Since the choice of treatments for a primary bipolar I disorder major depressive episode versus a unipolar major depressive episode are significantly different, this information will help guide clinicians in how to proceed.
As we have become more sophisticated in our ability to diagnose psychiatric disorders, a large hurdle remains: the ability to differentiate between a primary bipolar I disorder (BDI) major depressive episode versus a unipolar major depressive episode in a newly presenting patient that meets clear diagnostic criteria for a DSM-5 major depressive episode. Significantly, as has been the case with previous editions of the psychiatric Diagnostic and Statistical Manual of Mental Disorders, the DSM-5 criteria for a major depressive episode is identical for both a unipolar depression and a bipolar depression.
Misdiagnosis and resulting issues
From an epidemiological perspective, 17% of individuals in the US will have at least one unipolar major depressive episode in their life, in contrast to 1% that will be diagnosed with BDI and up to 4% that will be diagnosed with bipolar II disorder (BDII). (In both bipolar I and II disorders, depression is a more common mood state than mania/hypomania.) A complicating epidemiological reality is that 50% of patients that ultimately are diagnosed as having BDI initially present with a major depressive episode (rather than mania or hypomania), and many will have recurrent depressive episodes with no periods of mania or hypomania for up to 5 years after their first depressive episode. This often leads to the wrong diagnosis, and consequently a less optimal treatment.
For example, according to a commonly referenced publication,1 69% of 600 patients diagnosed with bipolar disorder were initially misdiagnosed, and the most common misdiagnosis was unipolar depression. Even more alarming, it took 10 or more years for one third of these initially misdiagnosed patients to be accurately diagnosed with bipolar disorder.
Similar rates of misdiagnosis were found in a study of children (mean age=10.3 years) with prepubertal major depressive disorder who were participants in a clinical trial of nortriptyline for childhood depression.2 At approximately 10 year follow-up (mean age=20.7), 33.3% had subsequently been diagnosed with BDI and 48.6% with “Bipolar I disorder or bipolar II disorder or hypomania.” The authors concluded, “High rates of switching to mania are an important consideration for treatment of prepubertal major depressive disorder because of concerns that antidepressants may worsen childhood mania.”
This presents a treatment challenge, as the treatment varies considerably depending on the primary diagnosis. In addition, treating an individual with BDI with antidepressant medications can contribute to a poorer long-term outcome. Increased mood instability, shorter periods of time between mood episodes, less significant psychosocial stressors inducing a mood episode, and poorer response to treatment can result when BDI diagnosis is missed.
If an individual with bipolar depression is treated with an antidepressant medication, especially in the absence of a co-prescribed mood stabilizer (eg, lithium or divalproex), there is a risk for destabilizing the patient’s mood into a manic state, a manic state with mixed features, or a depressive state with mixed features, all of which can result in considerable morbidity and possibly mortality. Additionally, chronic antidepressant treatment in a patient with bipolar disorder can accelerate mood instability.
The DSM change
A novel change in DSM-5 is the elimination of the DSM-IV-TR diagnosis of Bipolar I Disorder, Mixed Episode (the current episode meeting criteria simultaneously for a major depressive episode and a manic episode for at least one week). This was replaced by a new specifier for both bipolar disorder and unipolar depression called mixed features. The mixed features specifier is listed if the primary mood state co-exists with three symptoms usually associated with the opposite mood state. Evidence is accumulating that major depression with mixed features may represent a population of depressed patients at increased risk of a switch to hypomania or mania during antidepressant therapy and possibly a more severe course of illness.
The antidepressant question
Since the publication of the 2007 New England Journal of Medicine Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study3 comparing treatment of depressed patients with bipolar disorder on a mood stabilizer demonstrated no statistical difference between adding a placebo versus an antidepressant to the patient’s primary mood stabilizer, a healthy dialogue has transpired as to whether or not there is a role for antidepressants in the treatment of bipolar depression. Although clinicians continue to argue this point, the growing consensus is that antidepressant medications should be avoided in the treatment of BDI. Established bipolar depression expert S. Nassir Ghaemi, MD, went so far as to say, “Before you can figure out what to do, you need to know what not to do… Stop using antidepressants. That’s half the story.”4
Additionally, none of the US FDA-approved antidepressants for the treatment of a unipolar depressive episode (approximately 29 in total) are FDA approved to treat bipolar depression. (Note of clarity: some will argue that fluoxetine is approved for bipolar depression in its formulation/combination with olanzapine. However, this argument is not valid, as fluoxetine is not approved as a monotherapy.) The first medications to be FDA- approved for treating bipolar depression was the olanzapine-fluoxetine combination in 2003. The only other medications currently FDA approved to treat bipolar depression are quetiapine (approved in 2006) and lurasidone (approved in 2013). There have been many failed double-blind/placebo-controlled trials of other agents over the years, further highlighting the difficulty of treating bipolar depression.
Tools to get to the right diagnosis
When a new patient presents for treatment of a major depressive episode, it is prudent for the clinician to spend time in the clinical interview obtaining history that may aid in the differentiation of a bipolar depression from a unipolar depression. Differentiating BDI depression from unipolar depression can be straightforward if the patient (or their family/advocate/guardian) is an accurate historian or if they can provide comprehensive past treatment records of mood episodes. If the patient has a past episode of mania or mania with mixed features, the diagnosis of BDI can be made and antidepressant medications should be avoided. Unfortunately, getting a comprehensive and accurate psychiatric history can be difficult for many reasons. In addition, it is common for patients to not view episodes of hypomania as problematic (in fact, patients may experience hypomania as a productive and enjoyable mood state). This may result in lack of reporting.
Although laborious, a detailed initial psychiatric evaluation is needed and should include: a family history (especially in first degree relatives), details of any prior mood episodes, past treatments that may have unmasked symptoms suggestive of mania or hypomania, symptoms that may have preceded substance use disorders, effects of any past treatment with antidepressants (ie, for previously treated depression, anxiety disorders, premenstrual dysphoric disorder, obsessive compulsive disorder, posttraumatic stress disorder, or other disorders). Similarly, obtaining additional history from a partner, family member or friend can assist in a more informed clinical assessment as to what the primary psychiatric disorder may be.
The Mood Disorder Questionnaire (MDQ), developed by Hirschfeld and colleagues5 can serve as a screening tool and should be given to depressed patients to evaluate the likelihood of a prior manic or hypomanic episode. The MDQ consists of 13 yes/no questions derived from the DSM-IV criteria for bipolarity and clinical experience. If the patient checks off seven or more “yes” answers, several of these “yes” symptoms co-occurred, and this resulted in at least moderate psychosocial impairment, then there is a good likelihood of a past manic or hypomanic episode. The MDQ was validated in a study of 198 patients being treated in outpatient psychiatry clinics and demonstrated that patients with a screening score of 7 or more “yes” answers achieved a sensitivity of 0.73 and a specificity of 0.90 for identifying patients with bipolar spectrum disorder.5 Thus, although the MDQ is not diagnostic for bipolarity, it can help guide the evaluating clinician as to how to direct the clinical interview.
A recent study demonstrated the importance of obtaining a good family history. The study6 was designed to identify characteristics that would predict conversion from unipolar depression to bipolar depression and followed 91,587 Danish patients diagnosed with unipolar depression from 1995 through 2016. During the follow-up period, which included 702,710 person-years, a parental history of bipolar disorder was the strongest predictor of conversion.
If the past psychiatric history reveals prior episodes of mania, mania with mixed features or significant hypomania, the current major depressive episode should be treated as a BDI depression and antidepressant medications should be avoided. If the patient has never had a prior manic/hypomanic episode, differentiating BDI from unipolar depression is more challenging.
Over the past two decades, researchers have attempted to identify additional risk factors that may tip the evaluation scale more toward a likely diagnosis of either a unipolar depression or a BDI. The Table lists risk factors that should be assessed that would support a diagnosis of BDI depression as opposed to unipolar depression. However, it is important to note that none of these risk factors are diagnostic for bipolarity.
Ultimately, the decision to treat a patient who presents with a DSM-5 major depressive episode as an episode of unipolar depression versus BDI depression is made after factoring all of the information available at the time of treatment initiation. It is helpful to think of a balanced scale, with one side containing information suggesting the diagnosis of unipolar depression and the other side BDI depression. After adding all of the elements of the evaluation to the appropriate end of the scale, the likely diagnosis often becomes clear.
A patient who presents with a well-defined DSM-5 major depressive episode may have the primary diagnosis of either unipolar major depression or BDI depression. Since the choice of treatments are significantly different, obtaining a comprehensive initial history, utilizing scales like the MDQ, obtaining additional history from previous psychiatric treatment or from people that know the patient well can provide the clinician with an increasing degree of confidence in how to proceed. Unless hospitalization is indicated, or in the presence of other complicating factors, there is nothing wrong with delaying treatment for a day or a week while additional history is obtained. In the long run, it will pay off to begin a treatment that is more appropriate for the patient’s primary affective diagnosis.
Acknowledgement:Psychiatric Times extends a warm thank-you to Editorial Board members Dr. Ron Pies and Dr. John Miller for their support of this Special Report.
Dr Miller is Medical Director of Brain Health and Staff Psychiatrist at Seacoast Mental Health Center in Exeter, NH. Dr Miller notes he serves as a speaker/consultant for Sunovion and Otsuka/Lundbeck, and on the speaker’s bureau for Allergan and Teva. He is also on an advisory board for Alkermes and Janssen Virtual Feedback Committee, and has consulted for Align2Action.
1. Hirschfeld R, Lewis L, Vornik L. Perceptions and Impact of Bipolar Disorder: How Far Have We Really Come? Results of the National Depressive and Manic-Depressive Association 2000 Survey of Individuals With Bipolar Disorder. J Clin Psychiatry. 2003;64:161-174.
2. Geller B, Zimmerman B, Williams M, et al. Bipolar Disorder at Prospective Follow-Up of Adults Who Had Prepubertal Major Depressive Disorder. Am J Psychiatry. 2001;158:125-127.
3. Sachs G, Nierenberg A, Calabrese J, et al. Effectiveness of Adjunctive Antidepressant Treatment for Bipolar Depression. N Engl J Med. 2007;356:1711-1722
4. Ghaemi SN. Antidepressants in Bipolar Depression: An Update. Presented at the 29th Annual U.S. Psychiatric & Mental Health Congress; October 23, 2016; San Antonio, TX.
5. Hirschfeld R, Williams J, Spitzer R, et al. Development and Validation of Screening Instrument for Bipolar Spectrum Disorder: The Mood Disorder Questionnaire. Am J Psychiatry. 2000;157:1873-1875.
6. Musliner KL, Ãstergaard SD. Patterns and predictors of conversion to bipolar disorder in 91,587 individuals diagnosed with unipolar depression. Acta Psychiatr Scand. 2018; 137:422-432.