Longitudinally Measured Changes in Somnolence Severity With a Visual Analog Scale in a Randomized Lithium Versus Quetiapine-IR Study in Bipolar Disorder.

OBJECTIVE: The aim of this study was to use a visual analog scale (VAS) longitudinally measuring somnolence severity in patients with bipolar disorder. METHODS: A data set of patients with bipolar spectrum disorders who were randomized to lithium or quetiapine-IR for 16 weeks was used. The somnolence severity was measured with a VAS from 0 to 100 (VAS based), and somnolence frequency was recorded according to incident report (incidence based) at each visit. The rates of VAS-based and incidence-based somnolence and changes in somnolence severity from baseline to the end of study were compared between the lithium and quetiapine groups. Longitudinal changes in somnolence severity were analyzed with linear regression analysis. RESULTS: Of 42 patients randomized, only 3 scored 0 on the VAS at baseline. The rates of incidence-based and VAS-based somnolence were similar in the lithium and quetiapine-IR groups. The VAS change scores from baseline to each visit varied in both groups with significant decreases at weeks 6 and 12 in the quetiapine-IR group only. The decrease at week 6 in the quetiapine-IR group was significantly different from that in the lithium group. Patterns of changes in somnolence severity were inconsistent in both groups. A significant interaction between time course and the decrease in VAS scores was observed in the quetiapine-IR group, but not in the lithium group. CONCLUSIONS: Baseline somnolence was highly prevalent in patients with bipolar disorder. The change in somnolence severity was different between lithium-treated and quetiapine-treated patients. Quantifying somnolence longitudinally is important in clinical trials and practice.

Double-blind, placebo-controlled trial of pioglitazone for bipolar depression.

BACKGROUND: Objective of the present study was to conduct an 8-week double-blind, randomized, placebo-controlled trial to test the efficacy of pioglitazone in the treatment of bipolar depression. METHODS: 38 outpatients with bipolar disorder and current major depressive episode were randomized to pioglitazone (15-45 mg/day) or placebo. The use of concomitant mood stabilizers, antipsychotics, and antidepressants was permitted. The primary outcome measure was the 30-item Inventory of Depressive Symptomatology, Clinician Rated (IDS-C30) total score change from baseline to endpoint. Laboratory evaluations, including serum level of inflammatory and metabolic biomarkers, were conducted. RESULTS: 37 subjects were analyzed for efficacy (1 subject had no follow-up data). Mean reduction from baseline to week 8 in IDS-C30 score was-6.59 for pioglitazone and -11.63 for placebo. Mixed effects modeling indicated borderline statistically significant difference between the two groups (p = 0.056) in favor of placebo. On analysis of inflammatory and metabolic markers, a statistically significant negative correlation was noted between change in leptin levels and change in depression scores in the pioglitazone group (r = -0.61, p = 0.047) but not in the placebo group, the significance of which is unclear as the study failed to demonstrate antidepressant efficacy of pioglitazone over placebo. No serious adverse effects were reported, and pioglitazone was well-tolerated. LIMITATIONS: small sample size with inadequate power, concomitant use of other psychotropic medications, and lack of statistical adjustment for multiple testing. CONCLUSION: Current study does not support the antidepressant efficacy of pioglitazone in the treatment of bipolar depression. (240 words).

A Pilot Study of the Effectiveness of Lithium Versus Quetiapine Immediate Release Monotherapy in Patients With Bipolar Spectrum Disorders.

OBJECTIVE: The aim of this study was to compare the effectiveness of lithium versus quetiapine immediate release (IR) monotherapy in patients with bipolar I, II, or subthreshold bipolar disorder at any phase. METHODS: Eligible patients were randomized to lithium or quetiapine IR for 16 weeks. The difference in the time to discontinuation from study due to "all causes" between lithium and quetiapine IR groups and changes from baseline to 8 and 16 weeks in depression, mania, anxiety, quality of life (QOL), metabolic profiles, and proinflammatory markers were compared. RESULTS: Of the 42 patients randomized to lithium (n = 18) and quetiapine IR (n = 24), the median time to discontinuation due to "all causes" was 6 weeks (95% confidence interval, 2-12 weeks) in the lithium group and 8 weeks (95% confidence interval, 6 weeks to not calculable) in the quetiapine IR group. The mean time to discontinuation due to "all causes" was 7.7 ± 1.1 weeks for lithium versus 8.4 ± 0.8 weeks for quetiapine IR (P = 0.54). There was no significant difference between lithium and quetiapine IR in changes in the severity of depression, mania/hypomania, anxiety, and QOL as a whole or only in patients with depressive index episode. The decrease in total cholesterol was significantly larger with lithium than with quetiapine IR (P = 0.05) as a whole, but not only in patients with depression index episode. There was no other significant difference in changes in metabolic panels and inflammatory markers between the 2 groups. CONCLUSIONS: The difference in effectiveness between lithium and quetiapine IR monotherapy in a real-world bipolar population was minimal. Large-sample studies are needed to support or refute this finding.

A placebo controlled study of quetiapine-XR in bipolar depression accompanied by generalized anxiety with and without a recent history of alcohol and cannabis use.

OBJECTIVE: This study aims to compare treatment response in bipolar I or II depression and generalized anxiety disorder (GAD) with and without recent alcohol and/or cannabis use disorder (ALC/CAN) to quetiapine-XR (extended release) or placebo. METHODS: A randomized, double-blind, 8-week study of quetiapine-XR versus placebo in patients with bipolar I or II depression and GAD with or without a recent ALC/CAN was used to compare changes in Hamilton Depression Rating Scale-17, Hamilton Anxiety Rating Scale, the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16), Clinical Global Impression for Bipolar Disorder-Severity (CGI-BP-S), and Timeline Follow Back within and between groups. RESULTS: In the quetiapine-XR group, patients with a recent ALC/CAN (n = 22) had significant decreases in QIDS-SR-16 (-9.6 ± 1.6 vs. -3.7 ± 1.7) and CGI-BP-S (-1.6 ± 0.4 vs. -0.8 ± 0.03) than those without a recent ALC/CAN (n = 24). In the placebo group, both patients with a recent ALC/CAN (n = 23) and those without (n = 21) had similar reductions in these measures. The reduction of QIDS-SR-16 scores in patients with a recent ALC/CAN was also significantly different from that of their counterparts in the placebo group. Patients who received quetiapine-XR had larger decreases in the number of drinking days/week (p = 0.17) and number of cannabis joints/week (p = 0.09) compared to those who received placebo. CONCLUSION: Quetiapine-XR was superior to placebo in reducing QIDS-SR-16 total score in patients with a recent ALC/CAN. Patients taking quetiapine-XR used less alcohol and cannabis than patients on placebo, suggesting that quetiapine-XR may be of use in patients with bipolar disorder accompanied by GAD and other comorbidities.

A Randomized, Placebo-Controlled Pilot Study of Quetiapine-XR Monotherapy or Adjunctive Therapy to Antidepressant in Acute Major Depressive Disorder with Current Generalized Anxiety Disorder.

OBJECTIVES: To pilot efficacy and safety data of quetiapine-XR monotherapy or adjunctive therapy to antidepressant(s) in the acute treatment of MDD with current generalized anxiety disorder (GAD). METHODS: The Mini International Neuropsychiatric Interview was used to ascertain the diagnosis of DSM-IV Axis I disorders. Eligible patients were randomly assigned to quetiapine-XR or placebo for up to 8 weeks. Changes from baseline to endpoint in Hamilton Depression Rating Scale-17 items (HAMD-17), Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity (CGI-S), Quick Inventory of Depression Symptomatology-16 items Self-Report (QIDS-16-SR) total scores, and other outcome measures were analyzed with the last observation carried forward strategy and/or mixed-effects modeling for repeated measures. RESULTS: Of the 34 patients screened, 23 patients were randomized to receive quetiapine-XR (n = 11) or placebo (n = 12), with 5 and 4 completing the study, respectively. The mean dose of quetiapine-XR was 154 ± 91 mg/d. The change from baseline to endpoint in the total scores of HAMD-17, HAM-A, QIDS-16-SR, and CGI-S were significant in the quetiapine-XR group, but only the change in HAM-A total score was significant in the placebo group. The differences in these changes between the two groups were only significant in CGI-S scores, with the rest of numerical larger in the quetiapine-XR group. The most common side effects from quetiapine-XR were dry mouth, somnolence/sedation, and fatigue. CONCLUSIONS: In this pilot study, quetiapine-XR was numerically superior to placebo in reducing depressive and anxiety symptoms in patients with MDD and current GAD. Large sample studies are warranted to support or refute these preliminary findings.

Disagreement between self-reported and clinician-ascertained suicidal ideation and its correlation with depression and anxiety severity in patients with major depressive disorder or bipolar disorder.

OBJECTIVES: To study the disagreement between self-reported suicidal ideation (SR-SI) and clinician-ascertained suicidal ideation (CA-SI) and its correlation with depression and anxiety severity in patients with major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Routine clinical outpatients were diagnosed with the MINI-STEP-BD version. SR-SI was extracted from the 16 Item Quick Inventory of Depression Symptomatology Self-Report (QIDS-SR-16) item 12. CA-SI was extracted from a modified Suicide Assessment module of the MINI. Depression and anxiety severity were measured with the QIDS-SR-16 and Zung Self-Rating Anxiety Scale. Chi-square, Fisher exact, and bivariate linear logistic regression were used for analyses. RESULTS: Of 103 patients with MDD, 5.8% endorsed any CA-SI and 22.4% endorsed any SR-SI. Of the 147 patients with BPD, 18.4% endorsed any CA-SI and 35.9% endorsed any SR-SI. The agreement between any SR-SI and any CA-SI was 83.5% for MDD and 83.1% for BPD, with weighted Kappa of 0.30 and 0.43, respectively. QIDS-SR-16 score, female gender, and ≥4 year college education were associated with increased risk for disagreement, 15.44 ± 4.52 versus 18.39 ± 3.49 points (p = 0.0026), 67% versus 46% (p = 0.0783), and 61% versus 29% (p = 0.0096). The disagreement was positively correlated to depression severity in both MDD and BPD with a correlation coefficient R(2) = 0.40 and 0.79, respectively, but was only positively correlated to anxiety severity in BPD with a R(2) = 0.46. CONCLUSION: Self-reported questionnaire was more likely to reveal higher frequency and severity of SI than clinician-ascertained, suggesting that a combination of self-reported and clinical-ascertained suicidal risk assessment with measuring depression and anxiety severity may be necessary for suicide prevention.

Efficacy and safety of quetiapine-XR as monotherapy or adjunctive therapy to a mood stabilizer in acute bipolar depression with generalized anxiety disorder and other comorbidities: a randomized, placebo-controlled trial.

OBJECTIVE: To study the efficacy and safety of quetiapine-XR as monotherapy or adjunctive therapy to a mood stabilizer in acute bipolar I or II depression with comorbid generalized anxiety disorder (GAD) and other comorbidities. METHOD: The study was conducted from January 2007 to November 2011. The Mini-International Neuropsychiatric Interview was used to ascertain the diagnosis of DSM-IV bipolar disorder, GAD, and other Axis I disorders. Eligible patients were randomly assigned to quetiapine-XR or placebo for up to 8 weeks. The Hamilton Depression Rating Scale-17 items (HDRS-17) was used as a primary outcome to evaluate the difference between the 2 groups using the change from baseline to end of study. Last observation carried forward and mixed-effects modeling for repeated measures were used to analyze the primary and secondary outcome measures. RESULTS: Of the 120 patients screened, 100 patients were randomized to receive quetiapine-XR (n = 50) or placebo (n = 50). Twenty-six patients in the quetiapine-XR and 18 in the placebo group completed the study. The mean quetiapine-XR dose was 276 ± 50 mg/d (50-300 mg/d). There was no significant difference between the 2 groups in the change from baseline to end of study in HDRS-17 total score with an effect size of 0.19 favoring quetiapine-XR. There were also no significant differences between the 2 groups in secondary efficacy and safety outcome measures. CONCLUSIONS: Quetiapine-XR was not significantly superior to placebo in bipolar I or II depression with GAD and other comorbidities, suggesting that data from relatively "pure" bipolar patients may not be generalizable to a highly comorbid population. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00671853.

Validation of lay-administered mental health assessments in a large Army National Guard cohort.

To report the reliability and validity of key mental health assessments in an ongoing study of the Ohio Army National Guard (OHARNG). The 2616 OHARNG soldiers received hour-long structured telephone surveys including the post-traumatic stress disorder (PTSD) checklist (PCV-C) and Patient Health Questionnaire - 9 (PHQ-9). A subset (N = 500) participated in two hour clinical reappraisals, using the Clinician-Administered PTSD Scale (CAPS) and the Structured Clinical Interview for DSM (SCID). The telephone survey assessment for PTSD and for any depressive disorder were both highly specific [92% (standard error, SE 0.01), 83% (SE 0.02)] with moderate sensitivity [54% (SE 0.09), 51% (SE 0.05)]. Other psychopathologies assessed included alcohol abuse [sensitivity 40%, (SE 0.04) and specificity 80% (SE 0.02)] and alcohol dependence [sensitivity, 60% (SE 0.05) and specificity 81% (SE 0.02)].The baseline prevalence estimates from the telephone study suggest alcohol abuse and dependence may be higher in this sample than the general population. Validity and reliability statistics suggest specific, but moderately sensitive instruments.

Should an assessment of Axis I comorbidity be included in the initial diagnostic assessment of mood disorders? Role of QIDS-16-SR total score in predicting number of Axis I comorbidity.

BACKGROUND: Axis I comorbidity in mood disorders was common in epidemiological studies. This study was designed to investigate the prevalence, pattern, and number of Axis I comorbidities and the role of the Quick Inventory of Depression Symptomatology - 16 items-Self-Report (QIDS-16-SR) in predicting the number of comorbidities in major depressive disorder (MDD) or bipolar disorder (BPD). METHODS: Baseline data from the first 300 routine clinical outpatients diagnosed with the Mini International Neuropsychiatric Interview Systematic-Treatment-Enhancement - Program for BPD version 5.0.0 were used. Baseline severity was measured with QIDS-16-SR and Clinical Global Impression-Severity (CGI-S). RESULTS: Of 113 patients with MDD and 166 with BPD, the prevalence of any current anxiety disorder (AD), substance use disorder (SUD), and attention deficit hyperactivity disorder (ADHD) was 76% versus 74%, 14% versus 29%, and 8% versus 21%, respectively. The most common patterns of current comorbidity were MDD+AD (58.4%) for MDD, and BPD+AD (39.8%) and BPD+AD+SUD (11.4%) for BPD. More than 80% patients with MDD or BPD had ≥ 1 current comorbid disorder. About 20% patients with BPD and 10% with MDD had ≥ 4 other disorders. The number of comorbidities was positively associated with baseline severity and suicidal ideation in both MDD and BPD. A QIDS-16-SR of 10 had a positive predictive value of ≥ 90% in predicting ≥ 1 comorbidity in MDD and BPD. LIMITATIONS: The sample was modest and from a tertiary medical center. CONCLUSION: A thorough diagnostic assessment for Axis I comorbidity should be included in all patients with mood disorders, especially when a QIDS-16-SR of ≥ 10 points.

Potentially modifiable pre-, peri-, and postdeployment characteristics associated with deployment-related posttraumatic stress disorder among ohio army national guard soldiers.

PURPOSE: To evaluate potentially modifiable deployment characteristics-- predeployment preparedness, unit support during deployment, and postdeployment support-that may be associated with deployment-related posttraumatic stress disorder (PTSD). METHODS: We recruited a sample of 2616 Ohio Army National Guard (OHARNG) soldiers and conducted structured interviews to assess traumatic event exposure and PTSD related to the soldiers' most recent deployment, consistent with DSM-IV criteria. We assessed preparedness, unit support, and postdeployment support by using multimeasure scales adapted from the Deployment Risk and Resilience Survey. RESULTS: The prevalence of deployment-related PTSD was 9.6%. In adjusted logistic models, high levels of all three deployment characteristics (compared with low) were independently associated with lower odds of PTSD. When we evaluated the influence of combinations of deployment characteristics on the development of PTSD, we found that postdeployment support was an essential factor in the prevention of PTSD. CONCLUSIONS: Results show that factors throughout the life course of deployment-in particular, postdeployment support-may influence the development of PTSD. These results suggest that the development of suitable postdeployment support opportunities may be centrally important in mitigating the psychological consequences of war.

Safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania: a 12-week open-label study.

OBJECTIVE: To examine the safety and efficacy of olanzapine monotherapy in treatment-resistant bipolar mania. METHOD: Subjects (n = 18) who were acutely manic, did not respond to lithium, anticonvulsants, and neuroleptics, and/or had intolerable side effects to them in previous manic episodes were openly treated with olanzapine monotherapy (5-40 mg/d) for 12 weeks. The primary and secondary outcomes included the change from baseline to endpoint in Young Mania Rating Scale (YMRS) total score, Clinical Global Impression for Bipolar Disorder-Severity Scale (CGI-S), 17-item Hamilton Depression Rating Scale (HAM-D) and Positive and Negative Syndrome Scale (PANSS), and response and remission rate. RESULTS: The mean change in YMRS total score from baseline to endpoint was -23.3 ± 8.4 (p < 0.001). Fifteen (88.5%) patients achieved response (≥50% reduction in YMRS total score) and 14 (77.8%) achieved remission (YMRS total score ≤9 at endpoint). Mean changes from baseline to endpoint in CGI-S for mania and PANSS total score were significant, but not the changes in HAM-D total score or CGI-S for depression. The most common adverse events were sedation, self-reported weight gain, ≥7% increase in body weight, dizziness, and akathisia. CONCLUSIONS: These preliminary results suggest that olanzapine monotherapy is effective and relatively safe in patients with treatment-resistant bipolar mania. Randomized, double-blind, placebo-controlled study is warranted.

PTSD comorbidity and suicidal ideation associated with PTSD within the Ohio Army National Guard.

OBJECTIVE: To study the relation between posttraumatic stress disorder (PTSD) psychiatric comorbidity and suicidal ideation in a representative sample of Ohio Army National Guard soldiers. METHOD: Using retrospective data collected on the telephone from a random sample of 2,616 National Guard soldiers who enrolled in a 10-year longitudinal study (baseline data collected November 2008-November 2009), we examined (1) the prevalence of other psychopathologies among those with DSM-IV-diagnosed PTSD compared to those without PTSD and (2) the association between PTSD comorbidity and suicidal ideation (reporting thoughts of being better off dead or hurting themselves). All analyses were carried out using logistic regression. RESULTS: Of guard members with PTSD in the last year, 61.7% had at least 1 other psychopathology; 20.2% had at least 2 other co-occurring conditions. The most common co-occurring psychopathology was depression. While those with PTSD overall were 5.4 (95% CI, 3.8-7.5) times more likely to report suicidality than those without PTSD, those who had at least 2 additional conditions along with PTSD were 7.5 (95% CI, 3.0-18.3) times more likely to report suicidal ideation at some point in their lifetime than those with PTSD alone. CONCLUSIONS: Soldiers with PTSD were at increased risk for suicidality, and, among those with PTSD, those with at least 2 additional conditions were at the highest risk of suicidal ideation. Future research should address the mechanisms that contribute to multimorbidity in this population and the appropriate treatment methods for this high-risk group.

Acute efficacy of divalproex sodium versus placebo in mood stabilizer-naive bipolar I or II depression: a double-blind, randomized, placebo-controlled trial.

OBJECTIVE: To conduct an exploratory evaluation of the acute efficacy of extended-release divalproex sodium compared to placebo in patients with bipolar I or II depression. METHOD: Outpatients aged 18-70 years with mood stabilizer-naive bipolar I or II disorder experiencing a major depressive episode (DSM-IV) were randomly assigned to 6 weeks of divalproex sodium monotherapy or placebo. The primary outcome measure was mean change from baseline to week 6 on the Montgomery-Åsberg Depression Rating Scale (MADRS) total score. Secondary outcomes included rates of response and remission, changes in the Clinical Global Impressions-Bipolar (CGI-BP) Severity of Illness scores, and changes in anxiety symptoms as measured by the Hamilton Anxiety Rating Scale. The study was conducted between 2003 and 2007. RESULTS: Fifty-four subjects with bipolar I (n = 20) or bipolar II (n = 34) disorder were randomly assigned to divalproex or placebo; 67% (36 of 54) met DSM-IV criteria for rapid cycling. Divalproex treatment produced statistically significant improvement in MADRS scores compared with placebo from week 3 onward. The proportions of patients meeting response criteria were 38.5% (10 of 26) in the divalproex group versus 10.7% (3 of 28) for the placebo group (P = .017). The proportions of patients meeting remission criteria were 23.1% (6 of 26) for divalproex versus 10.7% (3 of 28) for placebo (P = .208). Subgroup analysis revealed no separation between divalproex and placebo for those with bipolar II diagnoses. Nausea, increased appetite, diarrhea, dry mouth, and cramps were the most common side effects. CONCLUSIONS: These data suggest that divalproex sodium is efficacious and reasonably well tolerated in the acute treatment of mood stabilizer-naive patients with bipolar depression, particularly for those with rapid-cycling type I presentations, and that confirmatory large-scale studies are indicated. TRIAL REGISTRATION: Clinicaltrials.gov Identifier: NCT00194116.

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.

OBJECTIVE: 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). METHOD: 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 randomized 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, or chi-square/Fisher's exact. RESULTS: 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). There were no significant differences in changes in YMRS total scores and rates of response or remission. CONCLUSIONS: Lamotrigine adjunctive therapy was well tolerated 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.