Major depressive disorder

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This editable Main Article is under development and subject to a disclaimer.

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## Contents

* 1 Cause/etiology
* 1.1 Epidemiology
* 2 Monoamine-Deficiency Hypothesis
* 3 Diagnosis
* 3.1 DSM-IV diagnostic criteria
* 3.2 Alternative diagnostic strategies
* 3.2.1 Patient Health Questionnaire 2
* 3.3 Patient Health Questionnaire 9
* 4 Treatment
* 4.1 Complementary alternative medicine
* 4.1.1 L-Methylfolate
* 4.1.2 S-adenosyl methionine (SAMe)
* 4.1.3 St. John's wort
* 4.2 Nonmedical therapy
* 4.3 Medications
* 4.3.1 Predictors of a response to treatment
* 4.3.1.1 Severity of depression
* 4.3.1.2 Genetic variations
* 4.3.2 Treatment failure
* 5 Screening
* 6 References

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.

## Cause/etiology[edit]

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.

### Epidemiology[edit]

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[edit]

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

## Diagnosis[edit]

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[edit]

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[edit]

#### Patient Health Questionnaire 2[edit]

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%

PHQ2  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[edit]

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]

## Treatment[edit]

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

### Complementary alternative medicine[edit]

#### L-Methylfolate[edit]

L-Methylfolate may not be helpful.[17]

#### S-adenosyl methionine (SAMe)[edit]

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

#### St. John's wort[edit]

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[edit]

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]

### Medications[edit]

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[edit]

##### Severity of depression[edit]

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
(HDRS)!!Number needed to treat[39]!!Clinical significance
(NICE)[42] Mild to moderate | < 19 | 16 | No

|
|
|

Severe | 19 - 22 | 11 | No
Very severe | > 22 |  4 | Yes

##### Genetic variations[edit]

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

#### Treatment failure[edit]

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[edit]

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

## References[edit]

1. ↑ Sullivan PF, Neale MC, Kendler KS (2000). "Genetic epidemiology of major depression: review and meta-analysis". Am J Psychiatry 157 (10): 1552–62. PMID 11007705. [e]
2. ↑ Major Depressive Disorder. (Online Mendelian Inheritance in Man, OMIM®. Johns Hopkins University, Baltimore, MD. MIM Number: 608516. World Wide Web URL: http://omim.org/.)
3. ↑ Regier DA, Narrow WE, Rae DS, Manderscheid RW, Locke BZ, Goodwin FK (1993). "The de facto US mental and addictive disorders service system. Epidemiologic catchment area prospective 1-year prevalence rates of disorders and services". Arch. Gen. Psychiatry 50 (2): 85–94. PMID 8427558. [e]
4. ↑ Kessler RC, McGonagle KA, Zhao S, et al (1994). "Lifetime and 12-month prevalence of DSM-III-R psychiatric disorders in the United States. Results from the National Comorbidity Survey". Arch. Gen. Psychiatry 51 (1): 8–19. PMID 8279933. [e]
5. ↑ Belmaker RH, Agam G (2008). "Major depressive disorder". N. Engl. J. Med. 358 (1): 55–68. DOI:10.1056/NEJMra073096. PMID 18172175. Research Blogging.
6. ↑ Cepoiu M, McCusker J, Cole MG, Sewitch M, Belzile E, Ciampi A (2008). "Recognition of depression by non-psychiatric physicians--a systematic literature review and meta-analysis". J Gen Intern Med 23 (1): 25–36. DOI:10.1007/s11606-007-0428-5. PMID 17968628. Research Blogging.
7. ↑ Mitchell A et al. (22 August 2009) Clinical diagnosis of depression in primary care: a meta-analysis. Lancet 2009;374(9690):609-619 DOI:10.1016/S0140-6736(09)60879-5 PMID 19640579
8. ↑ Spitzer RL, Kroenke K, Williams JB (1999). "Validation and utility of a self-report version of PRIME-MD: the PHQ primary care study. Primary Care Evaluation of Mental Disorders. Patient Health Questionnaire". JAMA 282 (18): 1737–44. PMID 10568646. [e]
9. ↑ Li C, Friedman B, Conwell Y, Fiscella K (2007). "Validity of the Patient Health Questionnaire 2 (PHQ-2) in identifying major depression in older people". J Am Geriatr Soc 55 (4): 596–602. DOI:10.1111/j.1532-5415.2007.01103.x. PMID 17397440. Research Blogging.
10. ↑ Kroenke K, Spitzer RL, Williams JB (2003). "The Patient Health Questionnaire-2: validity of a two-item depression screener.". Med Care 41 (11): 1284-92. DOI:10.1097/01.MLR.0000093487.78664.3C. PMID 14583691. Research Blogging.
11. ↑ Brody DS, Hahn SR, Spitzer RL, et al (1998). "Identifying patients with depression in the primary care setting: a more efficient method". Arch. Intern. Med. 158 (22): 2469–75. PMID 9855385. [e]
12. ↑ Kroenke K, Spitzer RL, Williams JB (2001). "The PHQ-9: validity of a brief depression severity measure". J Gen Intern Med 16 (9): 606–13. PMID 11556941. [e] Full text at PubMed Central
13. ↑ 13.0 13.1 Löwe B, Unützer J, Callahan CM, Perkins AJ, Kroenke K (2004). "Monitoring depression treatment outcomes with the patient health questionnaire-9". Med Care 42 (12): 1194–201. PMID 15550799. [e]
14. ↑ Patient Health Questionnaire, Item 9. Retrieved on 2008-01-14.
15. ↑ Manea L, Gilbody S, McMillan D (2012). "Optimal cut-off score for diagnosing depression with the Patient Health Questionnaire (PHQ-9): a meta-analysis.". CMAJ 184 (3): E191-6. DOI:10.1503/cmaj.110829. PMID 22184363. PMC PMC3281183. Research Blogging.
16. ↑ American Psychiatric Association 2010\.
17. ↑ Anonymous (2010). [L-Methylfolate (Deplin) for Depression and Schizophrenia]. The Medical Letter
18. ↑ Papakostas GI, Mischoulon D, Shyu I, Alpert JE, Fava M (2010). "S-adenosyl methionine (SAMe) augmentation of serotonin reuptake inhibitors for antidepressant nonresponders with major depressive disorder: a double-blind, randomized clinical trial.". Am J Psychiatry 167 (8): 942-8. DOI:10.1176/appi.ajp.2009.09081198. PMID 20595412. Research Blogging.
19. ↑ 19.0 19.1 Kasper S, Anghelescu IG, Szegedi A, Dienel A, Kieser M (2006). "Superior efficacy of St John's wort extract WS 5570 compared to placebo in patients with major depression: a randomized, double-blind, placebo-controlled, multi-center trial [ISRCTN77277298]". BMC Med 4: 14. DOI:10.1186/1741-7015-4-14. PMID 16796730. Research Blogging.
20. ↑ (2002) "Effect of Hypericum perforatum (St John's wort) in major depressive disorder: a randomized controlled trial". JAMA 287 (14): 1807–14. PMID 11939866. [e]
21. ↑ Linde K, Melchart D, Mulrow CD, Berner M (2002). "St John's wort and depression". JAMA 288 (4): 447–8; author reply 448–9. PMID 12132965. [e]
22. ↑ 22.0 22.1 Linde K, Berner MM, Kriston L (2008). "St John's wort for major depression". Cochrane Database Syst Rev (4): CD000448. DOI:10.1002/14651858.CD000448.pub3. PMID 18843608. Research Blogging.
23. ↑ Maratos A, Gold C, Wang X, Crawford M (2008). "Music therapy for depression". Cochrane Database Syst Rev (1): CD004517. DOI:10.1002/14651858.CD004517.pub2. PMID 18254052. Research Blogging.
24. ↑ Serfaty MA, Haworth D, Blanchard M, Buszewicz M, Murad S, King M (2009). "Clinical effectiveness of individual cognitive behavioral therapy for depressed older people in primary care: a randomized controlled trial.". Arch Gen Psychiatry 66 (12): 1332-40. DOI:10.1001/archgenpsychiatry.2009.165. PMID 19996038. Research Blogging.
25. ↑ Blake H, Mo P, Malik S, Thomas S (2009). "How effective are physical activity interventions for alleviating depressive symptoms in older people? A systematic review.". Clin Rehabil 23 (10): 873-87. DOI:10.1177/0269215509337449. PMID 19675114. Research Blogging.
26. ↑ Boelens PA, Reeves RR, Replogle WH, Koenig HG (2009). "A randomized trial of the effect of prayer on depression and anxiety.". Int J Psychiatry Med 39 (4): 377-92. PMID 20391859. [e]
27. ↑ Bay PS, Beckman D, Trippi J, Gunderman R, Terry C (2008). "The effect of pastoral care services on anxiety, depression, hope, religious coping, and religious problem solving styles: a randomized controlled study.". J Relig Health 47 (1): 57-69. DOI:10.1007/s10943-007-9131-4. PMID 19105001. Research Blogging.
28. ↑ 28.0 28.1 Trivedi MH, Rush AJ, Wisniewski SR, Nierenberg AA, Warden D, Ritz L et al. (2006). "Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice.". Am J Psychiatry 163 (1): 28-40. DOI:10.1176/appi.ajp.163.1.28. PMID 16390886. Research Blogging.
29. ↑ Qaseem A, Snow V, Denberg TD, Forciea MA, Owens DK, Clinical Efficacy Assessment Subcommittee of American College of Physicians (2008). "Using second-generation antidepressants to treat depressive disorders: a clinical practice guideline from the American College of Physicians.". Ann Intern Med 149 (10): 725-33. PMID 19017591. [e]
30. ↑ Gartlehner G, Gaynes BN, Hansen RA, Thieda P, DeVeaugh-Geiss A, Krebs EE et al. (2008). "Comparative benefits and harms of second-generation antidepressants: background paper for the American College of Physicians.". Ann Intern Med 149 (10): 734-50. PMID 19017592. [e] Review in: Evid Based Med. 2009 Jun;14(3):82
31. ↑ Gartlehner G, Hansen RA, Morgan LC, Thaler K, Lux L, Van Noord M et al. (2011). "Comparative benefits and harms of second-generation antidepressants for treating major depressive disorder: an updated meta-analysis.". Ann Intern Med 155 (11): 772-85. DOI:10.1059/0003-4819-155-11-201112060-00009. PMID 22147715. Research Blogging.
32. ↑ Blier P, Ward HE, Tremblay P, Laberge L, Hébert C, Bergeron R (2010). "Combination of antidepressant medications from treatment initiation for major depressive disorder: a double-blind randomized study.". Am J Psychiatry 167 (3): 281-8. DOI:10.1176/appi.ajp.2009.09020186. PMID 20008946. Research Blogging.
33. ↑ Papakostas GI, Petersen T, Mischoulon D, Ryan JL, Nierenberg AA, Bottiglieri T et al. (2004). "Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression.". J Clin Psychiatry 65 (8): 1090-5. PMID 15323594.
34. ↑ Papakostas GI, Petersen T, Mischoulon D, Green CH, Nierenberg AA, Bottiglieri T et al. (2004). "Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 2: predictors of relapse during the continuation phase of pharmacotherapy.". J Clin Psychiatry 65 (8): 1096-8. PMID 15323595.
35. ↑ Godfrey PS, Toone BK, Carney MW, Flynn TG, Bottiglieri T, Laundy M et al. (1990). "Enhancement of recovery from psychiatric illness by methylfolate.". Lancet 336 (8712): 392-5. PMID 1974941.
36. ↑ Taylor MJ, Carney SM, Goodwin GM, Geddes JR (2004). "Folate for depressive disorders: systematic review and meta-analysis of randomized controlled trials.". J Psychopharmacol 18 (2): 251-6. DOI:10.1177/0269881104042630. PMID 15260915. Research Blogging.
37. ↑ Roberts SH, Bedson E, Hughes D, Lloyd K, Menkes DB, Moat S et al. (2007). "Folate augmentation of treatment - evaluation for depression (FolATED): protocol of a randomised controlled trial.". BMC Psychiatry 7: 65. DOI:10.1186/1471-244X-7-65. PMID 18005429. PMC PMC2238748. Research Blogging.
38. ↑ Ford AH, Flicker L, Thomas J, Norman P, Jamrozik K, Almeida OP (2008). "Vitamins B12, B6, and folic acid for onset of depressive symptoms in older men: results from a 2-year placebo-controlled randomized trial.". J Clin Psychiatry 69 (8): 1203-9. PMID 18557664.
39. ↑ 39.0 39.1 39.2 Fournier JC, DeRubeis RJ, Hollon SD, Dimidjian S, Amsterdam JD, Shelton RC et al. (2010). "Antidepressant drug effects and depression severity: a patient-level meta-analysis.". JAMA 303 (1): 47-53. DOI:10.1001/jama.2009.1943. PMID 20051569. Research Blogging.
40. ↑ Gibbons RD, Hur K, Brown CH, Davis JM, Mann JJ (2012). "Benefits From Antidepressants: Synthesis of 6-Week Patient-Level Outcomes From Double-blind Placebo-Controlled Randomized Trials of Fluoxetine and Venlafaxine.". Arch Gen Psychiatry. DOI:10.1001/archgenpsychiatry.2011.2044. PMID 22393205. Research Blogging.
41. ↑ First, Michael B. (2007). Handbook of Psychiatric Measures, Second Edition. American Psychiatric Publishing, Inc. ISBN 1-58562-218-4.
42. ↑ National Institute for Clinical Excellence. Depression: Management of Depression in Primary and Secondary Care. London, England: National Institute for Clinical Excellence; 2009.
43. ↑ Paddock S, Laje G, Charney D, Rush AJ, Wilson AF, Sorant AJ et al. (2007). "Association of GRIK4 with outcome of antidepressant treatment in the STAR*D cohort.". Am J Psychiatry 164 (8): 1181-8. DOI:10.1176/appi.ajp.2007.06111790. PMID 17671280. Research Blogging.
44. ↑ 44.0 44.1 44.2 Rush AJ, Trivedi MH, Wisniewski SR, Stewart JW, Nierenberg AA, Thase ME et al. (2006). "Bupropion-SR, sertraline, or venlafaxine-XR after failure of SSRIs for depression.". N Engl J Med 354 (12): 1231-42. DOI:10.1056/NEJMoa052963. PMID 16554525. Research Blogging. Review in: Evid Based Ment Health. 2006 Nov;9(4):100
45. ↑ 45.0 45.1 Trivedi MH, Fava M, Wisniewski SR, Thase ME, Quitkin F, Warden D et al. (2006). "Medication augmentation after the failure of SSRIs for depression.". N Engl J Med 354 (12): 1243-52. DOI:10.1056/NEJMoa052964. PMID 16554526. Research Blogging.
46. ↑ http://dx.doi.org/10.4088/JCP.12m07777
47. ↑ Fava M, Rush AJ, Wisniewski SR, Nierenberg AA, Alpert JE, McGrath PJ et al. (2006). "A comparison of mirtazapine and nortriptyline following two consecutive failed medication treatments for depressed outpatients: a STAR*D report.". Am J Psychiatry 163 (7): 1161-72. DOI:10.1176/appi.ajp.163.7.1161. PMID 16816220. Research Blogging. Review in: Evid Based Ment Health. 2007 Feb;10(1):16
48. ↑ Marianna Mazza, Maria Rosaria Squillacioti1, Riccardo Daniele Pecora, Luigi Janiri1 & Pietro Bria (December 2008), "Beneficial acute antidepressant effects of aripiprazole as an adjunctive treatment or monotherapy in bipolar patients unresponsive to mood stabilizers: results from a 16-week open-label trial", Expert Opinion on Pharmacotherapy 9 (18): 3145-3149, DOI:10.1517/14656560802504490
49. ↑ Gilbody S, Sheldon T, House A (2008). "Screening and case-finding instruments for depression: a meta-analysis". CMAJ 178 (8): 997-1003. DOI:10.1503/cmaj.070281. PMID 18390942. Research Blogging.