Differential Diagnosis of Unipolar Vs Bipolar Depression​

Larry Culpepper, MD, MPH

Department of Family Medicine, Boston University School of Medicine and Boston Medical Center, Boston, Massachusetts

Misdiagnosis or missed diagnosis of bipolar disorder is widespread. However, physicians who learn to look for certain red flags can recognize which patients need to be screened for bipolar disorder. (For more information, see “Misdiagnosis of Bipolar Depression in Primary Care Practices.”) Early recognition and diagnosis of bipolar disorder in primary care is vital to appropriately treat the condition and improve patients’ well-being.

Two Effective Screening Tools

Two instruments that can be used in primary care practices, either alone or in combination, to screen for bipolar disorder are the Mood Disorder Questionnaire1 (MDQ) and the Composite International Diagnostic Interview2 (CIDI). The MDQ is a brief, self-report screen that can be used to identify patients most likely to have bipolar disorder. The CIDI, which was developed by the World Health Organization, is a clinician-administered tool that can identify threshold and subthreshold bipolar disorder, and therefore, may be the more efficient tool.

The CIDI 3.0 version is comprised of 3 core questions and 9 symptom questions. If a patient answers positively to either of the first 2 stem questions, the third question is then asked (AV 1). Only if the third question is answered positively does the clinician proceed to the remaining questions. This method is time efficient, and the CIDI has a more accurate positive predictive screening value than the MDQ, with sensitivity to detect 67% to 96% of true cases.2

AV 1. Using the CIDI to Screen for Bipolar Disorder (01:09)


The MDQ is also valuable in screening for bipolar disorder, but its sensitivity only ranges from 58% to 73%.1,3 A challenge with the MDQ relates to the self-administered nature of the screen because patients may fail to recognize the impact of their earlier symptomatology. Patients may not be aware that previous functional impairment such as behavioral or work issues were in fact due to symptoms of bipolar disorder. For example, a patient may not have the insight to recognize that her irritability, anger, and hostility cost her the job—the patient may have externalized the problem and believed that the boss was out to get her.

These symptoms, however, can often be recognized by a family member or close friend. With the patient’s permission, having a family member complete the MDQ from their perspective of the patient may provide valuable insight. Generally, the family member will report significantly more abnormality than the patient. Not only does this aid the clinician in the diagnostic process but it also shows whether the patient has insight into the illness and recognizes the association between symptoms and functional impairment. By engaging the patient’s family during the diagnostic process, clinicians can later enlist their help to assist the patient in adhering to treatment and to monitor the emergence of symptoms suggestive of new episodes or of illness relapse.

Screening may need to be conducted at different points in time. Because bipolar disease often evolves from what is initially recognizable only as unipolar depression, repeated use of the CIDI and MDQ can be helpful. When a patient who is being treated for unipolar depression begins having difficulties that suggest mania or hypomania, re-evaluating the diagnosis is wise.

The Misadventures of Therapy

Patients who are being treated for what appears to be unipolar depression may experience what J. Sloan Manning, MD, has called “the misadventures of therapy.”4 This situation can present in several forms. Patients may not respond to the usual antidepressant therapy.5 Conversely, patients may respond too quickly and vigorously to antidepressant treatment indicating the emergence of manic or hypomanic episodes, mixed episodes, or rapid cycling.6 In patients with these experiences, it is crucial for clinicians to determine whether the patient is actually suffering from bipolar disorder and adjust treatment to include a mood stabilizer.7


Paying the Price of Misdiagnosis

Consequences of a late or incorrect bipolar diagnosis are quite significant for the patient and for society. Patients with full-blown manic episodes tend to have violent, risky, and destructive behavior, which can lead to legal, work, and financial issues.8 The unfortunate domino effect of this type of behavior can cause the patient to become isolated, with limited social support and employment opportunities, which can decrease access to adequate care and, in turn, create further negative consequences.

AV 2. Health Care Costs for Patients With Unrecognized Bipolar Disorder (01:09)

Data from McCombs et al10

In addition to behavioral issues, actual health care costs are greater for patients who were misdiagnosed and received incorrect initial care. Patients with unrecognized bipolar disease who took antidepressant treatment for unipolar depression incurred significantly greater mean medical costs than those with recognized bipolar disorder in the 12 months after treatment began (P<.05).9 A 6-year retrospective analysis10 of antidepressant users reported that the costs per month grew exponentially for patients initially misdiagnosed with unipolar depression versus those that received a correct depression or bipolar diagnosis (AV 2). Additionally, patients misdiagnosed with bipolar disorder have more psychiatric hospitalization, medical emergency room visits, and psychiatric office visits, at an additional cost of $1641 per year over patients with recognized bipolar disease.11

Differential Diagnosis of Unipolar and Bipolar Depression

Although the key difference between unipolar depression and bipolar disorder is the presence of hypomanic or manic episodes (AV 3),12,13 other symptoms and clinical characteristics can offer clues. Evidence suggests that people with bipolar depression tend to exhibit more irritability, anxiety, agitation, and suicidal ideation than those with unipolar depression.14 Bipolar disorder is less associated with insomnia and somatic complaints than unipolar depression.15 Additionally, a family history of mania or hypomania among first-degree relatives, a history of 2 or more lifetime episodes of depression, and age at onset younger than 30 years are suggestive of a bipolar diagnosis rather than a unipolar one.13 Having a substance use disorder or prior suicide attempts are also associated more with bipolar than unipolar disorder.14 Until genetic and/or neuroimaging tests are available to distinguish between unipolar and bipolar depression, clinicians must watch for red flags in patients with depression that indicate that bipolar screening is necessary, both before and after treatment initiation.

AV 3. Major Depressive, Bipolar I, and Bipolar II Disorder Diagnoses for Patients Presenting in Major Depressive Episodes (N=5,635) (01:09)

Data from Angst et al13


Early and accurate diagnosis of bipolar disorder is critical for the benefit of the patient with depression. Unrecognized bipolar disease may result in behavior leading to marginalization of the patient in society, as well as higher costs for the patient, employer (if the patient has one), and the health care system. Paying close attention to potential red flags for bipolar disorder, using screening tools like the MDQ or CIDI, and involving the patient’s family can all be effective strategies in the diagnostic process. Unipolar depression can develop into bipolar disorder, and, therefore, rescreening over time is warranted if red flags arise.

Clinical Points

  • Be aware of red flags that indicate that a patient with depression should be screened for bipolar disorder
  • Use the MDQ and the CIDI screening tools for bipolar disorder prior to diagnosis as well as after treatment starts (if signs of potential bipolar disorder arise)
  • Involve the family in the diagnostic process, with the patient’s consent


MDQ = Mood Disorder Questionnaire
CIDI = Composite International Diagnostic Interview


  1. 1. Hirschfeld RMA, Williams JBW, Spitzer RL. Development and validation of a screening instrument for bipolar spectrum disorder: the Mood Disorder Questionnaire. Am J Psychiatry. 2000;157(11):1873–1875. PubMed
  2. 2. Kessler RC, Akiskal HS, Angst J, et al. Validity of the assessment of bipolar spectrum disorders in the WHO CIDI 3.0. J Affect Disord. 2006;96(3):259–269. PubMed
  3. 3. Hirschfeld RM, Cass AR, Holt DC, et al. Screening for bipolar disorder in patients treated for depression in a family medicine clinic. J Am Board Fam Pract. 2005;18(4):233–239. PubMed
  4. 4. Manning JS. Difficult-to-treat depressions: a primary care perspective. J Clin Psychiatry. 2003;64(suppl 1):24–31. Full Text
  5. 5. Correa R, Akiskal H, Gilmer W, et al. Is unrecognized bipolar disorder a frequent contributor to apparent treatment resistant depression? J Affect Disord. 2010;127(1–3):10–18. PubMed
  6. 6. Ghaemi SN, Boiman EE, Goodwin FK. Diagnosing bipolar disorder and the effect of antidepressants: a naturalistic study. J Clin Psychiatry. 2000;61(10):804–808. Abstract
  7. 7. Pacchiarotti I, Bond DJ, Baldessarini RJ, et al. The International Society for Bipolar Disorders (ISBD) Task Force report on antidepressant use in bipolar disorders [published online ahead of print September 13, 2013]. Am J Psychiatry. PubMed
  8. 8. Hirschfeld RM. Bipolar depression: The real challenge. Eur Neuropsychopharmacol. 2004;14(suppl 2):S83–S88. PubMed
  9. 9. Birnbaum HG, Shi L, Dial E, et al. Economic consequences of not recognizing bipolar disorder patients: a cross-sectional descriptive analysis. J Clin Psychiatry. 2003;64(10):1201–1209. Abstract
  10. 10. McCombs JS, Ahn J, Tencer T, et al. The impact of unrecognized bipolar disorders among patients treated for depression with antidepressants in the fee-for-services California Medicaid (Medi-Cal) program: a 6-year retrospective analysis. J Affect Disord. 2007;97(1–3):171–179. PubMed
  11. 11. Stensland MD, Schultz JF, Frytak JR. Depression diagnoses following the identification of bipolar disorder: costly incongruent diagnoses. BMC Psychiatry. 2010;10:39. PubMed
  12. 12. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Arlington, VA: American Psychiatric Association; 2013.
  13. 13. Angst J, Gamma A, Bowden CL, et al. Evidence-based definitions of bipolar-I and bipolar-II disorders among 5,635 patients with major depressive episodes in the Bridge Study: validity and comorbidity [published online ahead of print January 31, 2013]. Eur Arch Psychiatry Clin Neurosci. PubMed
  14. 14. Schaffer A, Cairney J, Veldhuizen S, et al. A population-based analysis of distinguishers of bipolar disorder from major depressive disorder. J Affect Disord. 2010;125(1–3):103–110. PubMed
  15. 15. Perlis RH, Brown E, Baker RW, et al. Clinical features of bipolar depression versus major depressive disorder in large multicenter trials. Am J Psychiatry. 2006;163(2):225–231. PubMed