Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates

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Abstract

Although antidepressants (ADs) are widely used in bipolar depression, there is weak evidence for their effectiveness and safety in this condition. Furthermore, there is a paucity of studies on the risk-benefit ratio of AD maintenance treatment in bipolar disorder (BD). We compared rehospitalization rates of patients with BD-I depressive episode who were discharged with mood stabilizers (MSs) and/or atypical antipsychotics (AAPs) with or without adjunctive AD. Ninety-eight patients with BD-I who were hospitalized with a depressive episode between 2005 and 2013 were retrospectively followed for 6-months and 1-year rehospitalization rates, as well as time to rehospitalization, according to treatment at discharge: MSs and/or AAPs with or without AD. Multivariable survival models adjusted for covariates known to influence rehospitalization were conducted. Six-months and 1-year rehospitalization rates were significantly lower in the adjunctive-AD treatment group compared to the no-AD group (9.2% vs. 36.4%, P = .001, power = 0.87 and 12.3% vs. 42.4%, P = .001, power = 0.89, respectively). Time to rehospitalization within 6-months and 1-year was significantly longer in the adjunctive-AD treatment group (169.9 vs 141 days, P = .001 and 335.6 vs 252.3 days, P = .001, respectively). Adjunctive-AD treatment at discharge reduced significantly the adjusted risk of rehospitalization within 6-months (HR = 0.081, 95% CI: 0.016–0.412, P = 0.002) and 1-year (HR = 0.149, 95% CI: 0.041–0.536, P = 0.004). Moreover, adjunctive-AD treatment did not increase rehospitalization rates of manic episode. In conclusion, adjunctive-AD therapy to MS/AAP at discharge from BD-I depressive episode hospitalization is associated with a lower rate of and a longer time to rehospitalization during a 1-year follow up period.

Introduction

Bipolar disorder (BD), ranked as the sixth-leading cause of disability worldwide (Merikangas et al., 2007), is a chronic mental illness characterized by recurrent manic and depressive episodes that usually begin in early adulthood and affects 1% to 4% of the general population (Henry et al., 2013). Although the occurrence of mania or hypomania distinguishes between BD and recurrent major depressive disorder, it is depression that dominates the course of bipolar disorder (Judd et al., 2002, Judd et al., 2003, Kupka et al., 2007, Thase, 2006), leading to poor quality of life, functional impairment and increased suicide risk (Judd et al., 2005, López et al., 2001). Quetiapine, olanzapine-fluoxetine treatment combination, lamotrigine and lurasidone, alone or in conjunction with lithium or valproate, are among the few evidence- based treatments for BD depression (WFSBP Task Force On Treatment Guidelines For Bipolar Disorders, 2010, Loebel et al., 2014). However, numerous patients are refractory to these medications or do not tolerate their side effects. Thus, there is an unmet need for an effective and safe antidepressant treatment for BD depression.

Although the effectiveness of antidepressants (ADs) is well established in unipolar depression, an incongruity exists between the wide use and the weak evidence for the effectiveness and safety of ADs in bipolar depression (Pacchiarotti et al., 2013). While findings from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study suggest adjunctive AD to mood stabilizers (MSs) to be inefficacious but safe with regard to treatment emergent affective switch (TEAS) risk (Sachs et al., 2007), a recent meta-analysis (McGirr et al., 2016) supports the effectiveness and safety of adjunctive modern ADs to MS or atypical antipsychotics (AAP) in the acute treatment of bipolar depression.

Even more controversial, is the use of adjunctive AD in the maintenance treatment of BD. Long-term trials involving addition of AD to ongoing MS treatments are scant and have yielded inconclusive findings (Pacchiarotti et al., 2013). Despite evidence from two large open studies that indicate that continuation of adjunctive AD may be beneficial in non-rapid cycling BD patients (Altshuler et al., 2003, Ghaemi et al., 2010),two meta-analyses of randomized controlled trails (Ghaemi et al., 2008, McGirr et al., 2016) found that compared with MS monotherapy, long-term adjunctive AD provided little protection from relapse of depression and tended to increased TEAS rates, resulting in an unfavorable risk-benefit ratio for long-term AD use in BD. Consequently, most guidelines recommend the use of AD only in combination with an antimanic agent and to consider discontinuation at twelve weeks in remission, in order to avoid TEAS (Goodwin et al., 2016).

Thus, further studies, reflecting more generalizable BD samples, are needed to evaluate the effectiveness and safety of adjunctive AD therapy in both acute and maintenance treatments of BD patients. In the current study, we used a naturalistic design of retrospective chart review to compare six-months and 1-year rehospitalization rates of BD-I patients hospitalized with depressive episode and treated at discharge with MS and/or AAP with or without ADs.

Section snippets

Population

We conducted a retrospective cohort study, using electronic medical record (EMR) review of all consecutive admissions to Geha Mental Health Center ([GMHC], Petach Tikva, Israel) between 1 January 2005 and 31 July 2013. GMHC is a large, tertiary referral mental health center covering catchment area of about 800,000 inhabitants with mixed ethnicity. We included patients in the study who met DSM-IV-TR criteria for bipolar I disorder (BD-I) and were admitted to GMHC during the study period due to

Study sample characteristics

During the study period, a total of 130 patients with BD-I were admitted due to a depressive episode. Of these 130 patients, 9 patients were excluded by the selection criteria. Out of the remaining 121 patients, 98 (81%) were treated with MS and/or AAP at discharge. Thus, 98 patients with BD-I depression were eligible for analysis and were sub grouped according to type of treatment at discharge: MS/AAP + AD and MS/AAP - AD (Table 1).

There was no significant difference between the two treatment

Discussion

The main finding in this retrospective cohort study, is that adjunctive AD therapy to MS and/or AAP, at discharge after a bipolar depressive episode hospitalization, is associated with a lower rate of and a longer time to rehospitalization due to a relapse of depressive episode or any type of mood episode in both six-months and 1-year follow-up periods, without increasing the rehospitalization rate due to emerging manic episode. Our results, in agreement with those of a recent meta-analysis of

Acknowledgments

This work was performed in partial fulfillment of the M.D. thesis requirements of the Sackler Faculty of Medicine, Tel Aviv University (Yahav Shvartzman).

Conflict of interest

The authors declare that they have no conflicts of interest concerning this article.

Contributors

Yahav Shvartzman contributed to the study design, data analysis, interpretation of data and drafting the manuscript.

Amir Krivoy contributed to the data acquisition and analysis, interpretation of data and revising the manuscript.

Avi Valevski contributed to the data acquisition and analysis, interpretation of data and revising the manuscript.

Shay Gur contributed to the data analysis, interpretation of data and

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