effects on dopamine and norepinephrine and may antagonize nicotinic receptors. Nicotine is also known to have antidepressant effects in some people, and bupropion may substitute for this effect.

Other antidepressants may also have a role in the treatment of smoking cessation. Nortriptyline has been shown to be helpful in smoking cessation, but the effects have not been as consistent as those seen with bupropion.

F. Eating Disorders

Bulimia nervosa and anorexia nervosa are potentially devastating disorders. Bulimia is characterized by episodic intake of large amounts of food (binges) followed by ritualistic purging through emesis, the use of laxatives, or other methods. Medical complica-tions of the purging, such as hypokalemia, are common and dan-gerous. Anorexia is a disorder in which reduced food intake results in a loss of weight of 15% or more of ideal body weight, and the person has a morbid fear of gaining weight and a highly distorted body image. Anorexia is often chronic and may be fatal in 10% or more of cases.

Antidepressants appear to be helpful in the treatment of buli-mia but not anorexia. Fluoxetine was approved for the treatment of bulimia in 1996, and other antidepressants have shown benefit in reducing the binge-purge cycle. The primary treatment for anorexia at this time is refeeding, family therapy, and cognitive behavioral therapy.

Bupropion may have some benefits in treating obesity. Nondepressed, obese patients treated with bupropion were able to lose somewhat more weight and maintain the loss relative to a similar population treated with placebo. However, the weight loss was not robust, and there appear to be more effective options for weight loss.

G. Other Uses for Antidepressants

Antidepressants are used for many other on- and off-label appli-cations. Enuresis in children is an older labeled use for some TCAs, but they are less commonly used now because of their side effects. The SNRI duloxetine is approved in Europe for the treatment of urinary stress incontinence. Many of the serotoner-gic antidepressants appear to be helpful for treating vasomotor symptoms in perimenopause. Desvenlafaxine is under consider-ation for FDA approval for the treatment of these vasomotor symptoms, and studies have suggested that SSRIs, venlafaxine, and nefazodone may also provide benefit. Although serotonergic antidepressants are commonly associated with inducing sexual adverse effects, some of these effects might prove useful for some sexual disorders. For example, SSRIs are known to delay orgasm in some patients. For this reason, SSRIs are sometimes used to treat premature ejaculation. In addition, bupropion has been used to treat sexual adverse effects associated with SSRI use, although its efficacy for this use has not been consistently dem-onstrated in controlled trials.

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