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1.  Cigarette smoking and subsequent risk of suicidal ideation among National Guard Soldiers 
Journal of affective disorders  2012;145(1):111-114.
Suicide rates are alarmingly high among military personnel, and particularly Army National Guard soldiers. Smoking is also disproportionately common in the military. In this study, we intend to investigate the relationship between cigarette smoking and suicidal ideation among a representative sample of national guard soldiers.
A representative sample of Ohio Army National Guard soldiers were followed prospectively and information was gathered on smoking, suicidal ideation and depression at baseline and one year later.
Smoking at baseline was associated with significantly increased likelihood of suicidal ideation at follow-up (OR=2.0 (1.3, 3.2)). This association persisted after adjusting for demographics and history of depression at baseline, but was no longer statistically significant after adjusting for depression at follow-up.
Measurement of smoking was somewhat limited.
Army National Guard soldiers who smoke have a greater risk of subsequent suicidal ideation. Depression concurrent with suicidal ideation appears to explain this relationship. If these results are replicated, screening of soldiers who smoke may be recommended as a proactive step towards mitigating the high risk of suicide in military personnel.
PMCID: PMC3701306  PMID: 23141668
military; smoking; suicide; epidemiology; depression
3.  Depressive Symptoms and Diabetes 
PMCID: PMC3904750  PMID: 19001617
4.  General Medical Burden in Bipolar Disorder: Findings from the LiTMUS Comparative Effectiveness Trial 
Acta psychiatrica Scandinavica  2013;129(1):10.1111/acps.12101.
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 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).
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; number NCT00667745).
PMCID: PMC3789858  PMID: 23465084
Bipolar disorder; medical comorbidity; obesity; lithium; effectiveness
5.  Lamotrigine as add-on treatment to lithium and divalproex: lessons learned from a double-blind, placebo-controlled trial in rapid-cycling bipolar disorder 
Bipolar disorders  2012;14(7):780-789.
A substantial portion of the morbidity associated with rapid-cycling bipolar disorder (RCBD) stems from refractory depression. This study assessed the antidepressant effects of lamotrigine as compared with placebo when used as add-on therapy for rapid-cycling bipolar depression non-responsive to the combination of lithium plus divalproex.
During Phase 1 of this trial, hypomanic, manic, mixed, and/or depressed outpatients (n = 133) aged 18–65 with DSM-IV RCBD type I or II were initially treated with the open combination of lithium and divalproex for up to 16 weeks. During Phase 2, subjects who did not meet the criteria for stabilization (n = 49) (i.e., remained or cycled into the depressed phase) were randomly assigned to double-blind, adjunctive lamotrigine (n = 23) or adjunctive placebo (n = 26). The primary endpoint was the mean change in depression symptom severity from the beginning of Phase 2 to the end of Phase 2 (week 12) on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Data were analyzed by analysis of covariance with last observation carried forward and a mixed-models analysis.
During Phase 1, a high rate of study discontinuations occurred due to intolerable side effects (13/133; 10%) and study non-adherence (22/133; 17%). Only 14% (19/133) stabilized on the open combination of lithium and divalproex. Among the 49 (37%) patients randomized to the double-blind adjunctive treatment phase, mean ± standard error change from baseline on the MADRS total score was −8.5 ± 1.7 points for lamotrigine and −9.1 ± 1.5 points for placebo (p = NS; mixed-models analysis). No significant differences were observed in the rates of response, remission, or bimodal response between lamotrigine and placebo.
The poor tolerability, lack of efficacy, and high rate of early discontinuation with the combination of lithium and divalproex suggests this regimen was ineffective for the majority of patients with RCBD. Among patients who did not stabilize on lithium and divalproex, the addition of lamotrigine was no more effective than placebo in reducing depression severity. The findings suggest an opportunity for several design modifications to enhance signal detection in future trials of RCBD. The main limitation is the small number of subjects randomized to double-blind treatment.
PMCID: PMC3640341  PMID: 23107222
rapid-cycling; bipolar depression; failed clinical trial; combination treatment; lamotrigine; lithium; divalproex
6.  Methods to Limit Attrition in Longitudinal Comparative Effectiveness Trials: Lessons from the Lithium Use for Bipolar Disorder (LiTMUS) Study 
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 Use for Bipolar Disorder (LiTMUS) Study.
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).
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.
Site differences and the effectiveness and tolerability data have not been analyzed yet.
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.
PMCID: PMC3700408  PMID: 22076437
Attrition; Randomized Clinical Trial Design; Bipolar disorder; Lithium
7.  Metabolic syndrome in patients enrolled in a clinical trial of aripiprazole in the maintenance treatment of bipolar I disorder 
The Journal of clinical psychiatry  2010;71(9):1138-1144.
To compare the effects of maintenance treatment with aripiprazole or placebo on the incidence of metabolic syndrome in bipolar disorder.
Patients with bipolar I disorder were stabilized on aripiprazole for 6–18 weeks prior to double-blind randomization to aripiprazole or placebo for 26 weeks. The rate of metabolic syndrome in each group was calculated at maintenance phase baseline (randomization) and endpoint for evaluable patients using an LOCF approach. Metabolic syndrome was defined using the National Cholesterol Education Program Adult Treatment Panel III criteria.
At entry into the maintenance phase, overall 45/125 patients (36.0%) met criteria for metabolic syndrome. Mean changes in the five components of metabolic syndrome (waist circumference, triglycerides, high-density lipoprotein cholesterol, blood pressure and glucose) from baseline to Week 26 were small except for a meaningful reduction in triglycerides (placebo −18.9 mg/dL; aripiprazole −11.5 mg/dL). By the end of the maintenance phase (endpoint, LOCF), 5/18 placebo-treated patients (27.8%) and 4/14 aripiprazole-treated patients (28.6%) no longer met metabolic syndrome criteria. The proportion of patients with metabolic syndrome was similar in the placebo and aripiprazole groups both at baseline and Week 26. There were no significant changes in any of the individual components of metabolic syndrome between aripiprazole- and placebo-treated patients during maintenance phase treatment.
The prevalence of metabolic syndrome in patients with bipolar disorder is higher than commonly reported in the general population. The effect of 26 weeks of treatment with aripiprazole on the incidence of metabolic syndrome and its components was similar to placebo.
PMCID: PMC3590811  PMID: 20492838
bipolar disorder; metabolic syndrome; cholesterol; obesity; triglycerides; blood pressure; maintenance trial
8.  A 6-Month, Double-Blind, Maintenance Trial of Lithium Monotherapy Versus the Combination of Lithium and Divalproex for Rapid-Cycling Bipolar Disorder and Co-Occurring Substance Abuse or Dependence 
To assess whether combination treatment with lithium and divalproex is more effective than lithium monotherapy in prolonging the time to mood episode recurrence in patients with rapid-cycling bipolar disorder (RCBD) and comorbid substance abuse and/or dependence.
A 6-month, double-blind, parallel group comparison was carried out in recently manic/hypomanic/mixed patients who had demonstrated a persistent bimodal response to combined treatment with lithium and divalproex. Subjects were randomly assigned to remain on combination treatment or to discontinue divalproex and remain on lithium monotherapy.
Of 149 patients enrolled into the open-label acute stabilization phase, 79% discontinued prematurely (poor adherence: 42%; nonresponse: 25%; intolerable side effects: 10%). Of 31 patients (21%) randomly assigned to double-blind maintenance treatment, 55% relapsed (24% into depression and 76% into a manic/hypomanic/mixed episode), 26% completed the study, and 19% were poorly adherent or exited prematurely. The median time to recurrence of a new mood episode was 15.9 weeks for patients receiving lithium monotherapy and 17.8 weeks for patients receiving the combination of lithium and divalproex (p=NS). The rate of relapse into a mood episode for those receiving lithium monotherapy or the combination of lithium and divalproex was 56% and 53%, respectively. The rate of depressive relapse in both arms was 13%, while the rate of relapse into a manic, hypomanic, or mixed episode was 44% for lithium monotherapy and 40% for the combination of lithium and divalproex.
A small subgroup of patients in this study stabilized after six months of treatment with lithium plus divalproex. Of those who did, the addition of divalproex to lithium conferred no additional prophylactic benefit over lithium alone. Although depression is regarded as the hallmark of RCBD in general, these data suggest that recurrent episodes of mania tend to be more common in presentations accompanied by comorbid substance use.
PMCID: PMC3587136  PMID: 19192457
Bipolar disorder; Rapid cycling; Dual-diagnosis; Substance use disorder; Maintenance trial; Placebo-controlled trial; Lithium; Divalproex; Combination pharmacotherapy
9.  Intensive Psychosocial Intervention Enhances Functioning in Patients With Bipolar Depression: Results From a 9-Month Randomized Controlled Trial 
The American journal of psychiatry  2007;164(9):1340-1347.
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.
PMCID: PMC3579578  PMID: 17728418
10.  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.
Psychosocial interventions have been shown to enhance pharmacotherapy outcomes in bipolar disorder.
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.
Randomized controlled trial.
Fifteen clinics affiliated with the Systematic Treatment Enhancement Program for Bipolar Disorder.
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.
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.
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.
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 Identifier: NCT00012558
PMCID: PMC3579612  PMID: 17404119
11.  Stability of symptoms across major depressive episodes in bipolar disorder 
Bipolar disorders  2009;11(8):867-875.
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.
PMCID: PMC3566555  PMID: 19922555
bipolar disorder; factor analysis; major depression; mixed state; psychosis; subtype; suicide; symptom stability
12.  Ziprasidone with Adjunctive Mood Stabilizer in the Maintenance Treatment of Bipolar I Disorder: Long-term Changes in Weight and Metabolic Profiles 
This analysis was conducted to compare the effects of adjunctive ziprasidone or placebo on metabolic parameters among patients receiving maintenance treatment with lithium or valproate. We also tested whether metabolic syndrome (MetS) and other risk factors were associated with baseline characteristics and treatment response. In the stabilization phase (Phase 1), 584 bipolar I disorder (DSM-IV) patients received 2.5-4 months of open label ziprasidone (80-160 mg/d) plus lithium or valproic acid (ZIP+MS). Patients who achieved at least 8 weeks of clinical stability were subsequently randomized into Phase 2 to 6-months of double-blind treatment with ZIP+MS (N=127) vs. placebo+MS (N=113). At baseline of Phase 1, MetS was found in 111 participants (23%). Participants with MetS (vs. non-MetS participants) were more likely to be aged 40 years or older, had significantly more severe manic symptoms, higher abdominal obesity, and higher BMI. Increase in abdominal obesity was associated with lower manic symptom improvement (p<0.05, as assessed by MRS change score) during Phase 1, while symptom improvement differed across racial groups. In the Phase 2 double-blind phase, the ZIP+MS group had similar weight and metabolic profiles compared to the placebo+MS group across visits. These results corroborate existing findings on ziprasidone which exhibits a neutral weight and metabolic profile in the treatment of schizophrenia and bipolar patients. Our findings suggest that MetS is highly prevalent in patients with bipolar disorder, may be associated with greater manic symptom severity, and may predict treatment outcomes.
PMCID: PMC3225596  PMID: 21798721
Metabolic syndrome; medical comorbidity; treatment remission; ziprasidone
13.  Use of Insulin Sensitizers for the Treatment of Major Depressive Disorder: A Pilot Study of Pioglitazone for Major Depression Accompanied by Abdominal Obesity 
Journal of Affective Disorders  2011;136(3):1164-1173.
This study was conducted to examine the safety and efficacy of pioglitazone, a thiazolidinedione insulin sensitizer, in adult outpatients with major depressive disorder.
In a 12-week, open-label, flexible-dose study, 23 patients with major depressive disorder received pioglitazone monotherapy or adjunctive therapy initiated at 15mg daily. Subjects were required to meet criteria for abdominal obesity (waist circumference >35 in. in women and >40 in. in men) or metabolic syndrome. The primary efficacy measure was the change from baseline to Week 12 on the Inventory of Depressive Symptomatology (IDS) total score. Partial responders (≥25% decrease in IDS total score) were eligible to participate in an optional extension phase for an additional three months.
Pioglitazone decreased depression symptom severity from a total IDS score of 40.3 ± 1.8 to 19.2 ± 1.8 at week 12 (p<.001). Among partial responders (≥ 25% decrease in IDS total score), an improvement in depressive symptoms was maintained during an additional 3-month extension phase (total duration = 24 weeks) according to IDS total scores (p<.001). Patients experienced a reduction in insulin resistance from baseline to Week 12 according to the log homeostasis model assessment (−0.8 ± 0.75; p<.001) and a significant reduction in inflammation as measured by log highly- sensitive C-reactive protein (−0.87 ± 0.72; p<.001). During the current episode, the majority of participants (74%, n=17), had already failed at least one antidepressant trial. The most common side effects were headache and dizziness; no patient discontinued due to side effects.
These data are limited by a small sample size and an open-label study design with no placebo control.
Although preliminary, pioglitazone appears to reduce depression severity and improve several markers of cardiometabolic risk, including insulin resistance and inflammation. Larger, placebo-controlled studies are indicated.
PMCID: PMC3225727  PMID: 21782251
14.  Antipsychotic-Induced Extrapyramidal Side Effects in Bipolar Disorder and Schizophrenia 
Newer atypical antipsychotics have been reported to cause a lower incidence of extrapyramidal side effects (EPS) than conventional agents. This review is to compare antipsychotic-induced EPS relative to placebo in bipolar disorder (BPD) and schizophrenia.
English-language literature cited in Medline was searched with terms antipsychotics, placebo-controlled trial, and bipolar disorder or schizophrenia and then with antipsychotic (generic/brand name), safety, akathisia, EPS, or anticholinergic use, bipolar mania/depression, BPD, or schizophrenia, and randomized clinical trial. Randomized, double-blind, placebo-controlled, monotherapy studies with comparable doses in both BPD and schizophrenia were included. Absolute risk increase and number needed to treat to harm (NNTH) for akathisia, overall EPS, and anticholinergic use relative to placebo were estimated.
Eleven trials in mania, 4 in bipolar depression, and 8 in schizophrenia were included. Haloperidol significantly increased the risk for akathisia, overall EPS, and anticholinergic use in both mania and schizophrenia, with a larger magnitude in mania, an NNTH for akathisia of 4 versus 7, EPS of 3 versus 5, and anticholinergic use of 2 versus 4, respectively Among atypical antipsychotics, only ziprasidone significantly increased the risk for overall EPS and anticholinergic use in both mania and schizophrenia, again with larger differences in mania, an NNTH for overall EPS of 11 versus 19, and anticholinergic use of 5 versus 9. In addition, risks were significantly increased for overall EPS (NNTH = 5) and anticholinergic use (NNTH = 5) in risperidone-treated mania, akathisia in aripiprazole-treated mania (NNTH = 9) and bipolar depression (NNTH = 5), and overall EPS (NNTH = 19) in quetiapine-treated bipolar depression.
Bipolar patients, especially in depression, were more vulnerable to having acute antipsychotic-induced movement disorders than those with schizophrenia.
PMCID: PMC3489178  PMID: 18344731
15.  Number Needed to Treat to Harm for Discontinuation Due to Adverse Events in the Treatment of Bipolar Depression, Major Depressive Disorder, and Generalized Anxiety Disorder With Atypical Antipsychotics 
The Journal of clinical psychiatry  2010;72(8):1063-1071.
To estimate the number needed to treat to harm (NNTH) for discontinuation due to adverse events with atypical antipsychotics relative to placebo during the treatment of bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD).
Data Sources
English-language literature published and cited in MEDLINE from January 1966 to May 2009 was searched with the terms antipsychotic, atypical antipsychotic, generic and brand names of atypical antipsychotics, safety, tolerability, discontinuation due to adverse events, somnolence, sedation, weight gain, akathisia, or extrapyramidal side effect; and bipolar depression, major depressive disorder, or generalized anxiety disorder, and randomized, placebo-controlled clinical trial. This search was augmented with a manual search.
Study Selection
Studies with a cumulative sample of ≥ 100 patients were included.
Data Extraction
The NNTHs for discontinuation due to adverse events, somnolence, sedation, ≥ 7% weight gain, and akathisia relative to placebo were estimated with 95% confidence intervals to reflect the magnitude of variance.
Data Synthesis
Five studies in bipolar depression, 10 studies in MDD, and 4 studies in GAD were identified. Aripiprazole and olanzapine have been studied in bipolar depression and refractory MDD. Only quetiapine extended release (quetiapine-XR) has been studied in 3 psychiatric conditions with different fixed dosing schedules. For aripiprazole, the mean NNTH for discontinuation due to adverse events was 14 in bipolar depression, but was not significantly different from placebo in MDD. For olanzapine, the mean NNTHs were 24 in bipolar depression and 9 in MDD. The risk for discontinuation due to adverse events during quetiapine-XR treatment appeared to be associated with dose. For quetiapine-XR 300 mg/d, the NNTHs for discontinuation due to adverse events were 9 for bipolar depression, 8 for refractory MDD, 9 for MDD, and 5 for GAD.
At the same dose of quetiapine-XR, patients with GAD appeared to have a lower tolerability than those with bipolar depression or MDD, Due to flexible dosing, the risk for discontinuation due to adverse events in the treatment of bipolar depression, MDD, or GAD with other atypical antipsychotics could not be compared.
PMCID: PMC3457049  PMID: 21034695
16.  Correlates of Historical Suicide Attempt in Rapid-Cycling Bipolar Disorder: A Cross-Sectional Assessment 
The Journal of clinical psychiatry  2009;70(7):1032-1040.
A rapid-cycling course in bipolar disorder has previously been identified as a risk factor for attempted suicide. This study investigated factors associated with suicide attempts in patients with rapid-cycling bipolar I or II disorder.
Cross-sectional data at the initial assessment of patients who were enrolled into 4 clinical trials were used to study the factors associated with suicide attempt. An extensive clinical interview and the Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid-cycling bipolar disorder, substance use disorders, anxiety disorders, psychosis, and other clinical variables. Chi-square, t test, and logistic regression or Poisson regression were used to analyze the data where appropriate, with odds ratios (ORs) for relative risk estimate. The data were collected from September 1995 to June 2005.
In a univariate analysis, 41% of 561 patients had at least 1 lifetime suicide attempt. Earlier age of depression onset, bipolar I subtype, female sex, unmarried status, and a history of drug use disorder, panic disorder, sexual abuse, and psychosis were associated with significantly higher rates of attempted suicide (all p<.05). After considering 31 potential confounding factors in the stepwise logistic regression model (n = 387), any Axis I comorbidity (OR=2.68, p = .0219), female sex (OR= 2.11, p = .0005), psychosis during depression (OR = 1.84, p = .0167), bipolar I subtype (OR= 1.83, p = .0074), and history of drug abuse (OR = 1.62, p = .0317) were independent predictors for increased risk of attempted suicide. However, white race was associated with a lower risk for suicide attempt (OR = 0.47, p = .0160). Psychosis during depression (p = .0003), bipolar I subtype (p = .0302), and physical abuse (p = .0195) were associated with increased numbers of suicide attempts by 248%, 166%, and 162%, respectively; white race was associated with a 60% decrease in the number of suicide attempts (p=.0320).
In this highly comorbid group of patients with rapid-cycling bipolar disorder, 41% had at least 1 suicide attempt. Among the demographics, female sex was positively associated, but white race was negatively associated, with the risk for suicide attempt. Independent clinical variables for increased risk and/or number of attempted suicides were any Axis I comorbidity, psychosis during depression, bipolar I subtype, a history of drug abuse, and physical abuse.
PMCID: PMC3457055  PMID: 19653978
17.  Lamotrigine Adjunctive Therapy to Lithium and Divalproex in Depressed Patients with Rapid Cycling Bipolar Disorder and a Recent Substance Use Disorder: A 12 Week, Double-Blind, Placebo-Controlled Pilot Study 
Psychopharmacology bulletin  2010;43(4):5-21.
To pilot the efficacy and safety data of lamotrigine adjunctive therapy to lithium and divalproex in patients with rapid-cycling bipolar disorder (RCBD) and a recent substance use disorder (SUD).
Structured Clinical interviews were used to ascertain DSM-IV diagnosis of RCBD, SUDs, and other Axis I disorders. Patients who did not meet the criteria for a bimodal response after up to 16-weeks of open-label treatment with lithium plus divalproex, as measured by MADRS (Montgomery-Asberg Depression Rating Scale) ≤ 19, YMRS (Young Mania Rating Scale) ≤ 12 and GAF (Global Assessment of Functioning) ≥ 51 for 4 weeks, were rendomized to a 12-week, double-blind addition of lamotrigine or placebo to lithium plus divalproex. Primary and secondary outcomes were analyzed with ANCOVA, t-test, of chi-square/Fisher's exact.
Of 98 patients enrolled into the study, 36 were randomized to receive lamotrigine (n = 18) or placebo (n = 18), and 8 patients per arm completed the study. No patient discontinued due to adverse events. The change in MADRS total score from baseline to endpoint was –9.1 ± 11.2 in lamotrigine-treated patients versus –4.5 ± 13.1 in placebo-treated patients (p = 0.27). Therre were no significant differences in changes in YMRS total scores and rates of response or remission.
Lamotrigine adjunctive therapy was well toletated in patients previously non-responsive to initial treatment of lithium plus divalproex. A larger study is warranted to determine the efficacy and safety of adjunctive lamotrigine versus placebo in RCBD with a recent SUD.
PMCID: PMC3442254  PMID: 21240149
Bipolar disorder; substance use disorder; mood stabilizer; lamotrigine; placebo-controlled trial; treament-refractory
18.  Comparisons of the tolerability and sensitivity of quetiapine-XR in the acute treatment of schizophrenia, bipolar mania, bipolar depression, major depressive disorder, and generalized anxiety disorder 
Quetiapine extended-release (quetiapine-XR) has been studied in patients with schizophrenia, bipolar mania, bipolar depression, major depressive disorder (MDD), and generalized anxiety disorder (GAD). The purpose of this study was to compare the tolerability and sensitivity of quetiapine-XR among these psychiatric conditions. The discontinuation due to adverse events (DAEs) and reported somnolence in randomized, double-blind, placebo-controlled studies of quetiapine-XR in these psychiatric conditions were examined. The absolute risk reduction or increase and the number needed to treat to benefit (NNTB) or harm (NNTH) for DAEs and reported somnolence of quetiapine-XR ≥300 mg/d relative to placebo were estimated. Data from one study in schizophrenia (n=465), one in mania (n=316), one in bipolar depression (n=280), two in refractory MDD (n=624), two in MDD (n=669) and three in GAD (n=1109) were available. The risk for DAEs of quetiapine-XR relative to placebo was significantly increased in bipolar depression (NNTH=9), refractory MDD (NNTH=8), MDD (NNTH=9), and GAD (NNTH=5), but not in schizophrenia and mania. The risk for reported somnolence of quetiapine-XR relative to placebo was significantly increased in schizophrenia (600 mg/d NNTH=15 and 800 mg/d NNTH=11), mania (NNTH=8), bipolar depression (NNTH=4), refractory MDD (NNTH=5), MDD (NNTH=5) and GAD (NNTH=5). These results suggest that patients with GAD had the poorest tolerability during treatment with quetiapine-XR, but they had a similar sensitivity as those with bipolar depression and MDD. Patients with schizophrenia or mania had a higher tolerability and a lower sensitivity than those with bipolar depression, MDD, or GAD.
PMCID: PMC3433839  PMID: 20875219
Atypical antipsychotic; bipolar disorder; generalized anxiety disorder; major depressive disorder; schizophrenia
19.  A Comparison of the Life Goals Program and Treatment as Usual for Individuals With Bipolar Disorder 
This randomized controlled study of 164 outpatients with bipolar disorder in a community mental health center who received standardized psychoeducation (Life Goals Program [LGP]) or treatment as usual sought to determine whether there were differences between the groups in medication adherence attitudes and behaviors.
Patients were randomly assigned to treatment as usual (N=80) or treatment as usual plus LGP (N=84) and were assessed at baseline and at the three-, six-, and 12-month follow-up. Primary outcomes were change in score from baseline on the Drug Attitude Inventory (DAI) and on self-reported treatment adherence behaviors (SRTAB).
At baseline, there were no significant differences between the two groups. Slightly less than half (N=41, 49%) of the LGP group participated in most or all (four to six) LGP sessions, 14% (N=12) participated in one to three sessions, and 37% (N=31) did not participate in any sessions. At the 12-month follow-up there was improvement among all patients, with no significant differences between the two groups, in DAI scores, SRTAB, symptoms, psychopathology, and functional status. Greater depressive severity at baseline was associated with more negative attitudes toward treatment over time, although this finding was not significant (p=.056). Secondary analysis of persons in the LGP group found that compared with those who did not go to any LGP sessions, those with partial or full participation in LGP sessions had improved attitudes toward medication at the three- and six-month follow-up, but no difference was found between the three LGP subgroups by the 12-month follow-up.
There were no differences between two groups in treatment attitudes at the 12-month follow-up. Low attendance rates mitigated effects on primary outcomes. Effects of LGP may become lost over time without ongoing intervention, and individuals with depression may have reduced response to LGP.
PMCID: PMC3148581  PMID: 19723732
20.  Personal and Societal Construction of Illness Among Individuals With Rapid-Cycling Bipolar Disorder: A Life-Trajectory Perspective 
Bipolar disorder is a chronic mental illness associated with substantial impairment in quality of life and function. Although there has been tremendous growth in understanding bipolar disorder with respect to treatments, very little study has focused on the viewpoint of affected individuals. The purpose of this study was to examine the subjective experience of illness among 19 men and women with rapid cycling bipolar disorder receiving treatment at an academic psychiatry clinic.
Personal constructs of illness with respect to life-trajectory and societal reaction to the individual, specifically the issue of stigma, were evaluated using a semistructured, open-ended anthropological interview.
Participants perceived bipolar disorder as a disease with biologic underpinnings. Stigma was a major issue for all individuals. In common with individuals without serious mental illness, individuals with bipolar disorder work at mastering developmental tasks appropriate for their life stage. At times, younger individuals appeared to have difficulty separating their own identity from the effects of illness. For older individuals with bipolar disorder, life was perceived to be disrupted by bipolar disorder, with early plans and dreams often “derailed.”
Although bipolar disorder may severely alter an individual’s planned life trajectory, accomplishment of life goals can at least partially offset the sense of loss that is often seen in bipolar illness.
PMCID: PMC3148582  PMID: 18070834
Bipolar disorder; stigma; rapid cycling; life course; aging; subjective experience
21.  Medical comorbidity in bipolar disorder: relationship between illnesses of the endocrine/metabolic system and treatment outcome 
Bipolar disorders  2010;12(4):404-413.
The present study examined the relationship between medical burden in bipolar disorder and several indicators of illness severity and outcome. It was hypothesized that illnesses of the endocrine/metabolic system would be associated with greater psychiatric symptom burden and would impact the response to treatment with lithium and valproate.
Data were analyzed from two studies evaluating lithium and valproate for rapid-cycling presentations of bipolar I and II disorder. General medical comorbidity was assessed by the Cumulative Illness Rating Scale (CIRS). Descriptive statistics and logistic regression analyses were conducted to explore the relationships between medical burden, body mass index (BMI), substance use disorder status, and depressive symptom severity.
Of 225 patients enrolled, 41.8% had a recent substance use disorder, 50.7% were male, and 69.8% had bipolar I disorder. The mean age of the sample was 36.8 (SD = 10.8) years old. The mean number of comorbid medical disorders per patient was 2.5 (SD = 2.5), and the mean CIRS total score was 4.3 (SD = 3.1). A significant positive correlation was observed between baseline depression severity and the number of organ systems affected by medical illness (p = 0.04). Illnesses of the endocrine/metabolic system were inversely correlated with remission from depressive symptoms (p = 0.02), and obesity was specifically associated with poorer treatment outcome. For every 1-unit increase in BMI, the likelihood of response decreased by 7.5% [odds ratio (OR) = 0.93, 95% confidence interval (CI): 0.87–0.99; p = 0.02] and the likelihood of remission decreased by 7.3% (OR = 0.93, 95% CI: 0.87–0.99; p = 0.03). The effect of comorbid substance use on the likelihood of response differed significantly according to baseline BMI. The presence of a comorbid substance use disorder resulted in a lower odds of response, but only among patients with a BMI ≥ 23 (p = 0.02).
Among patients with rapid-cycling bipolar disorder receiving lithium and valproate, endocrine/metabolic illnesses, including overweight and obesity, appear to be associated with greater depressive symptom severity and poorer treatment outcomes.
PMCID: PMC2913710  PMID: 20636638
endocrine; inflammation; insulin resistance; lithium; medical comorbidity; obesity; substance use disorders; treatment response; valproate
22.  Initiation of stimulant and antidepressant medication and clinical presentation in juvenile bipolar I disorder 
Bipolar disorders  2008;10(2):334-341.
The primary purpose of this study was to examine the extent to which the initiation of stimulant and antidepressant medication was associated with the subsequent onset of juvenile bipolar I disorder (BP I). Another aim was to investigate differences in clinical presentation between youths prescribed stimulant or antidepressant medication before and after the onset of juvenile BP I disorder.
Youths between the ages of 5 and 17 years meeting full, unmodified DSM-IV diagnostic symptom criteria for BP were included in this study. Data regarding the age of onset of BP I, psychiatric comorbidities, and current symptoms of mania and depression were obtained. Medication history was recorded as part of the assessment interview with parents and youths.
Of the 245 youths with BP I, 65% (n = 160) were treated with stimulant medication; 32% (56/173) were treated after the onset of BP I, and 19% (32/173) were treated before the onset of BP I. Forty-six percent (113/245) were treated with antidepressant medication; 33% (67/206) were treated after the onset of BP I, and 3% (7/206) were treated before the onset of BP I. Patients who were treated with stimulants after the onset or BP I were significantly more likely to be younger (p < 0.0001). Patients who were treated with antidepressants before the onset of BP I were significantly more likely to be older and to have lower levels of mania on the Young Mania Rating Scale at assessment (p < 0.01)
Data from this retrospective case series do not support the association between initial stimulant or antidepressant use and the onset of BP I or presenting symptoms of depression or manic symptoms.
PMCID: PMC3005589  PMID: 18271913
adolescents; antidepressants; bipolar disorder; children; stimulants
23.  Medical and Substance Use Comorbidity in Bipolar Disorder 
Journal of affective disorders  2008;116(1-2):64-69.
National Comorbidity Survey data indicate that bipolar disorder is characterized by high lifetime rates of co-occurring anxiety and substance use disorders (SUDs). Although compelling evidence suggests SUD comorbidity predicts non-response to treatment, the relationship between medical comorbidity and treatment response has not been studied adequately. In an attempt to understand the impact of medical comorbidity on treatment outcome, an analysis was conducted to inform the relationship between co-occurring medical illness, the phenomenology of bipolar disorder, and response to treatment with mood stabilizers.
A total of 98 adult outpatients with rapid-cycling bipolar I or II disorder and co-occurring SUDs were prospectively treated with the combination of lithium and valproate for up to 24 weeks. A logistic regression analysis was conducted to explore the relationship between phenomenology, response to mood stabilizers, and medical comorbidity as assessed by the Cumulative Illness Rating Scale (CIRS). High and low medical comorbidity burden were defined as a CIRS total score ≥ 4 and ≤ 3, respectively.
Every patient enrolled into this study had at least 1 medical illness (most commonly respiratory, 72%) and on average had 4.9 different medical conditions. Over half of patients (52%) exhibited illnesses across four or more different organ systems, 24% had uncontrollable medical illnesses, and the mean overall total CIRS score was 5.56. The average body mass index (BMI) was 28.1 with 38% being overweight and 29% being obese. High medical burden was observed in 64% and was most strongly predicted by a diagnosis of bipolar I disorder (OR=34.9, p=0.002, 95%CI=3.9–316.1). A history of attempted suicide (OR=10.3, p=0.01, 95%CI=1.7–62.0), a history of physical abuse (OR=7.6, p=0.03, 95%CI=1.3–45.7) and advancing age (OR=1.2, p<0.001, 95%CI=1.1–1.3) also independently predicted a high burden of general medical problems. Only 21% (N=21) of subjects enrolled into this study showed a bimodal response to treatment with lithium plus valproate, and neither BMI nor any summary CIRS measure predicted response.
Rapid cycling with co-occurring substance use is not only associated with poor response to mood stabilizers, but is also a harbinger of serious medical problems. A high burden of medical comorbidity was associated with the bipolar I subtype, a history of attempted suicide, a history of physical abuse, and advancing age.
PMCID: PMC2866135  PMID: 19100627
24.  Developing a Ten Item Mania Scale from the Parent General Behavior Inventory for Children and Adolescents 
Bipolar disorder is being diagnosed and treated in children and adolescents at a rapidly increasing rate, despite the lack of validated instruments to help screen for the condition or differentiate it from more common disorders. The goal of the present study was to develop and validate a brief (10 item) instrument in a large sample of outpatients presenting with a variety of different DSM-IV diagnoses, including frequent comorbid conditions.
Parents completed the Parent General Behavior Inventory (P-GBI), a 73 item mood inventory, as part of a screening assessment that included a semi-structured psychiatric interview of both the parent and the child to determine the child’s diagnoses.
637 youths completed the diagnostic assessment and the mood inventory. A 10 item form derived from this 73 item inventory had good reliability (.92), correlated .95 with the original scale, and showed significantly better discrimination of bipolar disorders (Area Under ROC Curve [AUROC] of .856 versus .832 for full scale, p < .005), with good precision for estimation of individual scores for cases up to two standard deviations elevated on the latent trait. The 10-item scale also did well discriminating bipolar from unipolar (AUROC = .86) and bipolar from ADHD cases (AUROC = .82).
Findings suggest that parents most notice elated mood, high energy, irritability, and rapid changes in mood and energy as the prominent features of juvenile bipolar disorder.
PMCID: PMC2777983  PMID: 18452343
25.  Differential Interactions between Comorbid Anxiety Disorders and Substance Use Disorder in Rapid Cycling Bipolar I or II Disorder 
Journal of affective disorders  2008;110(1-2):167-173.
Anxiety disorders (AD) and substance use disorders (SUD) commonly co-occur with bipolar disorder. This study was undertaken to assess AD-SUD-bipolar subtype interactions.
Extensive clinical interview and MINI were used to ascertain DSM-IV diagnoses of rapid cycling bipolar I (RCBPDI) or II (RCBPDII) disorder, SUDs, and ADs including generalized anxiety disorder (GAD), panic disorder (PD), and obsessive-compulsive disorder (OCD). Data at the initial assessment of four studies was used to compare the prevalence differences in ADs between RCBPDI and RCBPDII by using protocol-defined SUD categories, “Never,” “Lifetime, but not recent,” or “Recent.”
Five-hundred sixty-six of 568 patients (RCBPDI n=320, RCBPDII n=246) were eligible for analyses. In the “Never” group (n=191), patients with RCBPDI and RCBPDII had similar risk for ADs. In the “Lifetime, but not recent” group (n=195), RCBPDI patients had significantly higher risks for GAD (OR=3.29), PD (OR=2.95), but not OCD, compared with their RCBPDII counterparts. Similarly, in the “Recent” group (n=180), RCBPDI patients also had significantly higher risks for GAD (OR=3.6), PD (OR=3.8), but not OCD, compared with their RCBPDII counterparts.
Data were cross-sectional and not all ADs were included.
In this large cohort of patients with rapid cycling bipolar disorder, risk for having GAD, PD, but not OCD increased significantly in patients with bipolar I disorder compared to their bipolar II counterparts when a history of SUD was present. However, there were no significant differences in the risk for GAD, PD, or OCD between the subtypes among patients without a history of SUD.
PMCID: PMC2561239  PMID: 18234350
Rapid cycling bipolar disorder; anxiety disorder; substance use disorder; comorbidity; interaction

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