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Accepted Manuscript
Predictors of switch from depression to mania in bipolar disorder
Tomihisa Niitsu, Chiara Fabbri, Alessandro Serretti, M.D., Ph.D.
PII: S0022-3956(15)00117-X
DOI: 10.1016/j.jpsychires.2015.04.014
Reference: PIAT 2614
To appear in: Journal of Psychiatric Research
Received Date: 6 November 2014

Revised Date: 14 April 2015
Accepted Date: 14 April 2015
Please cite this article as: Niitsu T, Fabbri C, Serretti A, Predictors of switch from depression to mania in
bipolar disorder, Journal of Psychiatric Research (2015), doi: 10.1016/j.jpsychires.2015.04.014.
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Predictors of switch from depression to mania in bipolar disorder
Tomihisa Niitsu 1,2, Chiara Fabbri 1, Alessandro Serretti 1 *
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Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna,
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Italy
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Research Center for Child Mental Development, Chiba University Graduate School of
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Medicine, Chiba, Japan
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Running title: Predictors of manic switch in bipolar depression
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* Corresponding author: Alessandro Serretti, M.D., Ph.D.

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Department of Biomedical and NeuroMotor Sciences, University of Bologna,
Viale Carlo Pepoli 5, 40123 Bologna, Italy

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Tel +39 051 6584233; Fax +39 051 521030

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Email: alessandro.serretti@unibo.it
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Niitsu et al. Predictors of manic switch in bipolar depression
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Abstract
Manic switch is a relevant issue when treating bipolar depression. Some risk factors
have been suggested, but unequivocal findings are lacking. We therefore investigated
predictors of switch from depression to mania in the Systematic Treatment
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Enhancement Program for Bipolar Disorder (STEP-BD) sample. Manic switch was
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defined as a depressive episode followed by a (hypo)manic or mixed episode within the
following 12 weeks. We assessed possible predictors of switch using generalized linear
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mixed models (GLMM).
8403 episodes without switch and 512 episodes with switch (1720 subjects) were
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included in the analysis. Several baseline variables were associated with a higher risk of
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switch. They were younger age, previous history of: rapid cycling, severe manic
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symptoms, suicide attempts, amphetamine use and some pharmacological and
psychotherapeutic treatments. During the current depressive episode, the identified risk
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factors were: any possible mood elevation, multiple mania-associated symptoms with at
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least moderate severity, and comorbid panic attacks.
In conclusion, our study suggests that both characteristics of the disease history and
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clinical features of the current depressive episode may be risk factors for manic switch.
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Keywords: bipolar depression; manic switch; manic symptom; panic attack;
venlafaxine; suicide; rapid-cycling; amphetamine use; onset
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Highlights
− Manic switch is a primary issue when treating bipolar depression

− Concomitant manic symptoms and panic attacks are the strongest risk factors
− Antidepressant treatment may not represent a primary risk factor
−
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In low risk cases, younger age, past treatments or suicide attempts may be
relevant
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1. Introduction
Bipolar disorder (BD) is a chronic disease characterized by the alternation of
periods of (hypo)mania and depression, resulting in high personal and socio-economic
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burden in terms of poor quality of life, increased rates of suicide, direct and indirect
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costs (Ferrari et al. 2012; Conus et al. 2013; Fagiolini et al. 2013; Kleine-Budde et al.
2013; Whiteford et al. 2013). The course of BD is highly variable, thus the identification
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of individuals at higher risk of experiencing a more severe course has relevant
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implications for both patients and public health care.
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Switch from depression to (hypo)mania or mixed status is a critical issue since
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its high impact on disease severity. Indeed, patients with one or more episodes of switch
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have longer periods of illness lifetime and higher risk of suicide; further, they
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experience more comorbidities (e.g. substance abuse) (Maj et al. 2002; MacKinnon et al.
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2003; MacKinnon et al. 2003; MacKinnon et al. 2005). Thus, the identification of
switch risk factors represents a pivotal issue in order to prevent this detrimental event
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and improve BD prognosis. Previous studies investigated antidepressant (AD)-related
switch in patients with BD, and they suggested a number of risk factors (see
Supplementary Table S1 for a summary). On the basis of the results observed in the
largest samples, the most replicated risk factors were previous history of switch or rapid
cycling, younger onset age, and BD I diagnosis (Serretti et al. 2003; Perlis et al. 2010;
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Valenti et al. 2012). One of these studies was performed on the systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD) sample and it reported several
associations between switch and baseline clinical-demographic features (greater number
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of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder,
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previous suicide attempt, past history of AD-emergent switch, and greater manic
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symptom severity) (Perlis et al. 2010). Some of these risk factors were dependent from
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AD exposure (younger onset age in patients not treated with ADs; previous suicide
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attempt and BD type I diagnosis in AD-exposed patients).
Previous studies were mainly focused on the risk of switch during AD

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treatment (Supplementary Table S1), but some patients with BD experience switch even
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in the absence of AD treatment. Indeed, some randomized controlled trials (RCTs)

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suggested that a mood stabilizer plus adjunctive AD therapy, compared with a mood
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stabilizer plus a placebo or mood stabilizer monotherapy, showed no association with

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higher risk of AD-emergent affective switch (Keck et al. 2005; Sachs et al. 2007). The
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first of these RTCs (Sachs et al. 2007) was carried out on a subsample of the STEP-BD
study and its results could have been biased due to the intervention of clinicians in the
process of randomization (tendency to avoid the randomization of patients at higher risk
of switch). Despite the risk of inclusion bias deriving from this type of study design,
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several neurobiological mechanisms support the risk of spontaneous switch (Salvadore
et al. 2010), thus risk factors of switch should not be investigated only in relation to
concomitant AD treatment.
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Previous studies focused on the risk of AD-induced mood switch suggested that
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tricyclic ADs (Boerlin et al. 1998; Bottlender et al. 2001; Nemeroff et al. 2001;
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Bottlender et al. 2004), monoamine oxidase inhibitors (MAOIs) (Boerlin et al. 1998)
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and venlafaxine (Leverich et al. 2006; Post et al. 2006) may be associated with higher
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risk than SSRIs or bupropion.
All the above-mentioned studies (with the exception of a small naturalistic

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study (Boerlin et al. 1998)) investigated a patient-based phenotype of switch from

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depression to (hypo)mania, i.e. they compared patients with and without switch, but
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they did not consider an episode-based phenotype, i.e. the comparison between
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depressive episodes followed or not by switch. Despite the fact that the disease course
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usually keeps a similar pattern in the same patient during time (van Rossum et al. 2008;
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Uher et al. 2013), the recurrence of acute episodes increases the level of functional
impairment (Bonnin et al. 2013) and it possibly affects the clinical features and
frequency of the following episodes. Thus, the specific features of each episode should
be considered in addition to the general characteristics of BD in each patient in order to
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provide an accurate prognosis and suitable treatment interventions.
Given the hypothesized clinical relevance of each episode in every subject, the
present study investigated the clinical predictors of switch from major depressive
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episodes to (hypo)manic/mixed episodes including into the analysis all the depressive
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episodes occurring for each patient during follow-up. Previous evidence suggested that
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the risk of switch is not influenced only by concomitant AD treatment, thus supporting
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our choice. Thus, baseline clinical-demographic characteristics, past clinical history, and
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current clinical characteristics (including treatment) at each depressive episode were
investigated for a possible correlation with the risk of switch from depression to
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(hypo)manic/mixed state.
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2. Methods
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2.1. Study Overview

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STEP-BD was a large, multi-center and naturalistic cohort study, conducted in

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the USA between 1999 and 2005. The aim of STEP-BD was to evaluate prospective
outcomes among patients with bipolar disorder treated in a naturalist setting. STEP-BD
clinicians were encouraged to treat patients in accordance with contemporary practice
guidelines. The study design was approved by the Human Subjects Panel from each site.
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More detailed methods of the STEP-BD are described elsewhere (Sachs et al. 2003;
Perlis et al. 2006).
2.2. Participants
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Entry criteria involved meeting DSM-IV criteria for BD I, II or not otherwise
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specified, or schizoaffective disorder bipolar type, and ability to provide informed
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consent. All patients were outpatients; inpatients were eligible to enter the study
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following discharge (Sachs et al. 2003; Perlis et al. 2006). Overall, 4360 participants
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were included. Participants received pharmacological interventions as clinically
indicated and clinicians were encouraged to follow the principles of evidence-based

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treatment and published guidelines, updated annually in the STEP-BD Clinicians

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Handbook. The protocol promoted the application of evidence-based treatments at

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regular clinical assessments during follow-up, in accordance with the needs of the
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participant and did not follow compliance to a specific treatment algorithm. This
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naturalistic study employed ongoing assessments of treatment and outcome information.

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For the present study, further inclusion criteria were: (i) 6 months (180 days) or
more follow-up duration; (ii) at least one depressive clinical episode during follow-up,
according to the Clinical Monitoring Form (CMF) (Sachs et al. 2002; Sachs et al. 2003)
of the STEP-BD Standard Care Pathway (SCP).
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2.3. Assessments
The diagnosis of BD was assessed with the Mini International
Neuropsychiatric Interview (MINI) (Sheehan et al. 1998) and Affective Disorder
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Evaluation (ADE) form (Sachs et al. 2003; Sachs 2004) upon study entry together with
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a socio-demographic form (Demographic Form (DF)) (Sachs et al. 2003; Sachs 2004).
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The CMF was used as source document for key prospective outcome measures and
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provided the progress note in the patient’s medical record (Sachs et al. 2002).
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Regarding symptoms of depression and mania, sums of classified scores for
depression (SUM-D) and mania (SUM-M) were calculated using the Scoring
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Conventions and Rules for Imputation (Sachs et al. 2002).

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2.4. Definition of “depressive episode with switch” and “patient with switch”
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We used the clinical status variable in the CMF form to define the occurrence
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of switch. A “depressive episode with switch” was defined as a depressive episode that
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was followed by a manic, hypomanic or mixed episode within 12 weeks (84 days). The
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12 weeks cut-off was chosen according to previous literature (Vieta et al. 2009). The
other depressive episodes were defined as “depressive episode without switch”. Patients
with at least one “depressive episode with switch” during follow-up were defined as
“patients with switch”, otherwise they were considered “patients without switch”.
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2.5 Hypothesis under analysis
The risk of switch from depression to (hypo)manic/mixed state was tested for
association with: 1) past clinical history, including previous treatments and disease
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course; 2) clinical-demographic characteristics at study inclusion; and 3) the clinical
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features of the current depressive episode, including treatment(s).
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2.6. Statistical analysis
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We employed a generalized linear mixed model (GLMM) (Stroup 2012) for
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investigating predictors of switch, because this model allowed the inclusion of data
from all depressive episodes for each patient. A dichotomous variable coding for the
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affective switch was used as dependent variable, and a binomial distribution was
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applied. Identification ID Number of each patient was considered as a random effect,

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while the other clinical variables were considered as fixed effects.

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To identify possible confounders mediating the association between switch and

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clinical variables, several regression models were constructed in a stepwise manner.

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Schemas of data structure and of each model are shown in Supplementary Figure S1.
Firstly, we assessed crude associations between switch and each clinical variable
(Model 1). Secondly, on the base of clinical considerations and STEP-BD design, we
included baseline demographic and socio-economic status (SES) variables and
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STEP-BD time-related variables as covariates (age, gender, ethnicity, education,
employment, annual personal income, marital status, total follow-up duration, and time
from baseline to a depressive episode (Model 2)), in accordance to the criteria reported
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in Supplementary Figure S1. Then a combination of variables describing past clinical
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history was selected and included in Model 3 together with significant (see below for
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further details) covariates of Model 2. Similarly, a combination of variables describing
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baseline clinical features was selected and included in Model 4 together with significant
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covariates of Model 3. Finally, a combination of variables describing current (at
depressive episode) clinical features was selected and included in Model 5 together with
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significant covariates of Model 4. The variables included in each model were selected
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according to three criteria that were applied in the following order. 1) To avoid the
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inclusion of ineffective variables and loss of sample size, the following selection criteria
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were applied: (i) p < 0.05 with a moderate effect (F-value > 5.00); (ii) available data
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from at least 6000 depressive episodes (about 1200 patients). 2) If two or more
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candidate variables were similar in terms of clinical implications, the most inclusive and
clinically meaningful one was selected, e.g. history of AD treatment was selected rather
than history of sertraline treatment. 3) Stepwise combinations of the candidate variables
were added to each model (Models 2-4), and the combination minimizing both the
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corrected Akaike’s Information Criterion (AICc) and the Bayesian Information Criterion
(BIC) was selected and included into the following model. The AICc and BIC are useful
criteria to choose the models that best fit the data (Stroup 2012; Vrieze 2012). Possible
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multicollinearity among the selected covariates was investigated. A correlation matrix of
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all the candidate variables was scanned for the presence of very high correlation (|r| >
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0.90), and the variance inflation factor and tolerance were calculated (see
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Supplementary Figure S1). No evidence of multicollinearity among the selected
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covariates was found.
Regarding dichotomous variables that were found associated with the risk of
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switch, odds ratio (OR) were also reported. Nevertheless, we underline that these OR
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were calculated on episode-based data (not subject-based data) and did not take into
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consideration the effect of covariates (among which the random covariate that
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represented the subject).

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For comparisons between patients with switch and patients without switch,
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t-test, Mann-Whitney U test and chi-square test with two-tailed p-values were used as
appropriate. All statistical analyses were performed using SPSS version 21.0 (IBM,
Tokyo, Japan) with alpha value of 0.05. A conservative alpha value was chosen because
the present analyses were based on hypotheses with previous evidence in literature.
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3. Results
3.1. Participant flow
CMF data were available for 3721 patients. Of these, 946 patients were
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excluded because of short follow-up duration (< 6 months). Among the remaining
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patients, 974 patients were excluded because they did not show any depressive episode
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during follow-up. Further 78 patients were excluded because their baseline data from
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ADE and/or DF forms were unavailable. Finally, three patients reported transsexual
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gender and were excluded because of the small size of the group. The final sample
included 1720 patients (Supplementary Figure S2).

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Among the included patients, 1368 patients showed no switch during follow-up,
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while 352 patients showed at least one switch (Table 1). A total of 8915 depressive
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episodes were available, among which 8403 (5898 from patients without switch and
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2505 from patients with switch) were labeled as “episodes without switch”, while 512
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were labeled as “episodes with switch”.

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3.2. Baseline clinical characteristics in patients with and without switch
In patients with switch, the total and mean annual number of depressive
episodes during follow-up was higher than those of patients without switch (both p <
0.001, Table 1). Lifetime diagnosis did not differ between the groups with and without
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switch (Table 1). In patients with switch a higher prevalence of females and patients
with low annual income was observed (p = 0.022 and p = 0.013, respectively). Age at
the first (hypo)manic episode in patients with switch was younger (p = 0.043).
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Regarding other demographic and SES characteristics at baseline, there was no
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significant difference between the groups.
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3.3. Predictors of switch
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3.3.1. Demographic variables at baseline
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In Model 1, a younger age at baseline and a shorter time from baseline to the
first depressive episode were associated with the risk of switch (F = 9.891, p = 0.002, β
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= -0.011; F = 4.151, p = 0.042, β = <-0.001, respectively; Supplementary Table S2). In

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Model 2, after adjustment for demographic, SES, and STEP-BD time-related variables,
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these associations continued to be significant (F = 7.788, p = 0.005, β = -0.012; F =

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4.198, p = 0.041, β = <-0.001; respectively).

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3.3.2. Past history of disease

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In Model 1, a younger age at onset of the first (hypo)manic episode was
associated with switch (F = 5.320, p = 0.021, β = -0.010; Supplementary Table S2),
although this association was not observed in Model 2. A higher number of previous
(hypo)manic, depressive and total episodes, and history of last year rapid cycling were
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associated with the risk of switch. In Model 2, history of suicide attempt, and history of
amphetamine or opiates use showed association with switch. History of ethanol abuse
treatment was associated with switch in Model 2, although the number of observations
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available for this variable was relatively small. Regarding past treatment history in
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Model 2, lower risk of switch was associated with each type of AD treatment (all ADs,
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SSRIs and non-SSRIs), some specific AD treatments (bupropion, sertraline, MAOI and
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heterocyclic ADs) and a higher number of ADs used (all ADs and non-SSRIs). Further,
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a higher risk of switch was associated with past history of switch (based on patient’s
attributions) caused by SSRIs and some specific drugs (fluoxetine, sertraline,

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paroxetine). Past treatment with quetiapine or clozapine was associated with the risk of
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switch, although the prevalence of past clozapine treatment was relatively small. Past
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history of psychotherapy was associated with a lower risk of switch. Among the above
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variables, a combination was selected to be included in Model 3 according to the criteria

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stated above (2.5. Statistical analysis), as reported in Table 2.

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3.3.3. Clinical status at baseline
In Model 3, a higher number of days with elevated mood over the last 2 weeks
and a higher score of Clinical Global Impression - Bipolar disorder (CGI-BP) -
Elevation subscale in the last month were associated with switch (Supplementary Table
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S3). Consistently, higher scores of SUM-M and higher scores of mania-associated
symptoms, as well as ideas of reference, were risk factors for switch. On the other hand,
dysthymia showed association with a lower risk of switch. There was no association
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between switch and treatments at baseline in Model 3. From the above variables, a
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combination was selected to be included in Model 4 according to the criteria stated
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above (2.5. Statistical analysis), as reported in Table 2.
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3.3.4. Clinical variables at current depressive episode
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In Model 4, mood elevation and irritability over a last 4-7 day period, and a
higher percent of days with elevated mood over the past 10 days, were associated with
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the risk of switch (Table 3). Regarding current associated symptoms at depressive
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episodes, a higher score of SUM-M and two or more mania-associated symptoms with
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at least moderate severity showed association with switch. Comorbidity with panic
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attacks was associated with switch. Although there was no association between
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venlafaxine treatment during the current depressive episode and switch in Model 1 (F =
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0.633, p = 0.426, β = 0.108, Table 3), this association was found after adjustment for
covariates in Model 4 (F = 4.310, p = 0.038, β = 0.360). Among the above variables, a
combination was selected to be included in Model 5 according to the criteria stated
above (2.5. Statistical analysis), as reported in Table 2.
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3.3.5. Full-adjusted model for prediction of switch
A summary of switch predictors found by Model 5 is shown in Table 4. Mood
elevation over the last 4-7 day period before the depressive episode was associated with
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the risk of switch (F = 6.491, p = 0.002; for probable mood elevation, β = 0.547, p =
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0.012; for definite mood elevation, β = 0.738, p = 0.005). Two or more mania-associated
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symptoms with at least moderate severity during the depressive episode were associated
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with switch (F = 6.687, p = 0.010, β = 0.340). Comorbidity with panic attacks during
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the depressive episode was associated with higher risk of switch (F = 7.376, p = 0.007,
β = 0.376). Even when the effect of past history of panic disorder (PD) was included as
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covariate in addition to the other covariates of Model 5, this association continued to be

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significant (F = 7.345, p = 0.007, β = 0.387).

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The presence of at least one of these three identified risk factors in depressive episodes
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followed or not by switch was reported in Table 5. When all the three risk factors were
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present the OR of switch is 7.28 (95% CI 4.15-12.78, p<0.001). The three risk factors
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identified by Model 5 provided a positive predictive value for predicting switch of 0.25
and a negative predictive value of 0.96.
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4. Discussion
This study investigated the clinical-demographic predictors of switch from a
depressive phase to a (hypo)manic or mixed phase in patients with BD. The large,
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prospective and long term STEP-BD sample (Sachs et al. 2003) was analyzed for this
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purpose. After adjustment for covariates, the variables associated with the risk of switch
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were any possible mood elevation, multiple mania-associated symptoms with at least
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moderate severity, comorbid panic attacks, and venlafaxine treatment during the index
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depressive episode.
To our knowledge, this is the first large study that investigated the predictors of
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manic switch in a prospective design and using an episode-based approach, i.e.

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including all the ascertained depressive episodes in each patient during follow-up.
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Indeed, previous studies used a patient-based approach, i.e. they compared patients with
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switch versus patients without switch (see Supplementary Table S1), with the exception
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of a study on a very small sample (Boerlin et al. 1998). In addition to this

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methodological difference, the present study used a multivariate regression approach
that allowed to estimate the effect size and independence of each variable of interest.
Crude associations (i.e. associations found using models without covariates) provided a
rough evidence considering the complexity of the switch phenomenon. Thus, variables
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showing crude associations were included as covariates in multivariate models in a
stepwise fashion. This approach represents a further methodological difference
compared to a previous study performed on the same sample (Perlis et al. 2010).
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The association between manic symptoms during the index depressive episode
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and switch could represent an expected finding, since manic symptoms often
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accompany bipolar depressive episodes (Goldberg et al. 2009). However, manic
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symptoms may be easily overlooked when they appear less prominent compared to
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depressive symptoms (Goldberg et al. 2009). Therefore, our results confirmed the
clinical importance of carefully monitoring both depressive and manic symptoms during
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bipolar depressive episodes. Further, higher manic symptom severity at inclusion in the
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study was also associated with switch, consistently with previous findings (Houston et
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al. 2007; Perlis et al. 2010).

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The comorbidity with panic attacks was demonstrated as a promising predictor

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of manic switch in depressive patients with BD and it was not investigated in the
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previous study on the STEP-BD sample (Perlis et al. 2010). Anxiety disorders,
including PD, were reported as the most common psychiatric comorbidities among
STEP-BD patients (51.2% lifetime; 30.5% current) (Simon et al. 2004; Bowden et al.
2012). In our sample, 36.8% of patients reported a probable or definite past history of
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PD at baseline. Past history of PD showed association with switch only before
adjustment for covariates (Model 1), suggesting a weaker effect size than comorbid
panic attacks during the current depressive episode (but possibly this is due to the lower
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accuracy of past history recollection compared to current evaluations). Anyway, the
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observation of more frequent previous history of PD in patients with switch supports the
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hypothesis that PD could share some pathogenic mechanisms with BD at high switch
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risk rather than panic symptoms could simply be an epiphenomenon of the imminent
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switch. Indeed, comorbidity between PD and BD with clinical markers of severity
demonstrated familiar aggregation (Goes et al. 2012). Further, the diagnosis of PD was
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demonstrated to increase the risk of rapid mood switching in BD (MacKinnon et al.

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2003). Broadly speaking, higher comorbidity with anxiety disorders were previously
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identified as a risk factor for rapid switching in BD (Nwulia et al. 2008) and for higher
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mental health service use (Sala et al. 2012). Thus, current anxiety symptoms and
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particularly comorbid panic attacks should be carefully investigated during bipolar

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depressive phases.
Regarding AD treatment during bipolar depressive episodes,
venlafaxine treatment showed an association with switch only after adjustment for
potential baseline risk factors of switch. Anyway, in bivariate models venlafaxine
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treatment did not increase the risk of switch neither in low risk depressive episodes
(showing none of the other three risk factors identified by Model 5: OR=1.04, 95%
CI=0.83-1.83, p=0.32) nor in high risk depressive episodes (with at least one of the
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other three risk factors identified by Model 5: OR=0.86, 95%CI=0.56-1.33, p=0.53).
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Thus venlafaxine treatment may show a marginal effect on the risk of switch that is
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probably highly influenced by the interaction with other clinical variables. Previous
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studies investigating mood switch during AD treatment found heterogeneous results.
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Previous meta-analyses suggested that the rate of treatment-emergent switch occurred
more often with tri- and tetra-cyclics (Peet 1994) and venlafaxine (Gijsman et al. 2004;
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Sidor and Macqueen 2011) than with SSRIs and bupropion. One study (Post et al. 2006)
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reported that venlafaxine as adjunctive therapy to mood stabilizers increased the risk of
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mood switch compared to bupropion or sertraline, especially in patients with a history

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of rapid cycling. In contrast, a retrospective study reported no difference in the

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incidence of switch between venlafaxine, bupropion and SSRIs monotherapy in rapid

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cycling patients, while monotherapy with second-generation ADs as a group showed
association with treatment-induced mania in rapid cyclers (Gao et al. 2008). Given that
in the STEP-BD sample the prescription of TCAs and MAOIs was very infrequent, we
cannot exclude that this study did not find any effect of these ADs on switch risk
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because of the lack of statistical power.
Several clinical-demographic variables showed evidence of association in
non-adjusted models (Models 2-5, Supplementary Figure S1). In detail, history of
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previous AD treatment and number of AD(s) prescribed, history of suicide attempt,
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history of amphetamine or opiate use, higher number of previous (hypo)manic and
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depressive episodes, last year rapid cycling, younger age at onset and at inclusion in the
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study represent potential risk factors with probable low effect size that did not survive in
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multi-regression models. An impact of these variables should not be excluded especially
in patients with absent or mild manic symptoms and no comorbid panic attacks.
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Younger age was associated with switch even after adjustment for demographic
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and SES covariates including STEP-BD time-related variables. This finding is not
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supported by a previous quite large study investigating this variable (Serretti et al. 2003)
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and it is difficult to conclude whether age at baseline could be a risk factor of switch or
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a confounder, i.e. age may impact on medication choice by clinicians. Thus, the
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meaning of demographic and SES variables as risk factors of switch should be
considered with caution.
According to previous evidence (Perlis et al. 2010; Valenti et al. 2012), the
present study confirmed that age at onset in patients with switch is younger than in
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patients without switch. However, an earlier age at onset of the first (hypo)manic
episode showed no association with switch in Model 2. Other disease history
characteristics that were associated with mood switch were a higher number of previous
PT
depressive episodes, last year rapid cycling, and history of suicide attempt, consistently
RI
with previous results (Perlis et al. 2010).
SC
A higher number of (hypo)manic episodes during lifetime was proposed as a
U
risk factor for switch. On the other hand, a previous retrospective study suggested that a
AN
lower number of previous manic episodes may be associated with switch (Serretti et al.
2003). The difficulty derived from the retrospective collection of the number of
M
episodes may have impacted on this result explaining the inconsistency with our present
D
findings.
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Previous history of substance-related disorders and some previous treatments

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were also identified as possible risk factors for mood switch. Indeed, history of
C
amphetamine use was associated with a higher risk of switch. The effect of
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amphetamine use (past two months) on the risk of switch during a depressive phase
showed an OR=1.92 in the present study. Abnormalities in catecholamine levels were
associated with both spontaneous and treatment-emergent switch (Salvadore et al. 2010).
Given their promoting effect on dopamine release and the inhibition of dopamine
23
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reuptake, amphetamines were demonstrated to precipitate hypomania in patients with
BD and induce a hypomanic-like status in healthy subjects (Jacobs and Silverstone
1986; Asghar et al. 2003). The impact of amphetamines on sleep may also mediate this
PT
effect. Regarding previous treatments, history of psychotherapy may predict lower risk
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of switch (OR=0.68). A recent study on the STEP-BD sample suggested that patients
SC
with excessively pessimistic or optimistic attributions may have a higher risk of manic
U
switch, despite psychotherapy per se was not investigated as a factor involved in switch
AN
risk. Thus, psychotherapy-induced cognitive flexibility may contribute to the reduction
of switch risk (Stange et al. 2013). In addition, evidence obtained thanks to STEP-BD
M
randomized interventions suggested that adjunctive psychosocial interventions but not

D
adjunctive ADs produced better outcomes than those achieved with mood stabilizers
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alone (Miklowitz et al. 2006; Miklowitz et al. 2007; Miklowitz et al. 2007; Bowden et
EP
al. 2012). Nevertheless, the lower frequency of psychotherapy in patients with switch
C
may be due to the tendency of avoiding this type of treatment in patients with more
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severe BD, resulting in a selection bias. Among pharmacological interventions, history
of previous quetiapine treatment and no history of previous AD treatment were
associated with switch. These variables most probably represent confounding factors
rather than predictors of switch. Considering the clinical guidelines for BD treatment at
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STEP-BD recruitment time (Sachs et al. 2000), it is likely that clinicians would
prescribe quetiapine to depressive patients with history of previous mood switch, while
they would try an AD in depressive patients without such history.
PT
Limitations of the present study should be mentioned. Firstly, switch from
RI
depression to mania was not directly reported in the CMF form thus it was derived from
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clinical status changes during follow-up. The CMF clinical status was based on several
U
clinical evaluations of depressive and manic symptoms that were tested for being switch
AN
risk factors. In other words, no independent instruments were used to assess the
diagnosis of depression (that was used to build the dependent variable) and some of the
M
clinical characteristics that were used as independent variables. Secondly, some possible
D
stratification factors could have biased our results. In particular, the effect of drug doses
TE
and drug combinations was not included, as well as different bipolar spectrum
EP
diagnoses. Anyway, other studies focusing on the phenomenon of switch considered the
C
diagnosis of manic/mixed episode as the inclusion criteria rather than a definite type of
AC
bipolar spectrum disorder (Vieta et al. 2009). Finally, the three risk factors identified by
Model 5 provide a negative predictive value of 0.96 but a positive predictive value of
0.25 only, thus they are useful only to exclude the risk of switch.
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5. Conclusion
Our study found that a number of past and baseline clinical-demographic
features may be risk factors of mood switch. In detail, younger age, higher number of
PT
previous (hypo)manic and depressive episodes, history of: rapid cycling, suicide attempt,
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amphetamine use and psychotherapy were past history characteristics that were
SC
associated with switch. More severe baseline manic symptoms and shorter time from
U
baseline to the first depressive episode were also associated with switch. After
AN
adjustment for covariates, our results suggested that three variables may be independent
predictors of manic switch, i.e. any possible mood elevation, multiple mania-associated
M
symptoms with at least moderate severity, and comorbid panic attacks during the index
D
depressive episode. Venlafaxine treatment may be a marginal risk factor for manic
TE
switch and it is probably influenced by other clinical variables. These findings may
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represent useful clinical information for monitoring the risk of manic switch when
C
treating depressive bipolar patients.

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26
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Supplementary online materials
Supplementary Figure S1: Schemas of data structure and models, criteria for covariate
selection and multicollinearity assessment.
PT
Supplementary Figure S2: Sample flowchart.
RI
Supplementary Table S1: summary of mood switch rates and risk factors of mood
SC
switch from depression to (hypo)mania in bipolar disorder (BD) according to previous
U
literature. AN
Supplementary Table S2: Associations between manic switch and demographic,
socio-economic, STEP-BD time-related variables and clinical past history.

M
Supplementary Table S3: Associations between switch and variables describing

D
clinical status at baseline.

TE
C EP
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Table 1. Demographic data for patients with and without switch.

Total sample Patients without switch Patients with switch Statistics df P
(N = 1720) (N = 1368) (N = 352)
PT
Total number of analyzed depressive 8915 5898 3017
episodes, episode
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Without switch, episode 8403 5898 2505
With switch, episode 512 - 512
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Total number of depressive episodes 4.92±6.57 (1720) 4.31±5.30 (1368) 8.57±8.69 (352) Z = 12.52 - <0.001***
during follow-up period, episode
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Total follow-up duration, day 762.3±422.5 (1720) 743.1±417.4 (1368) 836.9±434.6 (352) t = -3.73 1718 <0.001***
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Mean annual number of depressive 2.92±3.15 (1720) 2.63±2.97 (1368) 4.07±3.53 (352) Z = 10.08 - <0.001***
episodes during follow-up period,
M
episode/year
Lifetime diagnosis
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Bipolar I 64.5 (1109) 77.8 (863) 22.2 (246) χ2 = 5.67 3 0.129
TE
Bipolar II 29.0 (499) 82.6 (412) 17.4 (87)
Bipolar NOS 5.1 (88) 83.0 (73) 17.0 (15)
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Schizoaffective Bipolar type 1.4 (24) 83.3 (20) 16.7 (4)
Gender χ2 = 5.26 1 0.022*
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Male 40.0 (688) 82.3 (566) 17.7 (122)

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Female 60.0 (1032) 77.7 (802) 22.3 (230)

Age, year 40.8±12.3 (1720) 41.1±12.5 (1368) 39.8±11.5 (352) t = 1.97 583.8 0.050
Age at onset of mood disorder, year 16.9±8.5 (1691) 17.1±8.7 (1345) 16.3±7.8 (346) t = 1.81 585.0 0.071
2
Polarity at onset of mood disorder χ = 1.13 2 0.568
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Depression 58.0 (980) 80.1 (785) 19.9 (195)

a
Mixed 19.1 (323) 77.4 (250) 22.6 (73)
(Hypo)mania 22.9 (388) 79.9 (310) 20.1 (78)
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Duration of illness as mood disorder, year 23.9±12.6 (1691) 24.0±12.9 (1345) 23.4±11.4 (346) t = 0.88 593.9 0.377
Age at onset of (hypo)manic episode, year 21.7±10.2 (1623) 22.0±10.4 (1288) 20.7±9.6 (335) t = 2.03 1621 0.043*
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b
Duration of illness as bipolar disorder , 19.0±12.4 (1623) 19.1±12.6 (1288) 18.7±11.6 (335) t = 0.61 556.7 0.541
year
SC
Marital status χ2 = 0.59 2 0.744
Never married 34.4 (584) 79.8 (466) 20.2 (118)
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Married/living as married 38.8 (659) 78.8 (519) 21.2 (140)
AN
Separated/divorced/widowed 26.8 (454) 80.6 (366) 19.4 (88)
Race/ethnicity χ2 = 0.18 1 0.674
M
White/Caucasian 91.7 (1578) 79.7 (1257) 20.3 (321)
Others 8.3 (142) 78.2 (111) 21.8 (31)
D
Education χ2 = 2.34 1 0.127
TE
Technical School or less 54.0 (913) 78.2 (714) 21.8 (199)
College Diploma or more 46.0 (777) 81.2 (631) 18.8 (146)
EP
Employment status χ2 = 0.92 1 0.337
Others 69.7 (1174) 79.1 (929) 20.9 (245)
C
Full-time 30.3 (510) 81.2 (414) 18.8 (96)

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Annual personal income χ2 = 6.17 1 0.013*

Less than $20,000 62.9 (1038) 77.7 (807) 22.3 (231)
$20,000 or more 37.1 (612) 82.8 (507) 17.2 (105)
Medical insurance χ2 = 0.04 1 0.838
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No 15.9 (268) 80.2 (215) 19.8 (53)

Yes 84.1 (1417) 79.7 (1129) 20.3 (288)
Family history of bipolar illness χ2 = 0.02 1 0.888
PT
No 9.0 (151) 80.1 (121) 19.9 (30)
Yes 91.0 (1533) 79.6 (1221) 20.4 (312)
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Values represent mean ± SD (N) for continuous variables, and % (N) for categorical variables (vertical % values are reported in the column total sample and row % are
used to describe each categorical variable in the switch and non-switch groups). N represents number of patients. p < 0.05*, p < 0.01**, p < 0.001***
SC
Patients with at least one depressive episode with following manic switch during follow-up period were defined as “patients with switch, while the other patients were as
“patients without switch”.
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a, Both depressive and manic episodes were diagnosed within the year at onset of mood disorder. b, Duration since the first (hypo)manic episode was diagnosed.
AN
M
D
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C EP
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Table 2. Summary of the covariates selected from each Model.
Fixed Effect Fixed Coefficient
F P β (SE) t 95% CI P
Past history variables selected from Model 2 and included in Model 3
Number of (hypo)manic episodes in 6.267 0.012 0.249 (0.100) 2.503 0.054 – 0.445 0.012
lifetime (0-9 times/ 10 or more)
Number of depressive episodes in 9.176 0.002 0.336 (0.111) 3.029 0.118 – 0.553 0.002
PT
lifetime (0-9 times/ 10 or more)
History of the last-year rapid 6.982 0.008 0.276 (0.105) 2.642 0.071 – 0.482 0.008
RI
cycling (No/Yes)
Suicide attempt (No/Yes) 5.728 0.017 0.218 (0.091) 2.393 0.039 – 0.397 0.017
Amphetamine use (No/Yes) 5.710 0.017 0.515 (0.216) 2.390 0.093 – 0.937 0.017
SC
Antidepressants treatment (No/Yes) 6.407 0.011 -0.359 (0.142) -2.531 -0.637 – -0.081 0.011
Quetiapine treatment (No/Yes) 7.452 0.006 0.300 (0.110) 2.730 0.085 – 0.515 0.006
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Psychotherapy (No/Yes) 5.639 0.018 -0.220 (0.093) -2.375 -0.401 – -0.038 0.018
Clinical status variables at baseline selected from Model 3 and included in Model 4
AN
CGI-BP-Elevation subscale in the 14.036 <0.001 0.154 (0.154) 3.746 0.073 – 0.234 <0.001
last month
M
SUM-M at baseline 18.184 <0.001 0.109 (0.026) 4.264 0.059 – 0.159 <0.001
Clinical status variables at depressive episodes selected from Model 4 and included in Model 5
Mood elevation over a last 4-7 day 9.606 <0.001
D
period
TE
No -
Probable 0.682 (0.210) 3.248 0.271 – 1.094 0.001
Definite 0.838 (0.263) 3.186 0.323 – 1.354 0.001
EP
Multiple mania-associated 12.566 <0.001 0.449 (0.127) 3.545 0.201 – 0.698 <0.001
symptoms with at least moderate
severity (No/Yes)
C
Panic attacks (No/Yes) 10.796 0.001 0.448 (0.136) 3.286 0.181 – 0.715 0.001
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Abbreviations: CGI-BP, Clinical Global Impression scale-Bipolar disorder; SUM-M, Summary of classified scores
for mania.
The covariates in Model 2 consist of demographic, socio-economic status and the STEP-BD time-related variables;
age, gender, ethnicity, education, employment, annual personal income, marital status, total follow-up duration, and
time from baseline to a depressive episode. The combination of variables in each model was selected and included
together with the covariates of each model into the next step model. For each variable, F values indicate the effect size
and beta coefficients show whether the relationship between the variable and switch risk is positive or negative.
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Table 3. Associations between manic switch and variables of current clinical status at depressive episodes.
Total No. of Episodes Episodes with Model 1 (Crude) Model 4a (Baseline adjusted)
Patients / without switch switch
PT
Episodes
Fixed Effect Fixed Coefficient Fixed Effect Fixed Coefficient
RI
(N = 8403) (N = 512) F P β P F P β P
Current clinical symptoms at depressive episode
SC
% of days with elevated 1720/8908 4.0±13.6 (8397) 11.2±21.7 (511) 81.836 <0.001* 0.018 <0.001* 32.789 <0.001 0.016 <0.001**
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mood over the past 10 days ** ** *** *
AN
Mood elevation over a last 1718/8890 23.655 <0.001* 9.606 <0.001
4-7 day period ** ***
M
No 94.8 (7917) 5.2 (435) - -
Probable 87.6 (319) 12.4 (45) 0.769 <0.001* 0.682 0.001**
D
**
TE
Definite 83.3 (145) 16.7 (29) 1.112 <0.001* 0.838 0.001**
**
EP
% of days with irritability 1720/8906 36.3±39.2 (8396) 46.6±39.9 (510) 17.798 <0.001* 0.004 <0.001* 3.588 0.058 0.003 0.058
over the past 10 days ** **
C
Irritability over a last 4-7 1718/8859 7.701 <0.001* 4.536 0.011*

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day period **
No 95.1 (5419) 4.9 (279) - -
Probable 94.2 (1123) 5.8 (69) 0.116 0.372 -0.021 0.902
Definite 91.9 (1810) 8.1 (159) 0.386 <0.001* 0.364 0.004**
**
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Current associated symptoms at depressive episode
SUM_D# in CMF 1707/8664 7.72±2.11 (8170) 8.09±2.30 (494) 7.759 0.005** 0.054 0.005** 1.498 0.221 0.032 0.221
PT
Psychomotor agitation as a 1717/8856 0.31±0.43 (8350) 0.42±0.48 (506) 17.025 <0.001* 0.378 <0.001* 7.349 0.007** 0.328 0.007**
depressive symptom ** **
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Suicidal Ideation 1720/8895 0.37±0.43 (8384) 0.43±0.46 (511) 5.380 0.020* 0.221 0.020* 0.090 0.765 0.040 0.765
Sleep 1720/8901 0.88±0.52 (8390) 0.97±0.54 (511) 6.941 0.008** 0.215 0.008** 2.829 0.093 0.180 0.093
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Appetite 1720/8905 0.61±0.51 (8393) 0.66±0.52 (512) 2.767 0.096 0.139 0.096 0.425 0.515 -0.071 0.515
#
SUM_M in CMF 1714/8782 1.14±1.14 (8280) 1.67±1.46 (502) 57.770 <0.001* 0.246 <0.001* 15.665 <0.001 0.175 <0.001**
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Need for sleep 1720/8904 0.04±0.19 (8392) 0.07±0.26 (512) 8.100 0.004** 0.492 0.004** 0.422 0.516 0.168 0.516
Talking 1720/8908 0.06±0.19 (8396) 0.12±0.28 (512) 38.321 <0.001* 1.009 <0.001* 4.859 0.028* 0.505 0.028*
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Flight of Ideas 1719/8905 0.19±0.37 (8393) 0.35±0.48 (512) 51.573 <0.001* 0.671 <0.001* 16.608 <0.001 0.525 <0.001**
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** ** *** *
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Goal Directed Activity 1718/8858 0.51±0.52 (8391) 0.56±0.54 (511) 25.317 <0.001* 0.948 <0.001* 5.688 0.017* 0.628 0.017*
** **
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Psychomotor agitation as a 1716/8851 0.26±0.41 (8343) 0.38±0.47 (508) 23.607 <0.001* 0.448 <0.001* 9.821 0.002** 0.386 0.002**
manic symptom ** **
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High Risk Behavior 1719/8885 0.04±0.17 (8375) 0.09±0.26 (510) 28.670 <0.001* 0.933 <0.001* 7.697 0.006** 0.640 0.006**
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** **
Number of mania-associated 1720/8915 0.76±0.93 (8403) 1.11±1.17 (512)
symptoms with at least
##
moderate severity
1 or more symptoms 6.961 0.008** 0.956 0.328
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No 95.2 (4141) 4.8 (210) - -

Yes (1 or more) 93.4 (4262) 6.6 (302) 0.227 0.008** 0.109 0.328
Multiple symptoms 39.753 <0.001* 12.566 <0.001
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** ***
No (no or 1) 95.3 (6804) 4.7 (338) - -
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Yes (2 or more) 90.2 (1599) 9.8 (174) 0.592 <0.001* 0.449 <0.001**
** *
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Current psychoactive substance use and associated features at depressive episode
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Caffeine use, cups/day 1676/8288 1.41±2.01 (7811) 1.67±2.17 (477) 4.596 0.032* 0.040 0.032* 1.459 0.227 0.029 0.227
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Nicotine use, packs/day 1677/8316 0.30±0.57 (7840) 0.36±0.66 (476) 2.727 0.099 0.119 0.099 2.847 0.092 0.158 0.092
Panic attacks 1712/8768 10.967 0.001** 10.796 0.001**
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No 94.8 (6899) 5.2 (382) - -
Yes 91.9 (1366) 8.1 (121) 0.347 0.001** 0.448 0.001**
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Paranoid Ideation severity 1717/8846 0.13±0.46 (8335) 0.18±0.57 (511) 2.714 0.100 0.134 0.100 1.834 0.176 0.139 0.176
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Hallucinations severity 1717/8838 0.06±0.32 (8328) 0.10±0.44 (510) 5.358 0.021* 0.241 0.021* 1.967 0.161 0.185 0.161
Delusions severity 1715/8832 0.03±0.26 (8323) 0.06±0.33 (509) 2.930 0.087 0.218 0.087 0.710 0.399 0.125 0.399
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Current treatment at depressive episode
Valproate 1720/8915 3.421 0.064 0.013 0.908

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No 94.6 (6168) 5.4 (350) - -

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Yes 93.2 (2235) 6.8 (162) 0.172 0.064 0.014 0.908

Number of Current Mood 1720/8915 1.40±0.84 (8403) 1.53±0.93 (512) 6.684 0.010* 0.128 0.010* 3.078 0.079 0.113 0.079
Stabilizers (range: 0-6)
Venlafaxine 1720/8915 0.633 0.426 4.310 0.038*
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No 94.3 (7543) 5.7 (452) - -

Yes 93.5 (860) 6.5 (60) 0.108 0.426 0.360 0.038*
Values represent mean ± SD (N) for continuous variables, and % (N) for categorical variables. N represents number of depressive episodes.
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Variables with statistical significance (p < 0.05*, p < 0.01**, p < 0.001***) or trend (p < 0.10) in Model 1 or 4 are reported.
Abbreviations: CMF, Clinical Monitoring Form; SUM-D, Summary of classified scores for depression; SUM-M, Summary of classified scores for mania.
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a Sample size in Model 4: number of patients = 1052; number of depressive episodes = 5215.
#, SUM-D and SUM-M were calculated from the data “Associated Symptoms for the Past Week” using the imputation methods by Sachs et al. (2002).
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##, Number of mania-associated symptoms with at least moderate severity was counted from the data of mood elevation items in “Associated Symptoms for the Past Week”
using the imputation methods by Sachs et al. (2002). For each variable, F values indicate the effect size and beta coefficients show whether the relationship between the variable
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and switch risk is positive or negative.
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Table 4. Summary of predictors for manic switch at depressive episodes in patients with bipolar
disorder (Model 5).
Fixed Effect Fixed Coefficient
F P β (SE) t 95% CI P
Mood elevation over a last 4-7 day 6.491 0.002
period
No -
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Probable 0.547 (0.217) 2.519 0.121 – 0.972 0.012
Definite 0.738 (0.265) 2.784 0.218 – 1.258 0.005
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Multiple mania-associated symptoms 6.687 0.010 0.340 (0.131) 2.586 0.082 – 0.597 0.010
with at least moderate severity
(No/Yes)
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Panic attacks (No/Yes) 7.376 0.007 0.376 (0.138) 2.716 0.105 – 0.647 0.007
Sample size in the final Model 5: number of patients = 1052; number of depressive episodes = 5116.
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The covariates (fixed effects) in the final Model 5 consist of the covariates shown in Table 2 and its annotation.
Identification ID Number of each patient was considered as a random effect. For each variable, F values indicate the
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effect size and beta coefficients show whether the relationship between the variable and switch risk is positive or
negative.
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Table 5. Distribution of the three predictors of switch identified by Model 5 split by
switch group.
No switch Switch OR 95% CI P
Depressive episodes with 2.080 1.735-2.492 < 0.001***

None of the three predictors 95.7 (5546) 4.3 (249)
At least one of the three predictors 91.5 (2699) 8.5 (252)
Depressive episodes with 7.282 4.151-12.775 < 0.001***
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None of the three predictors 95.7 (5546) 4.3 (249)
All of the three predictors 75.4 (52) 24.6 (17)
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Values represent % (N) for categorical variables. N represents the number of depressive episodes.
The three identified predictors of switch at depressive episodes are any possible mood elevation, multiple
mania-associated symptoms with at least moderate severity, and panic attacks.
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Acknowledgements
Data and biomaterials were collected for the Systematic Treatment
Enhancement Program for Bipolar Disorder (STEP-BD), a multi-center, longitudinal
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(5-8 year) project selected from responses to RFP #NIMH-98-DS-0001, “Treatment for
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Bipolar Disorder.” The project was led by Gary Sachs, M.D., and coordinated by
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Massachusetts General Hospital in Boston, MA. The NIMH grant number was
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2N01MH080001-001. AN
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Conflict of Interest
Dr. Serretti is or has been a consultant / speaker for: Abbott, Astra Zeneca,
Clinical Data, Boheringer, Bristol Myers Squibb, Eli Lilly, GlaxoSmithKline, Janssenn,
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Lundbeck, Pfizer, Sanofi, and Servier. The other authors have no conflict of interest to
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declare.
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Contributors
Dr. Niitsu prepared the dataset, performed statistical analyses, and wrote the
first draft of the manuscript. Dr. Fabbri and Dr. Serretti assisted in the preparation of the
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dataset and statistical analyses and revised the manuscript. All authors have approved
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the final manuscript.
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Role of Funding Source
The work of Dr. Niitsu was supported by a grant for research abroad from
SENSHIN Medical Research Foundation, Japan. The funding body had no role in the
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study design, the collection of data, the writing of this report and decision to submit it
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for publication.
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Supplementary Table S1: summary of mood switch rates and risk factors of mood switch from depression to (hypo)mania in bipolar disorder (BD) according to
previous literature. AD=antidepressant medication. PL=placebo. * The number and percent of patients with mood switch were reported. § These studies were
specifically focused on the study of switch risk factors after the introduction of an antidepressant treatment. # These studies were specifically focused on the
study of switch risk associated with antidepressant medications.
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Study Design Diagnosis Sample size Switch* Risk factors
(Serretti et al. Observational BD I and II 416 169 (40.6%) Older age, absence of delusions, depressive
2003) retrospective polarity at onset, less previous manic episodes,
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previous history of switch, BD I, no maintenance
with mood stabilizers
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(Valenti et al. Experimental BD I and II 221 54 (24.4%) Earlier age at onset, higher rate of previous
2012) § prospective switches, lower rate of AD response
(Perlis et al. Observational BD I and II 2166 - 461 (21.3%) in the whole group Younger onset age in patients not treated with
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2010) retrospective - 289 (19.6%) in the group treated with ADs, greater number of past depressive episodes,
an AD greater manic symptom severity, recent or
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lifetime rapid cycling, alcohol use disorder,
previous suicide attempt in AD-exposed patients,
history of switch while treated with ADs, BD I in
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AD-exposed patients
(Altshuler et al. Experimental BD I and II 184 17 (9.2%) BD I
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2006) § prospective
(Leverich et al. Experimental BD I, II and 159 - 31 (19.3%) during acute phase (10 BD I, mood stabilizer + venlafaxine compared to
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2006) § prospective BD not weeks) mood stabilizer + sertraline or bupropion
otherwise - 58 (36.8%) during continuation phase
specified
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(Bottlender et al. Observational BD I 158 39 (24.7%) Number of mixed depressive symptoms at
2004) and retrospective baseline, treatment with tricyclic ADs, no
(Bottlender et al. treatment with a mood stabilizer
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2001)
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(Boerlin et al. Observational BD I 29 with a 22 episodes (28%) Higher number of previous manic episodes,
1998) retrospective total of 79 tricyclic ADs and monoamine oxidase inhibitors
depressive compared to fluoxetine
episodes
(Henry et al. Observational BD I and II 44 12 (27.3%) High hyperthymia score (Semistructured
2001) prospective Affective Temperament Interview) and treatment
with a mood stabilizer different from lithium
(Post et al. 2006)# RCT BD I, II and 174 - 2 (4%) for bupropion + mood stabilizer Mood stabilizer + venlafaxine compared to mood
ACCEPTED MANUSCRIPT
BD not - 4 (7%) for sertraline + mood stabilizer stabilizer + sertraline or bupropion

otherwise - 10 (15%) for venlafaxine + mood
specified stabilizer
(Sachs et al. RCT BD I and II 366 - 18 (10.1%) for mood stabilizer + AD Adjunctive AD does not increase switch risk
2007)# - 20 (10.7%) for mood stabilizer + PL
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(Nemeroff et al. RCT BD I and II 117 - 3 (7.7%) for mood stabilizer + Imipramine compared with paroxetine
2001)# imipramine
- 1 (2.3%) for mood stabilizer + PL
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- 0 for mood stabilizer + paroxetine
(Keck et al. RCT BD I 833 - 21 (5.7%) for olanzapine /
2005)# - 25 (6.7%) for PL
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- 5 (6.4%) for olanzapine + fluoxetine
(Carlson et al. Observational BD I with 123 17 (22.4%) /
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2007) retrospective psychotic
features
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Supplementary Table S2. Associations between manic switch and demographic, socio-economic, STEP-BD time-related variables and clinical
past history.
Total Total Episodes Episodes with Model 1 (Crude) Model 2a (Demographic adjusted)
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No. of No. of without switch switch
Patien Episo
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ts des
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(N = 8403) (N = 512) F P Estim P F P Estim P
ate (β) ate (β)
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Demographic data and socio-economic status at baseline
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Age, year 1720 8915 42.3 ± 12.0 40.0 ± 11.3 9.891 0.002** -0.011 0.002** 7.788 0.005** -0.012 0.005**
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(8403) (512)
Gender 1720 8915 0.942 0.332 0.081 0.776
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Male 94.7 (3302) 5.3 (186) - -
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Female 94.0 (5101) 6.0 (326) 0.086 0.332 0.027 0.776
Ethnicity 1720 8915 0.075 0.784 0.335 0.563
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White 94.3 (7720) 5.7 (468) -
Others 93.9 (683) 6.1 (44) 0.042 0.784 -0.097 0563
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Education 1690 8762 0.489 0.485 0.045 0.832

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Technical School or less 94.1 (4501) 5.9 (284) - -

College Diploma or more 94.5 (3760) 5.5 (217) -0.061 0.485 -0.020 0.832
Employment status 1684 8739 0.007 0.936 0.188 0.665
Others 94.3 (6134) 5.7 (371) - -
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Full-time 94.4 (2108) 5.6 (126) -0.008 0.936 0.055 0.665

Annual Personal Income 1650 8536 0.757 0.384 0.629 0.428
Less than $20,000 94.1 (5342) 5.9 (334) - -
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$20,000 or more 94.8 (2710) 5.2 (150) -0.082 0.384 -0.097 0.428
Marital status 1697 8782 0.076 0.927 0.747 0.474
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Never Married 94.2 (2866) 5.8 (177) - -
Married 94.2 (3233) 5.8 (199) -0.002 0.982 0.140 0.224
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-0.040 0.724 0.103 0.421
94.5 (2180) 5.5 (127)
Separated/divorced/widowed
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Total follow-up duration, day 1720 8915 894.3 ± 434.1 877.9 ± 435.5 0.367 0.545 -0.000 0.545 1.016 0.313 0.000 0.313
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(8403) (512)
Time from baseline to a 1720 8915 395.4 ± 355.8 349.1 ± 346.4 4.151 0.042* -0.000 0.042* 4.198 0.041* -0.000 0.041*
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depressive episode (CMF (8403) (512)
assessment), day
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Age at onset and duration of illness
Age at onset of mood 1691 8793 17.6 ±

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8.8 16.6 ± 8.3 2.778 0.096 -0.009 0.096 0.307 0.580 -0.003 0.580
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disorder, year (8294) (504)
Duration of illness as mood 1691 8793 24.8 ± 12.2 23.3 ± 11.3 3.479 0.062 -0.007 0.062 0.307 0.580 0.003 0.580
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disorder, year (8289) (504)

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Age at onset of (hypo)manic 1623 8452 22.4 ± 10.4 20.8 ± 9.7 5.320 0.021* -0.010 0.021* 0.706 0.401 -0.004 0.401
episode, year (7964) (488)
Number of episodes before baseline
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No. of (hypo)manic episodes 1523 7640 5.592 0.018* 6.267 0.012*

in lifetime
0-9 times 95.1 (2821) 4.9 (144) - -
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10 or more 93.3 (4364) 6.7 (311) 0.227 0.018* 0.249 0.012*
No. of (hypo)mania in the 1565 8150 2.97 ± 7.02 3.76 ± 6.56 3.499 0.061 0.010 0.061 1.657 0.198 0.007 0.198
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last year (7690) (460)
No. of depressive episodes in 1534 7670 10.866 0.001** 9.176 0.002**
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lifetime
0-9 times 95.6 (2127) 4.4 (97) - -
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10 or more 93.3 (5080) 6.7 (366) 0.461 0.001** 0.336 0.002**
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No. of phases in lifetime 1127 5733 8.007 0.005** 6.586 0.010*
0-52 times 95.0 (3501) 5.0 (185) - -
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53 or more 92.3 (1895) 7.4 (152) 0.409 0.005** 0.384 0.010*
History of the last-year rapid 1353 6891 9.332 0.002** 6.982 0.008**
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cycling (No. of phases in the
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last year)
No (0-3 times) 95.0 (4438) 5.0 (234) - -
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Yes (>= 4 times) 92.5 (2053) 7.5 (166) 0.304 0.002** 0.276 0.008**
Estimated rapid cycling in 1099 5521 4.861 0.028* 3.155 0.076
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every year (No. of phases in

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every year)
No (0-3 times) 95.0 (3501) 5.0 (185) - -
Yes (>= 4 times) 92.6 (1895) 7.4 (152) 0.245 0.028* 0.203 0.076
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Psychiatric history before baseline
Panic 1707 8854 2.697 0.067 2.576 0.076
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No 94.7 (4937) 5.3 (276) - -
Probable 94.9.1 (930) 5.1 (50) -0.025 0.863 -0.101 0.510
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Definite 93.0 (2476) 7.0 (185) 0.205 0.027* 0.190 0.052
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GAD 1696 8742 2.995 0.050 2.310 0.099
No 94.6 (5597) 5.4 (321) - -
Probable 95.1 (807) 4.9 (42) -0.062 0.686 -0.045 0.777
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Definite 92.7 (1831) 7.3 (144) 0.228 0.022* 0.210 0.041*
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Suicide attempt 1682 8735 9.042 0.003** 5.728 0.017*
No 95.1 (4710) 4.9 (242) - -
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Yes 93.0 (3520) 7.0 (263) 0.259 0.003** 0.218 0.017*
Psychosis 1676 8667 3.432 0.064 3.241 0.072
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No 94.8 (5332) 5.2 (294) - -
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Yes 93.5 (2842) 6.5 (199) 0.165 0.064 0.169 0.072
Psychoactive substance use history before baseline
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Ethanol abuse treatment 693 3161 3.558 0.059 5.115 0.024*
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No 94.7 (2297) 5.3 (128) - -

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Yes 92.3 (679) 7.7 (57) 0.299 0.059 0.369 0.024*

Caffeine use for the past 2 1650 8550 1.92 ± 2.64 2.25 ± 2.99 3.992 0.046* 0.029 0.046* 2.862 0.091 0.028 0.091
months, c/d (8064) (486)
Nicotine use for the past 2 1651 8601 0.36 ± 1.00 0.47 ± 1.12 3.692 0.055 0.059 0.055 2.797 0.095 0.053 0.095
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months, p/d (8114) (487)

Marijuana use for the past 2 1685 8661 2.797 0.094 0.711 0.399
months
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No 94.5 (7218) 5.5 (422) - -
Yes 92.8 (947) 7.2 (74) 0.210 0.094 0.114 0.399
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Onset of Marijuana abuse, 512 2382 18.7 ± 7.2 17.4 ± 6.3 4.890 0.027* -0.037 0.027* 3.049 0.081 -0.035 0.081
year (2230) (152)
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Amphetamine use for the 1679 8633 5.860 0.016* 5.710 0.017*
past 2 months
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No 94.4 (7919) 5.6 (469) - -
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Yes 89.8 (220) 10.2 (25) 0.518 0.016* 0.515 0.017*
Amphetamine abuse 227 1042 5.463 0.020* 2.271 0.132
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No 93.8 (800) 6.2 (53) - -
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Yes 87.3 (165) 12.7 (24) 0.832 0.020* 0.592 0.132
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Cocaine abuse treatment 281 1339 3.831 0.051 3.097 0.079
No 93.3 (952) 6.7 (68) - -
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Yes 89.3 (285) 10.7 (34) 0.542 0.051 0.541 0.079
LSD abuse treatment 175 794 3.199 0.074 1.780 0.183
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No 93.2 (683) 6.8 (50) - -

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Yes 86.9 (53) 13.1 (8) 0.876 0.074 0.752 0.183

Opiates use for the past 2 1678 8623 4.581 0.032* 5.286 0.022*
months
No 94.4 (7931) 5.6 (469) - -
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Yes 90.1 (201) 9.9 (22) 0.485 0.032* 0.541 0.022*

Past treatment history before baseline
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Buproprion 1681 8706 4.321 0.038* 3.895 0.048*
No 93.5 (3714) 6.5 (257) - -
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Yes 95.0 (4496) 5.0 (239) -0.180 0.038* -0.177 0.048*
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Affective switch caused by 703 4078 4.169 0.041* 2.509 0.113
Buproprion
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No 95.4 (3152) 4.6 (152) - -
Yes 92.9 (719) 7.1 (55) 0.315 0.041* 0.261 0.113
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MAOI 1682 8706 7.068 0.008** 4.720 0.030*
No 93.9 (7259) 6.1 (470) - -
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Yes 97.0 (948) 3.0 (29) -0.424 0.008** -0.362 0.030*
Affective switch caused by 367 2241 2.817 0.093 2.708 0.100
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Citalopram
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No 95.1 (1776) 4.9 (91) - -
Yes 91.2 (341) 8.8 (33) 0.497 0.093 0.508 0.100
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Affective switch caused by 731 4410 7.571 0.006** 7.869 0.005**
Fluoxetine
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No 95.6 (3105) 4.4 (143) - -

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Yes 92.7 (1077) 7.3 (85) 0.367 0.006** 0.383 0.005**

Sertraline 1680 8655 5.430 0.020* 6.249 0.012*
No 93.5 (4011) 6.5 (279) - -
Yes 95.1 (4151) 4.9 (214) -0.203 0.020* -0.226 0.012*
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Affective switch caused by 609 3688 4.378 0.036* 4.300 0.038*

Sertraline
No 95.8 (2898) 4.2 (127) - -
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Yes 93.1 (617) 6.9 (46) 0.351 0.036* 0.360 0.038*
Affective switch caused by 572 3447 7.660 0.006** 7.617 0.006**
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Paroxetine
No 95.2 (2689) 4.8 (135) - -
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Yes 91.5 (570) 8.5 (53) 0.449 0.006** 0.473 0.006**
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Fluvoxamine
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No 94.3 (649) 5.7 (39) - -
Yes 79.6 (43) 20.4 (11) 1.138 0.061 1.121 0.117
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Venlafaxine 1681 8674 3.905 0.048* 2.977 0.084
No 93.7 (4869) 6.3 (328) - -
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Yes 95.1 (3306) 4.9 (171) -0.178 0.048* -0.162 0.084
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Heterocyclic (TCA) 1682 8697 3.858 0.050* 4.117 0.042*
No 93.9 (6493) 6.1 (421) - -
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Yes 95.6 (1705) 4.4 (78) -0.224 0.050* -0.246 0.042*
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Heterocyclic (TCA)
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No 96.0 (1237) 4.0 (52) - -

Yes 91.9 (182) 8.1 (16) 0.504 0.076 0.212 0.534
Number of Antidepressants 1720 8915 3.51 ± 2.37 3.11 ± 2.27 6.935 0.008** -0.049 0.008** 5.541 0.019* -0.046 0.019*
used before the baseline (8403) (512)
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PAR, FLUV, BUP, MIRT,
MAOI, VEN, NEF, TCA)
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Antidepressants used before 1720 8915 7.568 0.006** 6.407 0.011*
the baseline (CIT, FLUO,
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SER, PAR, FLUV, BUP,
MIRT, MAOI, VEN, NEF,
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TCA)
No 91.4 (687) 8.6 (65) - -
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Yes 94.5 (7716) 5.5 (447) -0.372 0.006** -0.359 0.011*
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Number of Antidepressants 1720 8915 0.51 ± 0.89 0.68 ± 1.13 10.682 0.001** 0.133 0.001** 10.181 0.001** 0.140 0.001**
causing Affective Switch (8403) (512)
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(0-11: CIT, FLUO, SER,
PAR, FLUV, BUP, MIRT,
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MAOI, VEN, NEF, TCA)
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Affective Switch caused by 1720 8915 3.069 0.080 2.259 0.133
Antidepressants (CIT,
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FLUO, SER, PAR, FLUV,
BUP, MIRT, MAOI, VEN,
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NEF, TCA)
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No 94.7 (5521) 5.3 (310) - -

Yes 93.5 (2882) 6.5 (202) 0.154 0.080 0.137 0.133
Number of SSRIs used 1720 8915 1.90 ± 1.33 1.76 ± 1.32 2.970 0.085 -0.056 0.085 3.081 0.079 -0.060 0.079
before the baseline (0-5: CIT, (8403) (512)
ACCEPTED MANUSCRIPT
FLUO, SER, PAR, FLUV)

SSRIs used before the 1720 8915 2.955 0.086 1.801 0.180
baseline (CIT, FLUO, SER,
PT
PAR, FLUV)
No 93.0 (1379) 7.0 (104) - -
RI
Yes 94.5 (7024) 5.5 (408) -0.187 0.086 -0.153 0.180
Number of SSRIs causing 1720 8915 0.32 ± 0.63 0.45 ± 0.85 11.705 0.001** 0.196 0.001** 13.361 < 0.217 <
SC
Affective Switch (0-5: CIT, (8403) (512) 0.001** 0.001**
FLUO, SER, PAR, FLUV) * *
U
Affective Switch caused by 1720 8915 7.341 0.007** 8.220 0.004**
AN
SSRIs (CIT, FLUO, SER,
PAR, FLUV)
M
No 94.8 (6360) 5.2 (351) - -
Yes 92.7 (2043) 7.3 (161) 0.255 0.007** 0.276 0.004**
D
Number of other 1720 8915 1.60 ± 1.40 1.35 ± 1.32 8.022 0.005** -0.091 0.005** 5.493 0.019* -0.079 0.019*
TE
Antidepressants used (8403) (512)
before the baseline (0-6:
EP
BUP, MIRT, MAOI, VEN,
NEF, TCA)
C
Other Antidepressants used 1720 8915 4.503 0.034* 3.547 0.060

AC
before the baseline (BUP,

MIRT, MAOI, VEN, NEF,
TCA)
No 93.1 (2147) 6.9 (160) - -
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Yes 94.7 (6256) 5.3 (352) -0.199 0.034* -0.183 0.060

Clozapine 1681 8680 8.163 0.004** 6.258 0.012*
No 94.4 (7930) 5.6 (468) - -
PT
Yes 89.4 (252) 10.6 (30) 0.563 0.004** 0.532 0.012*
Quetiapine 1682 8689 9.089 0.003** 7.452 0.006**
RI
No 94.7 (6803) 5.3 (378) - -
Yes 92.1 (1389) 7.9 (119) 0.317 0.003** 0.300 0.006**
SC
Number of Atypical 1720 8915 0.89 ± 1.05 1.04 ± 1.11 5.683 0.017* 0.092 0.017* 3.476 0.062 0.077 0.062
Antipsychotics used before (8403) (512)
U
the baseline (0-6: RIS,
AN
CLOZ, OLAN, QUET, ZIP,
ARI)
M
Atypical Antipsychotics used 1720 8915 4.216 0.040* 1.715 0.190
before the baseline (RIS,
D
TE
ARI)
No 95.0 (3821) 5.0 (200) - -
EP
Yes 93.6 (4582) 6.4 (312) 0.178 0.040* 0.119 0.190
Number of Antipsychotics 1720 8915 0.95 ± 1.14 1.10 ± 1.18 5.100 0.024* 0.080 0.024* 3.058 0.080 0.067 0.080
C
used before the baseline (0-7: (8403) (512)

AC
HAL, RIS, CLOZ, OLAN,

QUET, ZIP, ARI)
Antipsychotics used before 1720 8915 4.415 0.036* 1.881 0.170
the baseline (HAL, RIS,
ACCEPTED MANUSCRIPT

ARI)
No 95.1 (3751) 4.9 (195) - -
PT
Yes 93.6 (4652) 6.4 (317) 0.183 0.036* 0.125 0.170
Psychotherapy (Verbal 1682 8717 8.088 0.004** 5.639 0.018*
RI
therapy)
No 93.4 (4695) 6.6 (330) - -
SC
Yes 95.4 (3523) 4.6 (169) -0.254 0.004** -0.220 0.018*
Affective switch caused by 516 2995 5.306 0.021* 5.926 0.015*
U
psychotherapy (Verbal
AN
therapy)
No 95.6 (2667) 4.4 (124) - -
M
Yes 90.7 (185) 9.3 (19) 0.580 0.021* 0.639 0.015*
Values represent mean ± SD (N) for continuous variables, and % (N) for categorical variables. (N represents number of depressive episodes.)
D
Variables with statistical significance (p < 0.05*, p < 0.01**, p < 0.001***) or trend (p < 0.10) in Model 1 are reported.
TE
The covariates in Model 2 consist of demographic (DEM), socioeconomic status (SES) and the STEP-BD time-related variables: age, gender, ethnicity, education, employment,
annual personal income, marital status, total follow-up duration, and time from baseline to a depressive episode.
EP
The combination of yellow-colored variables describing past history features were selected and included together with the covariates of Model 2 into Model 3.
a Sample size in Model 2: number of patients = 1640; number of depressive episodes = 8506. For each variable, F values indicate the effect size and beta coefficients show
C
whether the relationship between the variable and switch risk is positive or negative.
AC
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Supplementary Table S3. Associations between switch and variables describing clinical status at baseline.
Total Total Episodes Episodes with Model 1 (Crude) Model 3a (+ Past history adjusted)
No. of No. of without switch switch
PT
Patien Episod
ts es
RI
(N = 8403) (N = 512) F P Estima P F P Estima P
SC
te (β) te (β)
Clinical symptoms at baseline
U
AN
No. of days with elevated 1719 8908 1.58 ± 3.20 2.64 ± 4.06 31.903 < 0.061 < 9.858 0.002** 0.047 0.002**
mood over the last 2 weeks (8396) (512) 0.001** 0.001**
M
* *
Severity of elevated mood 1154 6108 1.03 ± 1.18 1.42 ± 1.29 20.380 < 0.238 < 2.715 0.100 0.093 0.100
D
(5718) (390) 0.001** 0.001**
TE
* *
% of days with elevated 1668 8690 17.5 ± 19.4 21.7 ± 20.9 12.633 < 0.007 < 2.344 0.126 0.004 0.126
EP
mood in the last year (8190) (500) 0.001** 0.001**
* *
C
No. of days with irritability 1719 8908 5.16 ± 5.43 5.92 ± 5.53 5.141 0.023* 0.017 0.023* 0.736 0.391 0.009 0.391
AC
over the last 2 weeks (8396) (512)

Severity of irritability 1423 7629 1.74 ± 1.18 1.92 ± 1.21 6.046 0.014* 0.127 0.014* 0.883 0.347 0.049 0.347
(7167) (462)
Total bipolar index 1687 8714 69.8 ± 15.9 72.3 ± 15.0 6.142 0.013* 0.007 0.013* 0.152 0.697 0.001 0.697
(8214) (500)
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CGI-BP-Elevation subscale 1702 8844 1.86 ± 1.17 2.27 ± 1.47 33.768 < 0.185 < 14.036 < 0.154 <
in the last month (8337) (507) 0.001** 0.001** 0.001** 0.001**
* * * *
PT
CGI-BP-Overall in the last 1709 8865 3.59 ± 1.17 3.72 ± 1.14 2.948 0.086 0.064 0.086 0.695 0.405 0.040 0.405
month (8355) (510)
RI
Associated symptoms at baseline
SC
SUM-D# at baseline 1694 8728 6.38 ± 3.63 6.83 ± 3.74 3.765 0.052 0.023 0.052 0.995 0.319 0.017 0.319
(8232) (496)
U
Concentration at baseline 1716 8875 0.72 ± 0.56 0.78 ± 0.56 2.934 0.087 0.131 0.087 1.548 0.213 0.134 0.213
AN
(absolute value of the score of (8368) (507)
DEPCONCN)
M
Guilt at baseline (the score of 1710 8828 0.48 ± 0.54 0.56 ± 0.60 5.064 0.024* 0.172 0.024* 3.270 0.071 0.185 0.071
DEPGUILT) (8319) (509)
D
Distractibility as a depressive 1712 8876 0.54 ± 0.53 0.62 ± 0.54 5.597 0.018* 0.185 0.018* 2.502 0.114 0.172 0.114
TE
symptom at baseline (the score (8367) (509)
of DEPDIST)
EP
Psychomotor agitation as a 1714 8885 0.34 ± 0.47 0.44 ± 0.48 12.589 < 0.301 < 1.393 0.238 0.144 0.238
depressive symptom at (8378) (507) 0.001** 0.001**
C
baseline (the score of * *

DEPPMA)
AC
Sleep at baseline (absolute 1719 8908 0.79 ± 0.59 0.88 ± 0.64 7.293 0.007** 0.192 0.007** 1.899 0.168 0.129 0.168
value of the score of (8396) (512)
DEPSLEEP)
SUM-M# at baseline 1706 8829 1.80 ± 2.01 2.57 ± 2.49 40.921 < 0.115 < 18.184 < 0.109 <
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(8322) (507) 0.001** 0.001** 0.001** 0.001**

* * * *
Need for sleep at baseline 1719 8908 0.13 ± 0.38 0.24 ± 0.51 22.396 < 0.423 < 8.526 0.004** 0.360 0.004**
PT
(absolute value of the score (8396) (512) 0.001** 0.001**
of ELVSLEEP) * *
RI
Elevated Self-Esteem at 1719 8908 0.06 ± 0.22 0.11 ± 0.29 12.524 < 0.545 < 6.432 0.011* 0.544 0.011*
baseline (the score of (8396) (512) 0.001** 0.001**
SC
ELVSELFE) * *
Talking (the score of 1719 8908 0.21 ± 0.40 0.32 ± 0.49 21.582 < 0.423 < 7.642 0.006** 0.353 0.006**
U
ELVTALK) (8396) (512) 0.001** 0.001**
AN
* *
Flight of Ideas at baseline 1718 8895 0.32 ± 0.47 0.45 ± 0.51 19.316 < 0.363 < 10.030 0.002** 0.382 0.002**
M
(the score of ELVFOI) (8386) (509) 0.001** 0.001**
* *
D
Distractibility as a manic 1717 8901 0.52 ± 0.55 0.63 ± 0.57 10.576 0.001** 0.246 0.001** 8.913 0.003** 0.314 0.003**
TE
symptom at baseline (the (8390) (511)
score of ELVDISTR)
EP
Goal Directed Activity at 1710 8850 0.14 ± 0.33 0.23 ± 0.44 19.837 < 0.470 < 6.267 0.012* 0.347 0.012*
C
ELVGDACT) * *
AC
Psychomotor agitation as a 1716 8896 0.32 ± 0.46 0.44 ± 0.49 16.963 < 0.347 < 3.824 0.051 0.231 0.051
manic symptom at baseline (8384) (512) 0.001** 0.001**
(the score of ELVPMA) * *
High Risk Behavior at 1718 8899 0.09 ± 0.27 0.15 ± 0.33 14.479 < 0.500 < 6.244 0.012* 0.447 0.012*
ACCEPTED MANUSCRIPT

ELVHRB) * *
Associated features at baseline
PT
Paranoid ideation 1707 8817 11.118 0.001** 2.420 0.120
RI
No 94.7 (7104) 5.3 (400) - -
Yes 91.6 (1203) 8.4 (110) 0.362 0.001** 0.223 0.120
SC
Ideas of reference 1706 8815 6.824 0.009** 3.950 0.047*
No 94.4 (7724) 5.6 (454) - -
U
Yes 91.2 (581) 8.8 (56) 0.378 0.009** 0.397 0.047*
AN
Hallucinations 1706 8815 6.776 0.009** 1.044 0.307
No 94.4 (7886) 5.6 (467) - -
M
Yes 90.7 (419) 9.3 (43) 0.427 0.009** 0.209 0.307
Delusions 1706 8815 3.954 0.047* 0.432 0.511
D
No 94.4 (7925) 5.6 (474) - -
TE
Yes 91.3 (380) 8.7 (36) 0.352 0.047* 0.167 0.511
Dysthymia 1681 8761 5.435 0.020* 3.871 0.049*
EP
No 94.0 (7246) 6.0 (465) - -
Yes 96.6 (1014) 3.4 (36) -0.350 0.020* -0.422 0.049*
C
Treatment at baseline
AC
Bupropion at baseline 1720 8915 2.909 0.088 2.371 0.124

assessment
No 94.0 (7084) 6.0 (452) - -
Yes 95.6 (1319) 4.4 (60) -0.215 0.088 -0.255 0.124
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Fluvoxamine at baseline 1720 8915 2.716 0.099 0.059 0.808

assessment
No 94.3 (8297) 5.7 (500) - -
PT
Yes 89.8 (106) 10.2 (12) 0.503 0.099 -0.112 0.808
Number of SSRIs at baseline 1720 8915 0.29 ± 0.47 0.24 ± 0.45 2.823 0.093 -0.161 0.093 0.020 0.887 -0.018 0.887
RI
(0-5: CIT, FLUO, SER, PAR, (8403) (512)
FLUV)
SC
SSRIs at baseline (CIT, 1720 8915 3.592 0.058 0.079 0.779
FLUO, SER, PAR, FLUV)
U
No 93.8 (6011) 6.2 (394) - -
AN
Yes 95.3 (2392) 4.7 (118) -0.187 0.058 -0.037 0.779
Number of Antidepressants 1720 8915 0.62 ± 0.69 0.52 ± 0.64 5.418 0.020* -0.150 0.020* 0.882 0.348 -0.080 0.348
M
at baseline (0-10: CIT, (8403) (512)
FLUO, SER, PAR, FLUV,
D
BUP, MIRT, VEN, NEF,
TE
TCA)
Antidepressants at baseline 1720 8915 4.006 0.045* 0.180 0.672
EP
(CIT, FLUO, SER, PAR,
FLUV, BUP, MIRT, VEN,
C
NEF, TCA)
AC
No 93.6 (4201) 6.4 (288) - -

Yes 94.9 (4202) 5.1 (224) -0.171 0.045* -0.049 0.672
Quetiapine at baseline 1720 8915 6.469 0.011* 0.579 0.447
assessment
ACCEPTED MANUSCRIPT
No 94.5 (7573) 5.5 (438) - -

Yes 91.8 (830) 8.2 (74) 0.324 0.011* -0.152 0.447
Number of antipsychotics at 1720 8915 0.36 ± 0.52 0.42 ± 0.54 3.077 0.079 0.141 0.079 0.059 0.808 -0.027 0.808
PT
baseline (0-7: HAL, RIS, (8403) (512)
RI
ARI)
Antipsychotics at baseline 1720 8915 2.938 0.087 0.048 0.827
SC
(HAL, RIS, CLOZ, OLAN,
QUET, ZIP, ARI)
U
No 94.7 (5512) 5.3 (310) - -
AN
Yes 93.5 (2891) 6.5 (202) 0.151 0.087 -0.026 0.827
Values represent mean ± SD (N) for continuous variables, and % (N) for categorical variables. (N represents number of depressive episodes.)
M
Variables with statistical significance (p < 0.05*, p < 0.01**, p < 0.001***) or trend (p < 0.10) in Model 1 are reported.
The combination of variables describing past history features was selected and included together with the covariates of Model 2 into Model 3.
D
The combination of yellow-colored variables describing baseline clinical features were selected and included together with the covariates of Model 3 into Model 4.
TE
Abbreviations: CGI-BP, Clinical Global Impression scale-Bipolar disorder; SUM-D, Summary of classified scores for depression; SUM-M, Summary of classified scores for
mania.
EP
a Sample size in Model 3: number of patients = 1067; number of depressive episodes = 5297.
# SUM-D and SUM-M were calculated from the data “Associated Symptoms for the Past Week” using the imputation methods by Sachs et al. (2002).
C
For each variable, F values indicate the effect size and beta coefficients show whether the relationship between the variable and switch risk is positive or negative.
AC
ACCEPTED MANUSCRIPT
PT
Predictors of switch from depression to mania in bipolar
RI
disorder
U SC
Supplementary Figure S1.
AN
M
D
Tomihisa Niitsu1,2, Chiara Fabbri1, Alessandro Serretti1
TE
EP
1. Department of Biomedical and NeuroMotor Sciences, University of Bologna,
Bologna, Italy
C
2. Research Center for Child Mental Development, Chiba University Graduate

AC
School of Medicine, Chiba, Japan
Feb/11/2014 1
ACCEPTED MANUSCRIPT
Index
PT
RI
• The STEP-BD time course and analyzed datasets P3
SC
• Definitions of phenotypes (switch) P4
U
• Data structures and each model (Models 1 to 5) P5
AN
• How to select the combination of variables to include
M
in each model P10
D
• Multicollinearity diagnostics P11
TE
C EP
AC
2
ACCEPTED MANUSCRIPT
The STEP-BD time course and analyzed datasets

Baseline Clinical assessment Clinical assessment
PT
Time
RI
SC
ADE & DF CMF dataset
U
datasets
AN
Current data Current data
Demographic Dep. episode Dep. episode
M
SES
D
TE
Past history EP
Baseline data
C
AC
• Questionnaires
– ADE: Affective Disorders Evaluation
– DF: Demographic Form
– CMF: Clinical Monitoring Form
3
ACCEPTED MANUSCRIPT
Definitions of “Depressive episode with switch” and

“Patient with switch” using the CMF dataset
• Definition of “Depressive episode with switch”
PT
– Depressive episode followed by manic/hypomanic/mixed episode within 12
RI
weeks (84 days)
SC
Mania =< 12 weeks (84 days)
U
AN
M
Mood
Depressive Manic/hypo/
D
Time
episode mixed episode
TE
C EP
AC
Depression
• Definition of “Patient with Switch”

– Patient with at least one depressive episode with switch during total
follow-up period 4
ACCEPTED MANUSCRIPT
Associations of variables & Model 1: Crude (not adjusted)

Manic/hypomanic/
Baseline Depressive episode mixed episode
PT
(ADE & DF dataset) (CMF dataset) (CMF dataset)
Duration Time
RI
SC
DEM SES
U
AN
Past history
M
D
TE
Baseline data
Switch
C EP
Current data
AC
5
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Model 2: Adjusted for DEM, SES and Durations

Manic/hypomanic/
PT
Duration Time
RI
SC
DEM SES
U
AN
Past history
M
D
TE
Baseline data
Switch
C EP
Current data
AC
• Variables of past history

were associated with
switch via blue arrows.
6
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Model 3: Adjusted for the covariates in Model 2 + variables selected from the
significant variables of past history in Model 2
Manic/hypomanic/
PT
Duration Time
RI
SC
DEM SES
U
AN
Past history
M
D
TE
Baseline data
Switch
CEP
Current data
AC
• Variables of baseline
clinical data were
associated with switch via
green arrows. 7
ACCEPTED MANUSCRIPT
Model 4: Adjusted for the covariates in Model 3 + variables selected from the
significant variables baseline clinical data in Model 3
Manic/hypomanic/
PT
Duration Time
RI
SC
DEM SES
U
AN
Past history
M
D
TE
Baseline data
Switch
CEP
Current data
AC
• Variables of current
clinical data were
an orange arrow. 8
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Model 5 (Full adjusted): Adjusted for the covariates in Model 4 + variables

selected from the significant variables current clinical data in Model 4
Manic/hypomanic/
PT
Duration Time
RI
SC
DEM SES
U
AN
Past history
M
D
TE
Baseline data
Switch
CEP
Current data
AC
A
• Each variables of current
clinical data was
an orange arrow. B
9
ACCEPTED MANUSCRIPT
How to select the combination of variables to include in

each model (Model 3 – 5)
PT
1. Firstly, to avoid including practically ineffective variables as covariates
and losing sample size, the following selection criteria of the candidate
RI
variables were set；
SC
1. statistically significant with a moderate fixed effect (F > 5.00)
2. with available data from at least 6,000 episodes (about 1,200 patients)
U
AN
2. Secondly, if two or more candidate variables were similar in clinical
implications, the most inclusive and clinically meaningful one was
M
selected.
D
– e.g. history of ADs treatment was selected rather than history of sertraline
TE
treatment.
3. Finally, stepwise combinations of the candidate variables were added to
EP
each model (Model 2 – 4), and the combination minimizing both the
C
corrected Akaike’s Information Criterion (AICc) and the Bayesian

AC
Information Criterion (BIC) was selected and included into the next step
model.
– The AICc and BIC are useful tools to choose a better forecasting model (Vrieze,
2012).
10
ACCEPTED MANUSCRIPT
Multicollinearity diagnostics
• A correlation matrix of all the candidate variables was scanned for
PT
presence of very high correlation (|r| > 0.90). (Spearman’
correlation coefficient are used)
RI
• Variance inflation factor (VIF) > 10: The VIF indicates whether a
SC
predictor has a strong linear relationship with the other predictor(s).
U
(Myers, 1990)
AN
• Tolerance (= 1 / VIF) < 0.2: Values below 0.2 are worthy of concern,
M
below 0.1 indicate serious problems. (Menard, 1995)
D
– In SPSS, the VIF and tolerance could be provided using its linear regression
TE
model. (Fields, 2009)
C EP
AC
11
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Supplementary Figure S2. Flowchart of the sample selection from the STEP-BD study.
4,107 patients with clinical data of the Standard

Care Pathway (SCP).
Excluded: 386 (9.4%) patients had CMF

unavailable clinical data.
PT
RI
3,721 (90.6%) patients with clinical data of the
Clinical Monitoring Form (CMF).
SC
Excluded: 946 (25.4%) patients had short
follow-up duration (< 6 months).
U
AN
2,775 (74.6%) patients with at least 6 months
follow-up duration.
M
Excluded: 974 (35.1%) patients had no depressive

D
episode during follow-up.

TE
1,801 (64.9%) patients with at least one depressive

episode during follow-up.
EP
Excluded: 78 (4.3%) patients had unavailable

C
data for the Affective Disorder Evaluation (ADE)

form and /or Demographic form (DF).
AC
3 (0.2%) patients reported transsexual gender.
1,720 (95.5%) patients (8,915 depressive

episodes) were included.

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Accepted Manuscript

Predictors of switch from depression to mania in bipolar disorder

Tomihisa Niitsu, Chiara Fabbri, Alessandro Serretti, M.D., Ph.D.

To appear in: Journal of Psychiatric Research

Received Date: 6 November 2014

Predictors of switch from depression to mania in bipolar disorder

Tomihisa Niitsu 1,2, Chiara Fabbri 1, Alessandro Serretti 1 *

* Corresponding author: Alessandro Serretti, M.D., Ph.D.

Department of Biomedical and NeuroMotor Sciences, University of Bologna,

Viale Carlo Pepoli 5, 40123 Bologna, Italy

Tel +39 051 6584233; Fax +39 051 521030

predictors of switch from depression to mania in the Systematic Treatment

following 12 weeks. We assessed possible predictors of switch using generalized linear

symptoms, suicide attempts, amphetamine use and some pharmacological and

least moderate severity, and comorbid panic attacks.

Keywords: bipolar depression; manic switch; manic symptom; panic attack;

venlafaxine; suicide; rapid-cycling; amphetamine use; onset

− Manic switch is a primary issue when treating bipolar depression

Bipolar disorder (BD) is a chronic disease characterized by the alternation of

periods of (hypo)mania and depression, resulting in high personal and socio-economic

and improve BD prognosis. Previous studies investigated antidepressant (AD)-related

associations between switch and baseline clinical-demographic features (greater number

Previous studies were mainly focused on the risk of switch during AD

in the absence of AD treatment. Indeed, some randomized controlled trials (RCTs)

stabilizer plus a placebo or mood stabilizer monotherapy, showed no association with

process of randomization (tendency to avoid the randomization of patients at higher risk

several neurobiological mechanisms support the risk of spontaneous switch (Salvadore

All the above-mentioned studies (with the exception of a small naturalistic

study (Boerlin et al. 1998)) investigated a patient-based phenotype of switch from

be considered in addition to the general characteristics of BD in each patient in order to

provide an accurate prognosis and suitable treatment interventions.

2.1. Study Overview

STEP-BD was a large, multi-center and naturalistic cohort study, conducted in

clinicians were encouraged to treat patients in accordance with contemporary practice

Perlis et al. 2006).

indicated and clinicians were encouraged to follow the principles of evidence-based

treatment and published guidelines, updated annually in the STEP-BD Clinicians

Handbook. The protocol promoted the application of evidence-based treatments at

naturalistic study employed ongoing assessments of treatment and outcome information.

of the STEP-BD Standard Care Pathway (SCP).

The diagnosis of BD was assessed with the Mini International

Neuropsychiatric Interview (MINI) (Sheehan et al. 1998) and Affective Disorder

Conventions and Rules for Imputation (Sachs et al. 2002).

2.5 Hypothesis under analysis

applied. Identification ID Number of each patient was considered as a random effect,

while the other clinical variables were considered as fixed effects.

To identify possible confounders mediating the association between switch and

clinical variables, several regression models were constructed in a stepwise manner.

included baseline demographic and socio-economic status (SES) variables and

STEP-BD time-related variables as covariates (age, gender, ethnicity, education,

than history of sertraline treatment. 3) Stepwise combinations of the candidate variables

represented the subject).

3.1. Participant flow

included 1720 patients (Supplementary Figure S2).

were labeled as “episodes with switch”.

3.2. Baseline clinical characteristics in patients with and without switch

= -0.011; F = 4.151, p = 0.042, β = <-0.001, respectively; Supplementary Table S2). In

these associations continued to be significant (F = 7.788, p = 0.005, β = -0.012; F =

4.198, p = 0.041, β = <-0.001; respectively).

3.3.2. Past history of disease

In Model 1, a younger age at onset of the first (hypo)manic episode was

associated with switch (F = 5.320, p = 0.021, β = -0.010; Supplementary Table S2),

attributions) caused by SSRIs and some specific drugs (fluoxetine, sertraline,