Major depressive disorder

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Major depressive disorder, along with anxiety, is one of the most frequently occurring general psychiatric disorders. It is characterized by symptoms of depression, generalized melancholy, retreat from social contact, disrupted sleep patterns, akathisia, or a feeling of restlessness and increased movement, and anhedonia, or a diminished ability to experience pleasure.


The development of depression is influenced by a organic, environmental, and genetic factors, with genetics contributing about one third[1] or more[2]. The organic factors contributing to depression include a general systemic dysregulation that involves a disruption of neurotransmitters. This condition can be acute, or on-going, and is generally corrected, in both cases, through medication. Environmental factors can contribute to depression by either triggering a recurrent episode of chronic depression, or advancing a situational depression.


Community studies generally show a varying prevalence of depression, with estimates of occurrence between 5 and 7.5%. The one-year prevalence of major depressive disorder in the United States of America varies from 3% in the Epidemiological Catchment Area Study [3] to 10% in the National Co-morbity Study. [4]

Monoamine-Deficiency Hypothesis

Depression may be due to "deficiency in serotonin or norepinephrine neurotransmission in the brain."[5]


The core symptoms of depression are depressed mood and a lack of interest or pleasure from daily activities (anhedonia). Several additional features may be present, like lack of concentration, inappropriate guilt feelings, suicidal thoughts, psychomotor retardation or agitation and loss of libido. A diurnal variation, e.g. the symptoms are worse in the morning, may be present.

Primary care physicians and other non-psychiatrists physicians have difficulty diagnosing depression. Non-psychiatrists miss two-thirds of cases and unnecessarily treat other patients.[6][7].

DSM-IV diagnostic criteria

Note: The American Psychiatric Association, which publishes the Diagnostic and Statistical Manual of Mental Disorders, forbids the unauthorized reproduction of their diagnostic criteria. A narrative of the DSM-IV-TR criteria follows. The DSM-IV has created nine diagnostic criteria based on symptoms of depression. At least five of these should be present for two weeks in the absence of other explanations for the symptoms.

Alternative diagnostic strategies

Patient Health Questionnaire 2

The Patient Health Questionnaire (PHQ2) is a shorter questionnaire that may be as sensitive as the DSM-IV.[8] It has also been validated in elderly patients.[9] The accuracy of the PHQ2 with a score of 3 or more is:[10].

  • Sensitivity 83%
  • Specificity 92%

Question Not at all Several days More than half the days Nearly every day
Little interest or pleasure in doing things 0 1 2 3
Feeling down, depressed, or hopeless 0 1 2 3

"During the past month, have you often been bothered by:"

  1. "little interest or pleasure in doing things?"
  2. "feeling down, depressed, or hopeless?"

If the PHQ2 is positive, then the SALSA questionnaire may be used to increase specificity[11]. A positive test is one of the above answers positive and two of the answers below positive:

  1. Sleep disturbance nearly every day for the last 2 weeks?
  2. Have you experienced little interest or pleasure in doing things nearly every day for the last 2 weeks (Anhedonia)?
  3. Have you experienced Low Self esteem nearly every day for the last 2 weeks?
  4. Have you experienced decreased Appetite nearly every day for the last 2 weeks?"

Patient Health Questionnaire 9

If the patient is diagnosed with depression, the Patient Health Questionnaire 9 (PHQ9) may measure severity[12] and follow response to treatment.[13] A clinically relevant change is a PHQ-9 change of 5 or greater.[13] The PHQ-9 is available online in English and Spanish from the MacArthur Initiative.[14] A meta-analysis of accuracy is available.[15]


Clinical practice guidelines are available from the American Psychiatric Association.[16]

Complementary alternative medicine


L-Methylfolate may not be helpful.[17]

S-adenosyl methionine (SAMe)

S-Adenosylmethionine may be beneficial according to a randomized controlled trial.[18]

St. John's wort

Hypericum perforatum (St. John's wort) has conflicting evidence regarding its effectiveness.[19][20] For unclear reasons, the positive studies all were performed in Germany.[21][19] Publication bias has been especially noted in German studies of complementary alternative medicine.

A meta-analysis by the Cochrane Collaboration concluded:[22]

"the available evidence suggests that the hypericum extracts tested in the included trials a) are superior to placebo in patients with major depression; b) are similarly effective as standard antidepressants; c) and have fewer side effects than standard antidepressants. The association of country of origin and precision with effects sizes complicates the interpretation"

Nonmedical therapy

Music therapy may help.[23]

Cognitive behavioral therapy can reduce symptoms of major depression in geriatric patients although only a minority of patients have a reduction in symptoms of 50%.[24]

Exercise may help geriatric patients.[25]

Hypericum extracts (St John's wort) may help according to the Cochrane Collaboration. [22]

Direct contact person-to-person prayer may be useful according to randomized controlled trials. [26][27]


For more information, see: Second-generation antidepressant and Antidepressant.

According to the STAR*D randomized controlled trial, about 50% of patients with major depression have a response and about 30% of have remission of symptoms with usage of citalopram.[28]

Regarding the use of second-generation antidepressants, clinical practice guidelines by the American College of Physicians[29] with accompanying systematic review[30] and updated systematic review[31] recommend:

  • "when clinicians choose pharmacologic therapy to treat patients with acute major depression, they select second-generation antidepressants on the basis of adverse effect profiles, cost, and patient preferences"
  • "second-generation antidepressants did not significantly differ in efficacy, effectiveness, or quality of life. Mirtazapine had a significantly faster onset of action"
  • "when treating symptom clusters in patients with accompanying depression, second-generation antidepressants did not differ in efficacy in treating accompanying anxiety, pain, and somatization. Limited evidence suggests that some agents may be more effective in treating insomnia"
  • "most of the second-generation antidepressants had similar adverse effects...paroxetine was associated with an increased risk for sexual dysfunction."

Starting treatment with combination therapy may increase effectiveness.[32]

Low folate levels may be associated with treatment resistance[33] and increased risk of relapse after treatment of depression[34]. Folic acid supplementation may[35] or may not help. A systematic review of trials though 2004 concluded "limited available evidence suggests folate may have a potential role as a supplement to other treatment for depression. It is currently unclear if this is the case both for people with normal folate levels, and for those with folate deficiency.."[36] New trials are ongoing.[37] Folic acid may not[38] prevent depression.

Predictors of a response to treatment

Severity of depression

The effectiveness is antidepressants may[39] or may not[40] depend on the severity of a patient's depression. This relationship may be due to the declining effect of placebo among more severely depressed patients.

The effectiveness of antidepressants depending on severity of depression[39]
American Psychiatric Association
classification of severity[41]
Hamilton Depression Rating Scale
Number needed to treat[39] Clinical significance
Mild to moderate < 19 16 No
Severe 19 - 22 11 No
Very severe > 22  4 Yes

Genetic variations

Variations in the GRIK4 (glutamate receptor, ionotropic, kainate 4 protein) and HTR2A (5-hydroxytryptamine receptor) genes predict response to citalopram.[43]

Treatment failure

Treatment after SSRI (citalopram) failure
(STAR*D Studies)
Intervention Outcome
Medication Mean final dose Remision % Quit 2˚ ADRs (%)
Switch meds (NEJM 2006; PMID: 16554525[44])
Bupropion SR 283 mg 21% 27%
Sertraline (SSR) 136 mg 18% 21%
Venlafaxine ER (SNRI) 194 mg 25% 21%
Augment meds (NEJM 2006; PMID: 16554526[45])
Bupropion SR 268 mg 30% 13%
Buspirone 41 mg 30% 21%

When treated with monotherapy for depression, approximately 30% of patients have remission of symptoms while 50% have a response to medications.[28] For patients with inadequate response, either adding sustained-release bupropion ("bupropion was 200 mg per day during weeks 1 and 2, increasing to 300 mg per day by week 4 and to 400 mg per day (the final dose) during week 6") or buspirone (up to 60 mg per day) for augmentation as a second drug can cause remission in approximately 30% of patients (bupropion may be more effective than buspirone)[45], while switching medications can achieve remission in about 25% of patients[44]. Alternatively, "extended-release venlafaxine, the starting daily dose of 37.5 mg for 7 days was increased to 75 mg from day 8 to 14, to 150 mg from day 15 to 27, to 225 mg from day 28 to 41, to 300 mg from day 42 to 62, and to 375 mg from day 63 onward."[44]

The STAR*D trial has reported the frequency of re-emrgence of suicidality for different second levels of treatment.[46]

In level 3 of the STAR*D trials, patients who had failed two trials of a second-generation antidepressant, tended to better with nortriptyline than mirtazapine.[47]

Aripiprazole, originally introduced as an atypical antipsychotic agent, is approved as an adjunct to other antidepressants.[48]


Screening asymptomatic patients appears to have no impact on the care of patients with depression.[49]


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