Association Between Symptom Severity and Medication Adherence in Adolescents with Bipolar Disorder Demonstrating Suboptimal Adherence.

Objective: While medication non-adherence is common in bipolar disorder (BD), few studies have specifically assessed non-adherent BD adolescents and young adults (AYAs). This analysis, using screening and baseline data from an ongoing randomized controlled trial, examined the relationship between BD symptoms and adherence in poorly adherent AYAs. Methods: AYAs ages 13-21 had sub-optimal adherence defined as missing ⩾ 20% of prescribed BD medication. Mean sample (N = 36) age was 19.1 years (SD = 2.0), 66.7 % (N = 24) female, 25.0 % (n = 9) non-white. Adherence was measured via: 1) self-reported Tablets Routine Questionnaire (TRQ) and 2) electronic monitoring (SimpleMed pillbox). Symptoms were measured with the Hamilton Depression Rating Scale (HAM-D), the Young Mania Rating Scale (YMRS), and the Clinical Global Impression Scale (CGI). Results: Mean percentage of missed BD medications using TRQ was 34.9 (SD = 28.9) at screening and 30.6 (SD = 33.0) at baseline. Mean percentage of missed medication using SimpleMed at baseline was 42.1 (SD = 37.0). The correlation between TRQ and SimpleMed was r = 0.36 (p = 0. 13). Neither CGI nor age were correlated with adherence. Neither TRQ nor SimpleMed were significantly related to HAM-D. YMRS was positively associated with worse adherence for TRQ (r = 0.36, p = 0.03), but not significantly associated with SimpleMed. Adherence did not differ by other demographic attributes. Conclusion: Adherence levels varied widely in AYA with BD. Adherence monitoring increased adherence by approximately 4.5%, and use of electronic pill monitoring identified a greater proportion of missed medication vs. self-report. BD symptoms may not consistently identify AYA with adherence challenges.

Focal adhesion is associated with lithium response in bipolar disorder: evidence from a network-based multi-omics analysis.

Lithium (Li) is one of the most effective drugs for treating bipolar disorder (BD), however, there is presently no way to predict response to guide treatment. The aim of this study is to identify functional genes and pathways that distinguish BD Li responders (LR) from BD Li non-responders (NR). An initial Pharmacogenomics of Bipolar Disorder study (PGBD) GWAS of lithium response did not provide any significant results. As a result, we then employed network-based integrative analysis of transcriptomic and genomic data. In transcriptomic study of iPSC-derived neurons, 41 significantly differentially expressed (DE) genes were identified in LR vs NR regardless of lithium exposure. In the PGBD, post-GWAS gene prioritization using the GWA-boosting (GWAB) approach identified 1119 candidate genes. Following DE-derived network propagation, there was a highly significant overlap of genes between the top 500- and top 2000-proximal gene networks and the GWAB gene list (Phypergeometric = 1.28E-09 and 4.10E-18, respectively). Functional enrichment analyses of the top 500 proximal network genes identified focal adhesion and the extracellular matrix (ECM) as the most significant functions. Our findings suggest that the difference between LR and NR was a much greater effect than that of lithium. The direct impact of dysregulation of focal adhesion on axon guidance and neuronal circuits could underpin mechanisms of response to lithium, as well as underlying BD. It also highlights the power of integrative multi-omics analysis of transcriptomic and genomic profiling to gain molecular insights into lithium response in BD.

Using mHealth to improve adherence and reduce blood pressure in individuals with hypertension and bipolar disorder (iTAB-CV): study protocol for a 2-stage randomized clinical trial.

BACKGROUND: Cardiovascular disease in individuals with mental health conditions such as bipolar disorder is highly prevalent and often poorly managed. Individuals with bipolar disorder face significant medication adherence barriers, especially when they are prescribed multiple medications for other health conditions including hypertension. Poor adherence puts them at a disproportionate risk for poor health outcomes. As such, there is a need for effective interventions to improve hypertension medication adherence, particularly in patients that struggle with adherence due to mental health comorbidity. METHODS: This 5-year project uses a 2-stage randomized controlled trial design to evaluate a brief, practical adherence intervention delivered via interactive text messaging (iTAB-CV) along with self-monitoring of medication taking, mood, and home blood pressure (N = 100) compared to self-monitoring alone (N = 100). Prior to randomization, all participants will view an educational video that emphasizes the importance of medication for the treatment of hypertension and bipolar disorder. Those randomized to the texting intervention will receive daily text messages with predetermined content to address 11 salient domains as well as targeted customized messages for 2 months. This group will then be re-randomized to receive either a high (gradual taper from daily to weekly texts) or low booster (weekly texts) phase for an additional 2 months. All participants will be monitored for 52 weeks. The primary outcomes are systolic blood pressure and adherence to antihypertensive medication as determined by a self-reported questionnaire and validated with an automated pill-monitoring device. Secondary outcomes include adherence to bipolar disorder medications, psychiatric symptoms, health status, self-efficacy for medication-taking behavior, illness beliefs, medication attitudes, and habit strength. DISCUSSION: This study specifically targets blood pressure and mental health symptom control in people with bipolar and includes implementation elements in the study design intended to inform future scale-up. Promising pilot data and a theoretical model, which views sustained medication-taking behavior in the context of habit formation, suggests that this remotely delivered intervention may help advance care for this high-risk population and is amenable to both scale up and easy adaptation for other groups with poor medication adherence. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT04675593 ) on December 19, 2020.

A customized adherence enhancement program for adolescents and young adults with suboptimal adherence and bipolar disorder: Trial design and methodological report.

BACKGROUND: The onset of bipolar disorder (BD) is common during late adolescence and young adulthood (AYA). Suboptimal medication adherence is a critical yet modifiable risk factor for negative outcomes among AYAs with BD. METHODS: This research used an iterative process (e.g., focus groups, advisory board, cognitive interviews) to modify an existing adherence intervention to address suboptimal adherence in AYAs with BD. The modified version of Customized Adherence Enhancement for Adolescents and Young Adults (CAE-AYA) will be compared to an Enhanced Treatment as Usual condition (ETAU) in 40 AYAs intervention using a 6-month prospective, randomized controlled trial (RCT) in a high-risk group of 16-21 year old AYAs with BD with demonstrated non-adherence to their prescribed BD medications. CONCLUSIONS: This report describes the methodology and design of the ImprovinG adhereNce In adolescenTs with bipolar disordEr (IGNITE) study. If successful, the CAE-AYA approach has the potential to advance care for vulnerable youth with BD.

Correction of depression-associated circadian rhythm abnormalities is associated with lithium response in bipolar disorder.

BACKGROUND: Bipolar disorder (BD) is characterized by episodes of depression and mania and disrupted circadian rhythms. Lithium is an effective therapy for BD, but only 30%-40% of patients are fully responsive. Preclinical models show that lithium alters circadian rhythms. However, it is unknown if the circadian rhythm effects of lithium are essential to its therapeutic properties. METHODS: In secondary analyses of a multi-center, prospective, trial of lithium for BD, we examined the relationship between circadian rhythms and therapeutic response to lithium. Using standardized instruments, we measured morningness, diurnal changes in mood, sleep, and energy (circadian rhythm disturbances) in a cross-sectional study of 386 BD subjects with varying lithium exposure histories. Next, we tracked symptoms of depression and mania prospectively over 12 weeks in a subset of 88 BD patients initiating treatment with lithium. Total, circadian, and affective mood symptoms were scored separately and analyzed. RESULTS: Subjects with no prior lithium exposure had the most circadian disruption, while patients stable on lithium monotherapy had the least. Patients who were stable on lithium with another drug or unstable on lithium showed intermediate levels of disruption. Treatment with lithium for 12 weeks yielded significant reductions in total and affective depression symptoms. Lithium responders (Li-Rs) showed improvement in circadian symptoms of depression, but non-responders did not. There was no difference between Li-Rs and nonresponders in affective, circadian, or total symptoms of mania. CONCLUSIONS: Exposure to lithium is associated with reduced circadian disruption. Lithium response at 12 weeks was selectively associated with the reduction of circadian depressive symptoms. We conclude that stabilization of circadian rhythms may be an important feature of lithium's therapeutic effects. CLINICAL TRIALS REGISTRY: NCT0127253.

Effective engagement of a stakeholder advisory board in severe mental illness (SMI) research: A case study of a clinical trial to improve adherence among people with SMI and hypertension.

Objective: Poor adherence to antihypertensive medication occurs in 50-80% of patients. An ongoing randomized controlled trial (RCT) is evaluating a personalized mobile-health intervention in poorly adherent hypertensive persons with bipolar disorder. To enhance efficacy, the ongoing trial elicited guidance from a Stakeholder Advisory Board (SAB) comprised of patients, family members, clinicians, and health system administrators. Our goal is to describe the formation, role, decision-making process, and key contributions of the SAB as a means of demonstrating meaningful community engagement in mental health research. Methods: Using models and measures from the field of implementation science, eleven SAB members convened across three meetings followed by quantitative surveys that assessed SAB member satisfaction and engagement during the meeting. Results: Significant suggestions from the SAB included 1) expanding inclusion/exclusion criteria, and 2) operationalizing remote implementation of the RCT. Primary study implementation challenges identified by the SAB were 1) participant difficulty engaging in the mHealth intervention, and 2) identification of procedures for monitoring participant adherence to the RCT protocol and contacting under-engaged participants. Quantitative surveys indicated that all SAB members believed that the objectives of the meetings were clear, perceived that they were able to participate in the discussions, and that they were heard. Conclusions: Increasing evidence demonstrates the feasibility of engaging with SABs in clinical research and that this process improves intervention design, increases participant engagement, reduces mental health-related stigma, and produces more effective implementation strategies. We encourage future investigators to use an implementation science framework in partnership with SABs to refine their proposed interventions and improve clinical outcomes.

Cohort profile: the Ohio Army National Guard Mental Health Initiative (OHARNG-MHI).

PURPOSE: Rates of mental disorders in the United States military have increased in recent years. National Guard members may be particularly at risk for mental disorders, given their dual role as citizen-soldiers and their increased involvement in combat deployments during recent conflicts. The Ohio Army National Guard Mental Health Initiative (OHARNG-MHI) was launched to assess the prevalence, incidence, and potential causes and consequences of mental disorders in this unique population. METHODS: OHARNG-MHI is a decade-long dynamic cohort study that followed over 3,000 National Guard members yearly through structured telephone interviews. RESULTS: Findings thus far have applied a pre-, peri-, post-deployment framework, identifying factors throughout the life course associated with mental disorders, including childhood events and more recent events, both during and outside of deployment. An estimated 61% of participants had at least one mental disorder in their lifetime, the majority of which initiated prior to military service. Psychiatric comorbidity was common, as were alcohol use and stressful events. Latent class growth analyses revealed four distinct trajectory paths of both posttraumatic stress and depression symptoms across four years. Only 37% of soldiers with probable past-year mental disorders accessed mental health services in the subsequent year, with substance use disorders least likely to be treated. CONCLUSION: Strengths of this study include a large number of follow-up interviews, detailed data on both military and non-military experiences, and a clinical assessment subsample that assessed the validity of the telephone screening instruments. Findings, methods, and procedures of the study are discussed, and collaborations are welcome.

Clinical predictors of non-response to lithium treatment in the Pharmacogenomics of Bipolar Disorder (PGBD) study.

BACKGROUND: Lithium is regarded as a first-line treatment for bipolar disorder (BD), but partial response and non-response commonly occurs. There exists a need to identify lithium non-responders prior to initiating treatment. The Pharmacogenomics of Bipolar Disorder (PGBD) Study was designed to identify predictors of lithium response. METHODS: The PGBD Study was an eleven site prospective trial of lithium treatment in bipolar I disorder. Subjects were stabilized on lithium monotherapy over 4 months and gradually discontinued from all other psychotropic medications. After ensuring a sustained clinical remission (defined by a score of ≤3 on the CGI for 4 weeks) had been achieved, subjects were followed for up to 2 years to monitor clinical response. Cox proportional hazard models were used to examine the relationship between clinical measures and time until failure to remit or relapse. RESULTS: A total of 345 individuals were enrolled into the study and included in the analysis. Of these, 101 subjects failed to remit or relapsed, 88 achieved remission and continued to study completion, and 156 were terminated from the study for other reasons. Significant clinical predictors of treatment failure (p < 0.05) included baseline anxiety symptoms, functional impairments, negative life events and lifetime clinical features such as a history of migraine, suicidal ideation/attempts, and mixed episodes, as well as a chronic course of illness. CONCLUSIONS: In this PGBD Study of lithium response, several clinical features were found to be associated with failure to respond to lithium. Future validation is needed to confirm these clinical predictors of treatment failure and their use clinically to distinguish who will do well on lithium before starting pharmacotherapy.

Sequential Multiple Assignment Randomized Treatment (SMART) for Bipolar Disorder at Any Phase of Illness and at least Mild Symptom Severity.

Objectives: To sequentially study the effectiveness of lithium and divalproex monotherapy and adjunctive therapy with quetiapine or lamotrigine in the acute and continuation treatment of bipolar I or II disorder at any phase of illness and at least mild symptom severity. Methods: From June 2011 to December 2016, patients with bipolar I or II disorder (using DSM-IV diagnostic criteria) and CGI-S (Clinical Global Impression-Severity) ⩾ 3 were randomized to receive lithium or divalproex monotherapy for 2 weeks. Patients who had CGI-S-depression ⩾ 3 for 2 weeks at any time after 2-week monotherapy were randomly assigned to receive quetiapine or lamotrigine, or remaining on monotherapy for a total of 26 weeks. Results: The rates of early termination due to lack of efficacy and side effects and changes in BISS (Bipolar Inventory of Symptoms Scale) and CGI-S total score were not significantly different between lithium and divalproex. The completion rate was significantly higher with adjunctive therapy than with monotherapy. BISS and CGI-S total scores, and their sub-scores were significantly reduced with adjunctive therapy compared to monotherapy. Adjunctive therapy significantly increased survival times compared to monotherapy (hazard ratio = 6.8), and the monotherapy group had a significantly increased risk for not reaching sustained recovery from depression (hazard ratio = 12.7). Patients who did not need the 2nd randomization and remained on monotherapy had a significantly reduced hazard for discontinuation (hazard ratio = 3.8). Conclusions: The efficacy of lithium and divalproex as monotherapy was modest. Adjunctive lamotrigine and quetiapine to either one was well-tolerated and equally effective in reducing bipolar symptomatology, but adjunctive therapy should be initiated as early as possible when depression symptoms are present.

The association between lithium use and neurocognitive performance in patients with bipolar disorder.

Lithium remains the gold standard for the treatment of bipolar disorder (BD); however, its use has declined over the years mainly due to the side effects and the subjective experience of cognitive numbness reported by patients. In the present study, we aim to methodically test the effects of lithium on neurocognitive functioning in the largest single cohort (n = 262) of BD patients reported to date by harnessing the power of a multi-site, ongoing clinical trial of lithium monotherapy. At the cross-sectional level, multivariate analysis of covariance (MANCOVA) was conducted to examine potential group differences across neurocognitive tests [California Verbal Learning Test (CVLT trials 1-5,CVLT delayed recall), Wechsler Digit Symbol, Trail-making Test parts A and B (TMT-A; TMT-B), and a global cognition index]. At the longitudinal level, on a subset of patients (n = 88) who achieved mood stabilization with lithium monotherapy, we explored the effect of lithium treatment across time on neurocognitive functioning. There were no differences at baseline between BD patients that were taking lithium compared with those that were not. At follow-up a significant neurocognitive improvement in the global cognitive index score [F = 31.69; p < 0.001], CVLT trials 1-5 [F = 29.81; p < 0.001], CVLT delayed recall [F = 15.27; p < 0.001], and TMT-B [F = 6.64, p = 0.012] was detected. The cross-sectional and longitudinal (on a subset of 88 patients) investigations suggest that lithium may be beneficial to neurocognitive functioning in patients with BD and that at the very least it does not seem to significantly impair cognition when used therapeutically.

Manualized cognitive behavioral group therapy to treat vasomotor symptoms for women diagnosed with mood disorders.

OBJECTIVE: This 6-week, prospective, single-arm study examined the feasibility, acceptability, and preliminary efficacy of cognitive behavioral group therapy in peri- and postmenopausal women with mood disorders (major depression or bipolar) and problematic vasomotor menopausal symptoms. METHODS: 59 participants from an outpatient clinic with mood disorders and problematic vasomotor symptoms were enrolled. The primary outcomes were change from baseline to 6 weeks in Hot Flush Night Sweat Problem Rating, Hot Flash Related Daily Interference, and Quality of Life. Secondary outcomes were change in Hot Flush Frequency, depression, anxiety, perceived stress, anhedonia, beliefs and cognitive appraisals of menopause. ClinicalTrials.gov [identifier: NCT02860910]. RESULTS: On the Hot Flush Night Sweat Problem Rating, 39.3% improved 2 or more points, which was clinically relevant. Changes in Quality of Life (p = .001) and the Hot Flash Related Daily Interference Scale were also significant (p < .001). Significant results were found on most secondary outcomes (hot flush frequency on the Hot Flush Daily Diary, depression, anxiety, perceived stress (p < .001) and anhedonia (p = .001). One of six subscales (control subscale) on the cognitive appraisal of menopause significantly improved (p < .001). Three subscales on the beliefs measure did not change significantly (p = .05, p = .91, and p = .14). Six-week study retention was robust (N = 55, 93%) and 94.2% of individuals reported that cognitive behavioral group therapy sessions were useful. CONCLUSION: This exploratory study suggests that CBGT is acceptable, feasible, and efficacious in women with mood disorders and problematic menopause vasomotor symptoms. Further studies are needed using more rigorous and controlled methods.

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.

PPAR-γ agonism as a modulator of mood: proof-of-concept for pioglitazone in bipolar depression.

BACKGROUND: Insulin resistance and other cardio-metabolic 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 (PPAR)-γ agonist could reduce bipolar depression symptom severity. A secondary objective was to determine whether levels of highly sensitive C-reactive protein and interleukin (IL)-6 predicted treatment outcome. METHODS: Patients (n = 34) 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 ≥11) despite an adequate trial of a mood stabilizer received open-label, adjunctive treatment with the PPAR-γ agonist pioglitazone (15-30 mg/day) 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. RESULTS: 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 < 0.001). Self-reported depressive symptom severity and clinician-rated anxiety symptom severity significantly improved over 8 weeks as measured by the QIDS (p < 0.001) and Structured Interview Guide for the Hamilton Anxiety Scale (p < 0.001), respectively. Functional improvement also occurred as measured by the change in total score on the Sheehan Disability Scale (-17.9 ± 3.6; p < 0.001). 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 < 0.001). Higher baseline levels of IL-6 were associated with greater decrease in depression severity (parameter estimate ß = -3.89, standard error [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 < 0.01). CONCLUSIONS: Open-label administration of the PPAR-γ agonist pioglitazone was associated with improvement in depressive symptoms and reduced cardio-metabolic risk. Reduction in inflammation may represent a novel mechanism by which pioglitazone modulates mood. (ClinicalTrials.gov Identifier: NCT00835120).

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.