Episode accumulation associated with hastened recurrence and delayed recovery in bipolar disorder

Journal of Affective Disorders 227 (2018) 657–664

Contents lists available at ScienceDirect

Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad

Research paper

Episode accumulation associated with hastened recurrence and delayed recovery in bipolar disorder☆

T

Dong Yeon Parka, Dennis Dob, Lauren Changb, Saloni Shahb, Laura D. Yuenb, ⁎ Farnaz Hooshmandb, Po W. Wangb, Shefali Millerb, Terence A. Ketterb, a b

Department of Psychiatry, Seoul National Hospital, Seoul, South Korea Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, USA

A R T I C L E I N F O

A B S T R A C T

Keywords: Episode accumulation Bipolar disorder Recurrence Recovery

Aims: Assess episode accumulation (≥ 10 prior mood episodes) associations with demographic/baseline clinical characteristics and mood episode recurrence/recovery in bipolar disorder (BD). Methods: Stanford BD Clinic outpatients enrolled during 2000–2011 were assessed with Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation. Among recovered and syndromal mood episode patients, we assessed episode accumulation associations with demographic/baseline clinical characteristics and with recurrence/recovery (by Kaplan-Meier survival analyses, with mediators assessed with Cox Proportional Hazard Ratio (HR) analyses). Results: Among all 450 BD outpatients, almost twice as many had versus lacked episode accumulation (65.8% versus 34.2%), which was less common among 92 recovered versus 193 syndromal mood episode patients (51.1% versus 69.9%). Among recovered patients, episode accumulation was associated with 14/18 (77.7%) demographic/other baseline clinical characteristics, and hastened mood episode recurrence. Among syndromal mood episode patients, episode accumulation was associated with 13/18 (72.2%) demographic/other baseline clinical characteristics, and delayed mood episode recovery. Limitations: American tertiary BD clinic referral sample. Conclusion: Studies are needed to confirm episode accumulation is associated with hastened mood episode recurrence and delayed mood episode recovery in BD, and to further explore its’ associations with hastened mood elevation recurrence and delayed recovery from depressive and mood elevation episodes, considered separately.

1. Introduction Bipolar disorder (BD) is a common, severe, chronic mental illness entailing recurrent depressive and mood elevation (manic, hypomanic, or mixed) episodes, with episode recurrence in approximately half of BD patients by 1 year (Tohen et al., 1990; Tohen et al., 2003b). Nearly half of recovered BD patients have mood episode reccurence within 2 years, twice as often involving depression versus mood elevation (Perlis et al., 2006), with depressive versus mood elevation symptoms being not only more pervasive, but also entailing greater multi-dimensional impairment (Altshuler, Gitlin et al., 2002; Calabrese, Hirschfeld et al., 2004; Di Marzo, Giordano et al., 2006).

Affective illness may be not only recurrent, but also progressive (Post et al., 1986; Post, 1992). Animal models of increasing behavioral or neurophysiologic responsivity over time have been applied to affective disorder progression in clinically homologous (cocaine behavioral sensitization) (Brady, Lydiard et al., 1991) and nonhomologous (amygdala kindling) (Weiss and Post, 1995) fashions. Kraepelin noted affective illnesss progression entailed not only cycle acceleration (briefer well intervals) but also stress sensitization (episodes progressing from reactive to spontaneous) (Kraepelin, 1921)(Kramlinger and Post, 1996), so that the former could entail hastened episode recurrence. However, to date studies only partially support cycle acceleration with successive episodes, so only a subset of BD patients may have

Abbreviations: BD, bipolar disorder; CGI-BP-OS, Clinical Global Impression for Bipolar Disorder-Overall Severity; CI, 95% confidence interval; CMF, Clinical Monitoring Form; df, degrees of freedom; HR, hazard ratio; MINI, Mini International Neuropsychiatric Interview; SCID for DSM-IV, Structured Clinical Interview for the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders; SD, standard deviation; SPSS, Statistical Package for the Social Sciences; STEP-BD, Systematic Treatment Enhancement Program for Bipolar Disorder ☆ Revised for resubmission as an Original Article in Journal of Affective Disorders. ⁎ Correspondence to: 401 Quarry Road, Room 2124, Stanford, CA 94305-5723, USA. E-mail address: [email protected] (T.A. Ketter). https://doi.org/10.1016/j.jad.2017.11.071 Received 21 August 2017; Received in revised form 3 October 2017; Accepted 11 November 2017 Available online 15 November 2017 0165-0327/ © 2017 Elsevier B.V. All rights reserved.

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International Neuropsychiatric Interview (MINI) (Sheehan et al., 1998) was used to confirm bipolar and comorbid psychiatric disorder diagnoses. Clinical status at each follow-up visit was determined by symptom ratings on the STEP-BD Clinical Monitoring Form (CMF) (Sachs et al., 2002) while patients received naturalistic contemporary treatment (with monthly modal visit frequency) for up to 2 years. Patients were considered to be Currently Recovered at baseline if they had no more than two threshold-level DSM-IV depressive or manic symptoms (according to the STEP-BD ADE) for the prior 8 weeks at enrollment. Baseline Currently Recovered patients were considered to have had mood episode Recurrence when they met DSM-IV criteria for a syndromal manic, depressive or mixed episode (according to the STEP-BD CMF). Patients were considered to have a baseline Current Syndromal Mood Episode if they met DSM-IV criteria for a syndromal manic, depressive or mixed episode at enrollment (according to the STEP-BD ADE). Baseline Current Syndromal Mood Episode patients were considered to have Recovered,when they had no more than two thresholdlevel DSM-IV depressive or manic symptoms for at least 8 weeks, according to the STEP-BD CMF. Episode accumulation (having had ≥ 10 prior episodes) was determined from patient report, as assessed by the STEP-BD Affective Disorders Evaluation as well as from available medical records. Current mood symptoms were determined from patient report, as assessed by the STEP-BD Affective Disorders Evaluation at the time of enrollment, and reflected any mood symptoms in the ten days prior to enrollment for the primary analysis, and mood symptoms thresholded for occurring on at least four or seven of the ten days prior to enrollment for secondary analyses. As described below, clinical characteristics of participants were evaluated and prospective clinical course of participants meeting criteria for either Current Recovery (euthymic ≥ 8 weeks) or a Current Mood Episode (syndromal depressive/mood elevation episode) at enrollment were assessed. The STEP-BD protocol and the subsequent similar Stanford-specific Assessment, Monitoring, and Centralized Database protocol were approved by the Stanford University Administrative Panel on Human Subjects, and patients provided verbal and written informed consent prior to participation. Trained medical and research staff collected data on 6 demographic parameters and 19 illness characteristics/current mood symptoms. The demographic parameters assessed were: (A) Age (in years); (B) Gender; (C) Race/ Ethnicity; (D) Education; (E) Marital Status; and (F) Employment status. The illness characteristics/current mood symptoms assessed were: (1) Lifetime anxiety disorder; (2) Lifetime alcohol/substance use disorder; (3) Lifetime eating disorder; (4) Lifetime personality disorder; (5) Bipolar II Disorder; (5A) Lifetime psychosis (which is commonly associated with Bipolar I Disorder); (5B) Lifetime prior psychiatric hospitalization (which is also commonly associated with Bipolar I Disorder); (6) ≥ One first-degree relative with mood disorder; (7) Onset age (in years); (8) Childhood (age < 13 years) onset; (9) Illness duration (in years); (10) Long illness duration (≥ 15 years); (11) Episode accumulation (≥ 10 prior mood episodes); (12) Lifetime suicide attempt; (13) Rapid cycling (≥ 4 episodes) in prior year; (14) current CGI-BP-OS; and current (i.e., any in the prior 10 days) (15) Sadness; (16) Anhedonia; (17) Euphoria; (18) Irritability; and (19) Anxiety. Statistical analyses were performed using Statistical Package for the Social Sciences (SPSS) Version 23.0 software (IBM Corp.; Armonk, NY) on an Apple MacBook Air computer (Apple Corporation, Cupertino, CA). Prevalence and clinical correlates of episode accumulation were examined in currently recovered (i.e., euthymic ≥ 8 weeks) and current syndromal (depressive/mood elevation) mood episode patients. Analytical statistics included Fisher's Exact test comparisons of categorical data and independent-sample t-test comparisons of continuous variables. In addition, binary logistic regression was used to adjust for potential confounding variables. Primary longitudinal analyses consisted of Kaplan-Meier survival analyses (Log-Rank tests), which

episode acceleration (Goodwin and Jamison, 2007). Additionally, episode severity may increase with successive episodes, with minor progressing to more major episodes (Angst, 1986; Maj, Veltro et al., 1992; Kendler, Kessler et al., 1993) and treatment refractoriness increasing in both unipolar and bipolar mood disorders (Coryell et al., 1990; Thase, 1990; O'Connell et al., 1991; Post et al., 1992; Winokur et al., 1993), which could be reflected by delayed episode recovery. As many as half of BD patients may have illness progression (Kessing et al., 1998b), which has recently been approached from the perspective of bipolar illness staging (Kapczinski, Magalhaes et al., 2014), with larger episode numbers and rapid cycling considered proxies for later BD stages (Post et al., 2003; Ghaemi et al., 2010; Post et al., 2010; Tohen et al., 2010; Magalhães et al., 2012; Rosa et al., 2012). Thus, later compared to earlier BD stages have been associated with more challenging clinical course, neurobiology, and treatment resistance (Post et al., 2010; Vieta et al., 2011). Although some BD illness progression models focus more on interepisode functional deterioration (Kapczinski et al., 2009; Reinares et al., 2013), with more severe neurocognitive deficits associated with cumulative mood episodes (LopezJaramillo et al., 2010; Torres et al., 2010; Vieta, Popovic et al., 2013), others focus on later stages entailing mood episode accumulation (Berk et al., 2007a; Berk et al., 2007b; Post, 2010; Post et al., 2012). Consequently, later BD stages have been associated with multiple episodes and functional impairments (Kapczinski, Magalhaes et al., 2014). Indeed, multiple relapses have been associated with poor prognosis (Peters et al., 2016), with relapse risk being greater for patients with more prior episodes (Berk, Brnabic et al., 2011), and inter-epsode well interval durations being inversely related to numbers of prior episodes (Kessing et al., 1998a). Thus, later stage bipolar disorder has been associated with treatment refractoriness (Post, 2010; Post et al., 2012), to olanzapine (Berk et al., 2011), lithium (Swann et al., 1999; Ketter et al., 2006), antidepressants (in some (Ghaemi et al., 2010), but not other (Magalhães et al., 2012) studies), and adjunctive cognitive behavioral therapy (Scott et al., 2006) and family psychoeducation (Reinares et al., 2010), as well as interventions in general (Tohen et al., 2010). Although recurrence risk and treatment resistance generally increase with number of episodes, BD illness course is heterogeous, and thus far few studies have investigated the effect of number of prior episodes on time to and rate of recurrence/recovery among BD patients receiving contemporary pharmacotherapy (Kessing et al., 2004). In addition, associations of number of prior episodes with other risk factors has not been thoroughly investigated. We empirically assessed cylce acceleration (using hastened mood episode Recurrence as a proxy) and treatment resistance (using delayed mood episode Recovery as a proxy) suggested by kindling/staging BD models, using longitudinal data analyses to assess relationships between episode accumulation (≥ 10 prior episodes) and Recurrence/ Recovery in a cohort of patients referred to a Northern California BD specialty clinic who were administered naturalistic contemporary measurement- and evidence-based treatment. We focused on hastened Recurrence and delayed Recovery as these appeared relevant to cylce acceleration and treatment resistance suggested by BD kindling/staging models, respectively, and appeared particularly crucial to outcome. 2. Methods We included outpatients with BD I or BD II referred by community practitioners (primarily psychiatrists) to the Stanford University BD Clinic between 2000 and 2011. Patients were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation (ADE) (Sachs et al., 2003), which included the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (First et al., 1996) mood disorders module and Clinical Global Impression-Bipolar VersionOverall Severity (CGI-BP-OS) score (Spearing et al., 1997). The Mini 658

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3. Results

compared times to Recurrence/Recovery in patients with versus without episode accumulation. We used the standard approaches of censoring patients with mood elevation prior to depressive Recurrence in assessing time to depressive Recurrence, and censoring patients with depressive prior to mood elevation Recurrence in assessing time to mood elevation Recurrence (Tohen et al., 1990). Secondary metrics for patients with versus without episode accumulation for longitudinal severity included Kaplan-Meier estimated Recurrence/Recovery rates for significant longitudinal associations. Additional secondary analyses included Cox proportional hazard analyses (hazard ratios (HRs) and 95% confidence intervals (CIs)) of Recurrence/Recovery, as well as of potential mediators of statistically significant longitudinal illness severity findings. To select parameters for entry into mediator models, univariate Cox proportional hazard analyses were performed for all statistically significant clinical correlates of episode accumulation. Parameters with p < 0.05 were entered into a forward stepwise procedure, and covariates were included in the model if p < 0.05. Additionally, Cox proportional hazard analyses with time-dependent covariates were used to further characterize associations between episode accumulation and Recurrence/Recovery. To facilitate comparisons with prior studies, we also calculated observed and Kaplan-Meier estimated overall (all patients, any episode) Recurrence/Recovery rates. We used a two-tailed significance threshold with p < 0.05, with no correction for multiple comparisons.

Table 1 includes demographics, baseline illness characteristics, and current mood symptoms in currently recovered and current syndromal depression/mood elevation patients, stratified by episode accumulation. Among all 450 BD outpatients, almost twice as many had (65.8%, 296/450), versus lacked (34.2%, 154/450, Binomial test, p < 0.0001) episode accumulation. Episode accumulation was significantly less common among Recovered versus syndromal depression/mood elevation patients (51.1% versus 69.9%, Chi-square = 9.6, df = 1, p = 0.002).

3.1. Demographics and illness characteristics/current mood symptoms in recovered patients with versus without episode accumulation Among Recovered patients, rates of having and lacking episode accumulation were not significantly different (51.1% vs 48.9%, Binomial test p = 0.84). Recovered patients with versus without episode accumulation had significantly higher rates of female gender, lifetime anxiety disorder, childhood BD onset, long illness duration, suicide attempt, prior year rapid cycling, current sadness, anhedonia, euphoria, irritability, and anxiety, as well as earlier onset age, longer illness duration, and higher CGI-BP-OS. With the exception of current irritability, all of the above findings remained significant after controlling for gender. Of current mood symptoms (sadness, anhedonia, euphoria, irritability, and anxiety) dichotomized for having occurred on at least four and seven of the prior ten days, only current anxiety

Table 1 Demographics, illness characteristics, and current mood symptoms in bipolar disorder outpatients with versus without episode accumulation (≥ 10 prior mood episodes).

N (%) Demographics A. Age (years, mean ± SD) B. Female (%) C. Caucasian (%) D. College Degree (%) E. Married (current, %) F. Full-time employment (current, %) Comorbid Disorders (lifetime, %) 1. Anxiety 2. Alcohol/Substance Use 3. Eating 4. Personality Other Illness Characteristics 5. Bipolar II disorder (%) 5 A. Psychosis (lifetime, %) 5B. Psychiatric Hospitalization (lifetime, %) 6. ≥ One 1° Degree Relative w Mood Disorder (%) 7. Onset Age (years, mean ± SD) 8. Childhood (age < 13 years) Onset (%) 9. Illness Duration (years, mean ± SD) 10. Long illness Duration (≥ 15 years, %) 11. Episode accumulation (≥ 10, lifetime, %) 12. Suicide Attempt (lifetime, %) 13. Rapid Cycling (prior year, %) 14. CGI-BP-OS (current, mean ± SD) Current Mood Symptoms (any in prior 10 days, %) 15. Sadness 16. Anhedonia 17. Euphoria 18. Irritability 19. Anxiety

Recovered ≥ 10 Episodes

Recovered < 10 Episodes

Syndromal ≥ 10 Episodes

Syndromal < 10 Episodes

47 (51.1)

45 (48.9)

135 (69.9****)

58 (30.1)

37.1 ± 12.8 70.2** 80.9 55.3 48.9 31.9

35.0 ± 14.3 40.0 72.7 68.9 31.8 31.8

38.3 ± 12.9** 63.7 86.7 46.7 44.4* 28.8

33.0 ± 14.5 55.2 75.9 51.7 25.9 24.1

61.7* 57.4 12.8 10.6

35.6 40.0 4.4 2.2

77.8* 63.0 20.7 17.0

62.1 48.3 12.0 8.6

48.9 38.3 40.4 55.3 15.2 ± 7.1**** 25.5** 22.8 ± 13.2**** 66.0*** 100.0**** 38.3** 17.0* 2.4 ± 0.7*

28.9 55.6 53.3 37.8 23.5 ± 8.7 2.2 11.8 ± 10.8 33.3 0.0 11.1 2.4 2.0 ± 0.8

63.7** 32.6 26.7* 63.7* 15.5 ± 8.1**** 36.3**** 22.7 ± 12.1**** 72.6**** 100.0**** 40.4*** 39.3**** 5.3 ± 0.6

36.2 48.3 46.6 44.8 21.5 ± 9.2 6.9 11.4 ± 12.3 25.9 0.0 15.5 8.6 5.2 ± 1.2

29.8* 27.7** 23.4** 46.8* 55.3**

11.1 4.4 2.2 24.4 20.0

78.5* 79.3 47.4 75.6* 83.0

62.0 70.7 39.7 56.9 74.1

Boldface font indicates parameters with statistically significant relationships with episode accumulation; CGI-BP-OS indicates Clinical Global Impression for Bipolar Disorder-Overall Severity; Italic font indicates parameters associated with bipolar I disorder; SD indicates standard deviation; Syndromal indicates patients with current syndromal depression/mood elevation. Missing data: Recovered − 0.0–3.3%, Syndromal − 0.0–1.4%. * p < 0.05. ** p < 0.01. *** p < 0.001. **** p < 0.0001, ≥ 10 versus < 10 prior episodes.

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thresholded at both four and seven days had significant associations with episode accumulation in recovered patients (p = 0.002 and p = 0.02, respectively). In contrast, no other assessed demographic parameter and no other illness characteristic in Table 1 was significantly associated with episode accumulation among recovered patients. 3.2. Demographics and illness characteristics/current mood symptoms in syndromal depression/mood elevation patients with versus without episode accumulation Among syndromal depression/mood elevation patients, more than twice as many had versus lacked episode accumulation (69.9% versus 30.1%, Binomial test, p < 0.0001). Among syndromal depression/ mood elevation patients, episode accumulation was significantly associated with older age and being married, as well as higher rates of lifetime anxiety disorder, bipolar II disorder, having ≥ one first degree relative with mood disorder, childhood BD onset, long illness duration, prior suicide attempt, prior year rapid cycling, and current sadness and irritability, as well as earlier onset age, and longer illness duration. The inverse relationship between episode accumulation and prior psychiatric hospitalization was mediated by the association of bipolar I subtype with prior psychiatric hospitalization. All of the of the above findings remained significant after controlling for age and marital status. Current mood symptoms (sadness and irritability) dichotomized for having occurred on at least four and seven of the prior ten days were not significantly associated with episode accumulation in syndromal depression/mood elevation patients. Also, no other assessed demographic parameter and no other illness characteristic/current mood symptom in Table 1 was significantly associated with episode accumulation among syndromal depression/mood elevation patients. Aside from episode accumulation being significantly associated with euphoria in syndromal depression but not syndromal mood elevation patients, the patterns of associations of episode accumulation with Table 1 parameters were broadly similar in patients with syndromal depression and syndromal mood elevation.

Fig. 1. Episode accumulation (≥ 10 prior mood episodes) associated with hastened mood episode recurrence in bipolar disorder. Two-year survival analysis of time to mood episode recurrence in Recovered bipolar disorder patients indicated significantly hastened mood episode Recurrence in patients with (N = 47, black line on bottom) versus without (N = 45, gray line on top) episode accumulation (≥ 10 prior mood episodes, Log-Rank p = 0.003). Episode accumulation was also significantly associated with hastened mood episode Recurrence in patients with versus without episode accumulation using Cox Proportional Hazard analysis (Hazard Ratio (HR) = 2.4 (95% Confidence Interval (CI) = 1.3 – 4.3), p = 0.005). No illness characteristic with a statistically significant relationship with episode accumulation in Table 1 drove hastened mood episode Recurrence in patients with versus without episode accumulation. CI indicates 95% confidence interval; HR indicates hazard ratio.

95% CI = 1.0 – 8.6, p = 0.041) drove hastened depressive Recurrence in patients with versus without episode accumulation. Patients with episode accumulation had a non-significantly higher (slightly more than twice as high, with only slightly overlapping 95% CIs) KaplanMeier estimated depressive Recurrence rate of 66.9% (95% CI = 48.1% − 85.7%) versus 32.9% (95% CI = 15.5% − 50.3%). In contrast, episode accumulation was only non-significantly associated with hastened mood elevation Recurrence (Log-Rank p = 0.26, HR = 1.8; 95% CI 0.7 – 4.8; p = 0.26, not illustrated). The observed and Kaplan-Meier estimated overall (all 92 recovered patients, any episode polarity Recurrence) 2-year Recurrence rates were 49.0% and 66.0% (95% CI 54.2–77.8%), respectively. As expected, the observed and Kaplan-Meier estimated overall (all 92 Recovered patients, any episode polarity Recurrence) 1-year Recurrence rates were lower at 40.0% and 50.3% (95% CI 38.7–61.9%), respectively.

3.3. Episode accumulation in relationship to time to and frequency of mood episode recurrence Episode accumulation was significantly associated with hastened mood episode Recurrence (Log-Rank p = 0.003) in 47 vs. 45 recovered patients (Fig. 1). Episode accumulation was also significantly associated with hastened mood episode Recurrence in patients with versus without episode accumulation using Cox Proportional Hazard analysis (HR = 2.4, 95% CI = 1.3 – 4.3, p = 0.005). No illness characteristic with a statistically significant relationship with episode accumulation in Table 1 drove hastened mood episode Recurrence in patients with versus without episode accumulation. Currently Recovered patients with versus without episode accumulation had a barely non-significantly (i.e., with minimally (< 1%) overlapping 95% CIs) higher Kaplan-Meier estimated mood episode recurrence rate of 81.4% (95% CI = 67.1% − 95.7%) versus 50.4% (95% CI = 33.0% − 67.8%), with median and mean ± standard deviation times to recurrence of 260 and 328.9 ± 292.0 days, as well as 668 and 519.1 ± 272.8 days, respectively. Moreover, the rates of recurrence in both groups (81.4% and 50.4%) both tended to be high, although median times to recurrence (260 vs. 668 days for patients with versus without episode accumulation) both tended to be long, consistent with most (almost 90%) of these patients having conventional (as opposed to rapid) cycling in the prior year. In addition, episode accumulation was significantly associated with hastened depressive Recurrence (Log-Rank p = 0.005, not illustrated). Episode accumulation was also significantly associated with hastened depressive Recurrence using Cox Proportional Hazard analysis (HR = 2.8; 95% CI 1.3, 6.0; p = 0.008). Lifetime anxiety disorder (HR = 2.9, 95% CI = 1.2 – 6.9, p = 0.015) and prior year rapid cycling (HR = 3.0,

3.4. Episode accumulation in relationship to time to and frequency of mood episode recovery Episode accumulation was significantly related to delayed mood episode Recovery (Log-Rank p = 0.02, Fig. 2). in 135 vs. 58 syndromal depression/mood elevation patients (Fig. 1). Episode accumulation was also significantly associated with delayed mood episode Recovery in patients with versus without episode accumulation using Cox Proportional Hazard analysis (HR = 0.60; 95% CI = 0.39 − 0.93; p = 0.02). Any current irritability drove delayed mood episode Recovery in syndromal depression/mood elevation patients with versus without episode accumulation (HR = 0.56, 95% CI = 0.36 – 0.86, p = 0.008). However, current irritability thresholded for occurring on at least four or seven of the prior ten days did not mediate delayed mood episode Recovery in syndromal depression/mood elevation patients with versus without episode accumulation. Moreover, no other illness characteristic with a statistically significant relationship with episode accumulation in Table 1 drove delayed mood episode Recovery in patients with versus without episode accumulation. Current Syndromal Mood Episode patients with versus without episode accumulation had a non-significantly (albeit with only modestly (3.6%) overlapping 95% CIs) lower Kaplan-Meier estimated mood 660

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Episode accumulation was also significantly associated with 13/18 (72.2%) of demographic and other unfavorable illness characteristics among syndromal depression/mood elevation patients with BD. Moreover, episode accumulation was significantly associated with delayed Recovery, driven by current irritability (but no other assessed illness characteristic), and a non-significantly lower Recovery rate. However, there were only non-significant trends towards associations between episode accumulation and delayed depressive and mood elevation Recovery, considered separately. Recurrence in BD patients is common and preventing recurrence is essential to improve outcomes. Our median times to Recurrence for patients with versus without episode accumulation were 260 and 688 days, respectively, which tended to be consistent with a prior STEP-BD report by Perlis and associates (314 days) (Perlis et al., 2006), but (potentially accounted for at least in part by varying methodology) somewhat longer than median times to intervention for impending recurrence (or for recurrence) in recovered patients in contemporary randomized controlled bipolar maintenance registration studies, which were 184 days for lithium monotherapy and 197 days for lamotrigine monotherapy (Goodwin et al., 2004), and 174 days for olanzapine monotherapy (Tohen et al., 2006). However, in other contemporary randomized controlled bipolar maintenance registration studies, such median times to recurrence were not reported or not calcuable for oral aripiprazole monotherapy (Keck et al., 2006), adjunctive (added to lithium or valproate) oral aripiprazole (Marcus et al., 2011), aripiprazole long-acting injectable formulation (LAI) monotherapy (Calabrese et al., 2017), adjunctive (added to lithium or valproate) oral quetiapine extended release formulation (Suppes et al., 2013), risperidone LAI monotherapy (Quiroz et al., 2010), and adjunctive (added to lithium or valproate) oral ziprasidone (Bowden, 2011). According to Post and associates, emerging evidence has indicated that affective illness tends to be not only recurrent but also progressive, so that it is warranted to focus on neurobiologic mechanisms that could mediate long-lasting and progressive increases in vulnerability (Post et al., 1997). Post and associates’ kindling model represents processes with increased pathologic responsivity over time, putatively resulting in cycle acceleration. Our finding of the association between episode accumulation and hastened Recurrence is in accord with cycle acceleration suggested by the kindling model. The kinding model also suggests treatment resistance increases with recurrent mood episodes. Our finding of the association between episode accumulation and delayed Recovery is in accord with treatment resistance suggested by the kindling model. In a recent bipolar maintenance study for up to 52 weeks, Tohen and associates found that the number of prior mood episodes worked through the severity of depressive symptoms prior to remission (mediator) to affect rate of mood episode recurrence among olanzapinetreated patients (Tohen et al., 2012b). Peters and colleagues in a STEPBD report, found number of prior depressive episodes and illness duration emerged as the strongest predictors of Recovery rates and times to Recovery from depression using Cox proportional hazard models among bipolar patients undergoing intensive psychotherapy (Peters et al., 2014). Our findings with respect to time to Recovery were NOT generally in agreement with prior research, due to Recovery in our cohort being slow. Thus, in our study, times to Recovery were long for both patients with and without episode accumulation (335 and 197 days, respectively). By comparison, in contemporary bipolar depression randomized controlled acute treatment registration trials (usually lasting 6–8 weeks, i.e., longer than acute mania trials), median times to Response/ Remission (rather than median times to Recovery, which were not reported) have been substantially shorter (ranging from approximately 50–100% of full trial durations for active treatments and placebo, respectively) (Tohen et al., 2003a; Calabrese et al., 2005; Thase et al., 2006; Tohen et al., 2012a; Loebel et al., 2014a; Loebel et al., 2014b; Loebel et al., 2014a; Loebel et al., 2014b). Possible contributors to the phenomenon of long times to Recovery at Stanford included the

Fig. 2. Episode accumulation (≥ 10 prior mood episodes) associated with delayed mood episode recovery in bipolar disorder. Two-year survival analysis of time to mood episode Recovery in syndromal depression/mood elevation bipolar disorder patients indicated significantly delayed mood episode Recovery in patients with (N = 135, black line on right) versus without (N = 58, gray line on left) episode accumulation (≥ 10 prior mood episodes, Log-Rank p = 0.02). Episode accumulation was also significantly associated with delayed mood episode Recovery in patients with versus without episode accumulation using Cox Proportional Hazard analysis (HR = 0.6, CI = 0.4 – 0.9, p = 0.02). Current irritability (but no other illness characteristic with a statistically significant relationship with episode accumulation in Table 1) drove delayed mood episode Recovery in syndromal depression/mood elevation patients with versus without episode accumulation (HR = 0.56, 95% CI = 0.36 – 0.86, p = 0.008). CI indicates 95% confidence interval; HR indicates hazard ratio.

episode recovery rate of 80.1% (95% CI = 69.5% − 90.7%) versus 95.5% (95% CI = 87.10% − 103.9%), with median and mean ± standard deviation times to recovery for the two groups of 335 and 374.8 ± 310.9 days, as well as 197 and 274.5 ± 249.8 days, respectively. Although rates of recovery in both groups (80.1% and 95.5%) tended to be high, median times to recovery of 335 and 197 days for patients with versus without episode accumulation, respectively, were long, consistent with these patients having challenging (with only very slow to recover) episodes that resulted in referral to an academic Bipolar Disorder specialty clinic, albeit also consistent with most (almost 70%) of these patients having conventional (as opposed to rapid) cycling in the prior year. Indeed, although patients without versus with episode accumulation took approximately 40% fewer days to recover (197 versus 335 days), their median time to recovery was still more than 6 months. In contrast, episode accumulation only non-significantly tended to be associated with delayed depressive Recovery (Log-Rank p = 0.097) in 102 vs. 40 depressed patients (not illustrated) and delayed mood elevation Recovery (Log-Rank p = 0.051) in 33 vs. 18 patients with syndromal mood elevation (not illustrated). The observed and Kaplan-Meier estimated overall (all 193 syndromal depression/mood elevation patients) 2-year Recovery rates were 46.1% and 84.9% (95% CI 77.1–92.7%), respectively. As expected, the observed and Kaplan-Meier estimated overall (all 193 syndromal depression/mood elevation patients) 1-year Recovery rates were lower at 36.8% and 60.6% (95% CI 51.2–70.0%), respectively.

4. Discussion We found episode accumulation was significantly associated with 14/18 (77.7%) of demographic and other unfavorable illness characteristics among recovered BD patients. In addition, episode accumulation was significantly associated with hastened Recurrence, not driven by any assessed illness characteristic, and a barely non-significantly higher mood episode Recurrence rate. Moreover, episode accumulation was significantly associated with hastened depressive but not mood elevation Recurrence considered separately. 661

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Recurrence findings were not merely the result of intervening opposite polarity epsidoes, since such cases were censored. However, these strengths were accompanied by limitations that included the use of a sample referred to a suburban Northern California BD specialty clinic, limiting the generalizability of our findings in our relatively affluent, well educated but relatively underemployed, generally slow to recover (taking medians of 335 versus 197 days in patients with versus without episode accumulation), predominantly female sample of BD patients with medical insurance. Additionally, our sample size, though substantial, had insufficient statistical power to be able to assess relationships between episode accumulation and times to mood elevation Recurrence/Recovery, and relationships between episode accumulation and times to any mood episode Recovery, stratified by bipolar subtype, which in spite of not being a mediator, still might have confounded our findings. Furthermore, Recovered status/mood episode duration prior to enrollment was not included in our analyses of mood episode Recurrence/Recovery. Another limitation was the open naturalistic treatment design, in which patients received diverse uncontrolled (albeit contmporary, guideline-informed, measurementand evidence-based) interventions. Finally, we did not correct for multiple comparisons, which particularly limited interpretation of findings with p-values between 0.05 and 0.01. However, this liberal statistical approach increased assay sensitivity with respect to our ability to detect relationships between current irritability and baseline clinical characteristics as well as Recurrence/Recovery. Nevertheless, we contend that the association between episode accumulation and hastened Recurrence/delayed Recovery suggests that episode accumulation entails an important vulnerability towards longitudinal burden in BD. Given the large human and financial costs of BD, further examination of relationships between episode accumulation and Recurrence/Recovery is warranted in order to enhance clinical management.

rigorous (STEP-BD) definition of Recovery used, requiring at least 2 months of having minimal clinically significant mood symptoms, so that the shortest possible time to Recovery was approximately 60 days (longer than most randomized controlled acute bipolar depression and mania registration trials). Also, the long study duration (up to 2 years) likely contributed to not only our high Recovery rates (80.1–95.5%), but also our long times to Recovery. Moreover, patients referred to the Stanford Bipolar Disorder specialty clinic commonly had very challenging bipolar disorder, and only slowly recovered from episodes, whether or not they had episode accumulation. Even though Recovery rates were high (80.1% with versus 95.5% without episode accumulation), and times to Recovery were generally long, Current Mood Episode patients with versus without episode accumulation still took approximately 70% longer to recover (335 versus 197 days). In the current report, we found episode accumulation was associated with hastened depressive Recurrence, mediated by lifetime anxiety disorder for depressive (but not any episode) Recurrence. In prior reports from our group, current anxiety (Shah et al., 2017) and irritability (Yuen et al., 2016), and bipolar II subtype (Dell'Osso et al., 2017), were all associated with hastened depressive (but not any episode) Recurrence, all mediated by lifetime anxiety disorder. To our knowledge, our group's reports are among the first to find that lifetime anxiety disorder mediated hastened Recurrence in BD, although several groups have found that current comorbid anxiety disorder was associated with hastened depressive recurrence (Feske et al., 2000; Simon et al., 2004; Otto et al., 2006; Perlis et al., 2006). Thus, we found lifetime anxiety disorder mediated hastened depressive (but not any mood episode) Recurrence in Recovered patients with versus without episode accumulation. Moreover, we found that prior year rapid cycling, (having four or more affective episodes within the prior year (Dunner and Fieve, 1974)), which has been proposed as a later manifestation of bipolar illness, although not supported by all investigators (Coryell et al., 1992), was a driver of hastened depressive (but not any) episode Recurrence in patients with episode accumulation. There have been several prospective studies of the longuitudinal course of rapid cycling BD, which are relevant to our findings. Bauer and associates found rapid cycling was associated with greater number of prior episodes and female gender and suggested rapid cycling as a course modifier for BD (Bauer et al., 1994). Moreover, Schneck and associates reported that patients with prior year rapid cycling were more likely to have further recurrences (Schneck et al., 2008). Coryell and associates found that bipolar patients who developed rapid cycling suffered substantial depressive morbidity (Coryell et al., 2003). Taken together, our results are consistent with the notion that rapid cycling may reflect a sensitization produced by repeated episodes, as suggested by the kindling hypothesis. Regarding the relation beween anxiety disorders and rapid cycling, less is known. It has been observed that some forms of rapid cycling and panic disorder are phenomenologically linked by sudden shifts in affect. Indeed, the NIMH Bipolar Genetics Initiative study found that familial panic disorder increased the odds of rapid mood switching (MacKinnon et al., 2003). Phenomenological overlap between lifetime anxiety disorder and rapid cycling challenges the contention that BD and anxiety disorders are neurobiologically distinct disorders. Additional research is needed to assess potential differential relationships between lifetime anxiety disorder and number of prior episodes and hastened/delayed depressive Recurrence/Recovery. Our study has noteworthy strengths and limitations. Strengths included assessing relationships between episode accumulation and times to not only Recurrence but also Recovery, using validated instruments to assess diagnosis and longitudinal course, and having substantial numbers of both Recovered (N = 92) and syndromal depression/mood elevation (N = 193) well-characterized BD patients. In addition, our overall (all patients, any episode) Recurrence rates were in broad agreement with prior studies (Otto et al., 2006; Perlis, Ostacher et al., 2006; Vazquez et al., 2015). Moreover, our episode polarity-specific

Acknowledgment This research was supported by a Government of South Korea Overseas Research Fellowship (2014-I-0040), the Pearlstein Family Foundation, the Mitchell Foundation, and the Holland Foundation. These data were presented at the 169th Annual Meeting of the American Psychiatric Association. Atlanta, Georgia, May 13–17, 2016.

Competing interests (prior 36 months) DY Park, D Do, S Shah, LD Yuen, F Hooshmand, PW Wang: None. S Miller: Research; Merck and Company; Sunovion, Inc. T Ketter: Consultant; AstraZeneca Pharmaceuticals LP, Bristol-Myers Squibb Company, Cephalon, Inc., Eli Lilly and Company, GlaxoSmithKline, Pfizer, Inc., Astellas Pharmaceuticals, Merck & Co, Inc., Sepracor, Inc., Johnson & Johnson. Honoraria; Abbott Laboratories, GlaxoSmithKline, Otsuka Pharmaceuticals. Research; AstraZeneca Pharmaceuticals LP, Cephalon, Inc., Eli Lilly and Company, Pfizer, Inc., Sepracor, Inc. (via Quintiles, Inc.). Employee/Stock; Janssen Pharmaceuticals/Johnson & Johnson (spouse).

Funding sources This research was supported by a Government of South Korea Overseas Research Fellowship (2014-I-0040), the Pearlstein Family Foundation, the Mitchell Foundation, and the Holland Foundation. No pharmaceutical company funding. The funding sources had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication. 662

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