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1.  The International Society for Bipolar Disorders (ISBD) Task Force Report on Antidepressant Use in Bipolar Disorders 
The American journal of psychiatry  2013;170(11):1249-1262.
Objective
The risk-benefit profile of antidepressant medications in bipolar disorder is controversial. When conclusive evidence is lacking, expert consensus can guide treatment decisions. The International Society for Bipolar Disorders (ISBD) convened a task force to seek consensus recommendations on the use of antidepressants in bipolar disorders.
Method
An expert task force iteratively developed consensus through serial consensus-based revisions using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new or reworded items and items that needed to be rerated. This process resulted in the final ISBD Task Force clinical recommendations on antidepressant use in bipolar disorder.
Results
There is striking incongruity between the wide use of and the weak evidence base for the efficacy and safety of antidepressant drugs in bipolar disorder. Few well-designed, long-term trials of prophylactic benefits have been conducted, and there is insufficient evidence for treatment benefits with antidepressants combined with mood stabilizers. A major concern is the risk for mood switch to hypomania, mania, and mixed states. Integrating the evidence and the experience of the task force members, a consensus was reached on 12 statements on the use of antidepressants in bipolar disorder.
Conclusions
Because of limited data, the task force could not make broad statements endorsing antidepressant use but acknowledged that individual bipolar patients may benefit from antidepressants. Regarding safety, serotonin reuptake inhibitors and bupropion may have lower rates of manic switch than tricyclic and tetracyclic antidepressants and norepinephrine-serotonin reuptake inhibitors. The frequency and severity of antidepressant-associated mood elevations appear to be greater in bipolar I than bipolar II disorder. Hence, in bipolar I patients antidepressants should be prescribed only as an adjunct to mood-stabilizing medications.
doi:10.1176/appi.ajp.2013.13020185
PMCID: PMC4091043  PMID: 24030475
2.  Extreme Attributions Predict Transition from Depression to Mania or Hypomania in Bipolar Disorder 
Journal of psychiatric research  2013;47(10):1329-1336.
Background
Relatively little is known about psychological predictors of the onset of mania among individuals with bipolar disorder, particularly during episodes of depression. In the present study we investigated attributional style as a predictor of onset of hypomanic, manic or mixed episodes among bipolar adults receiving psychosocial treatment for depression. We hypothesized that “extreme” (i.e., excessively pessimistic or optimistic) attributions would predict a greater likelihood of developing an episode of mood elevation.
Method
Outpatients with DSM-IV bipolar I or II disorder (N=105) enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomly allocated to one of three types of intensive psychotherapy for depression or a brief psychoeducational intervention. Patients completed a measure of attributional style at baseline and were followed prospectively for up to one year. All analyses were by intent to treat.
Results
Logistic regressions and Cox proportional hazards models indicated that extreme (both positively- and negatively-valenced) attributions predicted a higher likelihood of (and shorter time until) transition from depression to a (hypo)manic or mixed episode (ps < .04), independent of the effects of manic or depressive symptom severity at baseline. Extreme attributions were also retrospectively associated with more lifetime episodes of (hypo)mania and depression (ps < .05).
Conclusions
Evaluating extreme attributions may help clinicians to identify patients who are at risk for experiencing a more severe course of bipolar illness, and who may benefit from treatments that introduce greater cognitive flexibility.
doi:10.1016/j.jpsychires.2013.05.016
PMCID: PMC3743936  PMID: 23791456
attributional style; cognitive style; cognitive vulnerability; mania; hypomania; manic switch
3.  Atypical antipsychotic agents; Peas in a pod or chalk and cheese? 
BMC Medicine  2014;12(1):126.
With escalating health expenditure and a shrinking purse, there is increased focus on the cost efficacy of still patented versus generic medications in general, and for atypical antipsychotics in particular. In a recent BMC Medicine article, Godman and colleagues presented data indicating poor uptake of the off patent atypical antipsychotic risperidone, arguing for authorities to mandate its greater use. This is under the assumption of clinical equivalence of atypical antipsychotics. This commentary argues that there are clinically meaningful differences between atypical antipsychotics and important inter-individual heterogeneity in clinical response and tolerability. Access to a broad range of atypical antipsychotics enables clinicians to tailor care, taking consideration of differential efficacy and adverse effects profile in order to meet the needs of individual patients with improved real world effectiveness of treatment. Restriction of agent choice risks detracting from optimal clinical care, with possible poorer outcomes and greater costs of care. A balance between encouraging use of cheapest in class agent and allowing access to various atypical agents for tailored care is likely to produce optimal health outcomes.
Please see related article: http://www.biomedcentral.com/1741-7015/12/98.
doi:10.1186/s12916-014-0126-1
PMCID: PMC4243724
Atypical antipsychotics; Risperidone; Bipolar; Schizophrenia; Generic; Health economics
4.  Prevalence of MTHFR C677T and MS A2756G polymorphisms in major depressive disorder, and their impact on response to fluoxetine treatment 
CNS spectrums  2012;17(2):76-86.
Objective
To examine the prevalence of the C677T polymorphism of the methylene tetrahydrofolate reductase (MTHFR) gene and the A2756G polymorphism of methionine synthase (MS), and their impact on antidepressant response.
Methods
We screened 224 subjects (52% female, mean age 39 ± 11 years) with SCID-diagnosed major depressive disorder (MDD), and obtained 194 genetic samples. 49 subjects (49% female, mean age 36 ± 11 years) participated in a 12-week open clinical trial of fluoxetine 20–60 mg/day. Association between clinical response and C677T and A2756G polymorphisms, folate, B12, and homocysteine was examined.
Results
Prevalence of the C677T and A2756G polymorphisms was consistent with previous reports (C/C=41%, C/T=47%, T/T=11%, A/A=66%, A/G=29%, G/G=4%). In the fluoxetine-treated subsample (n=49), intent-to-treat (ITT) response rates were 47% for C/C subjects and 46% for pooled C/T and T/T subjects (nonsignificant). ITT response rates were 38% for A/A subjects and 60% for A/G subjects (nonsignificant), with no subjects exhibiting the G/G homozygote. Mean baseline plasma B12 was significantly lower in A/G subjects compared to A/A, but folate and homocysteine levels were not affected by genetic status. Plasma folate was negatively associated with treatment response.
Conclusion
The C677T and A2756G polymorphisms did not significantly affect antidepressant response. These preliminary findings require replication in larger samples.
doi:10.1017/S1092852912000430
PMCID: PMC4117348  PMID: 22789065
Methylene Tetrahydrofolate Reductase; MTHFR; Methionine Synthase; MS; C677T; A2756G; depression; antidepressant; fluoxetine
5.  Adverse Clinical Events Among Medicare Beneficiaries Using Antipsychotic Drugs: Linking Health Insurance Benefits and Clinical Needs 
Medical care  2013;51(7):614-621.
Objective
Medicare Part D provides formulary protections for antipsychotics, but does not exempt these drugs from cost-sharing. We investigated the impact of Part D coverage on antipsychotic drug spending, adherence, and clinical outcomes among beneficiaries with varying indications for use.
Methods
We conducted a historical cohort study of Medicare Advantage beneficiaries who received antipsychotic drugs, with diagnoses of schizophrenia or bipolar disorder, or no mental health diagnoses (N=10,190). Half had a coverage gap; half had no gap because of low-income subsidies. Using fixed effects regression models, we examined changes in spending and adherence as beneficiaries experienced cost-sharing increases after reaching the gap. We examined changes in hospitalizations and emergency department visits using proportional hazard models.
Results
Across all diagnostic groups, monthly total antipsychotic spending decreased with cost-sharing increases in the gap compared with those with no gap (e.g., schizophrenia: −$123 [−$138, −$108]), and out-of-pocket spending increased (e.g., schizophrenia: $104 [$98, $110]). Adherence similarly decreased, with the largest declines among those with schizophrenia (−20.6 percentage points [−22.3, −18.9] in proportion of days covered). Among beneficiaries with schizophrenia and bipolar disorder, hospitalizations and emergency department visit rates increased with cost-sharing increases (e.g., schizophrenia: HR=1.32 [1.06, 1.65] for all hospitalizations), but did not among subjects without mental health diagnoses. Clinical event rates did not change among beneficiaries with low income subsidies without gaps.
Conclusions
There is evidence of interruptions in antipsychotic use attributable to Part D cost-sharing. Adverse events increased among beneficiaries with approved indications for use, but not among beneficiaries without such indications.
doi:10.1097/MLR.0b013e31829019c5
PMCID: PMC3687515  PMID: 23752219
Medicare; antipsychotics; benefit design
6.  Linkage Disequilibrium Mapping of the Chromosome 6q21–22.31 Bipolar I Disorder Susceptibility Locus 
We previously reported genome-wide significant evidence for linkage between chromosome 6q and bipolar I disorder (BPI) by performing a meta-analysis of original genotype data from 11 genome scan linkage studies. We now present follow-up linkage disequilibrium mapping of the linked region utilizing 3,047 single nucleotide polymorphism (SNP) markers in a case–control sample (N = 530 cases, 534 controls) and family-based sample (N = 256 nuclear families, 1,301 individuals). The strongest single SNP result (rs6938431, P=6.72× 10−5) was observed in the case–control sample, near the solute carrier family 22, member 16 gene (SLC22A16). In a replication study, we genotyped 151 SNPs in an independent sample (N = 622 cases, 1,181 controls) and observed further evidence of association between variants at SLC22A16 and BPI. Although consistent evidence of association with any single variant was not seen across samples, SNP-wise and gene-based test results in the three samples provided convergent evidence for association with SLC22A16, a carnitine transporter, implicating this gene as a novel candidate for BPI risk. Further studies in larger samples are warranted to clarify which, if any, genes in the 6q region confer risk for bipolar disorder.
doi:10.1002/ajmg.b.30942
PMCID: PMC4067321  PMID: 19308960
bipolar disorder; genetic; association; SLC22A16; 6q
7.  Retrospective age-at-onset of bipolar disorder and outcome during two-year follow-up: results from the STEP-BD study 
Bipolar disorders  2009;11(4):391-400.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1399-5618.2009.00686.x
PMCID: PMC3992980  PMID: 19500092
age of onset; bipolar disorder; chronicity; depression; maintenance; mania; recurrence
8.  Nutrition, Exercise, and Wellness Treatment in bipolar disorder: proof of concept for a consolidated intervention 
Background
This pilot study examines the proof of concept of a consolidated Nutrition, Exercise, and Wellness Treatment (NEW Tx) for overweight individuals with bipolar disorder.
Findings
Five participants completed NEW Tx, a 20-week individual cognitive behavioral therapy-based treatment comprising three modules: Nutrition teaches appropriate serving sizes and balanced diet; Exercise emphasizes increasing weekly physical activity; Wellness focuses on skills for healthy decision-making. Participants attended most sessions and reported high satisfaction with the treatment. Participants’ weight, cholesterol and trigyclerides decreased over the study duration as well as number of daily calories and sugar intake. We found that weekly exercise duration more than tripled over the study duration and depressive symptoms and functioning have improved.
Conclusions
These results offer proof of concept that consolidated NEW Tx is feasible and acceptable and has the potential to improve nutrition, exercise, wellness, and mood symptoms in bipolar disorder. Future iterations of NEW Tx will reflect the strengths and lessons learned from this study.
doi:10.1186/2194-7511-1-24
PMCID: PMC3961757  PMID: 24660139
Bipolar disorder; Exercise; Behavior therapy; Cognitive behavior therapy; Cardiovascular disease
9.  Do Comorbid Anxiety Disorders Moderate the Effects of Psychotherapy for Bipolar Disorder? Results From STEP-BD 
The American journal of psychiatry  2014;171(2):178-186.
Objective
At least 50% of individuals with bipolar disorder have a lifetime anxiety disorder. Individuals with both bipolar disorder and a co-occurring anxiety disorder experience longer illness duration, greater illness severity, and poorer treatment response. The study explored whether comorbid lifetime anxiety in bipolar patients moderates psychotherapy treatment outcome.
Method
In the Systematic Treatment Enhancement Program randomized controlled trial of psychotherapy for bipolar depression, participants received up to 30 sessions of intensive psychotherapy (family-focused therapy, interpersonal and social rhythm therapy, or cognitive-behavioral therapy) or collaborative care, a three-session comparison treatment, plus pharmacotherapy. Using the number needed to treat, we computed effect sizes to analyze the relationship between lifetime anxiety disorders and rates of recovery across treatment groups after 1 year.
Results
A total of 269 patients (113 women) with a comorbid lifetime anxiety disorder (N=177) or without a comorbid lifetime anxiety disorder (N=92) were included in the analysis. Participants with a lifetime anxiety disorder were more likely to recover with psychotherapy than with collaborative care (66% compared with 49% recovered over 1 year; number needed to treat=5.88, small to medium effect). For patients without a lifetime anxiety disorder, there was no difference between rates of recovery in psychotherapy compared with collaborative care (64% compared with 62% recovered; number needed to treat=50, small effect). Participants with one lifetime anxiety disorder were likely to benefit from intensive psychotherapy compared with collaborative care (84% compared with 53% recovered; number needed to treat=3.22, medium to large effect), whereas patients with multiple anxiety disorders exhibited no difference in response to the two treatments (54% compared with 46% recovered; number needed to treat=12.5, small effect).
Conclusions
Depressed patients with bipolar disorder and comorbid anxiety may be in particular need of additional psychotherapy for treating acute depression. These results need to be replicated in studies that stratify bipolar patients to treatments based on their anxiety comorbidity status.
doi:10.1176/appi.ajp.2013.13020225
PMCID: PMC3946300  PMID: 24077657
10.  Transdiagnostic Treatment of Bipolar Disorder and Comorbid Anxiety with the Unified Protocol: A Clinical Replication Series 
Behavior modification  2012;36(4):482-508.
Bipolar disorder (BD) is a chronic, debilitating disorder with recurrent manic and depressive episodes. Over 75% of bipolar patients have a current or lifetime diagnosis of a comorbid anxiety disorder. Comorbid anxiety in BD is associated with greater illness severity, greater functional impairment, and poorer illness-related outcomes. Effectively treating comorbid anxiety in individuals with BD has been recognized as one of the biggest unmet needs in the field of bipolar disorder. Recently, the Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP) was developed to be applicable to the full range of anxiety and mood disorders, based upon converging evidence from genetics, cognitive and affective neuroscience, and behavioral research suggesting common, core emotion-related pathology. Here, we present a preliminary evaluation of the efficacy of the UP for the treatment of BD with comorbid anxiety, in a clinical replication series consisting of three cases.
doi:10.1177/0145445512451272
PMCID: PMC3913370  PMID: 22822175
11.  General Medical Burden in Bipolar Disorder: Findings from the LiTMUS Comparative Effectiveness Trial 
Acta psychiatrica Scandinavica  2013;129(1):10.1111/acps.12101.
Objective
This study examined general medical illnesses and their association with clinical features of bipolar disorder.
Methods
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.
Results
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 percent 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).
Conclusions
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. (Funded by NIMH Contract N01MH80001; ClinicalTrials.gov number NCT00667745).
doi:10.1111/acps.12101
PMCID: PMC3789858  PMID: 23465084
Bipolar disorder; medical comorbidity; obesity; lithium; effectiveness
12.  Association Between Therapeutic Alliance, Care Satisfaction, and Pharmacological Adherence in Bipolar Disorder 
Journal of clinical psychopharmacology  2013;33(3):10.1097/JCP.0b013e3182900c6f.
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.
doi:10.1097/JCP.0b013e3182900c6f
PMCID: PMC3873324  PMID: 23609394
therapeutic alliance; clinical practice; medication adherence; bipolar disorder; treatment
13.  Andrew C Leon 
Neuropsychopharmacology  2012;37(13):2890.
doi:10.1038/npp.2012.201
PMCID: PMC3499720
14.  Nutrition, Exercise, and Wellness Treatment in bipolar disorder: proof of concept for a consolidated intervention 
Background
This pilot study examines the proof of concept of a consolidated Nutrition, Exercise, and Wellness Treatment (NEW Tx) for overweight individuals with bipolar disorder.
Findings
Five participants completed NEW Tx, a 20-week individual cognitive behavioral therapy-based treatment comprising three modules: Nutrition teaches appropriate serving sizes and balanced diet; Exercise emphasizes increasing weekly physical activity; Wellness focuses on skills for healthy decision-making. Participants attended most sessions and reported high satisfaction with the treatment. Participants' weight, cholesterol and trigyclerides decreased over the study duration as well as number of daily calories and sugar intake. We found that weekly exercise duration more than tripled over the study duration and depressive symptoms and functioning have improved.
Conclusions
These results offer proof of concept that consolidated NEW Tx is feasible and acceptable and has the potential to improve nutrition, exercise, wellness, and mood symptoms in bipolar disorder. Future iterations of NEW Tx will reflect the strengths and lessons learned from this study.
doi:10.1186/2194-7511-1-24
PMCID: PMC3961757  PMID: 24660139
Bipolar disorder; Exercise; Behavior therapy; Cognitive behavior therapy; Cardiovascular disease
15.  Sleep Disturbance in Euthymic Bipolar Patients 
Objective
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.
Method
A cohort of bipolar I and II subjects participating in the Systematic Treatment Enhancement Program for Bipolar Disorder who were euthymic for at least eight 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.
Results
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.
Conclusions
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.
doi:10.1177/0269881111421973
PMCID: PMC3787715  PMID: 21965189
Bipolar disorder; sleep disturbance; relapse prevention; treatment
16.  Extreme Attributions Predict the Course of Bipolar Depression: Results from the STEP-BD Randomized Controlled Trial of Psychosocial Treatment 
Objective
Little is known about predictors of recovery from bipolar depression or moderators of treatment response. In the present study we investigated attributional style (a cognitive pattern of explaining the causes of life events) as a predictor of recovery from episodes of bipolar depression and as a moderator of response to psychotherapy for bipolar depression.
Method
106 depressed outpatients with DSM-IV bipolar I or II disorder enrolled in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD) were randomized to intensive psychotherapy for depression (n=62), or collaborative care (n=44), a minimal psychoeducational intervention. The primary outcome was recovery status at each study visit as measured by the Clinical Monitoring Form. Attributional style was measured at baseline using the Attributional Style Questionnaire. Data were collected between 1998 and 2005.
Results
All analyses were by intention to treat. Extreme attributions predicted a lower likelihood of recovery (p=.01, OR=0.93, 95% CI=.88-.98) and longer time until recovery (p<.01, OR=0.96, 95% CI=.93-.99), independent of the effects of initial depression severity. Among individuals with more pessimistic attributional styles, initial depression severity predicted a lower likelihood of recovery (p=.01, OR=0.64, 95% CI=.45-.91) and longer time until recovery (p<.001, OR=0.76, 95% CI=.66-.88). There was no difference in recovery rates between intensive psychotherapy and collaborative care (OR=0.90, 95% CI=0.40-2.01) in the full sample.
Conclusions
These results suggest that extreme, rigid attributions may be associated with a more severe course of depression, and that evaluating attributional style may help clinicians to identify patients who are at risk for experiencing a more severe course of depression.
doi:10.4088/JCP.12m08019
PMCID: PMC3646511  PMID: 23561230
17.  Mindfulness-based Cognitive Therapy for Non-remitted Patients with Bipolar Disorder 
CNS neuroscience & therapeutics  2011;18(2):133-141.
Introduction
Bipolar disorder is characterized by recurrent episodes of depression and/or mania along with inter-episodic mood symptoms that interfere with psychosocial functioning. Despite periods of symptomatic recovery, many individuals with bipolar disorder continue to experience substantial residual mood symptoms that often lead to the recurrence of mood episodes.
Aims
The present study explored whether a new mindfulness-based cognitive therapy (MBCT) for bipolar disorder would increase mindfulness, reduce residual mood symptoms, and increase emotion regulation abilities, psychological well-being, positive affect and psychosocial functioning. Following a baseline clinical assessment, 12 individuals with DSM-IV bipolar disorder were treated with 12 group sessions of MBCT.
Results
At the end of treatment, as well as at the 3-months follow-up, participants showed increased mindfulness, lower residual depressive mood symptoms, less attentional difficulties, and increased emotion regulation abilities, psychological well-being, positive affect and psychosocial functioning.
Conclusions
These findings suggest that treating residual mood symptoms with MBCT may be another avenue to improving mood, emotion regulation, well-being and functioning in individuals with bipolar disorder.
doi:10.1111/j.1755-5949.2011.00236.x
PMCID: PMC3738005  PMID: 22070469
Bipolar Disorder; Residual Symptoms; Well-being; Mindfulness-based Cognitive Therapy; Cognitive-Behavior Therapy
18.  Methods to Limit Attrition in Longitudinal Comparative Effectiveness Trials: Lessons from the Lithium Use for Bipolar Disorder (LiTMUS) Study 
Background
High attrition rates which occur frequently in longitudinal clinical trials of interventions for bipolar disorder limit the interpretation of results.
Purpose
The aim of this article is to present design approaches that limited attrition in the Lithium Use for Bipolar Disorder (LiTMUS) Study.
Methods
LiTMUS was a 6-month randomized, longitudinal multi-site comparative effectiveness trial that examined bipolar participants who were at least mildly ill. Participants were randomized to either low to moderate doses of lithium or no lithium, in addition to other treatments needed for mood stabilization administered in a guideline-informed, empirically supported, and personalized fashion (N=283).
Results
Components of the study design that may have contributed to the low attrition rate of the study included use of: (1) an intent-to-treat design; (2) a randomized adjunctive single-blind design; (3) participant reimbursement; (4) intent-to-attend the next study visit (includes a discussion of attendance obstacles when intention is low); (5) quality care with limited participant burden; and (6) target windows for study visits.
Limitations
Site differences and the effectiveness and tolerability data have not been analyzed yet.
Conclusions
These components of the LiTMUS study design may have reduced the probability of attrition which would inform the design of future randomized clinical effectiveness trials.
doi:10.1177/1740774511427324
PMCID: PMC3700408  PMID: 22076437
Attrition; Randomized Clinical Trial Design; Bipolar disorder; Lithium
19.  Residual Symptoms in Depressed Outpatients Who Respond by 50% But Do Not Remit to Antidepressant Medication 
Little is known about the quantity or quality of residual depressive symptoms in patients with major depressive disorder (MDD) who have responded but not remitted with antidepressant treatment. This report describes the residual symptom domains and individual depressive symptoms in a large representative sample of outpatients with nonpsychotic MDD who responded without remitting after up to 12 weeks of citalopram treatment in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. Response was defined as 50% or greater reduction in baseline 16-item Quick Inventory of Depressive Symptomatology—Self-Report (QIDS-SR16) by treatment exit, and remission as a final QIDS-SR16 of less than 6. Residual symptom domains and individual symptoms were based on the QIDS-SR16 and classified as either persisting from baseline or emerging during treatment. Most responders who did not remit endorsed approximately 5 residual symptom domains and 6 to 7 residual depressive symptoms. The most common domains were insomnia (94.6%), sad mood (70.8%), and decreased concentration (69.6%). The most common individual symptoms were midnocturnal insomnia (79.0%), sad mood (70.8%), and decreased concentration/decision making (69.6%). The most common treatment-emergent symptoms were midnocturnal insomnia (51.4%) and decreased general interest (40.0%). The most common persistent symptoms were midnocturnal insomnia (81.6%), sad mood (70.8%), and decreased concentration/decision making (70.6%). Suicidal ideation was the least common treatment-emergent symptom (0.7%) and the least common persistent residual symptom (17.1%). These findings suggest that depressed outpatients who respond by 50% without remitting to citalopram treatment have a broad range of residual symptoms. Individualized treatments are warranted to specifically address each patient's residual depressive symptoms.
doi:10.1097/JCP.0b013e31820ebd2c
PMCID: PMC3677201  PMID: 21346613
depression; STAR*D; residual; symptoms; treatment response
20.  Customization in Prescribing for Bipolar Disorder 
Health Economics  2011;21(6):653-668.
For many disorders, patient heterogeneity requires physicians to customize their treatment to each patient’s needs. We test for the existence of customization in physicians’ prescribing for bipolar disorder, using data from a naturalistic clinical effectiveness trial of bipolar disorder treatment (STEP-BD), which did not constrain physician prescribing. Multinomial logit is used to model the physician’s choice among five combinations of drug classes. We find that our observed measure of the patient’s clinical status played only a limited role in the choice among drug class combinations, even for conditions such as mania that are expected to affect class choice. However, treatment of a patient with given characteristics differed widely depending on which physician was seen. The explanatory power of the model was low. There was variation within each physician’s prescribing, but the results do not suggest a high degree of customization in physicians’ prescribing, based on our measure of clinical status.
doi:10.1002/hec.1737
PMCID: PMC3164906  PMID: 21506194
Bipolar disorder; pharmaceuticals; prescribing decisions; personalization
21.  Development of an Integrated Psychosocial Treatment to Address the Medical Burden Associated with Bipolar Disorder 
Journal of psychiatric practice  2011;17(3):224-232.
We developed an integrated psychosocial treatment for bipolar disorder to decrease the disproportionate medical burden associated with this illness. Three treatment modules, Nutrition/weight loss, Exercise, and Wellness Treatment (NEW Tx) were administered in twelve 60-minute group sessions over 14 weeks. After the first group (N = 4) had completed the treatment, it was revised, and then a second group (N = 6) completed the revised treatment. Participants completed all of the study assessments and attended 82% of the sessions. Both groups added over 100 minutes of weekly exercise to their baseline duration. Participants in the second group showed improvements in their quality of life, depressive symptoms, and weight. It appears that NEW Tx may be a feasible intervention with promising pilot data for reducing the medical burden in bipolar disorder, but future research is needed to further evaluate the efficacy of NEW Tx.
doi:10.1097/01.pra.0000398419.82362.32
PMCID: PMC3659403  PMID: 21587004
bipolar disorder; psychosocial treatment; diet; exercise; cognitive-behavioral therapy
22.  Psychosocial Treatments for Bipolar Depression: A 1-Year Randomized Trial From the Systematic Treatment Enhancement Program 
Archives of general psychiatry  2007;64(4):419-426.
Context
Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
Objective
To examine the benefits of 4 disorder-specific psychotherapies in conjunction with pharmacotherapy on time to recovery and the likelihood of remaining well after an episode of bipolar depression.
Design
Randomized controlled trial.
Setting
Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder.
Patients
A total of 293 referred outpatients with bipolar I or II disorder and depression treated with protocol pharmacotherapy were randomly assigned to intensive psychotherapy (n=163) or collaborative care (n=130), a brief psychoeducational intervention.
Interventions
Intensive psychotherapy was given weekly and biweekly for up to 30 sessions in 9 months according to protocols for family-focused therapy, interpersonal and social rhythm therapy, and cognitive behavior therapy. Collaborative care consisted of 3 sessions in 6 weeks.
Main Outcome Measures
Outcome assessments were performed by psychiatrists at each pharmacotherapy visit. Primary outcomes included time to recovery and the proportion of patients classified as well during each of 12 study months.
Results
All analyses were by intention to treat. Rates of attrition did not differ across the intensive psychotherapy (35.6%) and collaborative care (30.8%) conditions. Patients receiving intensive psychotherapy had significantly higher year-end recovery rates (64.4% vs 51.5%) and shorter times to recovery than patients in collaborative care (hazard ratio, 1.47; 95% confidence interval, 1.08–2.00; P=.01). Patients in intensive psychotherapy were 1.58 times (95% confidence interval, 1.17–2.13) more likely to be clinically well during any study month than those in collaborative care (P=.003). No statistically significant differences were observed in the outcomes of the 3 intensive psychotherapies.
Conclusions
Intensive psychosocial treatment as an adjunct to pharmacotherapy was more beneficial than brief treatment in enhancing stabilization from bipolar depression. Future studies should compare the cost-effectiveness of models of psychotherapy for bipolar disorder.
Trial Registration
clinicaltrials.gov Identifier: NCT00012558
doi:10.1001/archpsyc.64.4.419
PMCID: PMC3579612  PMID: 17404119
23.  Stability of symptoms across major depressive episodes in bipolar disorder 
Bipolar disorders  2009;11(8):867-875.
Objective
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1111/j.1399-5618.2009.00764.x
PMCID: PMC3566555  PMID: 19922555
bipolar disorder; factor analysis; major depression; mixed state; psychosis; subtype; suicide; symptom stability
24.  Mindfulness-Based Cognitive Therapy for Bipolar Disorder: Effects on Cognitive Functioning 
Journal of Psychiatric Practice  2011;17(6):410-419.
Bipolar disorder is associated with impairments in cognition, including difficulties in executive functioning, even when patients are euthymic (neither depressed nor manic). The purpose of this study was to assess changes in self-reported cognitive functioning in patients with bipolar disorder who participated in an open pilot trial of mindfulness-based cognitive therapy (MBCT). Following MBCT, patients reported significant improvements in executive functioning, memory, and ability to initiate and complete tasks, as measured by the Behavior Rating Inventory of Executive Function (BRIEF) and the Frontal Systems Behavior Scale (FrSBe). Changes in cognitive functioning were correlated with increases in mindful, nonjudgmental observance and awareness of thoughts, feelings, and sensations, and were not associated with decreases in depression. Improvements tended to diminish after termination of treatment, but some improvements, particularly those in executive functioning, persisted after 3 months. These results provide preliminary evidence that MBCT may be a treatment option that can be used as an adjunct to medication to improve cognitive functioning in bipolar disorder.
doi:10.1097/01.pra.0000407964.34604.03
PMCID: PMC3277324  PMID: 22108398
bipolar disorder; executive functioning; cognitive functioning; mindfulness; mindfulness-based cognitive therapy (MBCT); psychosocial treatment
25.  Association study of 21 circadian genes with bipolar I disorder, schizoaffective disorder, and schizophrenia 
Bipolar Disorders  2009;11(7):701-710.
Objective
Published studies suggest associations between circadian gene polymorphisms and bipolar I disorder (BPI), as well as schizoaffective disorder (SZA) and schizophrenia (SZ). The results are plausible, based on prior studies of circadian abnormalities. As replications have not been attempted uniformly, we evaluated representative, common polymorphisms in all three disorders.
Methods
We assayed 276 publicly available ‘tag’ single nucleotide polymorphisms (SNPs) at 21 circadian genes among 523 patients with BPI, 527 patients with SZ/SZA, and 477 screened adult controls. Detected associations were evaluated in relation to two published genome-wide association studies (GWAS).
Results
Using gene-based tests, suggestive associations were noted between EGR3 and BPI (p = 0.017), and between NPAS2 and SZ/SZA (p = 0.034). Three SNPs were associated with both sets of disorders (NPAS2: rs13025524 and rs11123857; RORB: rs10491929; p < 0.05). None of the associations remained significant following corrections for multiple comparisons. Approximately 15% of the analyzed SNPs overlapped with an independent study that conducted GWAS for BPI; suggestive overlap between the GWAS analyses and ours was noted at ARNTL.
Conclusions
Several suggestive, novel associations were detected with circadian genes and BPI and SZ/SZA, but the present analyses do not support associations with common polymorphisms that confer risk with odds ratios greater than 1.5. Additional analyses using adequately powered samples are warranted to further evaluate these results.
doi:10.1111/j.1399-5618.2009.00756.x
PMCID: PMC3401899  PMID: 19839995
association; bipolar disorder; circadian; gene; schizoaffective disorder; schizophrenia

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