Research paperAntidepressant-induced hypomania/mania in patients with major depression: Evidence from the BRIDGE-II-MIX study
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.
Section snippets
Patients and methods
The BRIDGE-II-Mix Study was a multicentre, international, non-interventional, cross-sectional study. The study was conducted between June 2009 and July 2010 in 239 centres in Bulgaria, Egypt, Morocco, Netherlands, Portugal, Russia, Spain and Turkey. The chosen centres reflected the psychiatric healthcare provision for each country, representative of the country's practice and regional diversity. The number of investigators per country ranged from 62 in Spain to 18 in Egypt. Each centre was
Results
The mean proportion of patients who were hospitalized for the full sample was 26.0%. 2811 patients agreed to participate and provided complete data; these constituted the full analysis population. Demographic features were generally similar across countries.
From a total of 2811 patients with MDE, n = 1872 (66.59%) were diagnosed with Major Depressive Disorder, n = 464 (16.51%) with Bipolar Disorder, and finally n = 475 (16.90%) were diagnosed with MDD and AIHM.
Discussion
In this post-hoc analysis of the BRIDGE-II-MIX Study, we found that about 1 out of 6 patients (16.7%) diagnosed with Major Depressive Disorder (MDD) presented a past history of AIHM. The emergence of new mania-like responses to AD-treatment in patients diagnosed as having a Major Depressive Disorder (MDD) has been assessed by several authors. Baldessarini et al. (2013) found that 8.1% of unipolar patients presented a lifetime history of AIHM during the course of the illness. Another
Limitations
The main strengths of the BRIDGE-MIX II study include the large sample size, and the wide range of care settings, both hospital and community, from eight countries across three continents. Furthermore, narrow exclusion criteria increase the generalizability of the findings. The first limitation is the widely varying rates of hospitalized patients across countries, ranging from 1.0% to 57.8%, which reflect economically driven policies on the use of hospitalization-based treatment. A second
Conclusion
In conclusion, hypomania/mania that first manifests during treatment with ADs poses important questions for clinical practice. Our results strongly support the DSM-5 inclusion of such patients within the rubric of BD. Patients developing mood switches with ADs showed important differences from MDD, including distinct clinical features, such as first degree familiarity for BD, mixed and atypical presentations. Differences with other MDD and BD were also found concerning the higher number of
Funding source
The sponsor of this study (Sanofi-Aventis) was involved in the study design, conduct, monitoring, and preparation of the final data base, but not in the content of this report. All investigators recruited received fees from the sponsor in recognition of their participation in the study on a per patient basis. The corresponding author had full access to all the data and had final responsibility for data analyses, preparation of the report, and the decision to submit for publication.
Acknowledgements
None.
References (41)
- et al.
Validating antidepressant-associated hypomania (bipolar III): a systematic comparison with spontaneous hypomania (bipolar II)
J. Affect. Disord.
(2003) - et al.
Antidepressant-associated mood-switching and transition from unipolar major depression to bipolar disorder: a review
J. Affect. Disord.
(2013) - et al.
Treatment-induced manic switch in the course of unipolar depression can predict bipolarity: cluster analysis based evidence
J. Affect. Disord.
(2011) - et al.
Antidepressant-associated chronic irritable dysphoria (ACID) in STEP-BD patients
J. Affect. Disord.
(2008) - et al.
Psychomotor agitation in major depressive disorder is a predictive factor of mood-switching
J. Affect. Disord.
(2015) - et al.
The primacy of mania: a reconsideration of mood disorders
Eur. Psychiatry
(2009) - et al.
Genetics of emergent suicidality during antidepressive treatment--data from a naturalistic study on a large sample of inpatients with a major depressive episode
Eur. Neuropsychopharmacol.
(2013) - et al.
Mania and depression. Mixed, not stirred
J. Affect. Disord.
(2011) - et al.
Factors associated with initial treatment response with antidepressants in bipolar disorder
Eur. Neuropsychopharmacol.
(2011) - et al.
Association between the so-called "activation syndrome" and bipolar II disorder, a related disorder, and bipolar suggestive features in outpatients with depression
J. Affect. Disord.
(2013)
Bipolar depression: clinical correlates of receiving antidepressants
J. Affect. Disord.
Diagnostic criteria for bipolarity based on an international sample of 5,635 patients with DSM-IV major depressive episodes
Eur. Arch. Psychiatry Clin. Neurosci.
Prevalence and characteristics of undiagnosed bipolar disorders in patients with a major depressive episode: the BRIDGE study
Arch. Gen. Psychiatry
Major depressive disorder with subthreshold bipolarity in the National Comorbidity Survey Replication
Am. J. Psychiatry
Do we need to flick the switch? The need for a broader conceptualization of iatrogenic course aggravation in clinical trials of bipolar disorder
Psychiatry Clin. Neurosci.
The safety, tolerability and risks associated with the use of newer generation antidepressant drugs: a critical review of the literature
Psychother. Psychosom.
The global assessment scale. A procedure for measuring overall severity of psychiatric disturbance
Arch. Gen. Psychiatry
Correlates of treatment-emergent mania associated with antidepressant treatment in bipolar depression
Am. J. Psychiatry
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