Background

Misdiagnosis of bipolar disorder (BP) is common in psychiatry clinics, with at least 20.8 − 61.5% of patients with BP being mistakenly diagnosed as having major depressive disorder (MDD) [1,20]. Further research with the inclusion of more somatic symptoms is needed to test whether patients with either subtype of BP are less physically vulnerable during depressive phases than those with MDD.

Regarding psychiatric comorbidities, each of the two groups of BP cases had significantly higher prevalence than MDD cases of the majority of the tested comorbidities. Specifically, all four forms of anxiety disorders, as well as OCD and eating disorders co-occurred more frequently in BP-II than in MDD, and three (current and lifetime panic disorders, agoraphobia without panic and antisocial personality disorder) of the nine tested comorbidities were more likely to be endorsed by BP-I cases than MDD cases. Overall, in contrast to the BP-I and MDD comparisons, there were more salient differences in comorbidity patterns between BP-II and MDD. This is consistent with previous findings by Angst et al. [42], but differs from other studies reporting either few differences in comorbidities between BP-I and BP-II versus MDD [12] or higher prevalence of comorbid anxiety disorders in BP-I than MDD and BP-II patients [9]. In addition to its high prevalence, comorbid anxiety in BP contributes to adverse illness course, poorer functioning and lower life quality and raises challenges in pharmacological treatment [43]. However, there has been no increase in research interest in this topic over the last two decades, and important issues such as the conceptualization, etiology of anxiety in BP and treatment (in particular, psychological therapy) for anxiety in patients with BP are still under-researched [43]. Future studies on this topic are needed.

In the multivariate logistic regression using MDD as the reference diagnosis, several predictors were significantly associated with BP diagnoses. Some associations (recurrence, antisocial personality disorder and absence of weight loss) were non-specific to BP subtypes and others were specific to BP-I (male gender, suicide attempt and panic disorder) or BP-II (less illness severity, psychotic features, concurrent agoraphobia without panic, and absence of terminal insomnia and somatic anxiety). Previously reported predictors of BP diagnoses based on multivariate regression analysis included more episodes being characteristic of BP-I [2, 12], psychotic features being characteristic of BP-I and BP-II [2] or BP-I [11, 12], mixed features being characteristic of BP-II [11, 12], anxiety disorders being characteristic of BP-I [9] or BP-II [42], and any personality disorder being characteristic of BP-I and BP-II [9], with a few of them being replicated in the present analyses. Despite findings from previous studies and ours using the multivariate regression models for discriminating between BP and MDD diagnoses, synthesis of findings is limited by the use of different definitions of variables, assessment instruments and comparison groups across studies.

Strengths and limitations

The strengths of this study include the large sample size, broad inclusion criteria and minimal exclusion criteria, as well as use of a structured diagnostic interview applied by well trained psychiatrists to obtain a more accurate diagnostic picture. There are a number of limitations. First, in this post-hoc analysis based on data from screening stages of a published clinical trial, the study sample is not representative of the overall naturalistic clinical population as patients who had already had a diagnosis of bipolar disorder before the start of this study and those who met criteria for bipolar disorder as judged by research psychiatrists at the first screening stage were excluded. That said we could only enroll participants with undiagnosed BP who were actually misdiagnosed as MDD. However, misclassification bias in this analysis should be small according to the stringent diagnostic assessment and this may provide an opportunity for clinicians to better understand the facets of bipolar depression that are extremely difficult to differentiate from MDD. Second, a causal relationship between clinical features and diagnoses cannot be determined due to the cross-sectional nature of the study. Third, the sample size of the BP-I group was relative small and prevalence of some comorbid conditions was relatively low, which might lower the statistical power of comparisons. Fourth, information like age at onset, family history of mental illness, number of episodes, mixed features and response to antidepressants (e.g. treatment resistance and antidepressant-induced agitated, anxious, mixed, or manic/hypomanic state), which may be potential distinguishers between diagnoses were not collected. Finally, the potential influence of current treatment for patients who were not medication-naïve on clinical presentation cannot be ruled out. Furthermore, the fact that few patients with BP were taking psychotropic medications limited our ability to compare medication use between groups or to explore potential associations between medication use and diagnosis.

Conclusion

Our results provide supportive evidence that symptom profiles and comorbidity patterns differ significantly between misdiagnosed bipolar I and bipolar II versus MDD, with more complex clinical differences existing between BP-II and MDD in contrast to the BP-I and MDD comparisons. This has implications for improving diagnostic decision making by identifying potential distinguishers of the two bipolar subtypes from MDD.

Given that our diagnoses were based on DSM-IV TR which have now been updated, future research based on the DSM-5 and/or ICD-11 could focus on: misdiagnosis or overdiagnosis of bipolar disorder in real-world clinical settings, implications of DSM-5/ICD-11 changes in diagnostic criteria for bipolar disorder on diagnostic prevalence of this illness, clinical presentation of depressive episodes of bipolar disorder and bipolar spectrum disorder compared to MDD, predictors of conversion from unipolar depression to bipolar disorder, strategies for improving accurate diagnosis of bipolar disorder in routine clinical practice, as well as the etiology and treatment for psychiatric comorbidities (e.g. anxiety disorders) in bipolar disorder.