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Seasonal pattern of manic episode admissions among bipolar I disorder patients is associated with male gender and presence of psychotic features
Journal of Affective Disorders 190 (2016) 123–127
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Seasonal pattern of manic episode admissions among bipolar I disorder patients is associated with male gender and presence of psychotic features Eldar Hochman a,b,n, Avi Valevski a,b, Roy Onn a,b, Abraham Weizman a,b,c, Amir Krivoy a,b,c a
Geha Mental Health Center, Petach-Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel c Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel b
art ic l e i nf o
a b s t r a c t
Article history: Received 21 July 2015 Received in revised form 29 September 2015 Accepted 2 October 2015
Background: Bipolar I disorder (BD-I) patients demonstrate disrupted chronobiology expressed as seasonal variation in mood symptoms. The seasonal pattern (SP) specifier of mood disorders was recently extended by the DSM-5, to be applied to manic episodes. However, the significance of seasonality of manic episodes for the course of BD-I is unknown. In the present study we sought to identify clinical and demographic features that discriminate between BD-I patients with and without SP of manic admissions. Methods: BD-I patients (n ¼148) admitted at least twice with the same mood exacerbation type, were retrospectively followed between 2005 and 2013. Demographic and clinical characteristics were compared between BD-I patients with or without SP of manic admissions. Results: SP of manic episode admissions, found in 31 (26%) of 117 BD-I patients with repeated manic episode admissions, was associated with higher rates of male gender (p ¼0.01), presence of psychotic features (p ¼0.01) and comorbid substance use disorder (po 0.05) compared to patients without SP. In a multivariate analysis, SP of manic episode admissions was associated with the presence of psychotic features (OR 8.42, 95% CI: 1.05–67.65, po0.05) and male gender (OR 3.23, 95% CI: 1.08–9.65, po 0.05), but not with comorbidity of substance use disorder (OR 1.79, 95% CI: 0.71–4.50, p ¼0.24). Limitations: Seasonal psychological/environmental factors contributing to the emergent of mood episodes could not be ruled out. Conclusions: Our results suggest that SP of manic admissions is associated with male gender and the presence of psychotic features, thus might be associated with more severe form of the disorder. & 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Seasonal pattern Psychotic features Substance use disorder
1. Introduction Accumulating data support the hypothesis that disrupted chronobiology may represent a core element of bipolar disorder (BD) and might play a role in the pathophysiology of this disorder (Salvatore et al., 2012; Scott, 2011). BD patients demonstrate irregular chronobiology expressed as disrupted sleep and circadian rhythms and greater seasonal fluctuations in mood and behavior compared to unipolar depression patients or healthy controls (Geoffroy et al., 2014). Seasonal variability of symptoms among BD patients and its significance for the course of the disorder were traditionally studied by exploring the seasonal distribution of admissions rates of BD patients and the association between n Corresponding author at: Geha Mental Health Center, P.O. Box 102, Petach Tikva 4910002 Israel. Fax: þ 972 3 9258388. E-mail address: [email protected] (E. Hochman).
http://dx.doi.org/10.1016/j.jad.2015.10.002 0165-0327/& 2015 Elsevier B.V. All rights reserved.
seasonal pattern (SP) of acute bipolar mood episode with specific clinical and demographic characteristics (Geoffroy et al., 2014). According to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), SP was restricted to depressive episodes. Consequently, in the past decades, SP was mostly studied for depressive episodes, and was found among 25% of BD patients. SP of depressive episodes among BD patients was found to be associated with bipolar II disorder (BD-II), rapid cycling, depressive onset and depressive predominant polarity, while data regarding gender differences according to SP are inconclusive (Arnold, 2003; Friedman et al., 2006; Goikolea et al., 2007). Previous studies using DSM-III criteria for SP,that were applied for both depressive and manic episodes, have identified around 15% of BD patients with SP of manic episodes and these patients presented more severe clinical profile (Geoffroy et al., 2014; Hunt et al., 1992). Recognizing the accumulating data supporting the presence of SP both in manic and depressive episodes, the SP specifier of mood
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disorders was extended by the DSM, Fifth Edition (DSM-5) to be applied to manic/hypomanic episodes (American Psychiatric Association., 2013). However, data regarding the significance of manic episode seasonality for the course of BD are scarce. In the current study we aimed to identify clinical and demographic features that discriminate between bipolar I disorder (BD-I) patients with and without SP of manic episode admissions.
2. Methods 2.1. Population We conducted a retrospective cohort study, using electronic medical records (EMR) review of all consecutive admissions to Geha Mental Health Center (GMHC, Petach Tikva, Israel) between January 1, 2005, and July 31, 2013. GMHC is a tertiary care referral mental health center that provides psychiatric care to more than 1500 patients admitted annually. The center serves a population of about 450,000. Patients are referred to the center by general practitioners, outpatient psychiatrists or are self-referred and all of them are admitted through the emergency room. Out of 6084 patients admitted during the study period we identified 540 patients diagnosed as having DSM-IV-TR BD-I or BD-II according to the EMR review. The type of psychiatric exacerbation leading to each admission was classified as DSM-IV-TR manic, major depressive or mixed episode as established by a consensus of two senior psychiatrists following a psychiatric interview during the time of each hospitalization. To avoid confounding effects we excluded from the study mood episode admissions that were attributed to a substance use or a medical condition as well as patients under 18 years of age. Furthermore, BD-II patients were excluded from this study for two reasons: first, small number of patients and second, a higher probability for subthreshold hypomanic symptoms that might increase selection bias errors. In order to determine a SP for each type of mood episode (manic, major depressive or mixed), only patients with repeated admissions (at least two) of the same type of mood episode, during the study period, were included in the study. Subsequently, BD-I patients were sub-grouped according to the type of the repeated mood episodes leading to admission (repeated manic episodes group, repeated major depressive episodes group and repeated mixed episodes group). The total number of patients included in the study was 148 with 402 repeated admissions due to acute mood episodes. Five of the patients met the inclusion criteria for more than one type of repeated mood episodes group (i.e., had at least two admissions for each type of mood episode, either depressive or manic) and were included in both types of repeated mood episodes group (Table 1). To differentiate among separate episodes in a patient with multiple admissions, we included in the study only the first admission if the patient had been readmitted within an 8-week period unless the polarity was reversed, in such cases both admissions were included (Lee et al., 2007). The study was approved by the GMHC Review Board. 2.2. Measures Demographic and clinical data were collected retrospectively from the patients' EMR. Demographic data included age at first admission during the study period and gender. Clinical data included number of admissions per year during the study period, the type of mood episode leading to each admission (as described above), the presence of psychotic features during each mood episode (either delusions or hallucinations during the mood episode according to DSM-IV-TR), history of suicide attempt,
Table 1 Seasonal pattern and demographic characteristics [Mean7 SD or N (%)] of Bipolar I disorder inpatients sub-grouped according to the type of repeated mood episodes leading to admission. Characteristics
Number of patients Number of admissions Gender Female Male Age (yrs)b Patients with Seasonal pattern
Type of repeated mood episodes groupa Repeated manic episodes group
Repeated major depressive episodes group
Repeated mixed episodes group
117 313
33 83
3 6
41 (35%) 76 (65%) 36.8 7 14.8 31 (26%)
22 (67%) 11 (33%) 51.6 716.5 7 (21%)
2 (67%) 1 (33%) 45.0 714.5 1 (33%)
SD ¼ standard deviation. a Patients with repeated (at least two) admissions of the same type of mood episode (manic, major depressive or mixed) were classified according to the type of repeated mood episodes leading to admission. b Age (yrs) at first admission during the study period.
psychiatric comorbidities including substance use disorder, anxiety disorders and personality disorders (according to DSM-IV-TR criteria) and the type of psychotropic drugs at discharge from the hospital after the last admission. For each patient, the presence of SP was determined, in a retrospective approach, separately for each type of a repeated mood episode leading to admission (manic, major depressive or mixed) according to DSM-5 criteria (consisting of temporal relationship between the time of repeated admissions of specific type of mood episode and a particular time (season) of the year, seasonal mood episodes substantially outnumber non-seasonal mood episodes during the study period and in the last two years of the study there have been only seasonal episodes). The season for each mood episode admission was determined according to admission date. Importantly, the SP was not determined for specific season but for each patient according to the time of repeated admissions. The duration of the various Israeli seasons were defined as follows: Winter: December–February; Spring: March–May; Summer: June–September; Fall: October–November (Shapira et al., 2004). 2.3. Statistical analysis SPSS ver. 20 (SPSS inc, Chicago, IL) was used for statistical analysis. Descriptive statistics were expressed as Mean7SD, or rate (%). Demographic and clinical characteristics were compared between BD-I patients with or without SP of admissions (for each type of repeated mood episodes). Contingency tables were used to compare rates of gender, presence of psychotic features, history of suicide attempt, psychiatric comorbidities and type of psychotropic drugs at discharge from the hospital. Independent Student's t-test was used to compare age at first admission during the study period and the number of admissions per year. Differences in seasonal distribution of mood episode admission rates were analyzed by one-way ANOVA (Shapira et al., 2004). A logistic regression analysis was conducted with SP of manic episode as a dependent variable (dichotomous) and the presence of psychotic features, male gender and a substance use disorder as covariates. Odds ratios, 95% confidence interval and statistical significance were calculated. P value ofo 0.05 was considered statistically significance.
E. Hochman et al. / Journal of Affective Disorders 190 (2016) 123–127
3. Results For each type of repeated mood episode group (manic, major depressive or mixed) of BD-I patients, the proportion of patients with SP of admissions, the number of admissions during the study period and patients' gender and age are presented in Table 1. No difference was found in the seasonal distribution of admission rates for both manic and major depressive episodes, namely there was no association with a specific season within the year (data not shown). In a univariate analyses within BD-I 'repeated manic episodes group' patients, SP of manic episode admissions was associated with higher rates of male gender, presence of psychotic features during the manic episodes and substance use disorder compared to BD-I 'manic episode group' patients without SP of manic episodes admissions (Table 2). No significant differences were found between BD-I 'repeated manic episodes group' patients with or without SP of manic episode admissions in the age at first admission during the study period, diagnosis of other psychiatric comorbidities, rates of patients with history of suicide attempts and the number of manic episodes during the study period (Table 2). In the BD-I 'repeated major depressive episodes group' patients no significant differences were found between patients with or without SP of major depressive episode admissions with respect to demographic and clinical characteristics (Table 3). In a multivariate analysis using a logistic regression model, adjusting for demographic and clinical covariates that were significant in the univariate analyses, the presence of psychotic features during manic episodes and male gender, but not comorbidity of substance use disorder, were predictors of a SP of manic episode admissions among BD-I 'repeated manic episodes group' patients (Table 4).
4. Discussion
Table 2 Demographic and clinical characteristics [Mean7 SD or N (%)] of 'Repeated manic episodes group' of Bipolar I disorder patients with or without seasonal pattern of manic episode admissions.
Male Age (yrs)b With psychotic features History of suicide attempts Mixed episodec Psychiatric comorbidity Substance use disorder Personality disorder Anxiety disorder Treatmentd Mood stabilizer & APD Two mood stabilizers Manic episode admissions per year
Seasonal pattern of Manic episode (N ¼ 117 patients)
P valuea
Yes (N ¼ 31)
No (N ¼86)
26 (83.9%) 35.9 716.94 30 (96.8%) 4 (12.9%)
50 (58.1%) 37.2 714.16 66 (76.7%) 11 (13.4%)
0.01 NS 0.01 NS
1 (3.2%)
7 (8.1%)
NS
21 (67.7%) 7 (22.6%) 1 (3.2%)
39 (47.0%) 26 (30.2%) 7 (8.1%)
0.04 NS NS
19 (61.3%) 5 (16.1%) 0.53 7 0.25
58 (67.4%) 9 (10.5%) 0.55 7 0.31
NS NS NS
APD ¼ antipsychotic drug. NS ¼ not significant. SD ¼ standard deviation. a
P was based on independent-samples T test or χ² test. Age at the first admission during the study period 2005–2013. c Admission with mixed episode during study period. d Treatment on discharge from the hospital. b
Table 3 Demographic and clinical characteristics [Mean 7SD or N (%)] of 'Repeated major depressive episodes group' of Bipolar I disorder patients with or without seasonal pattern of depressive episode admissions. Characteristics
Male Age (yrs)b With psychotic features History of suicide attempts Mixed episodec Psychiatric comorbidity Substance use disorder Personality disorder Anxiety disorder Treatmentd Mood stabilizer & APD Two mood stabilizers Major depressive episode admissions per year
Seasonal pattern of major Depressive episode (N ¼33 patients)
P valuea
Yes (N ¼7)
No (N ¼ 26)
2 (28.6%) 60.8 7 9.40 3 (42.9%) 3 (42.9%)
9 (34.6%) 49.17 17.34 4 (15.4%) 5 (19.2%)
NS NS NS NS
0 (0.0%)
3 (11.5%)
NS
0 (0.0%) 2 (28.6%) 1 (14.3%)
3 (11.5%) 9 (34.6%) 1 (3.8%)
NS NS NS
3 (42.9%) 0 (0.0%) 0.42 7 0.13
12 (46.2%) 2 (7.7%) 0.36 7 0.18
NS NS NS
APD ¼ antipsychotic drug. NS ¼ not significant. SD ¼ standard deviation. a
P was based on independent-samples T test or χ² test. Age at the first admission during the study period 2005–2013. c Admission with mixed episode during study period. d Treatment on discharge from the hospital. b
Table 4 Multivariate analysis for seasonal pattern of manic episode admissions in 'Repeated manic episodes group' of bipolar I disorder patients. Characteristics
Adjusted OR (95% CI)
P Value
Psychotic features Male gender Substance use disorder
8.42 (1.05–67.65) 3.23 (1.08–9.65) 1.79 (0.71–4.50)
P o0.05 P o0.05 NS
NS ¼ not significant.
In our sample of BD-I patients, we found a SP of manic episode admissions in a quarter of the patients and a SP of depressive episode admissions in fifth of the patients. SP of manic episode
Characteristics
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admissions was found to be associated with increased rates of male gender, psychotic features during the manic episodes and comorbid substance use disorder. No significant differences were found between patients with or without SP of major depressive episode admissions with respect to demographic and clinical characteristics, however, these results should be interpreted with caution due to a small sample size of this patients' group. No significant difference was found in the seasonal distribution of admission rates for both manic and depressive episodes. In a multivariate analysis, the presence of psychotic features during manic episodes and male gender, but not comorbidity of substance use disorder, were predictors of a SP of manic episode admissions. In a series of cross-sectional retrospective studies, beginning in the late seventies, evidence for a significant seasonal trend for manic episode admission rate was found with a peak in spring– summer (Frangos et al., 1980; Myers and Davies, 1978; Symonds and Williams, 1976). Using the categorical system of DSM-III, few studies have examined the rate of SP of manic episodes in BD patients. In a prospective study, Hunt et al. found that 15% of 86 BD patients, followed over a 6-year period, met criteria for a SP of a manic relapse. In addition, Schaffer et al., in a retrospective study, found that seasonal mania occurred in 12.9% of their sample of BD patients (Hunt et al., 1992; Schaffer et al., 2003). Seasonal distribution of manic episode admissions or emergency room visits was further supported by latter studies (Lee et al., 2007; Volpe et al., 2010). Our results, based on a nine years retrospective cohort study, support the inclusion of manic episode in DSM-5 SP specifier of mood episodes, with 26% of BD patients repeatedly admitted with manic episodes exhibiting SP of manic episode
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admissions. Data regarding the association between SP of manic episodes and specific clinical and demographic characteristics are scarce. Using an ecological design on data derived from Taiwan national health insurance research database, Yang et al. examined the effects of age, gender, index admission and predominant polarity on BD seasonality (Yang et al., 2013). Their results suggest that seasonality was significant in female admissions for depressive episodes and in male admissions for manic episodes and that young adults displayed a higher degree of seasonality for acute admissions (Yang et al., 2013). In line with these findings, in our sample of BD-I patients, SP of manic episode admissions was found to be associated with male gender, supporting specific gender infradian rhythm vulnerability factors for manic exacerbations (Geoffroy et al., 2014). In contrast to the study conducted by Yang et al., in our study, patients' age at first admission during the study period did not discriminate between BD-I patients with and without SP of manic episode admissions. Several studies have reported elevated rates of psychotic features, during manic episodes, as high as 68% in BD patients (Canuso et al., 2008; Coryell et al., 2001). Our results suggest that SP of manic episode admissions is associated with increased risk for the presence of psychotic features during the manic episodes independent of gender or substance use disorder. Supporting evidence for seasonality of psychosis among BD patients comes from a study which investigated the existence of a seasonal distribution of three dimensions of mania: psychosis, aggression and suicidality (Volpe et al., 2008). In that study psychosis was associated with hours of sunshine of index month and with increasing hours of sunshine (Volpe et al., 2008). Psychotic features during manic episodes are associated with greater symptom severity, longer hospitalization, shorter time to relapse, higher morbidity, suicide risk and overall functional impairment (Coryell et al., 2001; Kessing, 2004; Martinez et al., 2005; Swann et al., 2004; Tohen et al., 2003). Thus, SP of manic episodes might be associated with a more severe form of the disorder and most likely with a poorer outcome. However, no difference was found in our sample between BD patients with or without SP of manic episode admissions regarding the rate of manic episode admissions per year or rate of treatment with combined mood stabilizers or mood stabilizer with antipsychotics on discharge. Further studies should investigate other measures for BD course severity according to SP of manic episodes. Previous studies have suggested a seasonal distribution of health service utilization rates for major mood episodes with main peak in spring–summer and smaller peak in autumn for manic episodes and main peak in early winter and smaller peak in summer for depressive episodes (Geoffroy et al., 2014). In Israel, previous reports showed inconsistent results. While Shapira et al. found seasonal distribution of BP depressive episode admissions with peak in spring–summer (Shapira et al., 2004), Valevski et al. found increased depressive admission rate during winter (Modai et al., 1994). One possible explanation for this discrepancy is the exclusion of BD patients with SP of depressive episodes, according to DSM-IV, in the study conducted by Shapira et al. In our study, no difference was found in the seasonal distribution of admission rates for both manic and depressive episodes. Similarly, several other studies failed to demonstrate seasonal distribution of major mood episodes among BD patients. For example, Hunt et al. found that 15% of their BD patients exhibited SP of manic episodes but there was no particular season in which manic episodes relapsed (Hunt et al., 1992). Finally, four prospective studies have failed to find a clear evidence of seasonal distribution in BD symptoms (Bauer et al., 2009; Christensen et al., 2003; Friedman et al., 2006; Murray et al., 2011). These findings do not support the notion of a simple linkage between lighter months and elevated mood in
ideographic seasonality (Murray et al., 2011). It is of note that certain affected patients tend to stay up later during the spring/ summer season and such disrupted sleep-wake cycle puts them at greater risk for relapse and exacerbation. Thus, the seasonal manic presentation of a subset of our cohort could be an epiphenomenon of a disrupted sleep-wake cycle, rather than a direct effect of longer periods of daylight. In summary, our results indicate SP of manic episode admissions among one quarter of BD-I patients. The SP of manic episode admissions was found to be associated with male gender and increased risk for the presence of psychotic features during the manic episodes, independent of gender or substance use disorder. These results suggest that SP of manic admissions might be associated with a more severe form of BD. Our findings support the existence of disrupted chronobiology in BD and the inclusion of SP specifier in DSM-5 diagnosis of manic episode. Furthermore, our results, together with previous data, should facilitate development of personalized chronobiological preventive and interventional strategies including frequent clinical follow-up around the sensitive season of the year, especially for male BD patients, and increased attention to the presence of psychotic features during manic episodes among patients with SP with application of corresponding adequate treatment. Our study was limited by its retrospective EMR review analysis, thus, seasonal psychological/environmental (e.g. stressful events, holidays) factors contributing to the emergence of mood episodes could not be ruled out. Second, our indication of the onset of mood episodes is derived from the hospital admission date. This may be a relatively good indicator for the onset of manic episodes, but depressive episodes admissions may be far away from their actual onset. Third, outpatient records for our BD patients were not available for analysis, thus, subthreshold mood fluctuations not leading to admission, mostly depressive and hypomanic episodes, may be underestimated. In order to partially overcome this limitation BD-II patients were excluded from the study. Fourth, data regarding the rate of patients with SP of both manic and depressive episodes could not be derived from this study as only five patients had at least two admissions for each type of mood episode and none of them had SP for both types of repeated mood episodes. The strengths of the present study include its longitudinal design, based on a nine years retrospective cohort study, the inclusion of clinical and demographic covariates such as medications and psychiatric comorbidities, and the utilization of the categorical system of DSM-5 for the retrospective determination of seasonality. Future large-scale, prospective, longitudinal studies are needed to examine the rates and characteristics of BD-I or BD-II patients with SP of manic/hypomanic episodes, including subthreshold symptoms not leading to admissions. Elucidation of the biological mechanisms involved in the disrupted chronobiology in a sub-group of manic BD patients may eventually lead to novel therapeutic targets for this population.
Author disclosure Contributors Eldar Hochman – study design, data collection and analysis, interpretation of data, preparation of manuscript. Avi Valevski – data analysis, interpretation of data, preparation of manuscript. Roy Onn – data analysis, interpretation of data, preparation of manuscript. Abraham Weizman – study design, interpretation of data, preparation of manuscript.
E. Hochman et al. / Journal of Affective Disorders 190 (2016) 123–127
Amir Krivoy – study design, data collection and analysis, interpretation of data, preparation of manuscript. All authors have approved the final version of the manuscript. Role of funding source No funding source was involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. All authors report no financial relationships with commercial interests.
Acknowledgments and disclosures The authors declare that they have no conflicts of interest concerning this article.
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Journal of Affective Disorders journal homepage: www.elsevier.com/locate/jad
Research report
Seasonal pattern of manic episode admissions among bipolar I disorder patients is associated with male gender and presence of psychotic features Eldar Hochman a,b,n, Avi Valevski a,b, Roy Onn a,b, Abraham Weizman a,b,c, Amir Krivoy a,b,c a
Geha Mental Health Center, Petach-Tikva, Israel Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel c Laboratory of Biological Psychiatry, Felsenstein Medical Research Center, Petach-Tikva, Israel b
art ic l e i nf o
a b s t r a c t
Article history: Received 21 July 2015 Received in revised form 29 September 2015 Accepted 2 October 2015
Background: Bipolar I disorder (BD-I) patients demonstrate disrupted chronobiology expressed as seasonal variation in mood symptoms. The seasonal pattern (SP) specifier of mood disorders was recently extended by the DSM-5, to be applied to manic episodes. However, the significance of seasonality of manic episodes for the course of BD-I is unknown. In the present study we sought to identify clinical and demographic features that discriminate between BD-I patients with and without SP of manic admissions. Methods: BD-I patients (n ¼148) admitted at least twice with the same mood exacerbation type, were retrospectively followed between 2005 and 2013. Demographic and clinical characteristics were compared between BD-I patients with or without SP of manic admissions. Results: SP of manic episode admissions, found in 31 (26%) of 117 BD-I patients with repeated manic episode admissions, was associated with higher rates of male gender (p ¼0.01), presence of psychotic features (p ¼0.01) and comorbid substance use disorder (po 0.05) compared to patients without SP. In a multivariate analysis, SP of manic episode admissions was associated with the presence of psychotic features (OR 8.42, 95% CI: 1.05–67.65, po0.05) and male gender (OR 3.23, 95% CI: 1.08–9.65, po 0.05), but not with comorbidity of substance use disorder (OR 1.79, 95% CI: 0.71–4.50, p ¼0.24). Limitations: Seasonal psychological/environmental factors contributing to the emergent of mood episodes could not be ruled out. Conclusions: Our results suggest that SP of manic admissions is associated with male gender and the presence of psychotic features, thus might be associated with more severe form of the disorder. & 2015 Elsevier B.V. All rights reserved.
Keywords: Bipolar disorder Seasonal pattern Psychotic features Substance use disorder
1. Introduction Accumulating data support the hypothesis that disrupted chronobiology may represent a core element of bipolar disorder (BD) and might play a role in the pathophysiology of this disorder (Salvatore et al., 2012; Scott, 2011). BD patients demonstrate irregular chronobiology expressed as disrupted sleep and circadian rhythms and greater seasonal fluctuations in mood and behavior compared to unipolar depression patients or healthy controls (Geoffroy et al., 2014). Seasonal variability of symptoms among BD patients and its significance for the course of the disorder were traditionally studied by exploring the seasonal distribution of admissions rates of BD patients and the association between n Corresponding author at: Geha Mental Health Center, P.O. Box 102, Petach Tikva 4910002 Israel. Fax: þ 972 3 9258388. E-mail address: [email protected] (E. Hochman).
http://dx.doi.org/10.1016/j.jad.2015.10.002 0165-0327/& 2015 Elsevier B.V. All rights reserved.
seasonal pattern (SP) of acute bipolar mood episode with specific clinical and demographic characteristics (Geoffroy et al., 2014). According to the Diagnostic and Statistical Manual of Mental Disorders, 4th Edition, Text Revision (DSM-IV-TR), SP was restricted to depressive episodes. Consequently, in the past decades, SP was mostly studied for depressive episodes, and was found among 25% of BD patients. SP of depressive episodes among BD patients was found to be associated with bipolar II disorder (BD-II), rapid cycling, depressive onset and depressive predominant polarity, while data regarding gender differences according to SP are inconclusive (Arnold, 2003; Friedman et al., 2006; Goikolea et al., 2007). Previous studies using DSM-III criteria for SP,that were applied for both depressive and manic episodes, have identified around 15% of BD patients with SP of manic episodes and these patients presented more severe clinical profile (Geoffroy et al., 2014; Hunt et al., 1992). Recognizing the accumulating data supporting the presence of SP both in manic and depressive episodes, the SP specifier of mood
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disorders was extended by the DSM, Fifth Edition (DSM-5) to be applied to manic/hypomanic episodes (American Psychiatric Association., 2013). However, data regarding the significance of manic episode seasonality for the course of BD are scarce. In the current study we aimed to identify clinical and demographic features that discriminate between bipolar I disorder (BD-I) patients with and without SP of manic episode admissions.
2. Methods 2.1. Population We conducted a retrospective cohort study, using electronic medical records (EMR) review of all consecutive admissions to Geha Mental Health Center (GMHC, Petach Tikva, Israel) between January 1, 2005, and July 31, 2013. GMHC is a tertiary care referral mental health center that provides psychiatric care to more than 1500 patients admitted annually. The center serves a population of about 450,000. Patients are referred to the center by general practitioners, outpatient psychiatrists or are self-referred and all of them are admitted through the emergency room. Out of 6084 patients admitted during the study period we identified 540 patients diagnosed as having DSM-IV-TR BD-I or BD-II according to the EMR review. The type of psychiatric exacerbation leading to each admission was classified as DSM-IV-TR manic, major depressive or mixed episode as established by a consensus of two senior psychiatrists following a psychiatric interview during the time of each hospitalization. To avoid confounding effects we excluded from the study mood episode admissions that were attributed to a substance use or a medical condition as well as patients under 18 years of age. Furthermore, BD-II patients were excluded from this study for two reasons: first, small number of patients and second, a higher probability for subthreshold hypomanic symptoms that might increase selection bias errors. In order to determine a SP for each type of mood episode (manic, major depressive or mixed), only patients with repeated admissions (at least two) of the same type of mood episode, during the study period, were included in the study. Subsequently, BD-I patients were sub-grouped according to the type of the repeated mood episodes leading to admission (repeated manic episodes group, repeated major depressive episodes group and repeated mixed episodes group). The total number of patients included in the study was 148 with 402 repeated admissions due to acute mood episodes. Five of the patients met the inclusion criteria for more than one type of repeated mood episodes group (i.e., had at least two admissions for each type of mood episode, either depressive or manic) and were included in both types of repeated mood episodes group (Table 1). To differentiate among separate episodes in a patient with multiple admissions, we included in the study only the first admission if the patient had been readmitted within an 8-week period unless the polarity was reversed, in such cases both admissions were included (Lee et al., 2007). The study was approved by the GMHC Review Board. 2.2. Measures Demographic and clinical data were collected retrospectively from the patients' EMR. Demographic data included age at first admission during the study period and gender. Clinical data included number of admissions per year during the study period, the type of mood episode leading to each admission (as described above), the presence of psychotic features during each mood episode (either delusions or hallucinations during the mood episode according to DSM-IV-TR), history of suicide attempt,
Table 1 Seasonal pattern and demographic characteristics [Mean7 SD or N (%)] of Bipolar I disorder inpatients sub-grouped according to the type of repeated mood episodes leading to admission. Characteristics
Number of patients Number of admissions Gender Female Male Age (yrs)b Patients with Seasonal pattern
Type of repeated mood episodes groupa Repeated manic episodes group
Repeated major depressive episodes group
Repeated mixed episodes group
117 313
33 83
3 6
41 (35%) 76 (65%) 36.8 7 14.8 31 (26%)
22 (67%) 11 (33%) 51.6 716.5 7 (21%)
2 (67%) 1 (33%) 45.0 714.5 1 (33%)
SD ¼ standard deviation. a Patients with repeated (at least two) admissions of the same type of mood episode (manic, major depressive or mixed) were classified according to the type of repeated mood episodes leading to admission. b Age (yrs) at first admission during the study period.
psychiatric comorbidities including substance use disorder, anxiety disorders and personality disorders (according to DSM-IV-TR criteria) and the type of psychotropic drugs at discharge from the hospital after the last admission. For each patient, the presence of SP was determined, in a retrospective approach, separately for each type of a repeated mood episode leading to admission (manic, major depressive or mixed) according to DSM-5 criteria (consisting of temporal relationship between the time of repeated admissions of specific type of mood episode and a particular time (season) of the year, seasonal mood episodes substantially outnumber non-seasonal mood episodes during the study period and in the last two years of the study there have been only seasonal episodes). The season for each mood episode admission was determined according to admission date. Importantly, the SP was not determined for specific season but for each patient according to the time of repeated admissions. The duration of the various Israeli seasons were defined as follows: Winter: December–February; Spring: March–May; Summer: June–September; Fall: October–November (Shapira et al., 2004). 2.3. Statistical analysis SPSS ver. 20 (SPSS inc, Chicago, IL) was used for statistical analysis. Descriptive statistics were expressed as Mean7SD, or rate (%). Demographic and clinical characteristics were compared between BD-I patients with or without SP of admissions (for each type of repeated mood episodes). Contingency tables were used to compare rates of gender, presence of psychotic features, history of suicide attempt, psychiatric comorbidities and type of psychotropic drugs at discharge from the hospital. Independent Student's t-test was used to compare age at first admission during the study period and the number of admissions per year. Differences in seasonal distribution of mood episode admission rates were analyzed by one-way ANOVA (Shapira et al., 2004). A logistic regression analysis was conducted with SP of manic episode as a dependent variable (dichotomous) and the presence of psychotic features, male gender and a substance use disorder as covariates. Odds ratios, 95% confidence interval and statistical significance were calculated. P value ofo 0.05 was considered statistically significance.
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3. Results For each type of repeated mood episode group (manic, major depressive or mixed) of BD-I patients, the proportion of patients with SP of admissions, the number of admissions during the study period and patients' gender and age are presented in Table 1. No difference was found in the seasonal distribution of admission rates for both manic and major depressive episodes, namely there was no association with a specific season within the year (data not shown). In a univariate analyses within BD-I 'repeated manic episodes group' patients, SP of manic episode admissions was associated with higher rates of male gender, presence of psychotic features during the manic episodes and substance use disorder compared to BD-I 'manic episode group' patients without SP of manic episodes admissions (Table 2). No significant differences were found between BD-I 'repeated manic episodes group' patients with or without SP of manic episode admissions in the age at first admission during the study period, diagnosis of other psychiatric comorbidities, rates of patients with history of suicide attempts and the number of manic episodes during the study period (Table 2). In the BD-I 'repeated major depressive episodes group' patients no significant differences were found between patients with or without SP of major depressive episode admissions with respect to demographic and clinical characteristics (Table 3). In a multivariate analysis using a logistic regression model, adjusting for demographic and clinical covariates that were significant in the univariate analyses, the presence of psychotic features during manic episodes and male gender, but not comorbidity of substance use disorder, were predictors of a SP of manic episode admissions among BD-I 'repeated manic episodes group' patients (Table 4).
4. Discussion
Table 2 Demographic and clinical characteristics [Mean7 SD or N (%)] of 'Repeated manic episodes group' of Bipolar I disorder patients with or without seasonal pattern of manic episode admissions.
Male Age (yrs)b With psychotic features History of suicide attempts Mixed episodec Psychiatric comorbidity Substance use disorder Personality disorder Anxiety disorder Treatmentd Mood stabilizer & APD Two mood stabilizers Manic episode admissions per year
Seasonal pattern of Manic episode (N ¼ 117 patients)
P valuea
Yes (N ¼ 31)
No (N ¼86)
26 (83.9%) 35.9 716.94 30 (96.8%) 4 (12.9%)
50 (58.1%) 37.2 714.16 66 (76.7%) 11 (13.4%)
0.01 NS 0.01 NS
1 (3.2%)
7 (8.1%)
NS
21 (67.7%) 7 (22.6%) 1 (3.2%)
39 (47.0%) 26 (30.2%) 7 (8.1%)
0.04 NS NS
19 (61.3%) 5 (16.1%) 0.53 7 0.25
58 (67.4%) 9 (10.5%) 0.55 7 0.31
NS NS NS
APD ¼ antipsychotic drug. NS ¼ not significant. SD ¼ standard deviation. a
P was based on independent-samples T test or χ² test. Age at the first admission during the study period 2005–2013. c Admission with mixed episode during study period. d Treatment on discharge from the hospital. b
Table 3 Demographic and clinical characteristics [Mean 7SD or N (%)] of 'Repeated major depressive episodes group' of Bipolar I disorder patients with or without seasonal pattern of depressive episode admissions. Characteristics
Male Age (yrs)b With psychotic features History of suicide attempts Mixed episodec Psychiatric comorbidity Substance use disorder Personality disorder Anxiety disorder Treatmentd Mood stabilizer & APD Two mood stabilizers Major depressive episode admissions per year
Seasonal pattern of major Depressive episode (N ¼33 patients)
P valuea
Yes (N ¼7)
No (N ¼ 26)
2 (28.6%) 60.8 7 9.40 3 (42.9%) 3 (42.9%)
9 (34.6%) 49.17 17.34 4 (15.4%) 5 (19.2%)
NS NS NS NS
0 (0.0%)
3 (11.5%)
NS
0 (0.0%) 2 (28.6%) 1 (14.3%)
3 (11.5%) 9 (34.6%) 1 (3.8%)
NS NS NS
3 (42.9%) 0 (0.0%) 0.42 7 0.13
12 (46.2%) 2 (7.7%) 0.36 7 0.18
NS NS NS
APD ¼ antipsychotic drug. NS ¼ not significant. SD ¼ standard deviation. a
P was based on independent-samples T test or χ² test. Age at the first admission during the study period 2005–2013. c Admission with mixed episode during study period. d Treatment on discharge from the hospital. b
Table 4 Multivariate analysis for seasonal pattern of manic episode admissions in 'Repeated manic episodes group' of bipolar I disorder patients. Characteristics
Adjusted OR (95% CI)
P Value
Psychotic features Male gender Substance use disorder
8.42 (1.05–67.65) 3.23 (1.08–9.65) 1.79 (0.71–4.50)
P o0.05 P o0.05 NS
NS ¼ not significant.
In our sample of BD-I patients, we found a SP of manic episode admissions in a quarter of the patients and a SP of depressive episode admissions in fifth of the patients. SP of manic episode
Characteristics
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admissions was found to be associated with increased rates of male gender, psychotic features during the manic episodes and comorbid substance use disorder. No significant differences were found between patients with or without SP of major depressive episode admissions with respect to demographic and clinical characteristics, however, these results should be interpreted with caution due to a small sample size of this patients' group. No significant difference was found in the seasonal distribution of admission rates for both manic and depressive episodes. In a multivariate analysis, the presence of psychotic features during manic episodes and male gender, but not comorbidity of substance use disorder, were predictors of a SP of manic episode admissions. In a series of cross-sectional retrospective studies, beginning in the late seventies, evidence for a significant seasonal trend for manic episode admission rate was found with a peak in spring– summer (Frangos et al., 1980; Myers and Davies, 1978; Symonds and Williams, 1976). Using the categorical system of DSM-III, few studies have examined the rate of SP of manic episodes in BD patients. In a prospective study, Hunt et al. found that 15% of 86 BD patients, followed over a 6-year period, met criteria for a SP of a manic relapse. In addition, Schaffer et al., in a retrospective study, found that seasonal mania occurred in 12.9% of their sample of BD patients (Hunt et al., 1992; Schaffer et al., 2003). Seasonal distribution of manic episode admissions or emergency room visits was further supported by latter studies (Lee et al., 2007; Volpe et al., 2010). Our results, based on a nine years retrospective cohort study, support the inclusion of manic episode in DSM-5 SP specifier of mood episodes, with 26% of BD patients repeatedly admitted with manic episodes exhibiting SP of manic episode
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admissions. Data regarding the association between SP of manic episodes and specific clinical and demographic characteristics are scarce. Using an ecological design on data derived from Taiwan national health insurance research database, Yang et al. examined the effects of age, gender, index admission and predominant polarity on BD seasonality (Yang et al., 2013). Their results suggest that seasonality was significant in female admissions for depressive episodes and in male admissions for manic episodes and that young adults displayed a higher degree of seasonality for acute admissions (Yang et al., 2013). In line with these findings, in our sample of BD-I patients, SP of manic episode admissions was found to be associated with male gender, supporting specific gender infradian rhythm vulnerability factors for manic exacerbations (Geoffroy et al., 2014). In contrast to the study conducted by Yang et al., in our study, patients' age at first admission during the study period did not discriminate between BD-I patients with and without SP of manic episode admissions. Several studies have reported elevated rates of psychotic features, during manic episodes, as high as 68% in BD patients (Canuso et al., 2008; Coryell et al., 2001). Our results suggest that SP of manic episode admissions is associated with increased risk for the presence of psychotic features during the manic episodes independent of gender or substance use disorder. Supporting evidence for seasonality of psychosis among BD patients comes from a study which investigated the existence of a seasonal distribution of three dimensions of mania: psychosis, aggression and suicidality (Volpe et al., 2008). In that study psychosis was associated with hours of sunshine of index month and with increasing hours of sunshine (Volpe et al., 2008). Psychotic features during manic episodes are associated with greater symptom severity, longer hospitalization, shorter time to relapse, higher morbidity, suicide risk and overall functional impairment (Coryell et al., 2001; Kessing, 2004; Martinez et al., 2005; Swann et al., 2004; Tohen et al., 2003). Thus, SP of manic episodes might be associated with a more severe form of the disorder and most likely with a poorer outcome. However, no difference was found in our sample between BD patients with or without SP of manic episode admissions regarding the rate of manic episode admissions per year or rate of treatment with combined mood stabilizers or mood stabilizer with antipsychotics on discharge. Further studies should investigate other measures for BD course severity according to SP of manic episodes. Previous studies have suggested a seasonal distribution of health service utilization rates for major mood episodes with main peak in spring–summer and smaller peak in autumn for manic episodes and main peak in early winter and smaller peak in summer for depressive episodes (Geoffroy et al., 2014). In Israel, previous reports showed inconsistent results. While Shapira et al. found seasonal distribution of BP depressive episode admissions with peak in spring–summer (Shapira et al., 2004), Valevski et al. found increased depressive admission rate during winter (Modai et al., 1994). One possible explanation for this discrepancy is the exclusion of BD patients with SP of depressive episodes, according to DSM-IV, in the study conducted by Shapira et al. In our study, no difference was found in the seasonal distribution of admission rates for both manic and depressive episodes. Similarly, several other studies failed to demonstrate seasonal distribution of major mood episodes among BD patients. For example, Hunt et al. found that 15% of their BD patients exhibited SP of manic episodes but there was no particular season in which manic episodes relapsed (Hunt et al., 1992). Finally, four prospective studies have failed to find a clear evidence of seasonal distribution in BD symptoms (Bauer et al., 2009; Christensen et al., 2003; Friedman et al., 2006; Murray et al., 2011). These findings do not support the notion of a simple linkage between lighter months and elevated mood in
ideographic seasonality (Murray et al., 2011). It is of note that certain affected patients tend to stay up later during the spring/ summer season and such disrupted sleep-wake cycle puts them at greater risk for relapse and exacerbation. Thus, the seasonal manic presentation of a subset of our cohort could be an epiphenomenon of a disrupted sleep-wake cycle, rather than a direct effect of longer periods of daylight. In summary, our results indicate SP of manic episode admissions among one quarter of BD-I patients. The SP of manic episode admissions was found to be associated with male gender and increased risk for the presence of psychotic features during the manic episodes, independent of gender or substance use disorder. These results suggest that SP of manic admissions might be associated with a more severe form of BD. Our findings support the existence of disrupted chronobiology in BD and the inclusion of SP specifier in DSM-5 diagnosis of manic episode. Furthermore, our results, together with previous data, should facilitate development of personalized chronobiological preventive and interventional strategies including frequent clinical follow-up around the sensitive season of the year, especially for male BD patients, and increased attention to the presence of psychotic features during manic episodes among patients with SP with application of corresponding adequate treatment. Our study was limited by its retrospective EMR review analysis, thus, seasonal psychological/environmental (e.g. stressful events, holidays) factors contributing to the emergence of mood episodes could not be ruled out. Second, our indication of the onset of mood episodes is derived from the hospital admission date. This may be a relatively good indicator for the onset of manic episodes, but depressive episodes admissions may be far away from their actual onset. Third, outpatient records for our BD patients were not available for analysis, thus, subthreshold mood fluctuations not leading to admission, mostly depressive and hypomanic episodes, may be underestimated. In order to partially overcome this limitation BD-II patients were excluded from the study. Fourth, data regarding the rate of patients with SP of both manic and depressive episodes could not be derived from this study as only five patients had at least two admissions for each type of mood episode and none of them had SP for both types of repeated mood episodes. The strengths of the present study include its longitudinal design, based on a nine years retrospective cohort study, the inclusion of clinical and demographic covariates such as medications and psychiatric comorbidities, and the utilization of the categorical system of DSM-5 for the retrospective determination of seasonality. Future large-scale, prospective, longitudinal studies are needed to examine the rates and characteristics of BD-I or BD-II patients with SP of manic/hypomanic episodes, including subthreshold symptoms not leading to admissions. Elucidation of the biological mechanisms involved in the disrupted chronobiology in a sub-group of manic BD patients may eventually lead to novel therapeutic targets for this population.
Author disclosure Contributors Eldar Hochman – study design, data collection and analysis, interpretation of data, preparation of manuscript. Avi Valevski – data analysis, interpretation of data, preparation of manuscript. Roy Onn – data analysis, interpretation of data, preparation of manuscript. Abraham Weizman – study design, interpretation of data, preparation of manuscript.
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Amir Krivoy – study design, data collection and analysis, interpretation of data, preparation of manuscript. All authors have approved the final version of the manuscript. Role of funding source No funding source was involved in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the article for publication. All authors report no financial relationships with commercial interests.
Acknowledgments and disclosures The authors declare that they have no conflicts of interest concerning this article.
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