Antidepressant-induced hypomania/mania in patients with major depression: Evidence from the BRIDGE-II-MIX study

Highlights

• Antidepressant-induced mood switches to hypomania/mania is a controversial topic.

• Clinical variables of 2811 patients with major depressive episode were collected.

• Clinical features of patients who presented switches are similar to bipolar patients.

• There’s a need to develop better ways to predict future risk of mania in MDE patients.

Abstract

Background

The issue of antidepressant-induced mood switches to hypomania, mania, or mixed states within the course of mayor depressive disorder (MDD) has been a controversial topic. The present post-hoc analysis of the BRIDGE-II-MIX study focuses on the clinical features of patients with history of antidepressant-induced hypomania/mania (AIHM) in a large international sample of patients with major depressive episode (MDE).

Methods

2811 subjects with major depression were enrolled in this multicentre cross-sectional study. Current mixed symptoms, socio-demographic and other clinical variables were collected and compared among MDD-AIHM, MDD and BD patients.

Results

475 patients out of 2811 had history of AIHM (16.90%). In the MDD-AIHM group, familiarity for BD and rates of atypical features and comorbid anxiety, eating and borderline personality disorders were similar to BD and significantly more frequent compared to MDD group. MDD-AIHM patients had more frequently more than 3 episodes and reported higher rates of treatment resistance, mood lability and irritability following treatment with antidepressants. Frequencies of depression with mixed features and (hypo)manic symptoms were similar in patients of MDD-AIHM and BD groups and significantly higher in both groups than in MDD.

Limitations

there were widely varying rates of hospitalized patients across countries and the participating centres were not randomly selected.

Conclusions

Our results strongly support the DSM-5 inclusion of MDD patients with AIHM within the rubric of bipolar disorder. Differences with other MDD and BD were also observed suggesting the possibility that MDD-AIHM may represent a specific sub-population, particularly sensitive to exogenous input from antidepressants.

Introduction

The issue of antidepressant-induced mood switches to hypomania, mania, or mixed states within the course of Major Depressive Disorder (MDD) has been a diagnostic controversial topic, since it has implications for Bipolar Disorder (BD) diagnosing as well as for clinical management of these patients. According to DSM IV-TR (American Psychiatric Association, 2000), a diagnosis of BD I or II disorder was excluded if a hypomanic/manic episode was not spontaneous but “induced by antidepressants or other somatotherapy”. On the contrary, the more recent DSM-5 (American Psychiatric Association, 2013) recognizes that hypomanic/manic episodes occurring during antidepressant (AD) treatment are, under certain conditions, accepted as criteria for BD, by adding that if a hypomanic/manic episode emerges during AD treatment and persists at a fully syndromal level beyond the physiological effect of that treatment there is sufficient evidence for a hypomanic/manic episode and, therefore, a bipolar I/II diagnosis. As a consequence, depressed patients developing mania or hypomania during AD treatment could be diagnosed as bipolar I or II according DSM-5 criteria and not with the diagnosis of “substance-induced disorder” as in the case of DSM IV-TR criteria (Terao and Tanaka, 2014).

Treatment with ADs has been associated with mania or other forms of excessive behavioral activation, but the nature of AD-induced hypomania/mania (AIHM) is still controversial (Carvalho et al., 2016). The risk of AIHM seems to be higher in bipolar disorder (BD) (Vieta, 2014, Tondo et al., 2010), even if the principal difficulty lies in attributing causality, as mood elevations and changes in cycle frequency occur unpredictably in the natural course of BD, making it difficult to distinguish spontaneous from AD-induced switching (Pacchiarotti et al., 2013, Licht et al., 2008).

In patients diagnosed with unipolar Major Depressive Disorder (MDD) it has been found that AIHM occurred at an average frequency of 8.18% of cases (Baldessarini et al., 2013), but it remains unclear to what extent AD-associated mood switches represent unrecognized BD, or a more direct pharmacologic effect independent of diagnosis (Baldessarini et al., 2013, Dumlu et al., 2011).

Two studies compared patients with AIHM with other bipolar (Akiskal et al., 2003) or unipolar patients (Dumlu et al., 2011). Of 493 consecutive DSM-IV major depressive patients included in the EPIDEP National Multisite French Study, 144 (29.2%) fulfilled the criteria for bipolar II with spontaneous hypomania, and 52 (10.5%) had AIHM. The authors concluded that the presence of higher rates of familial bipolarity in AIHM strongly favors their inclusion within the bipolar spectrum, representing a genetically less penetrant expression of BP-II (Akiskal et al., 2003). Another study included 217 consecutive depressive patients with DSM-IV BD type I (n = 58) or type II (n = 18) and recurrent (unipolar) MDD with (n = 61) and without (n = 80) a history of AIHM. Two-step cluster analysis revealed two different naturally occurring groups and switchers (77%), BD type I (94.8%) and type II (83.3%) patients clustered together. These findings are consistent with the view that AIHM belongs within the bipolar spectrum rather than to be a coincidental treatment complication (Dumlu et al., 2011).

Koukopoulos et al. (2007) postulated the existence of a mixed-agitated depression, defined as depression with excitatory symptoms, occurring in both unipolar depression and BD and frequently associated with AD use (Sani et al., 2014). Furthermore, an activation syndrome other than mania or hypomania characterized by anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness and impulsivity was observed during the first 3 months of AD treatment, in psychiatric patients with multiple diagnoses (Harada et al., 2008). Such risk may be particularly high in patients with juvenile depressive or anxiety disorders who are more likely to be treated with ADs and stimulants before a diagnosis of BPD (Offidani et al., 2013). Finally, a history of AIHM has found to be more frequent in presence of a major depressive episode with mixed features in two different studies including both bipolar and unipolar depressed patients (Perugi et al., 2015a, Pacchiarotti et al., 2013;).

The objective of Bipolar Disorders: Improving Diagnosis, Guidance and Education (BRIDGE)-II-MIX (Perugi et al., 2015a, Perugi et al., 2015b, Popovic et al., 2015) naturalistic study was to provide a reliable estimate of the frequency of mixed features in a large international sample of patients diagnosed with major depressive episode (MDE) according to several sets of criteria, then to compare the clinical validity by examining specific features, such as rate of bipolarity, family history, and presence of AIHM. Our working hypothesis was that clinical characteristics of patients with a history of mood switches under AD treatment are similar to those of patients with BD and, consequently, that AIHM belongs to realm of bipolar spectrum. The aim of the present post-hoc analysis is to compare clinical features and hypomanic symptoms distribution in patients with Major Depressive Disorder (MDD), with MDD and AIHM (MDD-AIHM) and with Bipolar Disorder (BD) within this large international sample. Differently from previous reports in the present sample we have the possibility to explore the rate of mixed features during the current episode and their prevalence in depressive patients with a history of AIHM in comparison with MDD and BD patients.