Ensure delivery by adding featureseries@email.emedicine.com to your address book.

PHARMACOLOGIC TREATMENT OF MAJOR DEPRESSIVE DISORDER

Major depressive disorder (MDD) is a common disorder that is associated with substantial symptom severity and functional impairment. The prevalence of MDD in the United States is 16.2% (Kessler, 2003), affecting 5-13% of medical outpatients (Mann, 2005). Approximately 16% of people have a major depressive episode during their lifetime, but only 25-50% of these people contact a health care provider. Fifty percent of patients are incapacitated by their depression and are unable to function at work or at home as a result. The ability to function is likely directly related to depressed mood, making effective treatment paramount (Ebmeier, 2006). The symptoms of approximately 50% of moderate-to-severe major depressive episodes respond to treatment with antidepressants. Unfortunately, major depression is often underdiagnosed and, when correctly diagnosed, it is often undertreated (Mann, 2005).

Recent controversy has surrounded the worsening of depressive symptoms and suicidality in pediatric and adult patients being treated with antidepressants. A recent study computerized large records to address this potential risk. The study found that the rate of suicide death is similar to that reported in other community samples and antidepressant clinical trails. The study did not suggest increased risk of death or suicide during the first month of antidepressant treatment. Consistent with other studies, no evidence was found for any difference in suicide risk between drug classes. While closer monitoring of antidepressant treatment is clearly needed, concerns regarding increased suicide risk with antidepressant treatment may, unfortunately, discourage treatment. Frequency of follow-up care after starting an antidepressant is often insufficient, and more systematic follow-up care improves both adherence to treatment and clinical outcomes. Improvement in follow-up care after initiation of antidepressant treatment is clearly needed (Simon, 2006).

Role of the selective serotonin reuptake inhibitors and atypical antidepressants

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed and often regarded as the first-line treatment for depression (Taylor, 2006). A large body of evidence from approximately 50 randomized, placebo-controlled trials indicates that SSRIs are effective in treating depression and are superior to placebo. Over 50 studies indicate that SSRIs have comparable effectiveness to tricyclic antidepressants (TCAs). Furthermore, specific differences between individual SSRIs have not been observed (APA, 2000). SSRIs are known to cause adverse effects, including gastrointestinal distress, weight changes, activation or insomnia, sexual adverse effects, and neurological effects such as headaches. SSRI use has also been rarely associated with serotonin syndrome. Although serotonin syndrome usually occurs from the simultaneous use of multiple serotonergic agents, it has also been known to occur during the use of a single agent.

Serotonin-norepinephrine reuptake inhibitors (SNRIs) have been shown to be superior to placebo at treating depressive symptoms and have comparable efficacy to TCAs. SNRIs include venlafaxine and duloxetine and cause adverse effects similar to those caused by SSRIs (APA, 2000). Duloxetine may offer a new treatment for patients with neuropathic pain and stress urinary incontinence as well as depression (Westanmo, 2005).

The dopamine-norepinephrine reuptake inhibitor (DNRI) bupropion has also been shown to have comparable efficacy in treating depressive symptoms to both TCAs and SSRIs. The adverse effects of bupropion include headaches, tremors, and seizures. The risk of seizures decreases at doses less than 450 mg and with divided dosing.

The norepinephrine-serotonin modulator (NSM) mirtazapine is commonly associated with weight gain, increased cholesterol levels, and sedation.

Serotonin modulators include nefazodone and trazodone and are less commonly used for depression. Trazodone is primarily used in clinical practice for its sedative properties (APA, 2000).

Role of TCAs and monoamine oxidase inhibitors

Hundreds of randomized controlled trials have established that TCAs improve the symptoms of MDD. Once widely prescribed for depression, these medications are limited by their toxicity in overdose and adverse effect profiles. TCAs can cause dangerous adverse effects, including orthostatic hypotension, arrhythmia, and anticholinergic effects.

Monoamine oxidase inhibitors (MAOIs) have been shown to have antidepressant effects similar to those of TCAs. MAOIs are not the first-line treatment for depressive symptoms because patients who take MAOIs must adhere to a diet low in tyramine to prevent a hypertensive crisis. MAOIs also carry greater drug interaction risks than other medications (Mann, 2005). They can be potentially lethal when combined with SSRIs, as they have the potential to cause serotonin syndrome. When prescribing, keep in mind that patients must wait 2 weeks after discontinuing an SSRI to start an MAOI and that patients must wait even longer (5 wk) with the SSRI fluoxetine, as it has a longer half-life than other SSRIs. Other adverse effects, such as orthostatic hypotension, weight gain, sexual adverse effects, headache, and insomnia, have been noted with MAOIs (APA, 2000). More recently, several placebo-controlled trials have demonstrated that selegiline, an MAOI transdermal patch, has antidepressant effects. Selegiline transdermal targets inhibition of brain monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B) enzyme activity without increasing the sensitivity to dietary tyramine. As a result, the transdermal patch provides the antidepressant effects of an MAOI without the need for the tyramine-restricted diet (Amsterdam, 2003).

Treatment guidelines for MDD

The treatment of MDD breaks down into 3 phases: acute, continuation, and maintenance. Antidepressants are often indicated during the acute phase. Because antidepressants are generally comparable between and within classes, they are largely selected based on anticipated adverse effects, tolerability, safety, patient preference, cost, and evidence basis. In clinical practice, SSRIs are often the first choice because of the favorable adverse effect profile. They are followed by SNRIs, DNRIS, NSMs, and TCAs. Oral MAOIs should be restricted to use in refractory depression (APA, 2000).

Once antidepressant therapy is initiated, patients should be carefully monitored for response to the medication, possible adverse effects, clinical condition, and safety (APA, 2000). Patients should also be monitored for antidepressant-induced mania (Goldberg, 2003). Frequent monitoring should address suicidality and medication compliance. Pharmacotherapy should be integrated with other treatments such as psychotherapy. If at least moderate improvement is not observed 6-8 weeks into treatment, physicians should consider changing the dose, augmenting the antidepressant, and adding or changing psychotherapy or electroconvulsive therapy (ECT). These changes in treatment should also be considered if patients have a substantial but incomplete response during the acute phase (APA, 2000).

During the continuation phase (the 16-20 wk following remission), patients should be maintained on their medication at the acute phase dose to prevent relapse. The decision to discontinue treatment should be based on the same factors that determined the acute phase treatment and should include risk factors for recurrence of MDD, such as frequency and severity of past episodes, persistence of dysthymic symptoms after recovery from a major depressive episode, and the presence of comorbid disorders (APA, 2000).

References

American Psychiatric Association. Practice guideline for the treatment of patients with major depressive disorder (revision). Am J Psychiatry 2000;157:1-45.

Amsterdam JD. A double-blind, placebo-controlled trial of the safety and efficacy of selegiline transdermal system without dietary restrictions in patients with major depressive disorder. J Clin Psychiatry 2003;64:208-14.

Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. The Lancet 2006;367:153-67.

Goldberg JF, Truman CJ. Antidepressant-induced mania: an overview of current controversies. Bipolar Disord 2003:5;407-20.

Kessler RC, Berglund PB, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003:289;3095-105.

Mann JJ. The medical management of depression. NEJM 2005;353:1819-34.

Simon GE, Savarino J, Operskalski B, Wang PS. Suicide risk during antidepressant treatment. Am J Psychiatry 2006;163:41-7.

Westanmo AD, Gayken J, Haight R. Duloxetine: a balanced and selective norepinephrine- and serotonin-reuptake inhibitor. Am J Health Syst Pharm 62;2481-90.