Exploratory study of ultraviolet B (UVB) radiation and age of onset of bipolar disorder.

BACKGROUND: Sunlight contains ultraviolet B (UVB) radiation that triggers the production of vitamin D by skin. Vitamin D has widespread effects on brain function in both developing and adult brains. However, many people live at latitudes (about > 40 N or S) that do not receive enough UVB in winter to produce vitamin D. This exploratory study investigated the association between the age of onset of bipolar I disorder and the threshold for UVB sufficient for vitamin D production in a large global sample. METHODS: Data for 6972 patients with bipolar I disorder were obtained at 75 collection sites in 41 countries in both hemispheres. The best model to assess the relation between the threshold for UVB sufficient for vitamin D production and age of onset included 1 or more months below the threshold, family history of mood disorders, and birth cohort. All coefficients estimated at P ≤ 0.001. RESULTS: The 6972 patients had an onset in 582 locations in 70 countries, with a mean age of onset of 25.6 years. Of the onset locations, 34.0% had at least 1 month below the threshold for UVB sufficient for vitamin D production. The age of onset at locations with 1 or more months of less than or equal to the threshold for UVB was 1.66 years younger. CONCLUSION: UVB and vitamin D may have an important influence on the development of bipolar disorder. Study limitations included a lack of data on patient vitamin D levels, lifestyles, or supplement use. More study of the impacts of UVB and vitamin D in bipolar disorder is needed to evaluate this supposition.

Mindfulness-Based Cognitive Therapy, Acceptance and Commitment Therapy, and Positive Psychotherapy for Major Depression.

OBJECTIVE: In the past two decades, newer psychotherapy treatments have emerged for the treatment of major depression. This review aimed to comprehensively synthesize the evidence for mindfulness-based cognitive therapy (MBCT), acceptance and commitment therapy (ACT), and positive psychotherapy (PPT) in treating a current episode of major depression. METHODS: A systematic search of the Ovid MEDLINE, Embase, PsycINFO, and Cochrane databases was conducted for randomized controlled trials of MBCT, ACT, and PPT for major depression. Standardized mean differences were calculated with Hedges' g to complete random-effects meta-analysis. Heterogeneity was assessed with the Cochran Q statistic and I2 statistic. Subgroup analysis was conducted to further investigate heterogeneity. RESULTS: A random-effects meta-analysis of 15 studies (MBCT, N=7; ACT, N=4; PPT, N=4) revealed that all three therapies showed efficacy in reducing symptoms of depression with a small favorable effect, compared with all control conditions (N=946; Hedges' g=0.34; 95% confidence interval=0.14, 0.54; p<0.001). Cochrane's Q statistic (Q=32, df=15, p=0.007) suggested significant heterogeneity (I2=53%). A mixed-effects model test for subgroup differences showed significant differences between active controls and treatment-as-usual controls (χ2=15.3, df=1, p<0.001). Overall quality of evidence and publication bias were low. CONCLUSIONS: Meta-analysis shows that MBCT and ACT may be superior to inactive or treatment-as-usual controls and that PPT may be comparable to active controls for reducing symptoms of major depression after an acute course of therapy. However, the quality of the evidence was low. High-quality studies are needed to confirm the efficacy of these interventions.

Exercise, Yoga, and Tai Chi for Treatment of Major Depressive Disorder in Outpatient Settings: A Systematic Review and Meta-Analysis.

OBJECTIVE: Exercise, yoga, and tai chi are commonly used complementary approaches for health and wellness. This review aims to synthesize the evidence for exercise, yoga, and tai chi in the outpatient treatment of major depressive disorder. STUDY SELECTION: A systematic search of the Ovid MEDLINE, EMBASE, PsycINFO, and Cochrane databases was conducted for randomized controlled trials of exercise, yoga, and tai chi for major depressive disorder. DATA EXTRACTION: Standardized mean differences were calculated and meta-analyzed using a random effects multilevel modeling framework. Heterogeneity and subgroup analysis was conducted. RESULTS: Twenty-five studies were included for final analysis (exercise: 15, yoga: 7, tai chi: 3). Overall, meta-analysis showed a moderate significant clinical effect. However, when only studies (6 studies) with the lowest risk of bias were included, the overall effect size was reduced to low to moderate efficacy. Overall quality of evidence was low. Heterogeneity and publication bias were high. CONCLUSIONS: The current meta-analysis of outpatient exercise, yoga, and tai chi for treatment of major depressive disorder suggests that adjunctive exercise and yoga may have small additive clinical effects in comparison to control for reducing depressive symptoms. The evidence for tai chi is insufficient to draw conclusions. The concerns with quality of studies, high heterogeneity, and evidence of publication bias preclude making firm conclusions.

Cell-type-Specific Patterned Stimulus-Independent Neuronal Activity in the Drosophila Visual System during Synapse Formation.

Stereotyped synaptic connections define the neural circuits of the brain. In vertebrates, stimulus-independent activity contributes to neural circuit formation. It is unknown whether this type of activity is a general feature of nervous system development. Here, we report patterned, stimulus-independent neural activity in the Drosophila visual system during synaptogenesis. Using in vivo calcium, voltage, and glutamate imaging, we found that all neurons participate in this spontaneous activity, which is characterized by brain-wide periodic active and silent phases. Glia are active in a complementary pattern. Each of the 15 of over 100 specific neuron types in the fly visual system examined exhibited a unique activity signature. The activity of neurons that are synaptic partners in the adult was highly correlated during development. We propose that this cell-type-specific activity coordinates the development of the functional circuitry of the adult brain.

Bioenergetics and synaptic plasticity as potential targets for individualizing treatment for depression.

Disruptions of bioenergetic signaling and neurogenesis are hallmarks of depression physiology and are often the product of dysregulation of the inflammatory, stress-response, and metabolic systems. These systems are extensively interrelated at the physiological level, yet the bulk of the literature to date addresses pathophysiological mechanisms in isolation. A more integrated understanding of the etiology, progression, and treatment response profiles of depression is possible through wider consideration of relevant preclinical and clinical studies that examine the result of disruptions in these systems. Here, we review recent data demonstrating the critical effects of bioenergetic disruption on neuroplasticity and the development and progression of depressive illness. We further highlight the interactive and dynamic nature of the inflammatory and stress response systems and how disruption of these systems influences bioenergetic signaling pathways critical to treatment outcomes. In so doing, we underscore the pressing need to reconsider the implications of treatment resistance and present a framework for developing novel, personalized treatment approaches for depression.

An Exploratory Study of Spectroscopic Glutamatergic Correlates of Cortical Excitability in Depressed Adolescents.

Introduction: Transcranial magnetic stimulation (TMS) research has suggested dysfunction in cortical glutamatergic systems in adolescent depression, while proton magnetic resonance spectroscopy (1H-MRS) studies have demonstrated deficits in concentrations of glutamatergic metabolites in depressed individuals in several cortical regions, including the anterior cingulate cortex (ACC). However, few studies have combined TMS and MRS methods to examine relationships between glutamatergic neurochemistry and excitatory and inhibitory neural functions, and none have utilized TMS-MRS methodology in clinical populations or in youth. This exploratory study aimed to examine relationships between TMS measures of cortical excitability and inhibition and concentrations of glutamatergic metabolites as measured by 1H-MRS in depressed adolescents. Methods: Twenty-four adolescents (aged 11-18 years) with depressive symptoms underwent TMS testing, which included measures of the resting motor threshold (RMT), cortical silent period (CSP), short-interval intracortical inhibition (SICI), and intracortical facilitation (ICF). Fourteen participants from the same sample also completed 1H-MRS in a 3 T MRI scanner after TMS testing. Glutamate + glutamine (Glx) concentrations were measured in medial ACC and left primary motor cortex voxels with a TE-optimized PRESS sequence. Metabolite concentrations were corrected for cerebrospinal fluid (CSF) after tissue segmentation. Pearson product-moment and Spearman rank-order correlations were calculated to assess relationships between TMS measures and [Glx]. Results: In the left primary motor cortex voxel, [Glx] had a significant positive correlation with the RMT. In the medial ACC voxel, [Glx] had significant positive correlations with ICF at the 10-ms and 20-ms interstimulus intervals (ISIs). Conclusion: These preliminary data implicate glutamate in cortical excitatory processes measured by TMS. Limitations included small sample size, lack of healthy control comparators, possible age- and sex-related effects, and observational nature of the study. Further research aimed at examining the relationship between glutamatergic metabolite concentrations measured through MRS and the excitatory and inhibitory physiology measured through TMS is warranted. Combined TMS-MRS methods show promise for future investigations of the pathophysiology of depression in adults as well as in children and adolescents.

Peripheral proinflammatory markers associated with ketamine response in a preclinical model of antidepressant-resistance.

Ketamine, N-methyl-d-aspartate (NMDA) receptor antagonist and anti-inflammatory agent, has rapid therapeutic effects in a subset of patients with more intractable forms of depression. Irregular proinflammatory cytokine and acute-reactive protein levels have been reported in clinical and preclinical depression research. We explored the association between the rapid antidepressant-like effects of ketamine and peripheral proinflammatory profile in a model of antidepressant-resistance. Male Wistar rats were pre-treated with ACTH-(1-24) 100µg/d or saline (0.9%) for 14d. Antidepressant-like effects were assessed with the forced swim test (FST). Ketamine (10mg/kg) significantly reduced immobility duration in saline-pretreated control animals. In contrast, a divergent response was observed in ACTH-pretreated antidepressant resistant animals, with 50% responders and 50% non-responders. Plasma samples were analyzed via enzyme-linked immunosorbent assay (ELISA) for interleukin 6 (IL-6), tumour necrosis factor alpha (TNFα) and C-reactive protein (CRP). Levels of CRP and TNFα differentiated ketamine responders and non-responders.

Hypovitaminosis D in psychiatric inpatients: clinical correlation with depressive symptoms, cognitive impairment, and prescribing practices.

OBJECTIVE: The association of hypovitaminosis D with measures of depressive symptoms and cognitive impairment remains unclear. This correlation and subsequent prescribing practices of vitamin D supplementation were evaluated in a population of psychiatric inpatients. METHODS: A retrospective study was conducted of 548 patients with a serum 25-hydroxyvitamin D [25(OH)D] level measured during hospitalization. Outcomes included the association of hypovitaminosis D with Patient Health Questionnaire (PHQ-9) and Folstein Mini-Mental State Exam (MMSE) scores, including an evaluation of vitamin D dosing upon hospital discharge. RESULTS: Two hundred three patients (37%) had hypovitaminosis D. The majority [183 (90%)] had moderate (10-24 ng/mL), while 20 (10%) had severe hypovitaminosis D (<10 ng/mL). There was no significant association between hypovitaminosis D and PHQ-9 or MMSE scores (p = 0.107 and p = 0.271, respectively). Overall, 33% of patients with moderate hypovitaminosis D and 45% of patients with severe hypovitaminosis D were newly prescribed vitamin D or received a dose increase. Initiation of vitamin D or increased vitamin D dose was significantly higher in patients with hypovitaminosis D (p < 0.001). CONCLUSIONS: No association was found between hypovitaminosis D and depressive symptoms or cognitive function. However, patients with hypovitaminosis D were more likely to be prescribed additional vitamin D at hospital discharge.

Comparing the Beck Depression Inventory-II (BDI-II) and Patient Health Questionnaire (PHQ-9) depression measures in an integrated mood disorders practice.

BACKGROUND: Patient self-assessment instruments are useful in screening, tracking, and documenting the course of depressive symptoms with minimal clinician time. Two popular instruments are the Beck Depression Inventory (BDI-II) and the Patient Health Questionnaire (PHQ-9). We compared the performance of these two instruments in a mood disorders setting. METHODS: A retrospective study of 625 patients who completed a PHQ-9 and BDI-II as part of routine clinical care (1) during initial outpatient evaluation between 2008 and 2009, and (2) on admission to an inpatient mood disorders unit between 2006 and 2009. Pearson correlation coefficients for total PHQ-9 and BDI-II scores were calculated for all patients, the outpatients, and the inpatients. RESULTS: Overall r=0.77, indicating strong correlation, more in the outpatients (n=287, r=0.81) than the inpatients (n=338, r=0.67). Mean PHQ-9 and BDI-II scores for the outpatients were 15.1 (SD 7.4) and 27.8 (SD 14.1) corresponding to "moderately severe" and "moderate" categories respectively; for inpatients, 18.9 (SD 5.7) and 33.8 (SD 11.5) corresponding to "moderately severe" and "severe." LIMITATIONS: Retrospective design and no monitoring of which instrument was completed first in case that influenced patient response to the second instrument CONCLUSIONS: PHQ-9 and BDI-II scores, as continuous but not categorical variables, in a mood disorders subspeciality setting are closely correlated and essentially interchangeable. There are practical applications to our findings, as the PHQ-9 is shorter and free.

Short TE (7) Li-MRS confirms Bi-exponential lithium T2 relaxation in humans and clearly delineates two patient subtypes.

PURPOSE: (i) To develop an MRS technique to measure (7) Li levels in human brain in a reasonable scan time, (ii) to develop a technique to quantify (7) Li T2 relaxation times as measured from human brain in patients taking lithium for the treatment of their bipolar disorder, and (iii) to confirm or refute the presence of bi-exponential (7) Li T2 relaxation in human brain. MATERIALS AND METHODS: We modified a spin-echo MRS pulse sequence to decrease its minimum echo time. With IRB approval, we performed lithium MRS with the modified pulse sequence on 13 euthymic bipolar patients stable on long-term lithium to treat their disease. RESULTS: We were able to achieve a total scan time per sample of 8:20; total scan time including imaging, calibration and MRS was approximately 1 h 15 min. We observed bi-exponential T2 relaxation in the majority of patients, with an average short decay time of 5.3 ± 1.4 ms and an average long decay time of 68.2 ± 10.2 ms. However, in two patients we observed strongly mono-exponential T2 relaxation with an average decay time of 47.4 ± 1.3 ms. CONCLUSION: (7) Li relaxation patterns may prove useful to distinguish between lithium-responsive and lithium nonresponsive bipolar patients.

Free T4 index and clinical outcome in patients with depression.

INTRODUCTION: Many studies of patients with major depression have reported that a significant decrease in serum free T(4) index is associated with specific treatments; what has been unanswered is whether these observations are generalizable. This study evaluated baseline thyroid function and its relationship to rapidity of treatment response as measured by hospital length of stay (HLOS). METHODS: Admission thyroid indices and HLOS data were harvested from the medical record of patients hospitalized for depression, both unipolar and bipolar. The relationship between admission thyroid indices and HLOS was evaluated using survival models. RESULTS: Controlling for age and year of discharge, an inverse relationship between FT(4) index (FT(4)I) and HLOS was present in men, but not in women. The mean HLOS stratified by gender and median FT(4)I was 50% shorter in men with a relatively high FT(4)I in comparison to the other three groups. LIMITATIONS: This is a retrospective study limited by the absence of a structured diagnostic psychiatric interview and prospective controlled antidepressant evaluation. CONCLUSION: These data would suggest that a relatively elevated FT(4) index in depressed men is associated with a faster antidepressant response time. Prospective study is encouraged to further clarify this potential thyroid/gender relationship and whether thyroid supplementation can accelerate the improvement in depression as measured by HLOS.

An overview of recent findings of the Stanley Foundation Bipolar Network (Part I).

AIM AND METHODS: Selected recent findings of the Stanley Foundation Bipolar Network are briefly reviewed and their clinical implications discussed. RESULTS: Daily prospective ratings on the NIMH-LCM indicate a high degree of residual depressive morbidity (three times that of hypomania or mania) despite active psychopharmacological treatment with a variety of modalities including mood stabilizers, antidepressants, and benzodiazepines, as well as antipsychotics as necessary. The rates of switching into brief to full hypomania or mania during the use of antidepressants is described, and new data suggesting the potential utility of continuing antidepressants in the small group of patients showing an initial acute and persistent response is noted. Bipolar patients with a history of major environmental adversities in childhood have a more severe course of illness and an increased incidence of suicide attempts compared with those without. Preliminary open data suggest useful antidepressant effects of the atypical antipsychotic quetiapine, while a double-blind randomized controlled study failed to show efficacy of omega-3 fatty acids (6 g of eicosapentaenoic acid compared with placebo for 4 months) in the treatment of either acute depression or rapid cycling. The high prevalence of overweight and increased incidence of antithyroid antibodies in patients with bipolar illness is highlighted. CONCLUSIONS: Together, these findings suggest a very high degree of comorbidity and treatment resistance in outpatients with bipolar illness treated in academic settings and the need to develop not only new treatment approaches, but also much earlier illness recognition, diagnosis, and intervention in an attempt to reverse or prevent this illness burden.

Low CSF somatostatin associated with response to nimodipine in patents with affective illness.

BACKGROUND: In patients with depression, treatment with nimodipine has been shown to increase cerebrospinal fluid (CSF) somatostatin (SRIF) and ameliorate baseline global cerebral hypometabolism. This study was conducted to assess whether a low baseline level of CSF SRIF was associated with response to nimodipine treatment. METHODS: Twenty-one depressed patients underwent lumbar puncture for analysis of CSF somatostatin-like immunoreactivity (SRIF-LI) during a medication-free period and after at least 6 weeks of nimodipine monotherapy. Twenty-five healthy control subjects were utilized as a comparison group. Clinical improvement was assessed using the Clinical Global Impression Scale for Bipolar Illness. RESULTS: As predicted, baseline CSF SRIF-LI was significantly lower in eventual nimodipine responders (33.1 +/- 2.8 pg/mol) compared to eventual nonresponders [41.9 +/- 2.6 pg/mL; t(19) = 1.98, p =.03, one-tailed]. CONCLUSIONS: Low baseline CSF somatostatin in depression may be associated with response to nimodipine, which in turn may be related to the ability of nimodipine to increase CSF somatostatin.