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1.  PPAR-γ Agonism as a Modulator of Mood: Proof-of-Concept for Pioglitazone in Bipolar Depression 
CNS drugs  2014;28(6):571-581.
Insulin resistance and other cardiometabolic risk factors predict increased risk of depression and decreased response to antidepressant and mood stabilizer treatments. This proof-of-concept study tested whether administration of an insulin-sensitizing peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist could reduce bipolar depression symptom severity. A secondary objective determined if levels of highly-sensitive C-reactive protein and Interleukin-6 (IL-6) predicted treatment outcome.
Thirty-four patients with bipolar disorder (I, II, or not otherwise specified) and metabolic syndrome/insulin resistance who were currently depressed (Quick Inventory of Depressive Symptoms (QIDS) total score ≥ 16) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR- γ agonist pioglitazone (15–30 mg/d) for 8 weeks. The majority of participants (76%, n=26) were experiencing treatment-resistant bipolar depression, having already failed two mood stabilizers or the combination of a mood stabilizer and a conventional antidepressant.
Supporting an association between insulin sensitization and depression severity, pioglitazone treatment was associated with a decrease in the total Inventory of Depressive Symptomatology (IDS-C30) score from 38.7±8.2 at baseline to 21.2±9.2 at week 8 (p<.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p<.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p<.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (−17.9±3.6; p<.001). Insulin sensitivity increased from baseline to week 8 as measured by the Insulin Sensitivity Index derived from an oral glucose tolerance test (0.98±0.3; p<.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate β=−3.89, SE=1.47, p=0.015). A positive correlation was observed between improvement in IDS-C30 score and change in IL-6 (r=0.44, p<01).
Open-label administration of the PPAR-γ agonist, pioglitazone, was associated with improvement in depressive symptoms and reduced cardiometabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. ( Identifier: NCT00835120)
PMCID: PMC4113193  PMID: 24715548
2.  Associations Among Obesity, Acute Weight Gain, and Response to Treatment with Olanzapine in Adolescent Schizophrenia 
The purpose of this study was to investigate associations between body weight and illness characteristics, including weight gain and therapeutic efficacy, in adolescents with schizophrenia.
Adolescents ages 13–17 years (n=107) with American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) schizophrenia enrolled in a 6 week, double-blind, placebo-controlled trial comparing olanzapine and placebo. Therapeutic response was assessed by the Brief Psychiatric Rating Scale for Children (BPRS-C). Secondary outcomes included the Clinical Global Impressions-Severity (CGI-S) scale and Positive and Negative Syndrome Scale (PANSS). Obesity was defined as sex-/age-adjusted body mass index (BMI)≥95th percentile. Linear regression was used to analyze the relationship between weight gain and psychiatric symptom improvement; logistic regression was conducted to identify predictors of baseline obesity.
Weight gain was significantly correlated with greater BPRS-C reduction among olanzapine-treated subjects (r=−0.31, p<0.01), whereas a trend was observed among placebo-treated subjects (r=−0.31, p=0.08). However, this relationship became nonsignificant when analyses were controlled for duration of olanzapine treatment (p=0.12), and a treatment by weight gain interaction did not emerge in a repeated-measures mixed model analysis that included time in the study (t=1.27, p=0.21). Additionally, weight gain ≥7% was not significantly associated with response or remission. Among 17 adolescents (16%) with obesity at study entry, obesity was not significantly associated with endpoint BPRS-C illness severity. However, girls (p=0.03), individuals hospitalized within the past year (p=0.02), and those with less severe overall (p=0.03) and negative symptoms (p=0.003) according to the CGI-S and PANSS negative subscale, respectively, were more likely to be obese at baseline.
Baseline obesity was associated with lower illness severity, which could be mediated by greater treatment adherence, leading to more weight gain. Olanzapine-related weight gain was not independently associated with symptomatic outcome when controlling for treatment duration. Additional studies are needed to extend these findings to other disorders and medications.
PMCID: PMC3804232  PMID: 24111982
3.  Cardiometabolic Health in Bipolar Disorder 
Psychiatric annals  2012;42(5):179-183.
PMCID: PMC4067699  PMID: 24970952
4.  Effect of adjunctive benzodiazepines on clinical outcomes in lithium- or quetiapine-treated outpatients with bipolar I or II disorder: Results from the Bipolar CHOICE trial 
Little is known about the longer-term effects of adjunctive benzodiazepines on symptom response during treatment in patients with bipolar disorders.
The study sample consisted of 482 patients with bipolar I or II disorder enrolled in a 6-month, randomized, multi-site comparison of lithium- and quetiapine-based treatment. Changes in clinical measures (BISS total and subscales, CGI-BP, and CGI-Efficacy Index) were compared between participants who did and did not receive benzodiazepine treatment at baseline or during follow-up. Selected outcomes were also compared between patients who did and did not initiate benzodiazepines during follow-up using stabilized inverse probability weighted analyses.
Significant improvement in all outcome measures occurred within each benzodiazepine exposure group. Benzodiazepine users (at baseline or during follow-up) experienced significantly less improvement in BISS total, BISS irritability, and CGI-BP scores than did benzodiazepine non-users. There were no significant differences in these measures between patients who did and did not initiate benzodiazepines during follow-up in the weighted analyses. There was no significant effect of benzodiazepine use on any outcome measure in patients with comorbid anxiety or substance use disorders.
This is a secondary analysis of data from a randomized effectiveness trial that was not designed to address differential treatment response according to benzodiazepine use.
Adjunctive benzodiazepines may not significantly affect clinical outcome in lithium- or quetiapine-treated patients with bipolar I or II disorder over 6 months, after controlling for potential confounding factors.
PMCID: PMC4113323  PMID: 24751304
benzodiazepines; bipolar disorder; lithium; quetiapine; clinical outcome
5.  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
6.  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
7.  Clinical Correlates of Patients With Rapid-Cycling Bipolar Disorder and a Recent History of Substance Use Disorder: A Subtype Comparison From Baseline Data of 2 Randomized, Placebo-Controlled Trials 
The Journal of clinical psychiatry  2008;69(7):1057-1063.
To compare clinical variables in patients with rapid-cycling bipolar I or II disorder and a recent history of substance use disorder (SUD).
Cross-sectional data from 2 studies of patients with rapid-cycling bipolar I disorder or rapid-cycling bipolar II disorder and a recent history of SUD were used to retrospectively assess the differences in clinical variables between the subtypes. The studies were conducted from November 1997 to February 2007 at University Hospitals Case Medical Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. Extensive clinical interview and the Mini-International Neuropsychiatric Interview were used to ascertain DSM-IV diagnoses of rapid-cycling bipolar disorder, SUDs, and other Axis I disorders and to collect clinical variables. The Addiction Severity Index (ASI), Global Assessment Scale (GAS), and the Medical Outcomes Study 36-ltem Short-Form Health Survey were used to measure the severity of impairment at the initial assessment. One-way analysis of variance or χ2 was used for significance tests. A Bonferroni adjustment was applied for multiple comparisons.
Of 245 patients with rapid-cycling bipolar disorder (rapid-cycling bipolar I disorder, N = 191; rapid-cycling bipolar II disorder, N = 54) and a recent history of SUD, the demographics were similar. A significantly higher rate of panic disorder was observed in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder (odds ratio = 3.72, 95% CI = 1.66 to 8.32, p = .008). A significantly higher psychiatric composite score on the ASI was also found in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder even after Bonferroni adjustment (p = .0007). There were no significant differences between the subtypes in the rates of previous hospitalization or suicide attempt, early childhood verbal, physical, or sexual abuse, lifetime substance abuse or dependence, the number of SUDs or mood episodes in the last 12 months, and total or other subscale scores on ASI and GAS.
Except for the significantly higher rate of comorbid panic disorder and higher psychiatric composite scores on the ASI in patients with rapid-cycling bipolar I disorder than in those with rapid-cycling bipolar II disorder, the other clinical variables were similar between the 2 groups.
PMCID: PMC4285700  PMID: 18588360
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.  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
10.  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
11.  Clinical Value of Early Partial Symptomatic Improvement in the Prediction of Response and Remission During Short-term Treatment Trials in 3,369 Subjects with Bipolar I or II Depression 
Journal of affective disorders  2010;130(1-2):171-179.
To evaluate the clinical value of early partial symptomatic improvement in predicting the probability of response during the short-term treatment of bipolar depression.
Blinded data from 10 multicenter, randomized, double-blind, placebo-controlled trials in bipolar I or II depression were used to determine if early improvement (≥ 20% reduction in depression symptom severity after 14 days of treatment) predicted later short-term response or remission. Sensitivity, specificity, efficiency, and positive and negative predictive values (PPV, NPV) were calculated using an intent to treat analysis of individual and pooled study data.
1,913 patients were randomized to active compounds (aripiprazole, lamotrigine, olanzapine/olanzapine-fluoxetine, and quetiapine), and 1,456 to placebo. In the pooled positive studies, early improvement predicted response and remission with high sensitivity (86% and 88%, respectively), but rates of false positives were high (53% and 59%, respectively). Pooled negative predictive values for response/remission (i.e. confidence in knowing the drug will not result in response or remission) were 74% and 82%, respectively, with low rates of false negatives (14% and 12%, respectively).
Early improvement in an individual patient does not appear to be a reliable predictor of eventual response or remission due to an unacceptably high false positive rate. However, the absence of early improvement appears to be a highly reliable predictor of eventual non-response, suggesting that clinicians can have confidence in knowing when a drug is not going to work during short-term treatment. Patients who fail to demonstrate early improvement within the first two weeks of treatment may benefit from a change in therapy.
PMCID: PMC3073691  PMID: 21071096
12.  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
14.  Depressive Symptoms and Diabetes 
PMCID: PMC3904750  PMID: 19001617
16.  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
17.  Screening for Bipolar Disorder in a County Jail at the Time of Criminal Arrest 
Journal of psychiatric research  2007;42(9):778-786.
This study assessed the operating characteristics of the Mood Disorder Questionnaire (MDQ) among offenders arrested and detained at a county jail.
The MDQ, a brief self-report instrument designed to screen for all subtypes of bipolar disorder (BP I, II and NOS) was voluntarily administered to adult detainees at the Ottawa County Jail in Port Clinton, Ohio. A confirmatory diagnostic evaluation was also performed using the Mini-International Neuropsychiatric Interview (MINI). The MDQ was scored using a standard algorithm requiring endorsement of 7/13 mood items as well as two items that assess whether manic or hypomanic symptoms co-occur and cause moderate to severe functional impairment. In addition to the standard algorithm for scoring the MDQ, modifications were also tested in an attempt to improve overall sensitivity.
Among 526 jail detainees who completed the MDQ, 37 (7%) screened positive for bipolar disorder. Of 164 detainees who agreed to a research diagnostic evaluation, 32 (19.5%) screened positive on the MDQ, while 55 (33.5%) met criteria for bipolar disorder according to the MINI. When administered to the sample of 164 adult jail detainees, the sensitivity of the MDQ was 0.47 and the specificity was 0.94. The MDQ was significantly better at detecting BP I (0.59) than BP II/NOS (0.19; p = 0.008). Modification of scoring the MDQ improved the sensitivity for detection of BP II from 0.23 to 0.54 with minimal decrease in specificity (0.84). The optimum sensitivity and specificity of the MDQ was achieved by decreasing the item threshold to 3/13 and eliminating the symptom co-occurrence and functional impairment items.
The MDQ was found to have limited utility as a screening tool for bipolar disorder in a correctional setting, particularly for the BP II subtype.
PMCID: PMC2475656  PMID: 17935734
Bipolar Disorder; Mood Disorder Questionnaire; Jail; Screening; Bipolar II; Psychometrics
18.  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
19.  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
20.  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
21.  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
22.  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
23.  Predictors of Non-Stabilization during the Combination Therapy of Lithium and Divalproex in Rapid Cycling Bipolar Disorder: A Post-hoc Analysis of Two Studies 
Psychopharmacology bulletin  2010;43(1):23-38.
To study predictors of non–stabilization (i.e., not bimodally stabilized for randomization or not randomized due to premature discontinuation) during open-label treatment with lithium and divalproex in patients with rapid-cycling bipolar disorder (RCBD) with or without comorbid recent substance use disorders (SUDs).
Data from the open-label phase of two maintenance studies were used. The reasons for non-stabilization were compared between patients with a recent SUD and those without. Predictors for non-stabilization were explored with logistic regression analyses.
Of 149 patients with recent SUD and 254 without recent SUD enrolled into the open-label acute stabilization phase, 21% and 24% were stabilized and randomized, respectively. Compared to those without recent SUD, patients with recent SUD were more likely to discontinue the study due to non-adherence to the protocol, 53% versus 37% (OR = 1.92) or refractory mania/hypomania, 15% versus 9% (OR = 1.87), but less likely due to refractory depression 16% versus 25% (OR = 0.58) or adverse events, 10% versus 19% (OR = 0.44). A history of recent SUDs, early life verbal abuse, female gender, and late onset of first depressive episode were associated with increased risk for non-stabilization with ORs of 1.85, 1.74, 1.10, and 1.04, respectively.
During open treatment with lithium and divalproex in patients with RCBD, a recent SUD, a lifetime history of verbal abuse, female gender, and late onset of first depression independently predicted non-stabilization. The non-stabilization for patients with SUD was related to non-adherence and refractory mania/hypomania.
PMCID: PMC3439803  PMID: 20581798
Bipolar disorder; anxiety disorder; substance use disorder; mood stabilizer; non-stabilization
24.  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
25.  Independent Predictors for Lifetime and Recent Substance Use Disorders in Patients with Rapid Cycling Bipolar Disorder: Focus on Anxiety Disorders 
We set out to study independent predictor(s) for lifetime and recent substance use disorder (SUDs) in patients with rapid cycling bipolar disorder (RCBD). Extensive Clinical Interview and Mini International Neuropsychiatric Interview were used to ascertain DSM-IV Axis I diagnoses of RCBD, anxiety disorders, and SUDs. Data from patients enrolling into four similar clinical trials were used. Where appropriate, univariate analyses with t-test or Chi-Square were applied. Stepwise logistic regression was used to examine the relationship among predictor variables and lifetime and recent SUDs. Univariate analysis showed that patients with co-occurring anxiety disorders (n=261) had significantly increased rates of lifetime (OR=2.1) and recent (OR=1.9) alcohol dependence as well as lifetime (OR=3.4) and recent (OR=2.5) marijuana dependence compared to those without co-occurring anxiety disorder (n=303). In logistic regression analyses, generalized anxiety disorder (GAD) was associated with increased risk for lifetime SUDs (OR=2.34), alcohol dependence (OR=1.73), and marijuana dependence (OR=3.36), and recent marijuana dependence (OR=3.28). A history of physical abuse was associated with increased risk for lifetime SUDs (OR=1.71) and recent marijuana dependence (OR=3.47). Earlier onset of first mania/hypomania was associated with increased risk for lifetime SUDs (5% per year) and recent marijuana dependence (12% per year) and later treatment with a mood stabilizer were also associated with increased risk for recent SUDs (8% per year). Positive associations between generalized anxiety disorder, later treatment with a mood stabilizer, and early childhood trauma and history of SUDs suggests that adequate treatment of comorbid anxiety, early treatment with a mood stabilizer, and prevention of childhood trauma may reduce the risk for the development of SUDs in patients with bipolar disorder.
PMCID: PMC2924768  PMID: 20716307

Results 1-25 (29)