Associate Professor - Med Center Line, Psychiatry and Behavioral Sciences
The purpose of this study is determine whether the use of topiramate is effective in the treatment of alcohol dependence (i.e. decreases drinking) in patients with bipolar disorder.
Stanford is currently not accepting patients for this trial.
Psychopharmacology remains the foundation of treatment for bipolar disorder, but medication adherence in this population is low (range 20-64%). We examined medication adherence in a multisite, comparative effectiveness study of lithium.The Lithium Moderate Dose Use Study (LiTMUS) was a 6-month, six-site, randomized effectiveness trial of adjunctive moderate dose lithium therapy compared with optimized treatment in adult out-patients with bipolar I or II disorder (N = 283). Medication adherence was measured at each study visit with the Tablet Routine Questionnaire.We found that 4.50% of participants reported missing at least 30% of their medications in the past week at baseline and non-adherence remained low throughout the trial (<7%). Poor medication adherence was associated with more manic symptoms and side-effects as well as lower lithium serum levels at mid- and post-treatment, but not with poor quality of life, overall severity of illness, or depressive symptoms.Participants in LiTMUS were highly adherent with taking their medications. The lack of association with possible predictors of adherence, such as depression and quality of life, could be explained by the limited variance or other factors as well as by not using an objective measure of adherence.
View details for DOI 10.1111/acps.12202
View details for Web of Science ID 000334221600004
This study was designed to identify genes whose expression in peripheral blood may serve as early markers for treatment response to lithium (Li) in patients with bipolar disorder. Although changes in peripheral blood gene-expression may not relate directly to mood symptoms, differences in treatment response at the biochemical level may underlie some of the heterogeneity in clinical response to Li. Subjects were randomized to treatment with (n=28) or without (n=32) Li. Peripheral blood gene-expression was measured before and 1month after treatment initiation, and treatment response was assessed after 6 months. In subjects treated with Li, 62 genes were differentially regulated in treatment responders and non-responders. Of these, BCL2L1 showed the greatest difference between Li responders and non-responders. These changes were specific to Li responders (n=9), and were not seen in Li non-responders or patients treated without Li, suggesting that they may have specific roles in treatment response to Li.
View details for DOI 10.1038/tpj.2013.16
View details for Web of Science ID 000333665400012
Motivated by genetic association data implicating L-type calcium channels in bipolar disorder liability, we sought to estimate the tolerability, safety, and efficacy of isradipine in the adjunctive treatment of bipolar depression.A total of 12 patients with bipolar I or II depression entered this pilot, proof-of-concept eight-week investigation and 10 returned for at least one post-baseline visit. They were initiated on isradipine at 2.5 mg and titrated up to 10 mg daily, with blinded assessments of depression using the Montgomery-Åsberg Depression Rating Scale (MADRS) as well as adverse effects.Among the 10 patients, three had bipolar II disorder; all but two reported current episode duration longer than six months. In all, four of 10 completed the study; no significant adverse events were observed, although one subject discontinued treatment per protocol because of possible hypomanic symptoms which had resolved prior to study visit. In a mixed-effects model, mean improvement in depression severity, assessed by MADRS, was 2.1 (standard error = 0.36) points/week (p < 0.001). Two of the 10 subjects remitted and four of the 10 subjects experienced 50% or greater symptomatic improvement with treatment.Isradipine merits further investigation for the treatment of bipolar depression. This preliminary trial illustrates the potential utility of genetic investigation in identifying psychiatric treatment targets.
View details for DOI 10.1111/bdi.12143
View details for Web of Science ID 000332208700013
View details for PubMedID 24372835
This study examined general medical illnesses and their association with clinical features of bipolar disorder.Data were cross-sectional and derived from the Lithium Treatment - Moderate Dose Use Study (LiTMUS), which randomized symptomatic adults (n = 264 with available medical comorbidity scores) with bipolar disorder to moderate doses of lithium plus optimized treatment (OPT) or to OPT alone. Clinically significant high and low medical comorbidity burden were defined as a Cumulative Illness Rating Scale (CIRS) score ≥4 and <4 respectively.The baseline prevalence of significant medical comorbidity was 53% (n = 139). Patients with high medical burden were more likely to present in a major depressive episode (P = .04), meet criteria for obsessive-compulsive disorder (P = .02), and experience a greater number of lifetime mood episodes (P = 0.02). They were also more likely to be prescribed a greater number of psychotropic medications (P = .002). Sixty-nine per cent of the sample was overweight or obese as defined by body mass index (BMI), with African Americans representing the racial group with the highest proportion of stage II obesity (BMI ≥35; 31%, n = 14).The burden of comorbid medical illnesses was high in this generalizable sample of treatment-seeking patients and appears associated with worsened course of illness and psychotropic medication patterns.
View details for DOI 10.1111/acps.12101
View details for Web of Science ID 000328209400004
This paper describes the development and use of the Medication Recommendation Tracking Form (MRTF), a novel method for capturing physician prescribing behavior and clinical decision making. The Bipolar Trials Network developed and implemented the MRTF in a comparative effectiveness study for bipolar disorder (LiTMUS). The MRTF was used to assess the frequency, types, and reasons for medication adjustments. Changes in treatment were operationalized by the metric Necessary Clinical Adjustments (NCA), defined as medication adjustments to reduce symptoms, optimize treatment response and functioning, or to address intolerable side effects. Randomized treatment groups did not differ in rates of NCAs, however, responders had significantly fewer NCAs than non-responders. Patients who had more NCAs during their previous visit had significantly lower odds of responding at the current visit. For each one-unit increase in previous CGI-BP depression score and CGI-BP overall severity score, patients had an increased NCA rate of 13% and 15%, respectively at the present visit. Ten-unit increases in previous Montgomery Asberg Depression Rating Scale (MADRS) and Young Mania Rating Scale (YMRS) scores resulted in an 18% and 14% increase in rates of NCAs, respectively. Patients with fewer NCAs had increased quality of life and decreased functional impairment. The MRTF standardizes the reporting and rationale for medication adjustments and provides an innovative metric for clinical effectiveness. As the first tool in psychiatry to track the types and reasons for medication changes, it has important implications for training new clinicians and examining clinical decision making. (ClinicalTrials.gov number NCT00667745).
View details for DOI 10.1016/j.jpsychires.2013.07.009
View details for Web of Science ID 000325841600019
OBJECTIVE Bipolar disorder is a severe, chronic mental illness with a high incidence of medical and psychological comorbidities that make treatment and prevention of future episodes challenging. This study investigated the use of services among outpatients with bipolar disorder to further understanding of how to maximize and optimize personalization and accessibility of services for this difficult-to-treat population. METHODS The Lithium Treatment-Moderate Dose Use Study (LiTMUS) was a six-month multisite, comparative effectiveness trial that randomly assigned 283 individuals to receive lithium plus optimized care-defined as personalized, guideline-informed care-or optimized care without lithium. Relationships between treatment service utilization, captured by the Cornell Service Index, and demographic and illness characteristics were examined with generalized linear marginal models. RESULTS Analyses with complete data (week 12, N=246; week 24, N=236) showed that increased service utilization was related to more severe bipolar disorder symptoms, physical side effects, and psychiatric and general medical comorbidities. Middle-aged individuals and those living in the United States longer tended to use more services than younger individuals or recent immigrants, respectively. CONCLUSIONS These data suggest that not all individuals with bipolar disorder seek treatment services at the same rate. Instead, specific clinical or demographic features may affect the degree to which one seeks treatment, conveying clinical and public health implications and highlighting the need for specific approaches to correct such discrepancies. Future research is needed to elucidate potential moderators of service utilization in bipolar disorder to ensure that those most in need of additional services utilize them.
View details for DOI 10.1176/appi.ps.201200479
View details for Web of Science ID 000327303800008
OBJECTIVES: We sought to understand the association of specific aspects of care satisfaction, such as patients' perceived relationship with their psychiatrist and access to their psychiatrist and staff, and therapeutic alliance with participants' likelihood to adhere to their medication regimens among patients with bipolar disorder. METHODS: We examined data from the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder, an effectiveness study investigating the course and treatment of bipolar disorder. We expected that participants (n = 3037) with positive perceptions of their relationship with their psychiatrist and quality of psychopharmacologic care, as assessed by the Helping Alliance Questionnaire and Care Satisfaction Questionnaire, would be associated with better medication adherence. We utilized logistic regression models controlling for already established factors associated with poor adherence. RESULTS: Patients' perceptions of collaboration, empathy, and accessibility were significantly associated with adherence to treatment in individuals with bipolar disorder completing at least 1 assessment. Patients' perceptions of their psychiatrists' experience, as well as of their degree of discussing medication risks and benefits, were not associated with medication adherence. CONCLUSIONS: Patients' perceived therapeutic alliance and treatment environment impact their adherence to pharmacotherapy recommendations. This study may enable psychopharmacologists' practices to be structured to maximize features associated with greater medication adherence.
View details for DOI 10.1097/JCP.0b013e3182900c6f
View details for Web of Science ID 000318871400009
Manic episodes are heterogeneous. Mixed states may differ in important clinical characteristics from other manic episodes. However, it has not been established whether mixed states are a distinct type of episodes, or a common basic structure exists across manic episodes.Using 2179 well-characterized subjects in the pretreatment phase of six randomized, clinical trials, we conducted rotated factor analysis followed by cluster analysis, using all items from the Young Mania Rating Scale and the Montgomery-Åsberg Depression Scale. Analyses were conducted for all subjects (n=2179) and for those in Diagnostic and Statistical Manual of Mental Disorders - Fourth Edition (DSM-IV) mixed (n=644) and non-mixed (n=1535) episodes separately.There were five factors characterized (in order of variance accounted for) as depression, mania, sleep disturbance, judgment/impulsivity and irritability/hostility. Cluster analysis identified five clusters. Three were predominately manic, with depression scores below average for the overall group. Two had high average depression scores; these clusters differed in irritability/hostility. Judgment/impulsivity scores were similar across factors. Essentially identical factors and clusters existed whether analyses were done in all subjects or only in subjects classified by DSM-IV as mixed or non-mixed.Exclusion criteria of studies may limit generalizability of findings.All manic episodes, whether mixed or non-mixed, shared a similar structure according to factor/cluster analysis. Patients with high depression factor scores were heterogeneous with respect to irritability. These data suggest that depressive symptoms should be considered a dimensional property across manic episodes, rather than as defining a specific type of episode.
View details for DOI 10.1016/j.jad.2012.05.061
View details for Web of Science ID 000311640300008
Lithium salts, once the mainstay of therapy for bipolar disorder, have tolerability issues at a higher dosage that often limit adherence. The authors investigated the comparative effectiveness of more tolerable dosages of lithium as part of optimized personalized treatment (OPT).The authors randomly assigned 283 bipolar disorder outpatients to 6 months of open, flexible, moderate dosages of lithium plus OPT or to 6 months of OPT alone. The primary outcome measures were the Clinical Global Impression Scale for Bipolar Disorder-Severity (CGI-BP-S) and "necessary clinical adjustments" (medication adjustments per month). Secondary outcome measures included mood symptoms and functioning. The authors also assessed sustained remission (defined as a CGI-BP-S score ≤2 for 2 months) and treatment with second-generation antipsychotics. The authors hypothesized that lithium plus OPT would result in greater clinical improvement and fewer necessary clinical adjustments.The authors observed no statistically significant advantage of lithium plus OPT on CGI-BP-S scores, necessary clinical adjustments, or proportion with sustained remission. Both groups had similar outcomes across secondary clinical and functional measures. Fewer patients in the lithium-plus-OPT group received second-generation antipsychotics compared with the OPT-only group (48.3% and 62.5%, respectively).In this pragmatic comparative effectiveness study, a moderate but tolerated dosage of lithium plus OPT conferred no symptomatic advantage when compared with OPT alone, but the lithium-plus-OPT group had less exposure to second-generation antipsychotics. Only about one-quarter of patients in both groups achieved sustained remission of symptoms. These findings highlight the persistent and chronic nature of bipolar disorder as well as the magnitude of unmet needs in its treatment.
View details for DOI 10.1176/appi.ajp.2012.12060751
View details for Web of Science ID 000313086200013
Sleep disturbance is a common feature during mood episodes in bipolar disorder. The aim of this study was to investigate the prevalence of such symptoms among euthymic bipolar patients, and their association with risk for mood episode recurrence. A cohort of bipolar I and II subjects participating in the Systematic Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least 8 weeks were included in this analysis. Survival analysis was used to examine the association between sleep disturbance on the Montgomery-Asberg Depression Rating Scale (MADRS) and recurrence risk. A total of 73/483 bipolar I and II subjects reported at least mild sleep disturbance (MADRS sleep item ?2) for the week prior to study entry. The presence of sleep problems was associated with a history of psychosis, number of previous suicide attempts, and anticonvulsant use. Sleep disturbance at study entry was significantly associated with risk for mood episode recurrence. Sleep disturbance is not uncommon between episodes for individuals with bipolar disorder and may be associated with a more severe course of illness. This suggests that sleep disturbance is an important prodromal symptom of bipolar disorder and should be considered a target for pharmacologic or psychosocial maintenance treatment.
View details for DOI 10.1177/0269881111421973
View details for Web of Science ID 000306508700007
View details for PubMedID 21965189
High attrition rates, which occur frequently in longitudinal clinical trials of interventions for bipolar disorder, limit the interpretation of results.The aim of this article is to present design approaches that limited attrition in the Lithium Treatment - Moderate dose Use Study (LiTMUS) for bipolar disorder.LiTMUS was a 6-month randomized, longitudinal multisite comparative effectiveness trial that enrolled bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium; other treatments needed for mood stabilization were administered in a guideline-informed, empirically supported, and personalized fashion to participants in both treatment arms.Components of the study design that may have contributed to low attrition (16%) among 283 participants randomized included the use of (1) an intent-to-treat design, (2) a randomized adjunctive single-blind design, (3) participant reimbursement, (4) assessment of intent to attend the next study visit (included a discussion of attendance obstacles when intention was low), (5) quality care with limited participant burden, and (6) target windows for study visits.The relationships between attrition and effectiveness and tolerability of treatment have not been analyzed yet.These components of the LiTMUS design may have limited attrition and may inform the design of future randomized comparative effectiveness trials among similar patients and those from other difficult-to-follow populations.
View details for DOI 10.1177/1740774511427324
View details for Web of Science ID 000300380200013
View details for PubMedID 22076437
The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) was funded as part of a National Institute of Mental Health initiative to develop effectiveness information about treatments, illness course, and assessment strategies for severe mental disorders. STEP-BD studies were planned to be generalizable both to the research knowledge base for bipolar disorder and to clinical care of bipolar patients. Several novel methodologies were developed to aid in illness characterization, and were combined with existing scales on function, quality of life, illness burden, adherence, adverse effects, and temperament to yield a comprehensive data set. The methods integrated naturalistic treatment and randomized clinical trials, which a portion of STEP-BD participants participated. All investigators and other researchers in this multisite program were trained in a collaborative care model with the objective of retaining a high percentage of enrollees for several years. Articles from STEP-BD have yielded evidence on risk factors impacting outcomes, suicidality, functional status, recovery, relapse, and caretaker burden. The findings from these studies brought into question the widely practiced use of antidepressants in bipolar depression as well as substantiated the poorly responsive course of bipolar depression despite use of combination strategies. In particular, large studies on the characteristics and course of bipolar depression (the more pervasive pole of the illness), and the outcomes of treatments concluded that adjunctive psychosocial treatments but not adjunctive antidepressants yielded outcomes superior to those achieved with mood stabilizers alone. The majority of patients with bipolar depression concurrently had clinically significant manic symptoms. Anxiety, smoking, and early age of bipolar onset were each associated with increased illness burden. STEP-BD has established procedures that are relevant to future collaborative research programs aimed at the systematic study of the complex, intrinsically important elements of bipolar disorders.
View details for DOI 10.1111/j.1755-5949.2011.00257.x
View details for Web of Science ID 000301343800010
View details for PubMedID 22070541
Newer generation antidepressant drugs, with improvements in safety and tolerability, have replaced tricyclic antidepressants as first-line treatment of depressive illness. However, no single antidepressant drug from any class has distinguished itself as the obvious first-line treatment of major depression. The choice of therapy is driven primarily by patient choice, with informed consent for the risks of adverse effects. Cost has become an additional factor in this decision as several of the newer antidepressant drugs are now available in generic form. Several augmentation and drug-switching strategies have demonstrated benefit in refractory illness. While no single strategy distinguished itself as superior to the others, some have been more rigorously tested. Ongoing efforts at improving effectiveness, time to response, and tolerability have led to novel drug therapies. Efforts at characterizing predictors of treatment outcomes now include pharmacogenetic studies.
View details for DOI 10.1017/S1461145711000083
View details for Web of Science ID 000297106000012
View details for PubMedID 21349226
It has been suggested that patients with major depressive disorder (MDD) who display pretreatment features suggestive of bipolar disorder or bipolar spectrum features might have poorer treatment outcomes.To assess the association between bipolar spectrum features and antidepressant treatment outcome in MDD.Open treatment followed by sequential randomized controlled trials.Primary and specialty psychiatric outpatient centers in the United States.Male and female outpatients aged 18 to 75 years with a DSM-IV diagnosis of nonpsychotic MDD who participated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study.Open treatment with citalopram followed by up to 3 sequential next-step treatments.Number of treatment levels required to reach protocol-defined remission, as well as failure to return for the postbaseline visit, loss to follow-up, and psychiatric adverse events. For this secondary analysis, putative bipolar spectrum features, including items on the mania and psychosis subscales of the Psychiatric Diagnosis Screening Questionnaire, were examined for association with treatment outcomes.Of the 4041 subjects who entered the study, 1198 (30.0%) endorsed at least 1 item on the psychosis scale and 1524 (38.1%) described at least 1 recent maniclike/hypomaniclike symptom. Irritability and psychoticlike symptoms at entry were significantly associated with poorer outcomes across up to 4 treatment levels, as were shorter episodes and some neurovegetative symptoms of depression. However, other indicators of bipolar diathesis including recent maniclike symptoms and family history of bipolar disorder as well as summary measures of bipolar spectrum features were not associated with treatment resistance.Self-reported psychoticlike symptoms were common in a community sample of outpatients with MDD and strongly associated with poorer outcomes. Overall, the data do not support the hypothesis that unrecognized bipolar spectrum illness contributes substantially to antidepressant treatment resistance.
View details for DOI 10.1001/archgenpsychiatry.2010.179
View details for Web of Science ID 000289165900004
View details for PubMedID 21135313
Some individuals with bipolar disorder transition directly from major depressive episodes to manic, hypomanic, or mixed states during treatment, even in the absence of antidepressant treatment. Prevalence and risk factors associated with such transitions in clinical populations are not well established, and were examined in the Systematic Treatment Enhancement Program for Bipolar Disorder study, a longitudinal cohort study. Survival analysis was used to examine time to transition to mania, hypomania, or mixed state among 2166 bipolar I and II individuals in a major depressive episode. Cox regression was used to examine baseline clinical and sociodemographic features associated with hazard for such a direct transition. These features were also examined for interactive effects with antidepressant treatment. In total, 461/2166 subjects in a major depressive episode (21.3%) transitioned to a manic/hypomanic or mixed state before remission, including 289/1475 (19.6%) of those treated with antidepressants during the episode. Among the clinical features associated with greatest transition hazard were greater number of past depressive episodes, recent or lifetime rapid cycling, alcohol use disorder, previous suicide attempt, and history of switch while treated with antidepressants. Greater manic symptom severity was also associated with risk for manic transition among both antidepressant-treated and antidepressant-untreated individuals. Three features, history of suicide attempt, younger onset age, and bipolar subtype, exhibited differential effects between individuals treated with antidepressants and those who were not. These results indicate that certain clinical features may be associated with greater risk of transition from depression to manic or mixed states, but the majority of them are not specific to antidepressant-treated patients.
View details for DOI 10.1038/npp.2010.122
View details for Web of Science ID 000284104400007
View details for PubMedID 20827274
To assess long-term effectiveness and safety of randomized antidepressant discontinuation after acute recovery from bipolar depression.In the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study, conducted between 2000 and 2007, 70 patients with DSM-IV-diagnosed bipolar disorder (72.5% non-rapid cycling, 70% type I) with acute major depression, initially responding to treatment with antidepressants plus mood stabilizers, and euthymic for 2 months, were openly randomly assigned to antidepressant continuation versus discontinuation for 1-3 years. Mood stabilizers were continued in both groups.The primary outcome was mean change on the depressive subscale of the STEP-BD Clinical Monitoring Form. Antidepressant continuation trended toward less severe depressive symptoms (mean difference in DSM-IV depression criteria = -1.84 [95% CI, -0.08 to 3.77]) and mildly delayed depressive episode relapse (HR = 2.13 [1.00-4.56]), without increased manic symptoms (mean difference in DSM-IV mania criteria = +0.23 [-0.73 to 1.20]). No benefits in prevalence or severity of new depressive or manic episodes, or overall time in remission, occurred. Type II bipolar disorder did not predict enhanced antidepressant response, but rapid-cycling course predicted 3 times more depressive episodes with antidepressant continuation (rapid cycling = 1.29 vs non-rapid cycling = 0.42 episodes/year, P = .04).This first randomized discontinuation study with modern antidepressants showed no statistically significant symptomatic benefit with those agents in the long-term treatment of bipolar disorder, along with neither robust depressive episode prevention benefit nor enhanced remission rates. Trends toward mild benefits, however, were found in subjects who continued antidepressants. This study also found, similar to studies of tricyclic antidepressants, that rapid-cycling patients had worsened outcomes with modern antidepressant continuation.clinicaltrials.gov Identifier: NCT00012558.
View details for DOI 10.4088/JCP.08m04909gre
View details for Web of Science ID 000277059300001
View details for PubMedID 20409444
Poor medication adherence is common among bipolar patients.We examined prospective data from 2 cohorts of individuals from the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (1999-2005) with bipolar disorder. Clinical and sociodemographic features associated with missing at least 25% of doses of at least 1 medication were assessed using logistic regression, and a risk stratification model was developed and validated.Of 3,640 subjects with 48,287 follow-up visits, 871 (24%) reported nonadherence on 20% or more study visits. Clinical features significantly associated (P < .05) with poor adherence included rapid cycling, suicide attempts, earlier onset of illness, and current anxiety or alcohol use disorder. Nonadherence during the first 3 months of follow-up was associated with less improvement in functioning at 12-month follow-up (P < .03). A risk stratification model using clinical predictors accurately classified 80.6% of visits in an independent validation cohort.Risk for poor medication adherence can be estimated and may be useful in targeting interventions.
View details for DOI 10.4088/JCP.09m05514yel
View details for Web of Science ID 000276273500011
View details for PubMedID 20331931
Bipolar disorder is highly comorbid with substance use disorders, and this comorbidity may be associated with a more severe course of illness, but the impact of comorbid substance abuse on recovery from major depressive episodes in these patients has not been adequately examined. The authors hypothesized that comorbid drug and alcohol use disorders would be associated with longer time to recovery in patients with bipolar disorder.Subjects (N=3,750) with bipolar I or bipolar II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were followed prospectively for up to 2 years. Prospectively observed depressive episodes were identified for this analysis. Subjects with a past or current drug or alcohol use disorder were compared with those with no history of drug or alcohol use disorders on time to recovery from depression and time until switch to a manic, hypomanic, or mixed episode.During follow up, 2,154 subjects developed a new-onset major depressive episode; of these, 457 subjects switched to a manic, hypomanic, or mixed episode prior to recovery. Past or current substance use disorder did not predict time to recovery from a depressive episode relative to no substance use comorbidity. However, those with current or past substance use disorder were more likely to experience switch from depression directly to a manic, hypomanic, or mixed state.Current or past substance use disorders were not associated with longer time to recovery from depression but may contribute to greater risk of switch into manic, mixed, or hypomanic states. The mechanism conferring this increased risk merits further study.
View details for DOI 10.1176/appi.ajp.2009.09020299
View details for Web of Science ID 000275056300010
View details for PubMedID 20008948
Benzodiazepines are widely prescribed to patients with bipolar disorder, but their impact on relapse and recurrence has not been examined.We examined prospective data from a cohort of DSM-IV bipolar I and II patients who achieved remission during evidence-guided naturalistic treatment in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study (conducted in the United States between 1999 and 2005). Risk for recurrence among individuals who did or did not receive benzodiazepine treatment was examined using survival analysis. Cox regression was used to adjust for clinical and sociodemographic covariates. Propensity score analysis was used in a confirmatory analysis to address the possible impact of confounding variables.Of 1,365 subjects, 349 (25.6%) were prescribed a benzodiazepine at time of remission from a mood episode. After adjusting for potential confounding variables, the hazard ratio for mood episode recurrence among benzodiazepine-treated patients was 1.21 (95% CI, 1.01-1.45). The effects of benzodiazepine treatment on relapse remained significant after excluding relapses occurring within 90 days of recovery, or stratifying the sample by propensity score, a summary measure of likelihood of receiving benzodiazepine treatment. In an independent cohort of 721 subjects already in remission at study entry, effects of similar magnitude were observed.Benzodiazepine use may be associated with greater risk for recurrence of a mood episode among patients with bipolar I and II disorder. The prescribing of benzodiazepines, at a minimum, appears to be a marker for a more severe course of illness.
View details for DOI 10.4088/JCP.09m05019yel
View details for Web of Science ID 000274762100010
View details for PubMedID 20193647
Lithium carbonate and valproate semisodium are both recommended as monotherapy for prevention of relapse in bipolar disorder, but are not individually fully effective in many patients. If combination therapy with both agents is better than monotherapy, many relapses and consequent disability could be avoided. We aimed to establish whether lithium plus valproate was better than monotherapy with either drug alone for relapse prevention in bipolar I disorder.330 patients aged 16 years and older with bipolar I disorder from 41 sites in the UK, France, USA, and Italy were randomly allocated to open-label lithium monotherapy (plasma concentration 0.4-1.0 mmol/L, n=110), valproate monotherapy (750-1250 mg, n=110), or both agents in combination (n=110), after an active run-in of 4-8 weeks on the combination. Randomisation was by computer program, and investigators and participants were informed of treatment allocation. All outcome events were considered by the trial management team, who were masked to treatment assignment. Participants were followed up for up to 24 months. The primary outcome was initiation of new intervention for an emergent mood episode, which was compared between groups by Cox regression. Analysis was by intention to treat. This study is registered, number ISRCTN 55261332.59 (54%) of 110 people in the combination therapy group, 65 (59%) of 110 in the lithium group, and 76 (69%) of 110 in the valproate group had a primary outcome event during follow-up. Hazard ratios for the primary outcome were 0.59 (95% CI 0.42-0.83, p=0.0023) for combination therapy versus valproate, 0.82 (0.58-1.17, p=0.27) for combination therapy versus lithium, and 0.71 (0.51-1.00, p=0.0472) for lithium versus valproate. 16 participants had serious adverse events after randomisation: seven receiving valproate monotherapy (three deaths); five lithium monotherapy (two deaths); and four combination therapy (one death).For people with bipolar I disorder, for whom long-term therapy is clinically indicated, both combination therapy with lithium plus valproate and lithium monotherapy are more likely to prevent relapse than is valproate monotherapy. This benefit seems to be irrespective of baseline severity of illness and is maintained for up to 2 years. BALANCE could neither reliably confirm nor refute a benefit of combination therapy compared with lithium monotherapy.Stanley Medical Research Institute; Sanofi-Aventis.
View details for DOI 10.1016/S0140-6736(09)61828-6
View details for Web of Science ID 000274305500026
View details for PubMedID 20092882
Few studies have addressed the physical and mental health effects of caring for a family member with bipolar disorder. This study examined whether caregivers' health is associated with changes in suicidal ideation and depressive symptoms among bipolar patients observed over one year.Patients (N = 500) participating in the Systematic Treatment Enhancement Program for Bipolar Disorder and their primary caregivers (N = 500, including 188 parental and 182 spousal caregivers) were evaluated for up to one year as part of a naturalistic observational study. Caregivers' perceptions of their own physical health were evaluated using the general health scale from the Medical Outcomes Study 36-item Short-Form Health Survey. Caregivers' depression was evaluated using the Center for Epidemiological Studies of Depression Scale.Caregivers of patients who had increasing suicidal ideation over time reported worsening health over time compared to caregivers of patients whose suicidal ideation decreased or stayed the same. Caregivers of patients who had more suicidal ideation and depressive symptoms reported more depressed mood over a one-year reporting period than caregivers of patients with less suicidal ideation or depression. The pattern of findings was consistent across parent caregivers and spousal caregivers.Caregivers, rightly concerned about patients becoming suicidal or depressed, may try to care for the patient at the expense of their own health and well-being. Treatments that focus on the health of caregivers must be developed and tested.
View details for Web of Science ID 000271899700008
View details for PubMedID 19922556
Recent data indicate that lithium use for bipolar disorder has declined over the last decade and that lithium largely has been replaced with alternate, commercially promoted medications that may or may not result in better outcomes.This article describes the rationale and study design of LiTMUS, a multi-site, prospective, randomized clinical trial of outpatients with bipolar disorder. LiTMUS seeks to address whether initiating therapy at lower doses of lithium as part of optimized treatment (OPT, guideline-informed, evidence-based, and personalized pharmacotherapy) improves outcomes and decreases the need for other medication changes across 6 months of therapy.LiTMUS will randomize 284 adults with bipolar disorder (Type I or II) across 6 study sites. The co-primary outcomes are overall illness severity on clinical global improvement scale for bipolar disorder and a novel measure, necessary clinical adjustments. This metric provides a composite that reflects both clinical response and tolerability. Other relevant outcomes include full symptomatic recovery, quality of life, suicidal behaviors, and moderators of suicidality.As of August 28th, 2009, we have consented 338 patients and randomized 281 for this study.The potential limitations of the study include an arbitrary definition of 'low, but effective' doses of lithium, lack of a placebo-controlled group, open treatment, and use of a new outcome measure (i.e., necessary clinical adjustments).We expect that this study will inform our understanding of the effectiveness of low to moderate doses of lithium therapy for individuals with bipolar disorder.
View details for DOI 10.1177/1740774509347399
View details for Web of Science ID 000272678800008
View details for PubMedID 19933719
Some studies suggest that depressive subtypes, defined by groups of symptoms, have predictive or diagnostic utility. These studies make the implicit assumption of stability of symptoms across episodes in mood disorders, which has rarely been investigated.We examined prospective data from a cohort of 3,750 individuals with bipolar I or II disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder study, selecting a subset of individuals who experienced two depressive episodes during up to two years of follow-up. Across-episode association of individual depressive or hypomanic/mixed symptoms was examined using the weighted kappa measure of agreement as well as logistic regression.A total of 583 subjects experienced two prospectively observed depressive episodes, with 149 of those subjects experiencing a third. Greatest evidence of stability was observed for neurovegetative features, suicidality, and guilt/rumination. Loss of interest and fatigue were not consistent across episodes. Structural equation modeling suggested that the dimensional structure of symptoms was not invariant across episodes.While the overall dimensional structure of depressive symptoms lacks temporal stability, individual symptoms including suicidality, mood, psychomotor, and neurovegetative symptoms are stable across major depressive episodes in bipolar disorder and should be considered in future investigations of course and pathophysiology in bipolar disorder.
View details for Web of Science ID 000271899700007
View details for PubMedID 19922555
Cigarette smoking in individuals with bipolar disorder has been associated with suicidal behavior, although the precise relationship between the two remains unclear.In this prospective observational study of 116 individuals with bipolar disorder, we examined the association between smoking and suicidality as measured by Linehan's Suicide Behaviors Questionnaire (SBQ) and prospective suicide attempts over a nine-month period. Impulsivity was measured by the Barratt Impulsiveness Scale.Smoking was associated with higher baseline SBQ scores in univariate and adjusted analyses, but was not significant after statistical adjustment for impulsivity in a regression model. A higher proportion of smokers at baseline made a suicide attempt during the follow-up period (5/31, 16.1%) compared to nonsmokers (3/85, 3.5%); p = 0.031, odds ratio = 5.25 (95% confidence interval: 1.2-23.5). Smoking at baseline also significantly predicted higher SBQ score at nine months.In this study, current cigarette smoking was a predictor of current and nine-month suicidal ideation and behavior in bipolar disorder, and it is likely that impulsivity accounts for some of this relationship.
View details for Web of Science ID 000270826100010
View details for PubMedID 19840000
Symptoms of bipolar disorder are increasingly recognized among children and adolescents, but little is known about the course of bipolar disorder among adults who experience childhood onset of symptoms.We examined prospective outcomes during up to two years of naturalistic treatment among 3,658 adult bipolar I and II outpatients participating in a multicenter clinical effectiveness study, the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). Age at illness onset was identified retrospectively by clinician assessment at study entry.Compared to patients with onset of mood symptoms after age 18 years (n = 1,187), those with onset before age 13 years (n = 1,068) experienced earlier recurrence of mood episodes after initial remission, fewer days of euthymia, and greater impairment in functioning and quality of life over the two-year follow-up. Outcomes for those with onset between age 13 and 18 years (n = 1,403) were generally intermediate between these two groups.Consistent with previous reports in smaller cohorts, adults with retrospectively obtained early-onset bipolar disorder appear to be at greater risk for recurrence, chronicity of mood symptoms, and functional impairment during prospective observation.
View details for DOI 10.1111/j.1399-5618.2009.00686.x
View details for Web of Science ID 000265934000006
View details for PubMedID 19500092
A growing body of research supports an important role for GABA in the pathophysiology of bipolar and other mood disorders. The purpose of the current study was to directly examine brain GABA levels in a clinical sample of bipolar patients. GENERAL METHODS: We used magnetic resonance spectroscopy (MRS) to examine whole brain and regional GABA, glutamate and glutamine in 13 patients with bipolar disorder compared to a matched group of 11 healthy controls.There were no significant differences in GABA, glutamate or glutamine between patients and controls.Further research is needed to better characterize the GABAergic and glutamatergic effects of pharmacotherapy, anxiety comorbidity and clinical state in bipolar disorder.
View details for DOI 10.1016/j.pnpbp.2008.12.025
View details for Web of Science ID 000265470500007
View details for PubMedID 19171176
Many subjects with bipolar disorder experience significant cognitive dysfunction, even when euthymic, but few studies assess biological correlates of or treatment strategies for cognitive dysfunction.Nineteen subjects with bipolar disorder in remission, who reported subjective cognitive deficits, were treated with open-label galantamine-ER 8-24 mg/day for 4 months. Ten healthy volunteers matched for age and gender were also assessed. Mood and subjective cognitive questionnaires were administered monthly. At the beginning and the end of the trial all subjects were administered neuropsychological tests, including tests of attention (Conners CPT) and episodic memory (CVLT). Bipolar subjects underwent proton magnetic resonance spectroscopy (1H-MRS) measurements before and after treatment, healthy volunteers completed baseline 1H-MRS. We acquired 1H-MRS data at 4.0 T from voxels centered on the left and right hippocampus to measure hippocampal N-acetyl aspartate (NAA, a measure of neuronal viability) and choline containing compounds (Cho, a marker of lipid metabolism and membrane turn-over).Compared to healthy volunteers, bipolar subjects had higher baseline subjective cognitive deficits and lower scores on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). After treatment, bipolar subjects experienced significant improvement of subjective cognitive scores and on objective tests of attention (Conner's CPT) and verbal episodic memory (CVLT). In the left hippocampus NAA increased and choline (Cho) decreased in bipolar subjects during treatment.Bipolar subjects had cognitive dysfunction; treatment with Galantamine-ER was associated with improved cognition and with increases in neuronal viability and normalization of lipid membrane metabolism in the left hippocampus. This study was registered on ClinicalTrials.gov (NCT00181636).
View details for DOI 10.1111/j.1755-5949.2009.00090.x
View details for Web of Science ID 000271517300003
View details for PubMedID 19889129
Functional magnetic resonance imaging (fMRI) studies have documented abnormalities in the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex in bipolar disorder in the context of working memory tasks. It is increasingly recognized that DLPFC regions play a role in mood regulation and the integration of emotion and cognition. The purpose of the present study was to investigate with fMRI the interaction between acute sadness and working memory functioning in individuals with bipolar disorder.Nine depressed individuals with DSM-IV bipolar I disorder (BP-I) and 17 healthy control participants matched for age, gender, education, and IQ completed a 2-back working memory paradigm under no mood induction, neutral state, or acute sadness conditions while undergoing fMRI scanning. Functional MRI data were analyzed with SPM2 using a random-effects model.Behaviorally, BP-I subjects performed equally well as control participants on the 2-back working memory paradigm. Compared to control participants, individuals with BP-I were characterized by more sadness-specific activation increases in the left DLPFC (BA 9/46) and left dorsal anterior cingulate (dACC).Our study documents sadness-specific abnormalities in the left DLPFC and dACC in bipolar disorder that suggest difficulties in the integration of emotion (sadness) and cognition. These preliminary findings require further corroboration with larger sample sizes of medication-free subjects.
View details for DOI 10.1111/j.1399-5618.2008.00633.x
View details for Web of Science ID 000261054400009
View details for PubMedID 19594508
Bipolar disorder (BPD) features cycling mood states ranging from depression to mania with intermittent phases of euthymia. Bipolar disorder subjects often show excessive goal-directed and pleasure-seeking behavior during manic episodes and reduced hedonic capacity during depressive episodes, indicating that BPD might involve altered reward processing. Our goal was to test the hypothesis that BPD is characterized by impairments in adjusting behavior as a function of prior reinforcement history, particularly in the presence of residual anhedonic symptoms.Eighteen medicated BPD subjects and 25 demographically matched comparison subjects performed a probabilistic reward task. To identify putative dysfunctions in reward processing irrespective of mood state, primary analyses focused on euthymic BPD subjects (n = 13). With signal-detection methodologies, response bias toward a more frequently rewarded stimulus was used to objectively assess the participants' propensity to modulate behavior as a function of reinforcement history.Relative to comparison subjects, euthymic BPD subjects showed a reduced and delayed acquisition of response bias toward the more frequently rewarded stimulus, which was partially due to increased sensitivity to single rewards of the disadvantageous stimulus. Analyses considering the entire BPD sample revealed that reduced reward learning correlated with self-reported anhedonic symptoms, even after adjusting for residual manic and anxious symptoms and general distress.The present study provides preliminary evidence indicating that BPD, even during euthymic states, is characterized by dysfunctional reward learning in situations requiring integration of reinforcement information over time and thus offers initial insights about the potential source of dysfunctional reward processing in this disorder.
View details for DOI 10.1016/j.biopsych.2007.12.001
View details for Web of Science ID 000257187700011
View details for PubMedID 18242583
We examined the relationship between mood symptoms and episodes in patients with bipolar disorder and burden reported by their primary caregivers.Data on subjective and objective burden reported by 500 primary caregivers for 500 patients with bipolar disorder participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were collected using semistructured interviews. Patient data were collected prospectively over 1 year. The relationship between patient course and subsequent caregiver burden was examined.Episodes of patient depression, but not mood elevation, were associated with greater objective and subjective caregiver burden. Burden was associated with fewer patient days well over the previous year. Patient depression was associated with caregiver burden even after controlling for days well.Patient depression, after accounting for chronicity of symptoms, independently predicts caregiver burden. This study underscores the important impact of bipolar depression on those most closely involved with those whom it affects.
View details for DOI 10.1111/j.1600-0447.2008.01201.x
View details for Web of Science ID 000256684000007
View details for PubMedID 18582347
Impulsivity and anxiety, common features of bipolar disorder (BD), are each associated with a number of negative outcomes in BD. The relationship between anxiety and impulsivity, however, has not been a focus of study in BD. In this paper, we present data regarding the association between anxiety and impulsivity as measured by the Barratt impulsiveness scale (BIS-11) in 114 outpatients with BD. Results revealed that patients with a comorbid anxiety disorder displayed significantly higher levels of impulsivity relative to patients without an anxiety disorder. Moreover, a broad range of anxiety-related symptom domains was associated with greater impulsivity. Exploratory analyses also revealed that baseline anxiety symptoms were associated with elevated impulsivity at 9-month follow-up, although these relationships were less robust after covariate adjustment. These data demonstrate that anxiety is positively associated with impulsivity in patients with BD. Further studies are needed to elucidate the implications of and reasons for this association.
View details for DOI 10.1016/j.janxdis.2007.09.001
View details for Web of Science ID 000256189100011
View details for PubMedID 17936573
Antidepressants treat major depressive disorder (MDD) with the burden of associated side effects and difficulties with compliance. The purpose of this article is to review the efficacy and effectiveness of antidepressants for MDD.The authors conducted a focused review of selected key issues and references relevant to the clinically relevant pharmacologic treatment of MDD. Principles of treatment are reviewed. Antidepressants reviewed include SSRIs, mixed norepinephrine or serotonin uptake inhibitors, dopamine or norepinephrine uptake inhibitors, norepinephrine uptake inhibitors, antidepressants with mixed properties, and monoamine oxidase inhibitors. Augmentation and psychotherapy strategies are reviewed.Antidepressant efficacy has been established in randomized clinical trials and effectiveness studies for acute and long-term treatment, but many patients do not achieve remission. Augmentation strategies and focused psychotherapy can be helpful.Antidepressants help most patients with MDD but some are resistant to treatment and have a difficult long-term course.
View details for DOI 10.1097/JOM.0b013e31816b5034
View details for Web of Science ID 000255108100007
View details for PubMedID 18404015
To examine the relationship of sleep disturbance with complicated grief (CG) in patients with bipolar disorder (BD).Adults with DSM-IV BD were asked if they ever experienced significant loss and, if so, completed the Inventory of Complicated Grief. Subjective sleep disturbance was assessed with the Pittsburgh Sleep Quality Index (PSQI). The association of CG with sleep disturbance was assessed in univariate t-tests, and in multivariate analyses controlling for the presence of anxiety disorder comorbidity and current bipolar recovery status.Individuals with CG had significantly higher mean PSQI scores (10.9 versus 7.9, p = 0.003) than those without CG. Further, within the group of BD participants who had experienced a significant loss, those with CG had significantly poorer sleep (p = 0.01). CG remained significantly associated with greater sleep impairment after adjustment for comorbid anxiety disorder and bipolar mood state. This additive impairment in sleep with CG comorbidity was evident for four of the PSQI component scales: sleep quality, sleep duration, sleep efficiency and sleep disturbance.Our data indicate a significant association of CG with poor sleep in individuals with BD. Disturbed sleep may be a mechanism by which CG increases the burden of illness in BD.
View details for Web of Science ID 000251414300016
View details for PubMedID 18076543
Psychosocial interventions are effective adjuncts to pharmacotherapy in delaying recurrences of bipolar disorder; however, to date their effects on life functioning have been given little attention. In a randomized trial, the authors examined the impact of intensive psychosocial treatment plus pharmacotherapy on the functional outcomes of patients with bipolar disorder over the 9 months following a depressive episode.Participants were 152 depressed outpatients with bipolar I or bipolar II disorder in the multisite Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study. All patients received pharmacotherapy. Eighty-four patients were randomly assigned to intensive psychosocial intervention (30 sessions over 9 months of interpersonal and social rhythm therapy, cognitive behavior therapy [CBT], or family-focused therapy), and 68 patients were randomly assigned to collaborative care (a 3-session psychoeducational treatment). Independent evaluators rated the four subscales of the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT) (relationships, satisfaction with activities, work/role functioning, and recreational activities) through structured interviews given at baseline and every 3 months over a 9-month period.Patients in intensive psychotherapy had better total functioning, relationship functioning, and life satisfaction scores over 9 months than patients in collaborative care, even after pretreatment functioning and concurrent depression scores were covaried. No effects of psychosocial intervention were observed on work/role functioning or recreation scores during this 9-month period.Intensive psychosocial treatment enhances relationship functioning and life satisfaction among patients with bipolar disorder. Alternate interventions focused on the specific cognitive deficits of individuals with bipolar disorder may be necessary to enhance vocational functioning after a depressive episode.
View details for DOI 10.1176/appi.apj.2007.07020311
View details for Web of Science ID 000249266600012
View details for PubMedID 17728418
Caring for a relative with schizophrenia or dementia is associated with reports of high caregiver burden, symptoms of depression, poor physical health, negligence of the caregiver's own health needs, elevated health service use, low use of social supports, and financial strain. This study presents the design and preliminary data on the costs and consequences of caring for a relative or friend with bipolar disorder from the Family Experience Study, a longitudinal study of the primary caregivers to 500 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder.Subjects were primary caregivers of 500 patients with bipolar disorder diagnosed by the Mini International Neuropsychiatric Interview and the Affective Disorder Evaluation. Caregivers were evaluated within 1 month after patients entered Systematic Treatment Enhancement Program using measures of burden, coping, health/mental health, and use of resources and costs.Eighty-nine percent, 52%, and 61% of caregivers, respectively, experienced moderate or higher burden in relation to patient problem behaviors, role dysfunction, or disruption of household routine. High burden caregivers reported more physical health problems, depressive symptoms, health risk behavior and health service use, and less social support than less burden caregivers. They also provided more financial support to their bipolar relative.Burdens experienced by family caregivers of people with bipolar disorder are associated with problems in health, mental health, and cost. Psychosocial interventions targeting the strains of caregiving for a patient with bipolar disorder are needed.
View details for Web of Science ID 000245392900009
View details for PubMedID 17430301
Episodes of depression are the most frequent cause of disability among patients with bipolar disorder. The effectiveness and safety of standard antidepressant agents for depressive episodes associated with bipolar disorder (bipolar depression) have not been well studied. Our study was designed to determine whether adjunctive antidepressant therapy reduces symptoms of bipolar depression without increasing the risk of mania.In this double-blind, placebo-controlled study, we randomly assigned subjects with bipolar depression to receive up to 26 weeks of treatment with a mood stabilizer plus adjunctive antidepressant therapy or a mood stabilizer plus a matching placebo, under conditions generalizable to routine clinical care. A standardized clinical monitoring form adapted from the mood-disorder modules of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, was used at all follow-up visits. The primary outcome was the percentage of subjects in each treatment group meeting the criterion for a durable recovery (8 consecutive weeks of euthymia). Secondary effectiveness outcomes and rates of treatment-emergent affective switch (a switch to mania or hypomania early in the course of treatment) were also examined.Forty-two of the 179 subjects (23.5%) receiving a mood stabilizer plus adjunctive antidepressant therapy had a durable recovery, as did 51 of the 187 subjects (27.3%) receiving a mood stabilizer plus a matching placebo (P=0.40). Modest nonsignificant trends favoring the group receiving a mood stabilizer plus placebo were observed across the secondary outcomes. Rates of treatment-emergent affective switch were similar in the two groups.The use of adjunctive, standard antidepressant medication, as compared with the use of mood stabilizers, was not associated with increased efficacy or with increased risk of treatment-emergent affective switch. Longer-term outcome studies are needed to fully assess the benefits and risks of antidepressant therapy for bipolar disorder. (ClinicalTrials.gov number, NCT00012558 [ClinicalTrials.gov].).
View details for DOI 10.1056/NEJMoa064135
View details for Web of Science ID 000245942600006
View details for PubMedID 17392295
Individuals with bipolar disorder are at increased risk for suicide attempts and completion. Although anxiety may be a modifiable suicide risk factor among bipolar patients, anxiety disorder comorbidity has not been highlighted as critical in identification of high-risk individuals nor has its treatment been integrated into suicide prevention strategies. In this study, ancillary to the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), 120 outpatients with bipolar disorder completed detailed assessment of suicidal ideation and behaviors. We examined the association of current and lifetime comorbid anxiety disorders with suicidal ideation and behaviors univariately and with adjustment for potential confounders in regression models. Lifetime anxiety disorders were associated with a more than doubling of the odds of a past suicide attempt, and current anxiety comorbidity was associated with a more than doubling of the odds of current suicidal ideation. Individuals with current anxiety disorders had more severe suicidal ideation, a greater belief suicide would provide relief, and a higher expectancy of future suicidal behaviors. However, some of these associations appeared to be better accounted for by measures of bipolar severity including an earlier age at bipolar onset and a lack of current bipolar recovery. Comorbid anxiety disorders may play a role in characteristics of bipolar disorder that then elevate risk for suicidal ideation and attempts. While further research is needed to establish the precise nature of these associations, our data support that the presence of comorbid anxiety disorders in individuals with bipolar disorder should trigger careful clinical assessment of suicide risk.
View details for DOI 10.1016/j.jpsychires.2006.08.004
View details for Web of Science ID 000243214000008
View details for PubMedID 17052730
Major depressive disorder often co-occurs with substance use disorders, especially alcohol use disorders, and the course of each of these problems seems be complicated by the other. Diagnosing and treating these patients is challenging. A significant difficulty for clinicians is deciding whether to treat a mood episode in a patient who has current substance use or a substance use disorder, and what is the optimal treatment for that patient. This article discusses the prevalence of depressive and substance use disorder, the course of illness of comorbid depression and substance use disorders, and treatment response.
View details for DOI 10.1016/j.psc.2006.12.009
View details for Web of Science ID 000245636000007
View details for PubMedID 17362804
Prior studies suggest an association between anxiety comorbidity and suicidal ideation and behaviors in bipolar disorder. However, the nature of this association remains unclear.We examined a range of anxiety symptoms, including panic, phobic avoidance, anxiety sensitivity, worry and fear of negative evaluation, in 98 patients with bipolar disorder. We predicted that each anxiety dimension would be linked to greater suicidal ideation and behavior as measured by Linehan's Suicide Behaviors Questionnaire (SBQ), greater depressive rumination, and poorer emotional processing and expression.Each anxiety dimension except fear of negative evaluation was associated with greater SBQ score, greater rumination, and lower levels of emotional processing in univariate analyses. Depressive rumination was a significant predictor of higher SBQ scores in a stepwise multivariate model controlling for age, gender, bipolar subtype, and bipolar recovery status; the association between the anxiety symptom dimensions and SBQ score was found to be redundant with depressive rumination. Emotional processing emerged as protective against suicidal ideation and behaviors in men only, while emotional expression was a significant predictor of lower SBQ scores for women and for the full sample; however, emotional expression was not significantly correlated with anxiety symptoms. Confirmatory analyses examining only those in recovery or recovered (n=68) indicated that the link between rumination and suicidality was not explained by depression.Interpretation is limited by the cross-sectional study design.These findings indicate that increased ruminations may mediate the association between anxiety and suicidal ideation/behavior. In men, lower emotional processing may also play a role in this relationship.
View details for DOI 10.1016/j.jad.2006.05.027
View details for Web of Science ID 000243734600011
View details for PubMedID 16820212
Little is known about the factors contributing to mental illness stigma among caregivers of people with bipolar disorder.A total of 500 caregivers of patients participating in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study were interviewed in a cross-sectional design on measures of stigma, mood, burden, and coping. Relatives and friends with bipolar disorder were assessed on measures of diagnosis and clinical status, determined by a days-well measure derived from psychiatrist ratings of DSM-IV episode status. Because patients' clinical status varied widely, separate models were run for patients who were euthymic for at least three-fourths of the past year (well group) and for those who met criteria for an affective episode for at least one-fourth of the previous year (unwell group). Stepwise multiple regression was used to identify patient, illness, and caregiver characteristics associated with caregiver stigma.In the unwell group, greater mental illness stigma was associated with bipolar I (versus II) disorder, less social support for the caregiver, fewer caregiver social interactions, and being a caregiver of Hispanic descent. In the well group, greater stigma was associated with being a caregiver who is the adult child of a parent with bipolar disorder, who has a college education, who has fewer social interactions, and who cares for a female bipolar patient.Mental illness stigma was found to be prevalent among caregivers of persons with bipolar disorder who have active symptoms as well as for caregivers of those who have remitted symptoms. Stigma is typically associated with factors identifying patients as "different" during symptomatic periods. Research is needed to understand how the stigma experienced by caregivers during stable phases of illness differs from the stigma experienced during patients' illness states.
View details for Web of Science ID 000243384200007
View details for PubMedID 17215411
The rate of smoking in people with bipolar disorder is much greater than in the general population, but the implications of smoking for the course of bipolar disorder have not been well studied. The purpose of this retrospective study was to examine the relationship between smoking, severity of bipolar disorder, suicidal behavior, and psychiatric and substance use disorder comorbidity.We evaluated 399 outpatients with bipolar disorder who were treated in a bipolar specialty clinic from December 1999 to October 2004. Diagnosis, mood state, course of illness, functioning, and psychiatric comorbidities were assessed using the Affective Disorders Evaluation and the Mini-International Neuropsychiatric Interview.Of the 399 patients evaluated, 155 (38.8%) had a history of daily smoking. Having ever smoked was associated with earlier age at onset of first depressive or manic episode, lower Global Assessment of Functioning scores, higher Clinical Global Impressions-Bipolar Disorder scale scores, lifetime history of a suicide attempt (47% for smokers vs. 25% for those who had never smoked), and lifetime comorbid disorders: anxiety disorders, alcohol abuse and dependence, and substance abuse and dependence. In a logistic regression model including these factors, suicide attempts and substance dependence were significantly associated with smoking in patients with bipolar disorder.Bipolar patients with lifetime smoking were more likely to have earlier age at onset of mood disorder, greater severity of symptoms, poorer functioning, history of a suicide attempt, and a lifetime history of comorbid anxiety and substance use disorders. Smoking may be independently associated with suicidal behavior in bipolar disorder.
View details for Web of Science ID 000243085800009
View details for PubMedID 17194268
Between 40% and 70% of people with bipolar disorder have a history of substance use disorder. A current or past comorbid substance use disorder may lead to worse outcomes for bipolar disorder, including more symptoms, more suicide attempts, longer episodes, and lower quality of life. Unfortunately, few treatments have been studied in patients with both illnesses, and large controlled trials are needed. Evidence from small studies suggests that some treatments proven for bipolar disorder (e.g., divalproex, lithium, quetiapine, lamotrigine, and psychotherapy) may decrease substance abuse or dependence. Both the bipolar disorder and the substance use disorder should be considered when determining the best management strategy. Once treatment has begun, clinicians should ensure that medication and psychotherapy are administered appropriately and that treatment is modified when there is inadequate response.
View details for PubMedID 17081077
The low prevalence of extrapyramidal symptoms associated with atypical antipsychotics has led to their widespread use during the past decade. Aripiprazole, the newest medication in this class, has been associated with extrapyramidal symptoms (eg, akathisia) and with improvement of tardive dyskinesia (TD), but to date it has not been associated with the development of TD. We report a case of TD associated with the use of aripiprazole 15 mg/day for 18 months for refractory depression. Symptoms of TD resolved within several weeks of discontinuation of aripiprazole.
View details for Web of Science ID 000238607600010
View details for PubMedID 16816781
To investigate seasonal and regional effects on bipolar I and II patients.The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) patients were prospectively examined for monthly change in prevalence rates of depressed and recovered clinical status over the year. General Estimating Equation modeling was used to assess the effect of season on prevalence rates. Additionally, patients were stratified by bipolar subtype and by region.A significantly higher prevalence rate of depression is observed in the northern sites, a significant prevalence by month effect is found only in the bipolar II patients.The prevalence of depression is greater in patients from the northern vs. southern STEP-BD sites. Seasonal peak prevalence rates of depression differ by region. Bipolar II patients were more ill year-round and demonstrated greater monthly fluctuation in prevalence rates of being ill than did bipolar I patients. We conclude that seasonal effects upon bipolar patients vary by region and bipolar subtype.
View details for DOI 10.1111/j.1600-0447.2005.00701.x
View details for Web of Science ID 000237347800009
View details for PubMedID 16677228
The validity of a primary/secondary substance use disorder (SUD) distinction was evaluated in the first 1000 patients enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder. Patients with primary SUD (n = 116) were compared with those with secondary SUD (n = 275) on clinical course variables. Patients with secondary SUD had fewer days of euthymia, more episodes of mania and depression, and a greater history of suicide attempts. These findings were fully explained by variations in age of onset of bipolar disorder. The order of onset of SUDs was not linked to bipolar outcomes when age of onset of bipolar disorder was statistically controlled. The primary/secondary distinction for SUD is not valid when variations in the age of onset of the non-SUD are linked to course characteristics.
View details for DOI 10.1080/10550490500528423
View details for Web of Science ID 000236579000004
View details for PubMedID 16595351
Clinicians have few evidence-based options for the management of treatment-resistant bipolar depression. This study represents the first randomized trial of competing options for treatment-resistant bipolar depression and assesses the effectiveness and safety of antidepressant augmentation with lamotrigine, inositol, and risperidone.Participants (N=66) were patients with bipolar I or bipolar II disorder enrolled in the NIMH Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD). All patients were in a current major depressive episode that was nonresponsive to a combination of adequate doses of established mood stabilizers plus at least one antidepressant. Patients were randomly assigned to open-label adjunctive treatment with lamotrigine, inositol, or risperidone for up to 16 weeks. The primary outcome measure was the rate of recovery, defined as no more than two symptoms meeting DSM-IV threshold criteria for a mood episode and no significant symptoms present for 8 weeks.No significant between-group differences were seen when any pair of treatments were compared on the primary outcome measure. However, the recovery rate with lamotrigine was 23.8%, whereas the recovery rates with inositol and risperidone were 17.4% and 4.6%, respectively. Patients receiving lamotrigine had lower depression ratings and Clinical Global Impression severity scores as well as greater Global Assessment of Functioning scores compared with those receiving inositol and risperidone.No differences were found in primary pairwise comparison analyses of open-label augmentation with lamotrigine, inositol, or risperidone. Post hoc secondary analyses suggest that lamotrigine may be superior to inositol and risperidone in improving treatment-resistant bipolar depression.
View details for Web of Science ID 000235031000010
View details for PubMedID 16449473
Little is known about clinical features associated with the risk of recurrence in patients with bipolar disorder receiving treatment according to contemporary practice guidelines. The authors looked for the features associated with risk of recurrence.The authors examined prospective data from a cohort of patients with bipolar disorder participating in the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) study for up to 24 months. For those who were symptomatic at study entry but subsequently achieved recovery, time to recurrence of mania, hypomania, mixed state, or a depressive episode was examined with Cox regression.Of 1,469 participants symptomatic at study entry, 858 (58.4%) subsequently achieved recovery. During up to 2 years of follow-up, 416 (48.5%) of these individuals experienced recurrences, with more than twice as many developing depressive episodes (298, 34.7%) as those who developed manic, hypomanic, or mixed episodes (118, 13.8%). The time until 25% of the individuals experienced a depressive episode was 21.4 weeks and until 25% experienced a manic/hypomanic/mixed episode was 85.0 weeks. Residual depressive or manic symptoms at recovery and proportion of days depressed or anxious in the preceding year were significantly associated with shorter time to depressive recurrence. Residual manic symptoms at recovery and proportion of days of elevated mood in the preceding year were significantly associated with shorter time to manic, hypomanic, or mixed episode recurrence.Recurrence was frequent and associated with the presence of residual mood symptoms at initial recovery. Targeting residual symptoms in maintenance treatment may represent an opportunity to reduce risk of recurrence.
View details for Web of Science ID 000235031000011
View details for PubMedID 16449474
Mood elevation, which includes mania, hypomania, and mixed states, was previously considered the defining symptom of bipolar disorder, but bipolar depression by comparison is actually a much more substantial challenge to diagnose and treat. Recent studies, including research by the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), found that patients with bipolar disorder spend longer periods of time in depressive episodes and are more likely to relapse to depression compared with mania or hypomania. However, the treatment of bipolar depression is hampered by the limited number and varying quality of available studies of pharmacologic treatments to guide clinical decision making. Clinicians should rely on studies with the highest level of evidence (category A) when prescribing appropriate antidepressant treatments. The standard care pathways outlined by STEP-BD to aid clinicians in treating varying phases of bipolar disorder provide data on the use of various treatments for bipolar depression and their outcomes. While some treatments have the potential to induce mania, others appear to have some efficacy without inducing mania.
View details for Web of Science ID 000240838500004
View details for PubMedID 17029492
Patients with bipolar disorder are among the most challenging to treat. These patients frequently present with complex mood and other symptoms that change over time, complex psychiatric and medical comorbid conditions, and multiple medications. Clinicians rarely systematically assess or measure all of these factors and instead rely on memory and general impressions. It is imperative that clinicians systematically track and monitor these relevant variables to ensure treatment decisions are based on precise clinical data. By integrating measurement and management, clinicians and patients can collaborate to assess the effectiveness of treatments and to make joint decisions about critical points at which to adjust treatment. This method was shown to be successful in the National Institute of Mental Health (NIMH) Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
View details for Web of Science ID 000240838500001
View details for PubMedID 17029489
Only a few small descriptive studies have examined the prevalence and correlates of tobacco use among bipolar patients. We predicted that poorly controlled manic, depressed and mixed states, and the presence of psychotic symptoms, would be associated with a greater prevalence of smoking among patients with bipolar disorder.We examined the prevalence of smoking in a cross-sectional sample of 1904 patients with bipolar disorder enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) database. We also examined the relationship between smoking and other factors including: bipolar subtype, current clinical status, illness severity (e.g., number of prior mood episodes), age of bipolar onset, gender, education, socioeconomic status, and concurrent substance use.At STEP-BD program entry, 31.2% of patients reported that they were smokers. Patients who were male, less educated, and/or had lower income were more likely to be smokers (P<.01). Additionally, patients with rapid cycling, comorbid psychiatric disorders, and/or substance abuse, and those experiencing a current episode of illness were more likely to be smokers (P<.0001). More lifetime depressive and manic episodes as well as greater severity of depressive and manic symptoms were associated with smoking (P<.001). Use of atypical antipsychotic medications was more prevalent among smokers (P=.04).Clinical and demographic variables are associated with smoking in this sample of bipolar patients. Longitudinal analyses are needed to determine how mood and bipolar symptoms interact with smoking over the episodic course of bipolar disorder. Additional studies should focus on whether controlling bipolar symptoms is associated with cessation of smoking.
View details for DOI 10.1016/j.genhosppsych.2005.05.003
View details for Web of Science ID 000232450100004
View details for PubMedID 16168792
Systematic studies of children and adolescents with a diagnosis of bipolar disorder show that rates of attention-deficit/hyperactivity disorder (ADHD) range from 60% to 90%, but the prevalence and implications of ADHD in adults with bipolar disorder are less clear.The first consecutive 1000 adults with bipolar disorder enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were assessed for lifetime ADHD. The retrospective course of bipolar disorder, current mood state, and prevalence of other comorbid psychiatric diagnoses were compared for the groups with and without lifetime comorbid ADHD.The overall lifetime prevalence of comorbid ADHD in this large cohort of bipolar patients was 9.5% (95% confidence interval 7.6%-11.4%); 14.7% of male patients and 5.8% of female patients with bipolar disorder had lifetime ADHD. Patients with bipolar disorder and ADHD had the onset of their mood disorder approximately 5 years earlier. After adjusting for age of onset, those with ADHD comorbidity had shorter periods of wellness and were more frequently depressed. We found that patients with bipolar disorder comorbid with ADHD had a greater number of other comorbid psychiatric diagnoses compared with those without comorbid ADHD, with substantially higher rates of several anxiety disorders and alcohol and substance abuse and dependence.Lifetime ADHD is a frequent comorbid condition in adults with bipolar disorder, associated with a worse course of bipolar disorder and greater burden of other psychiatric comorbid conditions. Studies are needed that focus on the efficacy and safety of treating ADHD comorbid with bipolar disorder.
View details for DOI 10.1016/j.biopsych.2005.01.036
View details for Web of Science ID 000229570500033
View details for PubMedID 15950022
To examine the potential impact of recovery from substance use disorder (SUD) on the course of bipolar disorder among patients diagnosed with both bipolar and substance use disorders according to DSM-IV criteria.As part of the multicenter Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), we examined bipolar disorder status (i.e., whether the patient is recovering or recovered), role functioning, and quality of life in the first 1000 patients to enter the STEP-BD study. We compared patients with no history of SUD, current SUD, and past SUD (i.e., lifetime SUD, but no current SUD) on these parameters. Data were collected between November 1999 and April 2001.A current clinical status of recovering or recovered from bipolar disorder was less likely among patients with current or past SUD compared to patients with no SUD (p < .002). Recovering/recovered status did not differ significantly between patients with current SUD versus past SUD. All 3 groups differed significantly on measures of role functioning as assessed by the Longitudinal Interval Follow-Up Evaluation-Range of Impaired Functioning Tool (LIFE-RIFT), with poorest role functioning among patients with current SUD, followed by patients with past SUD (p = .0002). Patients with current or past SUD reported significantly lower quality of life as measured by the LIFE-RIFT and the Quality of Life Enjoyment and Satisfaction Questionnaire and more lifetime suicide attempts (p < .001) than patients without an SUD; patients with past versus current SUD did not differ significantly on these measures.The results suggest that patients with bipolar disorder who experience sustained remission from an SUD fare better than patients with current SUD, but not as well as subjects with no history of SUD; differences among the 3 groups appear greatest in the area of role functioning.
View details for Web of Science ID 000229989000009
View details for PubMedID 15960566
View details for PubMedID 15273213
Early onset of mood symptoms in bipolar disorder has been associated with poor outcome in many studies; however, the factors that might contribute to poor outcome have not been adequately investigated.The first consecutive 1000 adult bipolar patients enrolled in the National Institute of Mental Health's Systematic Treatment Enhancement Program for Bipolar Disorder were assessed at study entry to determine details of their age of onset of mood symptoms. Clinical course, comorbidity, and functional status and quality of life were compared for groups with very early (age < 13 years), early (age 13-18 years), and adult (age > 18 years) onset of mood symptoms.Of 983 subjects in whom age of onset could be determined, 272 (27.7%) experienced very early onset, and 370 (37.6%) experienced early onset. Earlier onset was associated with greater rates of comorbid anxiety disorders and substance abuse, more recurrences, shorter periods of euthymia, greater likelihood of suicide attempts and violence, and greater likelihood of being in a mood episode at study entry.Very early or early onset of bipolar disorder might herald a more severe disease course in terms of chronicity and comorbidity. Whether early intervention might modify this risk merits further investigation.
View details for DOI 10.1016/j.biopsych.2004.01.022
View details for Web of Science ID 000220922100001
View details for PubMedID 15110730
Mirtazapine is a new antidepressant whose effects on presynaptic adrenergic receptors leads to increased serotonergic transmission, and thus its antidepressant and antianxiety effects. It is equal in practical effectiveness to any currently marked antidepressant but may exert its effects earlier than some others. It is safe, well-tolerated and a useful addition to the drugs currently available for the treatment of mood and anxiety disorders.
View details for DOI 10.1586/1473718.104.22.1685
View details for PubMedID 19810927
Childhood abuse has been implicated as a leading factor in the development of borderline personality disorder (BPD). Data in this report, drawn from an ongoing study of the therapeutic effect of fluoxetine in BPD patients, were gathered in an attempt to replicate previous findings indicating a history of physical abuse in 71% and sexual abuse in 67% of adult BPD subjects. Thirty-one subjects for a study of the pharmacological treatment of BPD or BPD traits met criteria for the study. Those who had been previously hospitalized for a psychiatric disorder, who had recently been suicidal, or who had recent histories of self-mutilation were excluded. Specific information about childhood abuse was gathered using questions from a previous study of abuse histories in BPD patients. All subjects were then interviewed in greater depth regarding past experiences of abuse as part of the ongoing study of the relationship of childhood attachment experience and adult psychopathology. Six of 31 subjects (19.4%) reported a definite history of childhood physical and/or sexual abuse. Four of these subjects met criteria for full BPD, and two met criteria for BPD traits. Three of 31 subjects reported a history of physical abuse (9.7%); five reported a history of sexual abuse (16.1%). Two of the six who reported abuse reported both physical and sexual abuse. A history of childhood abuse is not necessarily linked to the development of BPD or BPD traits in all individuals. The following hypothesis is suggested: BPD may represent a spectrum of symptomatic severity.(ABSTRACT TRUNCATED AT 250 WORDS)
View details for Web of Science ID A1993LP30200007
View details for PubMedID 8348804
View details for Web of Science ID 000300102400242
Recently, the 9(th) International Conference on Bipolar Disorder (ICBD) took place in Pittsburgh, PA, June 9-11, 2011. The conference focused on a number of important issues concerning the diagnosis of bipolar disorders across the life span, advances in neuroscience, treatment strategies for bipolar disorders, early intervention, and medical comorbidity. Several of these topics were discussed in four plenary sessions. This meeting report describes the major points of each of these sessions and included (1) strategies for moving biology forward; (2) bipolar disorder and the forthcoming new DSM-5 nomenclature; (3) management of bipolar disorders-both theory and intervention, with an emphasis on the medical comorbidities; and, (4) a review of several key task force reports commissioned by the International Society for Bipolar Disorder (ISBD).
View details for DOI 10.1111/j.1749-6632.2011.06336.x
View details for Web of Science ID 000301290100001
View details for PubMedID 22191553