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Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates
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Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates Yahav Shvartzmana, Amir Krivoya,b,c, Avi Valevskia,b, Shay Gura,b, Abraham Weizmana,b,c, Eldar Hochmana,b,c,n a
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel Geha Mental Health Center, Petach-Tikva, Israel c Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel b
Received 29 August 2017; received in revised form 4 December 2017; accepted 26 January 2018
KEYWORDS
Abstract
Antidepressants; Atypical antipsychotics; Mood stabilizers; Bipolar disorder; Depressive episode; Rehospitalization
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. Ninetyeight 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. & 2018 Elsevier B.V. and ECNP. All rights reserved.
n
Correspondence to: Geha Mental Health Center, P.O. Box 102, Petach Tikva 4910002, Israel. Fax: +972 3 9258388.
https://doi.org/10.1016/j.euroneuro.2018.01.010 0924-977X/& 2018 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
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1.
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, 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 (Grunze et al., 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.
2. 2.1.
Experimental procedures 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 an acute depressive episode. All patients were at least 18 years of age at the index hospitalization. The type of psychiatric diagnosis and exacerbation leading to each hospitalization (index hospitalization and rehospitalization) was classified as DSM-IV-TR BD-I manic, major depressive or mixed episode as established by consensus of two senior psychiatrists during each hospitalization and validated retrospectively by the study team according to the medical records. In order to increase the diagnostic clarity of the sample, we excluded from the study patients who met DSM-IV-TR criteria for BD-II, schizoaffective disorder, mood exacerbations related to substance use or to a general medical condition and hospitalizations not related to a primary major mood episode. We further excluded BD-I patients with rapid cycling pattern, as current data suggest negative risk-benefit ratio for AD use in this sub-population (Yatham et al., 2013). In a patient with multiple hospitalizations, we included in the study the first hospitalization as the index hospitalization. To ascertain a clear distinction between separate hospitalizations, a rehospitalization within a 1-week period following discharge from the index hospitalization (since 2005) was not considered as a new hospitalization unless the polarity was reversed in the second hospitalization. In the case of rehospitalization within 1 week following discharge, patients were followed for 1 year from their discharge from the second hospitalization. To examine the effects of specific medication regimens on rehospitalization rates, we included in the study all the patients who were treated at discharge with MS (lithium, valproate, carbamazepine or lamotrigine) and/or AAP (risperidone [including Risperdal Consta], olanzapine, quetiapine and ziprasidone) with or without an adjunctive AD (selective serotonin reuptake inhibitors [SSRI, including citalopram, escitalopram, sertraline, paroxetine, fluoxetine, fluvoxamine], norepinephrine dopamine reuptake inhibitors [NDRI, including bupropion], serotonin norepinephrine reuptake inhibitors [SNRI, including venlafaxine, duloxetine], tricyclic antidepressants [TCAs, including nortriptyline, imipramine, doxepine, clomipramine] and atypical antidepressants [including mirtazapine]). Three patients were treated with the combination of SSRI and SNRI or atypical AD. The classification of the type of AD treatment for these patients was determined by the second AD agent (SNRI/atypical). Concomitant typical antipsychotics (TAP) or anxiolytic medications at discharge from index hospitalization were noted and were considered as covariates in the analysis. Patients who were discharged from the index hospitalization without any antimanic agent or only with TAP were excluded from the study. Patients were divided into two groups according to the type of treatment at discharge: (i) MS and/or AAP with AD; (ii) MS and/or AAP without AD. The study was approved by the GMHC review board.
2.2.
Measures
The primary outcome measures of this study were six-months and 1-year rehospitalization rates due to major mood episode. The
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates secondary outcome was time to rehospitalization during the sixmonths and 1-year periods after discharge. Sociodemographic and clinical data, considered as surrogate measure of illness severity (thus, as potentially covariates), were collected from the patients’ EMRs. Demographic data included age at first lifetime psychiatric hospitalization, age at index hospitalization, gender, marital status, occupational status and country of birth. Clinical data included the type of mood episode leading to each hospitalization (due to small number of mixed episodes (one mixed episode in the MS/AAP + AD treatment group), mixed episodes were counted as manic episodes), the length of index hospitalization, the number of previous hospitalizations due to major mood episodes, the index hospitalization legal status (voluntary or involuntary), the presence of psychotic features during the mood episode (delusions or hallucinations during the mood episode according to DSM-IV-TR), history of suicide attempt, psychiatric comorbidities including substance use disorder, anxiety disorders and personality disorders (according to DSM-IV-TR criteria), physical comorbidities (cardiovascular, metabolic, renal, endocrine and liver diseases), the type and dosage of psychotropic medications (including long-acting injectable [LAI] antipsychotics) at discharge from the index hospitalization, serum lithium concentration (mmol/L), serum valproate concentration (μg/mL) and electroconvulsive treatment during index hospitalization.
2.3.
Statistical analysis
Rehospitalization rates and sociodemographic and clinical characteristics were compared between the two treatment groups (MS/ AAP + AD vs. MS/AAP - AD) using independent Student's t-test, and χ2-test (or Fisher's exact test as appropriate). Kaplan–Meier survival analysis was used to compare the mean time to rehospitalization between the two treatment groups. The multivariate Cox proportional hazards regression model was employed to assess the adjusted association between adjunctive AD treatment at discharge and the risk of rehospitalization controlling for variables for which a significant between-group difference was detected in the univariate analysis. A retrospective power analysis was used to evaluate sample power (Power and Precision program, Biostat, USA). All statistical tests were conducted by the SPSS ver. 23 (SPSS Inc, Chicago, IL) and statistical significance was set at 0.05.
3.
Results
3.1.
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
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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 groups with regard to the rate of MS, AAP, TAP, anxiolytic and LAI antipsychotic treatments at discharge (Table 1) and with regard to the mean daily dose of MSs, AAPs and TAPs or the serum levels of lithium and valproate at discharge (Supplementary Table 1). The two treatment groups were comparable in terms of baseline clinical and sociodemographic characteristics (Table 2), with the exception of increased length of index hospitalization in the MS/ AAP + AD group compared to the MS/AAP - AD group (Po.05), an increased rate of psychotic features in the MS/AAP - AD group compared to the MS/AAP + AD group (Po.05), a higher age at first hospitalization in the MS/AAP + AD group compared to the MS/AAP -AD group (Po.05) and increased number of previous hospitalizations in the MS/AAP - AD group compared to the MS/AAP + AD group (Po.05) (Table 2).
3.2.
Rehospitalization rates
Of the total sample (n = 98), 18 (18.4%) and 22 (22.4%) were rehospitalized due to any type of mood episode within six-months and 1-year following discharge from the index hospitalization, respectively. The distribution of the type of mood episodes leading to rehospitalization within six-months was: six with manic episodes (33.3%) and 12 with depressive episodes (66.7%), and within 1-year it was: eight manic episodes (36.4%) and 14 depressive episodes (63.6%). Rehospitalization rates within six-months and within 1-year due to any type of mood episode were significantly lower in the MS/ AAP + AD group (9.2%, n = 6 and 12.3%, n = 8, respectively) compared to the MS/AAP - AD group (36.4%, n = 12, χ2 = 10.74, P = .001, power = 0.87 and 42.4%, n = 14, χ2 = 11.40, P = .001, power = 0.89, respectively). Concerning the type of mood episode, rehospitalization rates within six-months due to manic or depressive episodes were significantly lower in the MS/AAP + AD group (1.5%, n = 1 and 7.7%, n = 5, respectively) compared to the MS/AAP - AD group (12.1%, n = 4, Fisher's exact test: P = .043 and 24.2%, n = 8, Fisher's exact test: P = .030, respectively). Similarly, rehospitalization rates within 1-year due to manic or depressive episodes were significantly lower in the MS/AAP + AD group (3.1%, n = 2 and 9.2%, n = 6, respectively) compared to the MS/AAP - AD group (18.2%, n = 6, Fisher's exact test: P = .016 and 24.2%, n = 8, χ2 = 4.02, P = .045, respectively). In order to evaluate the association between the class of the AD at discharge and rehospitalization rates, the MS/AAP + AD group was subdivided into two treatment groups: patients discharged with SSRI/NDRI and patients discharged with SNRI/TCA/atypical AD. No significant difference was found in the rehospitalization rates within six-months and 1-year due to any type of mood episode or
Table 1 Classification of the study groups according to type of treatment at discharge from index depressive hospitalization. Treatment [N (%)]
Total (N = 98) MS/AAP + AD (N = 65) MS/AAP -AD (N = 33) P-valuea
LITHIUM VALPROATE LAMOTRIGINE CARBAMAZEPINE AAP TAP Anxiolytics Long-acting injectable antipsychotics (AAP or TAP)
39 (39.8) 35 (35.7) 16 (16.3) 6 (6.1) 34 (34.7) 17 (17.3) 32 (32.7) 6 (6.1)
28 (43.1) 22 (33.8) 8 (12.3) 4 (6.2) 19 (29.2) 9 (13.8) 20 (30.8) 2 (3.1)
AAP, atypical antipsychotic; AD, antidepressant; MS, mood stabilizer; TAP, typical antipsychotic. a χ2 test or Fisher's exact test as appropriate. MS/AAP + AD versus MS/AAP – AD.
11 (33.3) 13 (39.4) 8 (24.2) 2 (6.1) 15 (45.5) 8 (24.2) 12 (36.4) 4 (12.1)
.352 .588 .131 1.000 .111 .199 .577 .175
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Table 2
Baseline clinical and sociodemographic characteristics of the study sample.
Gender, male, n (%) Born in Israel, n (%) Current employment status, working, n (%)a Marital status, married, n (%)a Index hospitalization Age at index hospitalization, years, mean (SD) Length of index hospitalization, days, mean (SD) Involuntary Hospitalization, n (%)a Psychotic features, n (%)a ECT at index hospitalization, n (%)a Age at first hospitalization, years, mean (SD)a Number of previous hospitalizations, mean (SD)a Psychiatric co-morbidity, n (%) Personality disorder Substance use disordera Anxiety disorder Physical co-morbidity, n (%)a History of suicide attempt, n (%)a
Total (N = 98)
MS/AAP + AD (N = 65)
MS/AAP – AD (N = 33)
52 56 36 38
32 34 25 27
20 22 11 11
(53.1) (57.1) (39.1) (40.4)
(49.2) (52.3) (40.3) (43.5)
(60.6) (66.7) (36.7) (34.4)
49.1 (16.4) 45.5 (52.9) 4 (4.8) 19 (21.3) 11 (12.5) 42.7 (18.2) 2.7 (3.7)
51.1 (16.2) 53.6 (51.6)* 3 (5.2) 9 (14.8)* 9 (15.3) 45.7 (19.4)* 2.1 (3.3)*
45.4 (16.3) 29.4 (52.5) 1 (3.8) 10 (35.7) 2 (6.9) 37.5 (14.9) 3.9 (4.4)
25 11 11 19 21
16 (24.6) 5 (8.5) 7 (10.8) 14 (23) 14 (24.1)
9 6 4 5 7
(25.5) (12.8) (11.2) (20.4) (25.6)
(27.3) (22.2) (12.1) (15.6) (29.2)
AAP, atypical antipsychotic; AD, antidepressant; ECT, electroconvulsive therapy; MS, mood stabilizer. a Missing data: age at first hospitalization (N = 81); ECT (N = 88); employment status (N = 92); history of suicide attempt (N = 82); involuntary admission (N = 84); marital status (N = 94); number of previous hospitalization (N = 83); physical co-morbidity (N = 93); psychotic features (N = 89); substance use disorder (N = 86). * P o 0.05 versus MS/AAP – AD.
due to manic or depressive episode between the two classes of AD groups (Supplementary Table 2).
3.3.
Time to rehospitalization
3.3.1. Six-months' period after discharge Mean time to rehospitalization during the 6-months' period after discharge, due to any type of mood episode, differed between the two treatment groups (Fig. 1). There was significantly longer time to rehospitalization for MS/AAP + AD group (169.9 days standard error [SE] = 4.5) compared to the MS/AAP - AD group (141 days [SE = 10.7], log-rank = 10.9, P = .001). Likewise, the mean time to rehospitalization due to manic or depressive episodes was significantly longer for the MS/AAP + AD group (177.4 days [SE = 2.5] and 172.3 [SE = 3.8], respectively) compared to the MS/AAP - AD group (168.2 days [SE = 6.5], log-rank = 5.8, P = .016 and 150.5 days [SE = 10.1], log-rank = 5.7, P = .016, respectively).
3.3.2. One-year period after discharge Mean time to rehospitalization during the 1-year period after discharge due to any type of mood episode was significantly longer for the MS/AAP + AD group (335.6 days [SE = 10.9]) compared to the MS/AAP - AD group (252.3 days [SE = 24.8], log-rank = 12.0, P = .001). Similarly, the mean time to rehospitalization due to manic or depressive episodes was significantly longer for the MS/AAP + AD group (358.2 days [SE = 5.5] and 341.9 days [SE = 9.8], respectively) compared to the MS/AAP - AD group (317.2 days [SE = 18.8], log-rank = 8.3, P = .004 and 288.6 days [SE = 23.7], log-rank = 4.7, P = .029, respectively).
Fig. 1 Time to rehospitalization due to any type of mood episode within six months following discharge according to the treatment at discharge (Kaplan-Meier survival analysis).
3.4.
Multivariable analysis
The multivariate Cox proportional hazards model was employed to assess the adjusted association between adjunctive AD treatment at discharge and the risk of rehospitalization controlling for variables for which a significant between-group difference was observed in the univariate analysis (age at first hospitalization,
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates
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Table 3 Adjusted hazard ratios for rehospitalization by adjunctive AD treatment at discharge from index depressive hospitalization (cox regression survival analysis).
Six months following discharge Due to any type of mood episode Due to manic episode Due to depressive episode One year following discharge Due to any type of mood episode Due to manic episode Due to depressive episode
β
χ2
Adjusted Hazards ratioa
P value
95% CI
-2.517 -1.951 -2.499
9.160 2.982 8.261
0.081 0.142 0.082
0.002 0.84 0.004
0.016–0.412 0.016–1.301 0.015–0.452
-1.906 -2.1 -2.21
8.483 2.146 8.379
0.149 0.122 0.110
0.004 0.143 0.004
0.041–0.536 0.007–2.033 0.025–0.490
AD, antidepressant. a Adjusted for: age at first hospitalization, length of index hospitalization, number of pervious hospitalizations and presence of psychotic features at index hospitalization.
length of index hospitalization, number of previous hospitalizations and presence of psychotic features at index hospitalization). According to this model, within six-months and 1-year periods following discharge, the MS/AAP + AD group had a significantly reduced adjusted risk of rehospitalization due to any type of mood episode or due to depressive episode compared to the MS/AAP - AD group (Table 3). No significant difference was found in the adjusted risk of rehospitalization due to manic episode between the two treatment groups (Table 3).
4.
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 randomized placebo-controlled trials (McGirr et al., 2016), indicate the effectiveness and safety of adjunctive AD to MS or AAP in the short-term treatment of bipolar depression. However, while in this meta-analysis prolonged treatment with adjunctive AD was associated with an increased risk of affective switch despite adequate mood stabilization (McGirr et al., 2016), in our study rehospitalization rate due to manic episode was not increased during the 1-year follow up. Our study encourages the use of adjunctive ADs to MSs or AAPs at least in the short-term treatment of bipolar depression.
4.1. Short- and long-term AD therapy in BD – naturalistic studies perspective Few naturalistic studies have investigated the effectiveness and safety of adjunctive AD to MS/AAP in BD. In the shortterm treatment, a large naturalistic study found AD treatment (with or without MS) to be similarly effective in a total of 1,036 patients with BD-I, BD-II, and unipolar depression with moderate risk of TEAS (Pacchiarotti et al., 2013; Tondo et al., 2013). Similarly, a comparable short-term effectiveness of TCAs in unipolar and BD depression was found in a
large retrospective analysis (Möller et al., 2001). However, in bipolar depressive episode with mixed features, shortterm adjunctive AD to MS did not shorten time to remission from depressive symptoms and was associated with aggravation of manic symptoms (Goldberg et al., 2007). Concerning long-term adjunctive AD treatment, an open question remains about the risk of mood destabilization due to either prolonged use or early discontinuation of ADs (Ghaemi et al., 2008; McGirr et al., 2016; Vieta and Garriga, 2016). In a retrospective chart review analysis, Vardi et al., found that adjunctive AD treatment on discharge following a bipolar depressive episode hospitalization had no significant impact on 1-year rehospitalization rates (Vardi et al., 2014). However, two large open studies indicate that continuation of adjunctive AD treatment may be beneficial in BD patients (Altshuler et al., 2003; Viktorin et al., 2014). In the first study, conducted by Altshuler et al., the risk of depressive relapse in patients with BD was significantly associated with discontinuation of AD within six-months after remission, while the risk of manic relapse was not associated with continuation of AD (Altshuler et al., 2003). In the second study, using Swedish national registries, Viktorin et al., found that among BD patients treated with a MS, no acute change in the risk of mania was observed during the 3-months after initiation of AD and even a decreased risk was observed during 3–9 months after AD treatment initiation (Viktorin et al., 2014). Our study, similarly to the naturalistic studies conducted by Altshuler et al., and Viktorin et al., demonstrates the effectiveness and safety of adjunctive AD treatment continuation in BD. The difference between our results and those found by Vardi et al., can be related to the definition of the studies’ primary outcome (Vardi et al., study: allcause rehospitalizaion rates; our study: rehospitalization rates due to a major mood episode). Due to the small number of mixed episodes leading to rehospitalization in our sample, the association between adjunctive AD therapy and the time-course of BD with mixed features could not be explored and further large-scale studies are needed to address this subject.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
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4.2. ADs prescription pattern and response predictors in BD The majority (66%) of patients in our study were prescribed adjunctive AD at discharge from a bipolar depressive episode hospitalization. These prescribing patterns are in accordance to previous reports, including those of STEP-BD study (Baldessarini et al., 2007; Ghaemi et al., 2006; Mauer et al., 2014), reflecting the wide use of ADs in BD treatment management despite the controversy about their effectiveness and safety. Regarding the type of AD class, although previous studies suggested increased risk of mood switch or destabilization with adjunctive TCAs or SNRIs compared to SSRIs or a NDRI (Pacchiarotti et al., 2013), no significant difference in rehospitalization rates were found in our sample between these AD classes. However, due to the small sample size this observation should be interpreted with caution. In order to improve the risk-benefit ratio of AD use in BD (increased effectiveness and tolerance), an ongoing treatment objective is to achieve a personalized choice of medicine based on predictors or moderators of treatment response (Goodwin et al., 2016; Pacchiarotti et al., 2011). Based on the available literature, possible predictors of short-term response to AD among BD patients include previous response to AD and a less severe illness course (Pacchiarotti et al., 2013, 2011; Post et al., 2012). Moreover, initial response to AD is considered a predictor of longterm responsiveness to adjunctive AD among BD patients (Altshuler et al., 2009; Pacchiarotti et al., 2013). In our study, BD patients that were discharged with adjunctive AD following a depressive episode hospitalization had a decreased rate of psychotic features at index hospitalization, a higher age at first hospitalization and a reduced number of previous hospitalizations compared to BD patients who were discharged without AD. Considering AD treatment at discharge as a proxy measure of short-term responsiveness to AD, our results support the observation made by previous studies that BD patients with a less severe illness course are more responsiveness to AD. Nevertheless, the association between adjunctive AD therapy and lower rate of rehospitalization, in our sample, remained significant in multivariable regression models after adjustment for illness course severity measures.
4.3.
Study strengths and limitations
This study has several strengths, including the use of naturalistic chart review design (which allows the generalization of the results to BD-I clinical practice) and the exclusion of AD monotherapy practice (that has been repeatedly shown as inappropriate in BD-I). Moreover, although a retrospective approach was employed, multiple variables were accessible to analysis, enabling good stratification of treatment groups and adjustment of covariates. However, some limitations must also be considered. First, it should be acknowledged that data on duration and adjustment of treatment following discharge were unavailable for our analysis and that treatment at discharge does not necessarily represent long-term maintenance treatment. For this reason, the analysis was restricted to periods of
six-months and 1-year following discharge, representing short-term and long-term treatments, respectively. Furthermore, we considered treatment at discharge as reflecting treating physician's final clinical judgment prior to discharge from their care. Second, this study was restricted to nonrapid cycling BD-I patients, limiting the generalizability of its results to the full spectrum of BD patients. Third, although multiple variables were considered in our analyses, some baseline clinical characteristics were not available for analysis, including severity scores of the depressive symptoms at index admission, response to previous treatments and documentation of long-term side effects. These unavailable variables may have affected the choice of treatments and thus may have biased our results. Yet, the presence of psychotic features and additional surrogate measures of illness severity (e.g., number of pervious hospitalizations) were included in the analysis. Fourth, the primary outcome of this study was six-months and 1-year rehospitalization rates. While rehospitalization rate is a naturalistic and clinically meaningful outcome, it does not include symptomatic or syndromal relapses that do not lead to hospitalization and may mask an increase in depressive episode recurrence rates. Finally, due to the limited number of patients eligible for analysis, we compared the impact of adjunctive ADs on rehospitalization rates in a pooled group of MSs and/or AAPs, assuming a shared protective effect, which may not be true for each class.
4.4.
Conclusion
The results of this study suggest that adjunctive AD therapy to adequate mood stabilization at discharge from BD-I depressive episode hospitalization is associated with an additional protection from depressive relapse in the shortand long-term management of bipolar depression, without increasing the risk of affective switch. These findings support a positive risk-benefit ratio for the use of adjunctive AD treatment in BD-I depression and are relevant to clinical practice. Further large-scale, prospective studies are needed to estimate the efficacy, safety and tolerability of adjunctive AD medications compared to other treatment alternatives for bipolar depression.
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.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates 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 revising the manuscript. Abraham Weizman contributed to the study design, data analysis, interpretation of data and revising the manuscript. Eldar Hochman is the principal investigator of the study. He contributed to the study design, data acquisition and analysis, interpretation of data, and drafting the manuscript. All authors contributed to and have approved the final manuscript. The content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in European Neuropsychopharmacology was made by the authors independently.
Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Appendix A.
Supplementary material
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.euroneuro. 2018.01.010.
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Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
www.elsevier.com/locate/euroneuro
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates Yahav Shvartzmana, Amir Krivoya,b,c, Avi Valevskia,b, Shay Gura,b, Abraham Weizmana,b,c, Eldar Hochmana,b,c,n a
Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel Geha Mental Health Center, Petach-Tikva, Israel c Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel b
Received 29 August 2017; received in revised form 4 December 2017; accepted 26 January 2018
KEYWORDS
Abstract
Antidepressants; Atypical antipsychotics; Mood stabilizers; Bipolar disorder; Depressive episode; Rehospitalization
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. Ninetyeight 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. & 2018 Elsevier B.V. and ECNP. All rights reserved.
n
Correspondence to: Geha Mental Health Center, P.O. Box 102, Petach Tikva 4910002, Israel. Fax: +972 3 9258388.
https://doi.org/10.1016/j.euroneuro.2018.01.010 0924-977X/& 2018 Elsevier B.V. and ECNP. All rights reserved.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
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1.
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, 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 (Grunze et al., 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.
2. 2.1.
Experimental procedures 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 an acute depressive episode. All patients were at least 18 years of age at the index hospitalization. The type of psychiatric diagnosis and exacerbation leading to each hospitalization (index hospitalization and rehospitalization) was classified as DSM-IV-TR BD-I manic, major depressive or mixed episode as established by consensus of two senior psychiatrists during each hospitalization and validated retrospectively by the study team according to the medical records. In order to increase the diagnostic clarity of the sample, we excluded from the study patients who met DSM-IV-TR criteria for BD-II, schizoaffective disorder, mood exacerbations related to substance use or to a general medical condition and hospitalizations not related to a primary major mood episode. We further excluded BD-I patients with rapid cycling pattern, as current data suggest negative risk-benefit ratio for AD use in this sub-population (Yatham et al., 2013). In a patient with multiple hospitalizations, we included in the study the first hospitalization as the index hospitalization. To ascertain a clear distinction between separate hospitalizations, a rehospitalization within a 1-week period following discharge from the index hospitalization (since 2005) was not considered as a new hospitalization unless the polarity was reversed in the second hospitalization. In the case of rehospitalization within 1 week following discharge, patients were followed for 1 year from their discharge from the second hospitalization. To examine the effects of specific medication regimens on rehospitalization rates, we included in the study all the patients who were treated at discharge with MS (lithium, valproate, carbamazepine or lamotrigine) and/or AAP (risperidone [including Risperdal Consta], olanzapine, quetiapine and ziprasidone) with or without an adjunctive AD (selective serotonin reuptake inhibitors [SSRI, including citalopram, escitalopram, sertraline, paroxetine, fluoxetine, fluvoxamine], norepinephrine dopamine reuptake inhibitors [NDRI, including bupropion], serotonin norepinephrine reuptake inhibitors [SNRI, including venlafaxine, duloxetine], tricyclic antidepressants [TCAs, including nortriptyline, imipramine, doxepine, clomipramine] and atypical antidepressants [including mirtazapine]). Three patients were treated with the combination of SSRI and SNRI or atypical AD. The classification of the type of AD treatment for these patients was determined by the second AD agent (SNRI/atypical). Concomitant typical antipsychotics (TAP) or anxiolytic medications at discharge from index hospitalization were noted and were considered as covariates in the analysis. Patients who were discharged from the index hospitalization without any antimanic agent or only with TAP were excluded from the study. Patients were divided into two groups according to the type of treatment at discharge: (i) MS and/or AAP with AD; (ii) MS and/or AAP without AD. The study was approved by the GMHC review board.
2.2.
Measures
The primary outcome measures of this study were six-months and 1-year rehospitalization rates due to major mood episode. The
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates secondary outcome was time to rehospitalization during the sixmonths and 1-year periods after discharge. Sociodemographic and clinical data, considered as surrogate measure of illness severity (thus, as potentially covariates), were collected from the patients’ EMRs. Demographic data included age at first lifetime psychiatric hospitalization, age at index hospitalization, gender, marital status, occupational status and country of birth. Clinical data included the type of mood episode leading to each hospitalization (due to small number of mixed episodes (one mixed episode in the MS/AAP + AD treatment group), mixed episodes were counted as manic episodes), the length of index hospitalization, the number of previous hospitalizations due to major mood episodes, the index hospitalization legal status (voluntary or involuntary), the presence of psychotic features during the mood episode (delusions or hallucinations during the mood episode according to DSM-IV-TR), history of suicide attempt, psychiatric comorbidities including substance use disorder, anxiety disorders and personality disorders (according to DSM-IV-TR criteria), physical comorbidities (cardiovascular, metabolic, renal, endocrine and liver diseases), the type and dosage of psychotropic medications (including long-acting injectable [LAI] antipsychotics) at discharge from the index hospitalization, serum lithium concentration (mmol/L), serum valproate concentration (μg/mL) and electroconvulsive treatment during index hospitalization.
2.3.
Statistical analysis
Rehospitalization rates and sociodemographic and clinical characteristics were compared between the two treatment groups (MS/ AAP + AD vs. MS/AAP - AD) using independent Student's t-test, and χ2-test (or Fisher's exact test as appropriate). Kaplan–Meier survival analysis was used to compare the mean time to rehospitalization between the two treatment groups. The multivariate Cox proportional hazards regression model was employed to assess the adjusted association between adjunctive AD treatment at discharge and the risk of rehospitalization controlling for variables for which a significant between-group difference was detected in the univariate analysis. A retrospective power analysis was used to evaluate sample power (Power and Precision program, Biostat, USA). All statistical tests were conducted by the SPSS ver. 23 (SPSS Inc, Chicago, IL) and statistical significance was set at 0.05.
3.
Results
3.1.
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
3
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 groups with regard to the rate of MS, AAP, TAP, anxiolytic and LAI antipsychotic treatments at discharge (Table 1) and with regard to the mean daily dose of MSs, AAPs and TAPs or the serum levels of lithium and valproate at discharge (Supplementary Table 1). The two treatment groups were comparable in terms of baseline clinical and sociodemographic characteristics (Table 2), with the exception of increased length of index hospitalization in the MS/ AAP + AD group compared to the MS/AAP - AD group (Po.05), an increased rate of psychotic features in the MS/AAP - AD group compared to the MS/AAP + AD group (Po.05), a higher age at first hospitalization in the MS/AAP + AD group compared to the MS/AAP -AD group (Po.05) and increased number of previous hospitalizations in the MS/AAP - AD group compared to the MS/AAP + AD group (Po.05) (Table 2).
3.2.
Rehospitalization rates
Of the total sample (n = 98), 18 (18.4%) and 22 (22.4%) were rehospitalized due to any type of mood episode within six-months and 1-year following discharge from the index hospitalization, respectively. The distribution of the type of mood episodes leading to rehospitalization within six-months was: six with manic episodes (33.3%) and 12 with depressive episodes (66.7%), and within 1-year it was: eight manic episodes (36.4%) and 14 depressive episodes (63.6%). Rehospitalization rates within six-months and within 1-year due to any type of mood episode were significantly lower in the MS/ AAP + AD group (9.2%, n = 6 and 12.3%, n = 8, respectively) compared to the MS/AAP - AD group (36.4%, n = 12, χ2 = 10.74, P = .001, power = 0.87 and 42.4%, n = 14, χ2 = 11.40, P = .001, power = 0.89, respectively). Concerning the type of mood episode, rehospitalization rates within six-months due to manic or depressive episodes were significantly lower in the MS/AAP + AD group (1.5%, n = 1 and 7.7%, n = 5, respectively) compared to the MS/AAP - AD group (12.1%, n = 4, Fisher's exact test: P = .043 and 24.2%, n = 8, Fisher's exact test: P = .030, respectively). Similarly, rehospitalization rates within 1-year due to manic or depressive episodes were significantly lower in the MS/AAP + AD group (3.1%, n = 2 and 9.2%, n = 6, respectively) compared to the MS/AAP - AD group (18.2%, n = 6, Fisher's exact test: P = .016 and 24.2%, n = 8, χ2 = 4.02, P = .045, respectively). In order to evaluate the association between the class of the AD at discharge and rehospitalization rates, the MS/AAP + AD group was subdivided into two treatment groups: patients discharged with SSRI/NDRI and patients discharged with SNRI/TCA/atypical AD. No significant difference was found in the rehospitalization rates within six-months and 1-year due to any type of mood episode or
Table 1 Classification of the study groups according to type of treatment at discharge from index depressive hospitalization. Treatment [N (%)]
Total (N = 98) MS/AAP + AD (N = 65) MS/AAP -AD (N = 33) P-valuea
LITHIUM VALPROATE LAMOTRIGINE CARBAMAZEPINE AAP TAP Anxiolytics Long-acting injectable antipsychotics (AAP or TAP)
39 (39.8) 35 (35.7) 16 (16.3) 6 (6.1) 34 (34.7) 17 (17.3) 32 (32.7) 6 (6.1)
28 (43.1) 22 (33.8) 8 (12.3) 4 (6.2) 19 (29.2) 9 (13.8) 20 (30.8) 2 (3.1)
AAP, atypical antipsychotic; AD, antidepressant; MS, mood stabilizer; TAP, typical antipsychotic. a χ2 test or Fisher's exact test as appropriate. MS/AAP + AD versus MS/AAP – AD.
11 (33.3) 13 (39.4) 8 (24.2) 2 (6.1) 15 (45.5) 8 (24.2) 12 (36.4) 4 (12.1)
.352 .588 .131 1.000 .111 .199 .577 .175
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Table 2
Baseline clinical and sociodemographic characteristics of the study sample.
Gender, male, n (%) Born in Israel, n (%) Current employment status, working, n (%)a Marital status, married, n (%)a Index hospitalization Age at index hospitalization, years, mean (SD) Length of index hospitalization, days, mean (SD) Involuntary Hospitalization, n (%)a Psychotic features, n (%)a ECT at index hospitalization, n (%)a Age at first hospitalization, years, mean (SD)a Number of previous hospitalizations, mean (SD)a Psychiatric co-morbidity, n (%) Personality disorder Substance use disordera Anxiety disorder Physical co-morbidity, n (%)a History of suicide attempt, n (%)a
Total (N = 98)
MS/AAP + AD (N = 65)
MS/AAP – AD (N = 33)
52 56 36 38
32 34 25 27
20 22 11 11
(53.1) (57.1) (39.1) (40.4)
(49.2) (52.3) (40.3) (43.5)
(60.6) (66.7) (36.7) (34.4)
49.1 (16.4) 45.5 (52.9) 4 (4.8) 19 (21.3) 11 (12.5) 42.7 (18.2) 2.7 (3.7)
51.1 (16.2) 53.6 (51.6)* 3 (5.2) 9 (14.8)* 9 (15.3) 45.7 (19.4)* 2.1 (3.3)*
45.4 (16.3) 29.4 (52.5) 1 (3.8) 10 (35.7) 2 (6.9) 37.5 (14.9) 3.9 (4.4)
25 11 11 19 21
16 (24.6) 5 (8.5) 7 (10.8) 14 (23) 14 (24.1)
9 6 4 5 7
(25.5) (12.8) (11.2) (20.4) (25.6)
(27.3) (22.2) (12.1) (15.6) (29.2)
AAP, atypical antipsychotic; AD, antidepressant; ECT, electroconvulsive therapy; MS, mood stabilizer. a Missing data: age at first hospitalization (N = 81); ECT (N = 88); employment status (N = 92); history of suicide attempt (N = 82); involuntary admission (N = 84); marital status (N = 94); number of previous hospitalization (N = 83); physical co-morbidity (N = 93); psychotic features (N = 89); substance use disorder (N = 86). * P o 0.05 versus MS/AAP – AD.
due to manic or depressive episode between the two classes of AD groups (Supplementary Table 2).
3.3.
Time to rehospitalization
3.3.1. Six-months' period after discharge Mean time to rehospitalization during the 6-months' period after discharge, due to any type of mood episode, differed between the two treatment groups (Fig. 1). There was significantly longer time to rehospitalization for MS/AAP + AD group (169.9 days standard error [SE] = 4.5) compared to the MS/AAP - AD group (141 days [SE = 10.7], log-rank = 10.9, P = .001). Likewise, the mean time to rehospitalization due to manic or depressive episodes was significantly longer for the MS/AAP + AD group (177.4 days [SE = 2.5] and 172.3 [SE = 3.8], respectively) compared to the MS/AAP - AD group (168.2 days [SE = 6.5], log-rank = 5.8, P = .016 and 150.5 days [SE = 10.1], log-rank = 5.7, P = .016, respectively).
3.3.2. One-year period after discharge Mean time to rehospitalization during the 1-year period after discharge due to any type of mood episode was significantly longer for the MS/AAP + AD group (335.6 days [SE = 10.9]) compared to the MS/AAP - AD group (252.3 days [SE = 24.8], log-rank = 12.0, P = .001). Similarly, the mean time to rehospitalization due to manic or depressive episodes was significantly longer for the MS/AAP + AD group (358.2 days [SE = 5.5] and 341.9 days [SE = 9.8], respectively) compared to the MS/AAP - AD group (317.2 days [SE = 18.8], log-rank = 8.3, P = .004 and 288.6 days [SE = 23.7], log-rank = 4.7, P = .029, respectively).
Fig. 1 Time to rehospitalization due to any type of mood episode within six months following discharge according to the treatment at discharge (Kaplan-Meier survival analysis).
3.4.
Multivariable analysis
The multivariate Cox proportional hazards model was employed to assess the adjusted association between adjunctive AD treatment at discharge and the risk of rehospitalization controlling for variables for which a significant between-group difference was observed in the univariate analysis (age at first hospitalization,
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates
5
Table 3 Adjusted hazard ratios for rehospitalization by adjunctive AD treatment at discharge from index depressive hospitalization (cox regression survival analysis).
Six months following discharge Due to any type of mood episode Due to manic episode Due to depressive episode One year following discharge Due to any type of mood episode Due to manic episode Due to depressive episode
β
χ2
Adjusted Hazards ratioa
P value
95% CI
-2.517 -1.951 -2.499
9.160 2.982 8.261
0.081 0.142 0.082
0.002 0.84 0.004
0.016–0.412 0.016–1.301 0.015–0.452
-1.906 -2.1 -2.21
8.483 2.146 8.379
0.149 0.122 0.110
0.004 0.143 0.004
0.041–0.536 0.007–2.033 0.025–0.490
AD, antidepressant. a Adjusted for: age at first hospitalization, length of index hospitalization, number of pervious hospitalizations and presence of psychotic features at index hospitalization.
length of index hospitalization, number of previous hospitalizations and presence of psychotic features at index hospitalization). According to this model, within six-months and 1-year periods following discharge, the MS/AAP + AD group had a significantly reduced adjusted risk of rehospitalization due to any type of mood episode or due to depressive episode compared to the MS/AAP - AD group (Table 3). No significant difference was found in the adjusted risk of rehospitalization due to manic episode between the two treatment groups (Table 3).
4.
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 randomized placebo-controlled trials (McGirr et al., 2016), indicate the effectiveness and safety of adjunctive AD to MS or AAP in the short-term treatment of bipolar depression. However, while in this meta-analysis prolonged treatment with adjunctive AD was associated with an increased risk of affective switch despite adequate mood stabilization (McGirr et al., 2016), in our study rehospitalization rate due to manic episode was not increased during the 1-year follow up. Our study encourages the use of adjunctive ADs to MSs or AAPs at least in the short-term treatment of bipolar depression.
4.1. Short- and long-term AD therapy in BD – naturalistic studies perspective Few naturalistic studies have investigated the effectiveness and safety of adjunctive AD to MS/AAP in BD. In the shortterm treatment, a large naturalistic study found AD treatment (with or without MS) to be similarly effective in a total of 1,036 patients with BD-I, BD-II, and unipolar depression with moderate risk of TEAS (Pacchiarotti et al., 2013; Tondo et al., 2013). Similarly, a comparable short-term effectiveness of TCAs in unipolar and BD depression was found in a
large retrospective analysis (Möller et al., 2001). However, in bipolar depressive episode with mixed features, shortterm adjunctive AD to MS did not shorten time to remission from depressive symptoms and was associated with aggravation of manic symptoms (Goldberg et al., 2007). Concerning long-term adjunctive AD treatment, an open question remains about the risk of mood destabilization due to either prolonged use or early discontinuation of ADs (Ghaemi et al., 2008; McGirr et al., 2016; Vieta and Garriga, 2016). In a retrospective chart review analysis, Vardi et al., found that adjunctive AD treatment on discharge following a bipolar depressive episode hospitalization had no significant impact on 1-year rehospitalization rates (Vardi et al., 2014). However, two large open studies indicate that continuation of adjunctive AD treatment may be beneficial in BD patients (Altshuler et al., 2003; Viktorin et al., 2014). In the first study, conducted by Altshuler et al., the risk of depressive relapse in patients with BD was significantly associated with discontinuation of AD within six-months after remission, while the risk of manic relapse was not associated with continuation of AD (Altshuler et al., 2003). In the second study, using Swedish national registries, Viktorin et al., found that among BD patients treated with a MS, no acute change in the risk of mania was observed during the 3-months after initiation of AD and even a decreased risk was observed during 3–9 months after AD treatment initiation (Viktorin et al., 2014). Our study, similarly to the naturalistic studies conducted by Altshuler et al., and Viktorin et al., demonstrates the effectiveness and safety of adjunctive AD treatment continuation in BD. The difference between our results and those found by Vardi et al., can be related to the definition of the studies’ primary outcome (Vardi et al., study: allcause rehospitalizaion rates; our study: rehospitalization rates due to a major mood episode). Due to the small number of mixed episodes leading to rehospitalization in our sample, the association between adjunctive AD therapy and the time-course of BD with mixed features could not be explored and further large-scale studies are needed to address this subject.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
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4.2. ADs prescription pattern and response predictors in BD The majority (66%) of patients in our study were prescribed adjunctive AD at discharge from a bipolar depressive episode hospitalization. These prescribing patterns are in accordance to previous reports, including those of STEP-BD study (Baldessarini et al., 2007; Ghaemi et al., 2006; Mauer et al., 2014), reflecting the wide use of ADs in BD treatment management despite the controversy about their effectiveness and safety. Regarding the type of AD class, although previous studies suggested increased risk of mood switch or destabilization with adjunctive TCAs or SNRIs compared to SSRIs or a NDRI (Pacchiarotti et al., 2013), no significant difference in rehospitalization rates were found in our sample between these AD classes. However, due to the small sample size this observation should be interpreted with caution. In order to improve the risk-benefit ratio of AD use in BD (increased effectiveness and tolerance), an ongoing treatment objective is to achieve a personalized choice of medicine based on predictors or moderators of treatment response (Goodwin et al., 2016; Pacchiarotti et al., 2011). Based on the available literature, possible predictors of short-term response to AD among BD patients include previous response to AD and a less severe illness course (Pacchiarotti et al., 2013, 2011; Post et al., 2012). Moreover, initial response to AD is considered a predictor of longterm responsiveness to adjunctive AD among BD patients (Altshuler et al., 2009; Pacchiarotti et al., 2013). In our study, BD patients that were discharged with adjunctive AD following a depressive episode hospitalization had a decreased rate of psychotic features at index hospitalization, a higher age at first hospitalization and a reduced number of previous hospitalizations compared to BD patients who were discharged without AD. Considering AD treatment at discharge as a proxy measure of short-term responsiveness to AD, our results support the observation made by previous studies that BD patients with a less severe illness course are more responsiveness to AD. Nevertheless, the association between adjunctive AD therapy and lower rate of rehospitalization, in our sample, remained significant in multivariable regression models after adjustment for illness course severity measures.
4.3.
Study strengths and limitations
This study has several strengths, including the use of naturalistic chart review design (which allows the generalization of the results to BD-I clinical practice) and the exclusion of AD monotherapy practice (that has been repeatedly shown as inappropriate in BD-I). Moreover, although a retrospective approach was employed, multiple variables were accessible to analysis, enabling good stratification of treatment groups and adjustment of covariates. However, some limitations must also be considered. First, it should be acknowledged that data on duration and adjustment of treatment following discharge were unavailable for our analysis and that treatment at discharge does not necessarily represent long-term maintenance treatment. For this reason, the analysis was restricted to periods of
six-months and 1-year following discharge, representing short-term and long-term treatments, respectively. Furthermore, we considered treatment at discharge as reflecting treating physician's final clinical judgment prior to discharge from their care. Second, this study was restricted to nonrapid cycling BD-I patients, limiting the generalizability of its results to the full spectrum of BD patients. Third, although multiple variables were considered in our analyses, some baseline clinical characteristics were not available for analysis, including severity scores of the depressive symptoms at index admission, response to previous treatments and documentation of long-term side effects. These unavailable variables may have affected the choice of treatments and thus may have biased our results. Yet, the presence of psychotic features and additional surrogate measures of illness severity (e.g., number of pervious hospitalizations) were included in the analysis. Fourth, the primary outcome of this study was six-months and 1-year rehospitalization rates. While rehospitalization rate is a naturalistic and clinically meaningful outcome, it does not include symptomatic or syndromal relapses that do not lead to hospitalization and may mask an increase in depressive episode recurrence rates. Finally, due to the limited number of patients eligible for analysis, we compared the impact of adjunctive ADs on rehospitalization rates in a pooled group of MSs and/or AAPs, assuming a shared protective effect, which may not be true for each class.
4.4.
Conclusion
The results of this study suggest that adjunctive AD therapy to adequate mood stabilization at discharge from BD-I depressive episode hospitalization is associated with an additional protection from depressive relapse in the shortand long-term management of bipolar depression, without increasing the risk of affective switch. These findings support a positive risk-benefit ratio for the use of adjunctive AD treatment in BD-I depression and are relevant to clinical practice. Further large-scale, prospective studies are needed to estimate the efficacy, safety and tolerability of adjunctive AD medications compared to other treatment alternatives for bipolar depression.
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.
Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010
Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelve-months rehospitalization rates 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 revising the manuscript. Abraham Weizman contributed to the study design, data analysis, interpretation of data and revising the manuscript. Eldar Hochman is the principal investigator of the study. He contributed to the study design, data acquisition and analysis, interpretation of data, and drafting the manuscript. All authors contributed to and have approved the final manuscript. The content of this manuscript, the ultimate interpretation, and the decision to submit it for publication in European Neuropsychopharmacology was made by the authors independently.
Role of funding source This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Appendix A.
Supplementary material
Supplementary data associated with this article can be found in the online version at doi:10.1016/j.euroneuro. 2018.01.010.
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Please cite this article as: Shvartzman, Y., et al., Adjunctive antidepressants in bipolar depression: A cohort study of six- and twelvemonths rehospitalization rates. European Neuropsychopharmacology (2018), https://doi.org/10.1016/j.euroneuro.2018.01.010