Clinical and psychopathological features associated with treatment-emergent mania in bipolar-II depressed outpatients exposed to antidepressants

https://doi.org/10.1016/j.jad.2018.02.085Get rights and content

Highlights

  • Treatment-emergent mania (TEM) has been reported inconsistently among Bipolar Disorder (BD) depressed patients receiving antidepressants.

  • TEM occurred in 38.46% of the assessed cases.

  • A typical antipsychotics (p = .005), lithium (≤ .001), cyclothymic/irritable/hyperthymic temperaments (p = ≤ .001; p = .001; p = .003, respectively), rapid-cycling (p = .005) and depressive mixed features (p = .003) differed between TEM+ vs. TEM patients upon descriptive statistics but not multivariate regression.

Abstract

Background

Treatment-emergent affective switch (TEAS), including treatment-emergent mania (TEM), carry significant burden in the clinical management of bipolar depression, whereas the use of antidepressants raises both efficacy, safety and tolerability concerns. The present study assesses the prevalence and clinical correlates of TEM in selected sample of Bipolar Disorder (BD) Type-II (BD-II) acute depression outpatients.

Methods

Post-hoc analysis of the clinical and psychopathological features associated with TEM among 91 BD-II depressed outpatients exposed to antidepressants.

Results

Second-generation antipsychotics (SGA) (p = .005), lithium (≤ .001), cyclothymic/irritable/hyperthymic temperaments (p = ≤ .001; p = .001; p = .003, respectively), rapid-cycling (p = .005) and depressive mixed features (p = .003) differed between TEM+ cases vs. TEM controls. Upon multinomial logistic regression, the accounted psychopathological features correctly classified as much as 88.6% of TEM+ cases (35/91 overall sample, or 38.46% of the sample), yet not statistically significantly [Exp(B) = .032; p = ns]. Specifically, lithium [B = − 2.385; p = .001], SGAs [B = − 2.354; p = .002] predicted lower rates of TEM+ in contrast to the number of lifetime previous psychiatric hospitalizations [B = 2.380; p = .002], whereas mixed features did not [B = 1.267; p = ns].

Limitations

Post-hoc analysis. Lack of systematic pharmacological history record; chance of recall bias and Berkson's biases. Permissive operational criterion for TEM. Relatively small sample size.

Conclusions

Cyclothymic temperament and mixed depression discriminated TEM+ between TEM cases, although only lithium and the SGAs reliably predicted TEM+/− grouping. Larger-sampled/powered longitudinal replication studies are warranted to allow firm conclusions on the matter, ideally contributing to the identification of clear-cut sub-phenotypes of BD towards patient-tailored-pharmacotherapy.

Introduction

Although both the Fourth (DSM-IV) and the Fifth (DSM-5) (APA, 2013) editions of the Diagnostic and Statistical Manual for Mental Disorders (DSM) pose mania as the hallmark of Bipolar Disorder (BD), it is depression the most enduring facet of the illness, often requiring intense treatment efforts (Grunze et al., 2010, Grunze et al., 2013).

Treatment-emergent affective switch (TEAS), including treatment-emergent mania (TEM) may occur at any stage of BD (Baldassano et al., 2011, Baldessarini et al., 2007) although no univocal consensus exists on the matter, neither about the conceptual definition or the plausible causal nexus between antidepressant(s) and subsequent mania (Ghaemi, 2010, Gijsman et al., 2004, Tohen et al., 2009).

Antidepressants represent the most routinely prescribed drugs for bipolar depression despite major tolerability concerns (Ghaemi et al., 2003, Ghaemi et al., 2001, Goldberg and Nassir Ghaemi, 2005), often concurring to cumbersome polypharmacy (Fornaro et al., 2016a).

Until recently, unipolar “endogenous” or “melancholic” major depression disorder (MDD)’ major depressive episodes (MDEs) have long been considered equivalent to bipolar MDEs, both from clinical, neurobiological and treatment-modality standpoints (Fountoulakis, 2014). Among other issues, the latter historical wisdom accounts for the dearth of modern randomized-controlled trials (RCTs) assessing the safety of antidepressant(s) for bipolar rather than unipolar depression (Fornaro et al., 2016c, Goodwin, 2012, Healy, 2008).

Yet, abrupt changes in mood polarity were described well before the beginning of the psychopharmacological era: manic features observed after a depressive episode were reported as “post-melancholic reactive hyperthymia”, while mania that evolved into depression was referred to as “reactive depression” (Angst and Sellaro, 2000).

Possibly, the use of mood-stabilizers (Malhi et al., 2009), second-generation antipsychotics (SGAs) (Fornaro et al., 2016d, Savas et al., 2007, Yatham et al., 2005), as well as development of novel pharmacological avenues (Fornaro et al., 2016b), has been hindered by the so-called “antidepressant view of the world” promoting jaunty prescriptions of antidepressant monotherapies among BD patients or complex polypharmacy which further hinders the understanding of the clinical epidemiology and neurobiology underpinning the TEM phenomena (Fornaro et al., 2011, Ghaemi et al., 2001, Klerman, 1971, Klerman, 1981, Klerman and Weissman, 1989).

The international guidelines for Bipolar Disorders (ISBD) either pose formal counter-recommendations or they either call for prudence concerning the use of antidepressants in BD, especially for long-term antidepressant-monotherapy (Anderson et al., 2008, Fornaro et al., 2012, Goodwin, 2009, Pacchiarotti et al., 2013, Parker et al., 2017, Tundo et al., 2015).

The need for better determination and dissemination of consensus on the nomenclature of the course and treatment outcome of BD is also compelling, since the appraisal of heterogeneous narrative and/or operational definitions for TEAS account for the inconsistency of the evidence on the matter (Tohen et al., 2009), ultimately hindering the understanding of the neurobiological bases underpinning complex and differential psychopathology of BD (Salvadore et al., 2010).

Switching from a depressive pole towards (hypo-)mania may occur either spontaneously within the natural course of BD (Baldessarini et al., 2013, Koukopoulos et al., 2013), often characterizing for waxing and waning course of depressive symptoms, or following substances exposure (herein including prescription drugs as the antidepressants) (Baldessarini et al., 2013), or after psychiatric-/general medical comorbidity triggering conversion of mood polarity (Bunney et al., 1972).

Whenever attributed to the “direct” effects of the antidepressant(s), even those patients originally diagnosed as MDD who turn-out to rapidly switch towards mania – notably, postulated as a potential hint for sub-threshold bipolarity (Offidani et al., 2013) – could be diagnosed as overt BD cases (Tondo et al., 2010), whereas “genuine” BD patients experiencing a (hypo-)mania likely due to the “direct” effect of antidepressant(s) may still be diagnosed as (recurrent) (hypo-)manic cases according to the DSM-5 criteria (Angst, 2013, APA, 2013, Terao and Tanaka, 2014). Regardless the hypothesized eventual continuum or causal nexus, improper use of antidepressant medications among bipolar spectrum patients associates with increased rates of (antidepressant-)chronic-induced dysphoria (ACID) (El-Mallakh et al., 2008), induction or worsening of rapid-cycling (Altshuler et al., 1995), course and/or mixed features and circadian rhythms impairment and/or history of treatment-resistance (Lee et al., 2013), increased risk for suicidal behaviors (Henry et al., 2001), and spontaneous report of lifetime mania/hypomania overall (Truman et al., 2007).

Burgeoning of evidence exists about TEM events among bipolar depression patients exposed to either antidepressant monotherapy or augmentation strategies, accounting for a broad range of risk factors (Frye et al., 2009, Malhi et al., 2015, Smith et al., 2007, Valentí et al., 2012).

Yet, corresponding the evidence on the matter is either tentative or inconsistent (Ghaemi et al., 2003, Licht et al., 2008, Malhi et al., 2015, Möller and Grunze, 2000, Parker et al., 2017), especially with respect to the eventual role played by otherwise clinically suggestive psychopathological features as predominant affective temperaments and subtle mixed features possibly experienced by some bipolar depression patients (Bottlender et al., 2004, Frye et al., 2009, Henry et al., 2001, Malhi, 2015, Möller and Grunze, 2000), as outlined by a recent large-scale systematic review and meta-analysis accounting for a broad-range of clinical and psychopathological putative predictors (Fornaro and et al., 2018).

The present study aims at assessing the prevalence and clinical features associated with acute onset of likely (Tohen et al., 2009) TEM events among BD-II outpatients exposed to antidepressants, encompassing a range of clinically-sensible putative psychopathological predictors of TEM. To the best of our knowledge, this is the first report of its kind to account for a broad range of clinical moderators at once.

Section snippets

Methods

The details about the study design and sampling methods adopted for the present cross-sectional post-hoc analysis have been documented elsewhere (Fornaro et al., 2013).

Results

A total of 91 patients from a pool of 220 could be reliably included in the present post-hoc analysis, since only a portion of the original sample carried sufficient and reliable information about TEM owing to the operational definitions outlined in the methods. The sample size is relatively large according to the assessment of the methodological quality of the reports on BD appraised in the literature (Soldani et al., 2005).

Discussion

In the last decade, there has been an upsurge of interest about the “TEM-spectrum” phenomena.

While the ‘spectrum concept’ invokes a continuum model for capturing mood dysregulation occurrence within BD-II cases (and beyond), there is little consensus, however, in regard to which disorders of sub-phenotypes of BD constitute the spectrum (Hadjipavlou et al., 2004).

Like many areas in medicine where we confront a chronic condition characterized by an irregular course of acute symptoms, BD poses

Acknowledgments

The authors have none to state.

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      As regards the rapid cycling course, a frequent condition in bipolar disorder (Carvalho et al., 2014), our findings suggest that the depressive symptoms play a role during a manic/hypomanic episode, favoring the "switching" from one mood polarity to the other (Maj et al., 2002). An inappropriate use of antidepressants in bipolar disorder may be a factor involved in this transition, since it may induce both mixed states and rapid cycling (Fornaro et al., 2018a; 2018b; Tortorella et al., 2015). Unfortunately, studies included in this meta-analysis did not provide sufficient data to estimating the effect of antidepressant treatment on ‘mixed mania’, which is a gap that future research should consider.

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