Depression Epidemiology and Its Treatment Evolution

Robert M. A. Hirschfeld, MD

Department of Psychiatry and Behavioral Sciences, University of Texas Medical Branch, Galveston

Epidemiology of Depression

AV 1. Lifetime Prevalence of Depression in US Adults By Age and Gender (00:22)

Data from Kessler et al1

Depression is a prevalent and pernicious illness with a mean age at onset of 26 years. Depression is considerably more frequent in women than in men (AV 1).1 In the United States, 8% of adults experience a major depressive episode in any 12-month period and about 20% have at least one episode in their lifetime.1

With regard to clinical course, nearly half of all patients experiencing an MDE recovered within 6 months; by 1 year, more than two-thirds; and by 2 years, 80%.2 This left 1 in 5 patients continuously depressed for 2 years, most of whom stayed depressed for at least 5 years (12%). Of those who recovered from a depressive episode, most had a recurrence (85% within 2 years). Over the long term (15-year follow-up), only 1 in 9 recovered from their episode of depression and stayed well.3

Depression exacts a heavy psychosocial toll. People with major depression have substantial long-term psychosocial disability and functional impairment4 and have at least some depressive symptoms more than half of the time.5 In fact, the WHO places depression as the third-highest in terms of disease burden in the world.6

A crucial issue to address when evaluating a patient who presents with depression is whether the patient has unipolar depression or bipolar depression. The clinical course and treatment differs substantially for these 2 disorders. The presence of bipolar disorder is easy to miss in depressed patients because many depressed bipolar patients fail to mention prior manic or hypomanic episodes. For example, one study7 of patients diagnosed with major depression found that 20% of participants had experienced mania or hypomania (8% bipolar I and 12% bipolar II).

Treatment Evolution

AV 2. Timeline: Somatic Treatments for Depression (00:39)

Abbreviations are defined before the References

Treatments for MDD, particularly pharmacologic treatments, have advanced considerably over the last 100 years (AV 2).

Seizure or convulsive treatments. The first somatic treatments for depression that emerged in the 20th century evolved from serendipitous observations of patients undergoing seizures. The Hungarian psychiatrist Ladislaus von Meduna induced seizures in the 1920s and 1930s with Metrazol in patients with schizophrenia. In the 1930s, insulin-induced hypoglycemic coma and seizures were found to calm patients with schizophrenia. In the late 1930s, Ugo Cerletti and Lucio Bini reported that they had induced seizures in Italy by passing electrical current through the brain—a technique that was much more controllable and safer than previous methods, beginning the first ECT treatments.

Amphetamine. During the 1930s came the first antidepressant medicine of the 20th century—amphetamine. Originally developed for the treatment of asthma and hay fever and subsequently found ineffective for schizophrenia and anxiety, amphetamine was shown to relieve mild depression, particularly anhedonia.8 Positive clinical trials comparing amphetamine with placebo led to its inclusion in AMA treatment guidelines for mood elevation in depression in 1937. By the mid 1940s, more than a million amphetamine tablets were being consumed daily in the United States, for not only mood elevation but also weight loss. Nonprescription abuse of amphetamine spread quickly, and safety concerns, coupled with the introduction of newer drugs in the 1960s, led to the decline of amphetamine to treat depression.


Tricyclic antidepressants. During World War II, a search for antimalarial drugs ushered in modern psychopharmacology with the creation of new agents. Modification of the phenothiazine dye methylene blue led to the synthesis of chlorpromazine in 1950.9 Although ineffective for malaria, chlorpromazine had powerful antihistaminic qualities, particularly sedation and anxiety reduction, and was beneficial in patients with mania and schizophrenia.10 By 1957, a compound closely related chemically to chlorpromazine—imipramine—was found to improve mood in patients with depression.11 These discoveries led to the development of several other TCAs that were widely used. The mechanism of action of the TCAs was to block the reuptake of specific neurotransmitters in the synapse—serotonin and norepinephrine—which produced an antidepressant effect.

Monoamine oxidase inhibitors. In the 1950s, George Crane observed that patients with tuberculosis who were treated with the MAOI iproniazid had substantially improved mood.12 Use of iproniazid as a mood elevator was discontinued because of substantial liver toxicity. Similar drugs that were less toxic, such as tranylcypromine and phenelzine, were developed. The mechanism of action of the MAOIs differs from that of the TCAs. The MAOIs increase synaptic catecholamines by inhibiting the enzyme monoamine oxidase, which metabolizes them. Currently, MAOIs may be the most effective medications available to treat depression, but their widespread use has been limited by dietary restrictions and the potential for serious adverse events through drug-drug interactions.

The catecholamine hypothesis. The presumed mechanism of action of the tricyclics and of the MAOIs led scientists to develop a comprehensive theory of the pathophysiology of depression—the catecholamine hypothesis. Simply put, this hypothesis states that depression results from a deficiency of catecholamines (particularly serotonin and norepinephrine) in synapses in the brain. Elation results from an excess of such amines.

Mixed-action antidepressants. In the 1980s and 1990s, medications with other mechanisms of action were developed.13 Trazodone and nefazodone inhibit norepinephrine and serotonin reuptake and act as an antagonist of serotonin. Bupropion has dual inhibition of norepinephrine and dopamine reuptake, and mirtazapine acts as an antagonist of noradrenergic and serotonergic neurotransmission.

Selective serotonin reuptake inhibitors. A major change in the treatment of depression occurred with the development of SSRIs. These medications were specific inhibitors of serotonin reuptake into afferent neurons.14 The FDA approved the first SSRI, fluoxetine, in 1987, and the development of several other SSRIs quickly followed.

The SSRIs do not necessarily offer increased efficacy over the TCAs or the MAOIs; they do, however, have attractive properties. Unlike TCAs, SSRIs are not lethal in overdose and do not cause cardiac arrhythmia problems.15 In general, the SSRIs cause less sedation and weight gain and have fewer anticholinergic side effects than earlier antidepressants15 and do not require dietary restrictions. Dose titration is generally simpler. The improved safety and tolerability profiles of SSRIs have led to their widespread use. They surpassed use of all other antidepressant agents by the mid-1990s.

Dual-reuptake inhibitors. In the 1990s, several dual-reuptake inhibitors were developed to inhibit both norepinephrine and serotonin reuptake. The intent was to provide greater efficacy than SSRIs and cause fewer side effects than other agents that affect both serotonin and norepinephrine (eg, MAOIs, TCAs, mixed-action agents) by avoiding additional action at other receptors.16 The best known SNRIs are venlafaxine, which was approved by the FDA in 1994, and duloxetine, approved in 2004.


Depression continues to be a pernicious, debilitating illness. Clinicians now have a wide variety of treatment options for patients who present with depression. Since the TCAs and MAOIs were developed, however, no truly novel mechanisms of action have arisen in the antidepressant armamentarium. Although many treatments were discovered serendipitously, the search for improved safety and tolerability has driven the recent evolution of treatment in an effort to increase patients’ adherence. Some of the current treatment options are considerably underused and clinicians should continue to be alert for new and better treatments.

For Clinical Use


  • Monitor patients with depression for any sign of manic or hypomanic symptoms
  • Address residual symptoms of depression
  • Consider treatments other than SSRIs for patients with depression


Drug Names

bupropion (Wellbutrin, Aplenzin, and others), duloxetine (Cymbalta), fluoxetine (Prozac and others), imipramine (Tofranil and others), isocarboxazid (Marplan), mirtazapine (Remeron and others), phenelzine (Nardil), trazodone (Oleptro and others), tranylcypromine (Parnate and others), venlafaxine (Effexor and others)


AMA = American Medical Association, ECT = electroconvulsive therapy, FDA = US Food and Drug Administration, MAOI = monoamine oxidase inhibitor, MDD = major depressive disorder, MDE = major depressive episode, NDRI = norepinephrine-dopamine reuptake inhibitor, SARI = serotonin agonist and reuptake inhibitor, SNRI = serotonin-norepinephrine reuptake inhibitor, SSRI = selective serotonin reuptake inhibitor, TCA = tricyclic antidepressant, TeCA = tetracyclic antidepressant, WHO = World Health Organization

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