Diagnostic Assessment of Major Depressive Disorder

George I. Papakostas, MD

Department of Psychiatry, Harvard Medical School and Massachusetts General Hospital, Boston

Diagnosing Major Depressive Disorder

The DSM-IV definition of MDD is the presence of at least 1 lifetime major depressive episode that is not accompanied by a history of an abnormal mood elevation, such as a mania or hypomania, and is not accompanied by concurrent psychotic symptoms.1 In addition, the major depressive episode must not be due to the effects of a substance, medical illness, or grief, and must result in significant functional impairment. The diagnosis of a major depressive episode includes the presence of at least 5 neurovegetative symptoms of depression (AV 1AV 1),1 1 of which must be either depressed mood or diminished interest or pleasure.

MDD is among the most common medical illnesses that afflict humanity. Data reported from the NCS-R2 estimate the lifetime prevalence of MDD to be 16.2% and the 12-month prevalence to be 6.6%, with a mean depressive episode duration of 16 weeks. Women are 1.7 times more likely than men to have MDD. The study classified 10.4% of the patients as having mild symptomatology, 38.6% as having moderate symptomatology, 38.0% as having severe symptomatology, and 12.9% as having very severe symptomatology.

MDD often is concurrent with other DSM-IV Axis I disorders. In the STAR*D study3 of 1,376 patients,
only 38.2% of patients with MDD had no comorbid disorder; 25.6% had 1 comorbid Axis I disorder, 16.1% had 2 comorbid disorders, and 20.2% had more than 2 comorbid disorders (AV 2AV 2).

Systematic Evaluation for Major Depressive Disorder

The first, most critical factor in the initial evaluation is the patient’s safety; ie, clinicians should assess the patient for suicidal ideation in order to determine if the patient is safe enough to be monitored in an outpatient clinic versus an inpatient setting. Assessing a patient’s safety includes identifying the risk factors for suicide, including a history of suicide attempts, any comorbid disorders that increase the risk of suicide (ie, substance use disorders, personality disorders, unstable medical illness), signs of hopelessness, plans to commit suicide, and the means as well as the willingness to carry out the suicidal ideation. Establishing safety also includes assessing protective factors, such as whether the patient states that he or she has reasons to live, whether he or she has a support system, and whether he or she is engaged in treatment, not only for Axis I disorders but also for any Axis II or III disorders that might be co-occurring with depression. A careful assessment of safety should also involve an assessment for homicidal ideation, as well as the ability of the patient to care for himself or herself. After determining the appropriate setting in which to safely treat the patient, the clinician may then continue with the assessment for MDD.

Differential diagnosis. Once the criteria for a major depressive episode1 have been met, the next step in the initial assessment for MDD is to rule out the presence or history of any manic or hypomanic episode. The management of bipolar depression differs substantially from the management of MDD, the former involving the use of atypical antipsychotics and anticonvulsants; antidepressant monotherapy should be avoided in bipolar depression.4 The presence of psychotic symptoms must also be ruled out because the optimal management of MDD with psychotic features involves the combination of an antidepressant with a neuroleptic.5


Accompanying symptoms. The next step in the assessment of the patient with MDD is to identify any accompanying symptoms that appear to hold prognostic treatment value. For example, hopelessness,6 anxiety,7 painful symptoms,8 and melancholic features9 are risk factors for poor response during antidepressant treatment. Therefore, establishing the presence or absence of these individual symptoms may lead to modified treatment approaches (ie, more frequent visits and a greater likelihood of increasing antidepressant doses early on for non or partial responders) that, in turn, may help optimize treatment outcome.

Axis I comorbidity. Examining for the presence of Axis I comorbidity should be the next step in the evaluation for MDD, primarily for 2 reasons. First, Axis I comorbidity has been found to confer a risk of poor acute treatment outcome (ie, lower remission rates) among patients with MDD (AV 3AV 3).9,10 In addition, the presence of a co-occurring Axis I disorder may require a modified treatment approach, depending on whether or not the antidepressant chosen has been found to also be effective in relieving the comorbid disorder. (For more information on MDD treatments see “Initial Treatment Approaches for Patients With Depression.”)

Medical comorbidity and other factors. The presence of general as well as specific medical comorbidity, such as hypercholesterolemia, obesity, hypofolatemia, or white matter hyperintensities, may increase the risk of poor response to antidepressants in patients with MDD.10-12 Certain social and demographic factors may also increase the risk of nonremission or nonresponse during antidepressant therapy (AV 4AV 4).10 A comprehensive assessment of these factors can, in turn, lead to modified therapeutic approaches (ie, more frequent follow-up periods, higher medication doses, an increased likelihood of combining 2 drugs or a drug with psychotherapy from the onset of therapy) aimed at optimizing outcomes for patients with MDD.


Patients complaining of 1 or more symptoms of depression, whether in a psychiatric or general medical clinic, should be carefully evaluated. Having established the presence of a major depressive episode, clinicians should then focus on:

  • Assessing for patient safety by ruling out suicidal ideation, homicidal ideation, and/or inability to care for oneself
  • Ruling out the presence of bipolar disorder and psychosis
  • Identifying accompanying symptoms, such as hopelessness, anxiety, pain, and melancholy, that may impact treatment response
  • Identifying psychiatric and medical comorbidities as well as sociodemographic factors that may also influence the likelihood of experiencing symptom remission following treatment

Clinicians should strive for a comprehensive assessment of patients who present with depressive symptoms in order to formulate an appropriate initial treatment plan and optimize outcomes for their patients with MDD.


DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision
MDD = major depressive disorder
NCS-R = National Comorbidity Survey Replication
STAR*D = Sequenced Treatment Alternatives to Relieve Depression

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  1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision. Washington, DC: American Psychiatric Association; 2000.
  2. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA. 2003;289(23):3095–3105.
  3. Rush AJ, Zimmerman M, Wisniewski SR, et al. Comorbid psychiatric features in depressed outpatients: demographic and clinical features. J Affect Disord. 2005;87(1):43–55.
  4. Fountoulakis KN, Vieta E. Treatment of bipolar disorder: a systematic review of available data and clinical perspectives. Int J Neuropsychopharmacol. 2008;11(7):999–1029.
  5. Rothschild AJ. Challenges in the treatment of depression with psychotic features. Biol Psychiatry. 2003;53(8):680–690.
  6. Papakostas GI, Petersen T, Homberger CH, et al. Hopelessness as a predictor of non-response to fluoxetine in major depressive disorder. Ann Clin Psychiatry. 2007;19(1):5–8.
  7. Fava M, Rush AJ, Alpert JE, et al. Difference in treatment outcome in patients with anxious versus nonanxious depression: a STAR*D report. Am J Psychiatry. 2008;165(3):342–351.
  8. Papakostas GI, McGrath P, Stewart J, et al. Psychic and somatic anxiety symptoms as predictors of response to fluoxetine in major depressive disorder. Psychiatry Res. 2008;161(1):116–120.
  9. Rush AJ, Wisniewski SR, Warden D, et al. Selecting among second-step antidepressant medication monotherapies: predictive value of clinical, demographic, or first-step treatment features. Arch Gen Psychiatry. 2008;65(8):870–880.
  10. Trivedi MH, Rush AJ, Wisniewski SR, et al. Evaluation of outcomes with citalopram for depression using measurement-based care in STAR*D: implications for clinical practice. Am J Psychiatry. 2006;163(1):28–40.
  11. Iosifescu DV, Nierenberg AA, Alpert JE, et al. The impact of medical comorbidity on acute treatment in major depressive disorder. Am J Psychiatry. 2003;160(12):2122–2127.
  12. Papakostas GI, Petersen T, Mischoulon D, et al. Serum folate, vitamin B12, and homocysteine in major depressive disorder, Part 1: predictors of clinical response in fluoxetine-resistant depression. J Clin Psychiatry. 2004;65(8):1090–1095.