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.

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.

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.

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).

Chronotype and cellular circadian rhythms predict the clinical response to lithium maintenance treatment in patients with bipolar disorder.

Bipolar disorder (BD) is a serious mood disorder associated with circadian rhythm abnormalities. Risk for BD is genetically encoded and overlaps with systems that maintain circadian rhythms. Lithium is an effective mood stabilizer treatment for BD, but only a minority of patients fully respond to monotherapy. Presently, we hypothesized that lithium-responsive BD patients (Li-R) would show characteristic differences in chronotype and cellular circadian rhythms compared to lithium non-responders (Li-NR). Selecting patients from a prospective, multi-center, clinical trial of lithium monotherapy, we examined morning vs. evening preference (chronotype) as a dimension of circadian rhythm function in 193 Li-R and Li-NR BD patients. From a subset of 59 patient donors, we measured circadian rhythms in skin fibroblasts longitudinally over 5 days using a bioluminescent reporter (Per2-luc). We then estimated circadian rhythm parameters (amplitude, period, phase) and the pharmacological effects of lithium on rhythms in cells from Li-R and Li-NR donors. Compared to Li-NRs, Li-Rs showed a difference in chronotype, with higher levels of morningness. Evening chronotype was associated with increased mood symptoms at baseline, including depression, mania, and insomnia. Cells from Li-Rs were more likely to exhibit a short circadian period, a linear relationship between period and phase, and period shortening effects of lithium. Common genetic variation in the IP3 signaling pathway may account for some of the individual differences in the effects of lithium on cellular rhythms. We conclude that circadian rhythms may influence response to lithium in maintenance treatment of BD.

Retrospective age-of-onset and projected lifetime prevalence of psychiatric disorders among U.S. Army National Guard soldiers.

BACKGROUND: The study of military-related mental health has been disproportionately focused on current symptomology rather than potentially more informative life course mental health. Indeed, no study has assessed age-of-onset and projected lifetime prevalence of disorders among reservists. METHODS: Age-of-onset and projected lifetime DSM-IV anxiety, mood, and substance use disorders were assessed in 671 Ohio Army National Guard soldiers aged 17-60 years. Between 2008 and 2012, face-to-face clinical assessments and surveys were conducted using the Structured Clinical Interview for DSM-IV and Clinician-Administered PTSD Scale. RESULTS: Lifetime prevalence of psychiatric disorders was 61%. Alcohol abuse/dependence (44%) and major depressive disorder (23%) were the most common disorders. The majority (64%) of participants reported disorders antedating enlistment. Median age-of-onset varied with anxiety disorders - particularly phobias and OCD - having the earliest (median=15 years) and mood disorders the latest median age-of-onset (median=21 years). LIMITATIONS: The study was limited by both the retrospective investigation of age-of-onset and the location of our sample. As our sample may not represent the general military population, our findings need to be confirmed in additional samples. CONCLUSIONS: Each psychiatric disorder exhibited a distinct age-of-onset pattern, such that phobias and OCD onset earliest, substance use disorders onset during a short interval from late-adolescence to early-adulthood, and mood disorders onset the latest. Our finding that the majority of participants reported disorders antedating enlistment suggests that an assessment of lifetime psychopathology is essential to understanding the mental health burden of both current and former military personnel.

Onset of Alcohol Use Disorders and Comorbid Psychiatric Disorders in a Military Cohort: Are there Critical Periods for Prevention of Alcohol Use Disorders?

Alcohol use disorders (AUD) are commonly comorbid with anxiety and mood disorders; however, a strategy for AUD prevention remains unclear in the presence of three competing etiological models that each recommends different high-risk groups. Therefore, the investigation of the three hypotheses in a characteristically unique cohort is critical to identifying pervasive characteristics of AUD that can inform a universal prevention strategy. The current study evaluated the temporality and onset of comorbid AUD and psychiatric disorders in a representative sample of 528 Ohio Army National Guard soldiers using structured clinical interviews from 2009 to 2012. We examined temporality both statistically and graphically to identify patterns that could inform prevention. General estimating equations with dichotomous predictor variables were used to estimate odds ratios between comorbid psychiatric disorders and AUDs. An annualized rate of 13.5 % persons per year was diagnosed with any AUD between 2010 and 2012. About an equal proportion of participants with comorbid psychiatric disorders and AUD initiated the psychiatric disorder prior to the AUD and half initiated the psychiatric disorder after the AUD. Regardless of onset, however, the majority (80 %) AUD initiated during a short interval between the ages of 16 and 23. Focused primary prevention during this narrow age range (16-23 years) may have the greatest potential to reduce population mental health burden of AUD, irrespective of the sequencing of comorbid psychiatric disorder.

Lifetime and 12-month use of psychiatric services among U.S. Army National Guard soldiers in Ohio.

OBJECTIVE: The individual and economic burden of psychiatric illnesses is substantial. Although treatment of psychiatric disorders mitigates the burden of illness, over half of military personnel with disorders do not receive mental health care. However, there is a paucity of research examining the relationship between psychiatric disorder categories and treatment-seeking behavior in representative military populations. This study aimed to document, by psychiatric disorder category, the annualized rate of Guard members who obtained psychiatric services and the factors associated with service utilization. METHODS: Face-to-face clinical assessments were conducted between 2008 and 2012 to assess lifetime and current psychiatric disorders and recent psychiatric service use among 528 Ohio Army National Guard soldiers. RESULTS: An annualized rate of 31% of persons per year accessed psychiatric services between 2010 and 2012. Persons with substance use disorders had the lowest annualized rate of service use, and these were the only disorders not predictive of accessing services. Current mood disorder, current anxiety disorder, and lifetime history of service use were the strongest predictors of recent service use. There were no socioeconomic or other group predictors of psychiatric service use. CONCLUSIONS: About half of the soldiers who could benefit from mental health services used them, yet soldiers with substance use disorders were predominantly going untreated. There were no differences in treatment utilization by group characteristics, suggesting no systematic barriers to care for particular groups. Efforts to encourage broader adoption of treatment seeking, particularly among persons with substance use disorders, are necessary to mitigate psychiatric health burden in this population.