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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.

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Bipolar disorder is heterogeneous in phenomenology, illness trajectory, and response to treatment. Despite evidence for the efficacy of multimodal-ity interventions, the majority of persons affected by this disorder do not achieve and sustain full syndromal recovery. It is eagerly anticipated that combining datasets across various information sources (e.g., hierarchical "multi-omic" measures, electronic health records), analyzed using advanced computational methods (e.g., machine learning), will inform future diagnosis and treatment selection. In the interim, identifying clinically meaningful subgroups of persons with the disorder having differential response to specific treatments at point-of-care is an empirical priority. This paper endeavours to synthesize salient domains in the clinical characterization of the adult patient with bipolar disorder, with the overarching aim to improve health outcomes by informing patient management and treatment considerations. Extant data indicate that characterizing select domains in bipolar disorder provides actionable information and guides shared decision making. For example, it is robustly established that the presence of mixed features - especially during depressive episodes - and of physical and psychiatric comorbidities informs illness trajectory, response to treatment, and suicide risk. In addition, early environmental exposures (e.g., sexual and physical abuse, emotional neglect) are highly associated with more complicated illness presentations, inviting the need for developmentally-oriented and integrated treatment approaches. There have been significant advances in validating subtypes of bipolar disorder (e.g., bipolar I vs. II disorder), particularly in regard to pharmacological interventions. As with other severe mental disorders, social functioning, interpersonal/family relationships and internalized stigma are domains highly relevant to relapse risk, health outcomes, and quality of life. The elevated standardized mortality ratio for completed suicide and suicidal behaviour in bipolar disorder invites the need for characterization of this domain in all patients. The framework of this paper is to describe all the above salient domains, providing a synthesis of extant literature and recommendations for decision support tools and clinical metrics that can be implemented at point-of-care.

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OBJECTIVE: Circadian rhythm disruption is commonly observed in bipolar disorder (BD). Daylight is the most powerful signal to entrain the human circadian clock system. This exploratory study investigated if solar insolation at the onset location was associated with the polarity of the first episode of BD I. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area of the Earth. METHODS: Data from 7488 patients with BD I were collected at 75 sites in 42 countries. The first episode occurred at 591 onset locations in 67 countries at a wide range of latitudes in both hemispheres. Solar insolation values were obtained for every onset location, and the ratio of the minimum mean monthly insolation to the maximum mean monthly insolation was calculated. This ratio is largest near the equator (with little change in solar insolation over the year), and smallest near the poles (where winter insolation is very small compared to summer insolation). This ratio also applies to tropical locations which may have a cloudy wet and clear dry season, rather than winter and summer. RESULTS: The larger the change in solar insolation throughout the year (smaller the ratio between the minimum monthly and maximum monthly values), the greater the likelihood the first episode polarity was depression. Other associated variables were being female and increasing percentage of gross domestic product spent on country health expenditures. (All coefficients: P ≤ 0.001). CONCLUSION: Increased awareness and research into circadian dysfunction throughout the course of BD is warranted.

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BACKGROUND: Bipolar disorder is associated with circadian disruption and a high risk of suicidal behavior. In a previous exploratory study of patients with bipolar I disorder, we found that a history of suicide attempts was associated with differences between winter and summer levels of solar insolation. The purpose of this study was to confirm this finding using international data from 42% more collection sites and 25% more countries. METHODS: Data analyzed were from 71 prior and new collection sites in 40 countries at a wide range of latitudes. The analysis included 4876 patients with bipolar I disorder, 45% more data than previously analyzed. Of the patients, 1496 (30.7%) had a history of suicide attempt. Solar insolation data, the amount of the sun's electromagnetic energy striking the surface of the earth, was obtained for each onset location (479 locations in 64 countries). RESULTS: This analysis confirmed the results of the exploratory study with the same best model and slightly better statistical significance. There was a significant inverse association between a history of suicide attempts and the ratio of mean winter insolation to mean summer insolation (mean winter insolation/mean summer insolation). This ratio is largest near the equator which has little change in solar insolation over the year, and smallest near the poles where the winter insolation is very small compared to the summer insolation. Other variables in the model associated with an increased risk of suicide attempts were a history of alcohol or substance abuse, female gender, and younger birth cohort. The winter/summer insolation ratio was also replaced with the ratio of minimum mean monthly insolation to the maximum mean monthly insolation to accommodate insolation patterns in the tropics, and nearly identical results were found. All estimated coefficients were significant at p < 0.01. CONCLUSION: A large change in solar insolation, both between winter and summer and between the minimum and maximum monthly values, may increase the risk of suicide attempts in bipolar I disorder. With frequent circadian rhythm dysfunction and suicidal behavior in bipolar disorder, greater understanding of the optimal roles of daylight and electric lighting in circadian entrainment is needed.

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In many international studies, rates of completed suicide and suicide attempts have a seasonal pattern that peaks in spring or summer. This exploratory study investigated the association between solar insolation and a history of suicide attempt in patients with bipolar I disorder. Solar insolation is the amount of electromagnetic energy from the Sun striking a surface area on Earth. Data were collected previously from 5536 patients with bipolar I disorder at 50 collection sites in 32 countries at a wide range of latitudes in both hemispheres. Suicide related data were available for 3365 patients from 310 onset locations in 51 countries. 1047 (31.1%) had a history of suicide attempt. There was a significant inverse association between a history of suicide attempt and the ratio of mean winter solar insolation/mean summer solar insolation. This ratio is smallest near the poles where the winter insolation is very small compared to the summer insolation. This ratio is largest near the equator where there is relatively little variation in the insolation over the year. Other variables in the model that were positively associated with suicide attempt were being female, a history of alcohol or substance abuse, and being in a younger birth cohort. Living in a country with a state-sponsored religion decreased the association. (All estimated coefficients p < 0.01). In summary, living in locations with large changes in solar insolation between winter and summer may be associated with increased suicide attempts in patients with bipolar disorder. Further investigation of the impacts of solar insolation on the course of bipolar disorder is needed.

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OBJECTIVE: To derive new criteria sets for defining manic and hypomanic episodes (and thus for defining the bipolar I and II disorders), an international Task Force was assembled and termed AREDOC reflecting its role of Assessment, Revision and Evaluation of DSM and other Operational Criteria. This paper reports on the first phase of its deliberations and interim criteria recommendations. METHOD: The first stage of the process consisted of reviewing Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, and recent International Classification of Diseases criteria, identifying their limitations and generating modified criteria sets for further in-depth consideration. Task Force members responded to recommendations for modifying criteria and from these the most problematic issues were identified. RESULTS: Principal issues focussed on by Task Force members were how best to differentiate mania and hypomania, how to judge 'impairment' (both in and of itself and allowing that functioning may sometimes improve during hypomanic episodes) and concern that rejecting some criteria (e.g. an imposed duration period) might risk false-positive diagnoses of the bipolar disorders. CONCLUSION: This first-stage report summarises the clinical opinions of international experts in the diagnosis and management of the bipolar disorders, allowing readers to contemplate diagnostic parameters that may influence their clinical decisions. The findings meaningfully inform subsequent Task Force stages (involving a further commentary stage followed by an empirical study) that are expected to generate improved symptom criteria for diagnosing the bipolar I and II disorders with greater precision and to clarify whether they differ dimensionally or categorically.

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BACKGROUND: The patients with schizophrenia are at increased risk for problems regarding metabolic parameters due to their lifestyle and antipsychotic treatment. OBJECTIVE: In this study, we aimed to evaluate the levels of adiponectin, leptin, irisin in patients with schizophrenia who were nondiabetic, nonobese and under antipsychotic treatment. METHOD: 5 ml sample of venous blood was collected from each participant. Blood cells were separated from the serum. The serum samples were stored in a -80°C freezer. Biochemical analyses were performed on these samples. Adiponectin, leptin and irisin levels were measured by Enzyme Linked Immunosorbent Assay method. RESULTS: The study included 88 subjects. Of them, 44 were patients with schizophrenia and 44 were healthy controls. There were no statistically significant results when the c-reactive protein, adiponectin, leptin and irisin levels were compared between the schizophrenia and the control group (p>0.05). CONCLUSION: In our study, adiponectin, leptin and irisin levels in patients with schizophrenia did not present a statistically significant difference from healthy controls. Therefore, there is a need for studies including more participants to investigate the level of irisin in patients with schizophrenia.

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BACKGROUND: Environmental conditions early in life may imprint the circadian system and influence response to environmental signals later in life. We previously determined that a large springtime increase in solar insolation at the onset location was associated with a younger age of onset of bipolar disorder, especially with a family history of mood disorders. This study investigated whether the hours of daylight at the birth location affected this association. METHODS: Data collected previously at 36 collection sites from 23 countries were available for 3896 patients with bipolar I disorder, born between latitudes of 1.4 N and 70.7 N, and 1.2 S and 41.3 S. Hours of daylight variables for the birth location were added to a base model to assess the relation between the age of onset and solar insolation. RESULTS: More hours of daylight at the birth location during early life was associated with an older age of onset, suggesting reduced vulnerability to the future circadian challenge of the springtime increase in solar insolation at the onset location. Addition of the minimum of the average monthly hours of daylight during the first 3 months of life improved the base model, with a significant positive relationship to age of onset. Coefficients for all other variables remained stable, significant and consistent with the base model. CONCLUSIONS: Light exposure during early life may have important consequences for those who are susceptible to bipolar disorder, especially at latitudes with little natural light in winter. This study indirectly supports the concept that early life exposure to light may affect the long term adaptability to respond to a circadian challenge later in life.

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OBJECTIVE: Individuals with bipolar disorder (BD) usually report significant disability and psychosocial impairment. Both the nature and causes associated with this impairment are poorly understood. In particular, research examining the impact of pharmacotherapy on the different aspects of psychosocial functioning in bipolar patients is currently lacking. The aim of this study was to assess to what extent the psychotropic medications used during psychiatric hospitalization and at discharge can predict clinical psychosocial functioning and the severity of the illness at follow-up in inpatients with bipolar disorder (BD). METHODS: Patients were 71 adult BD patients contacted on average 31 months after discharge who completed at the follow-up a telephone interview based on the Health of the Nation Outcome Scales (HoNOS). RESULTS: All the subjects completed the follow-up assessment between 5 and 75 months after discharge. The mean raw score for the HoNOS-6 was 5.70 ± 5.37. Patients with more severe behavior problems more often had been prescribed atypical antipsychotics and anticonvulsants at discharge. Patients with more severe psychosocial functioning problems more often had a history of suicide attempts, and were more often prescribed anxiolytics during hospitalization and less often prescribed lithium at discharge. CONCLUSIONS: Having been prescribed anxiolytics and atypical antipsychotics during hospitalization predicted reduced psychosocial functioning, whereas prescription of lithium at discharge was associated with better psychosocial functioning at follow-up. Future studies are needed in order to investigate how psychosocial functioning may be related in the long-term to pharmacological treatment in patients after discharge.

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BACKGROUND: The onset of bipolar disorder is influenced by the interaction of genetic and environmental factors. We previously found that a large increase in sunlight in springtime was associated with a lower age of onset. This study extends this analysis with more collection sites at diverse locations, and includes family history and polarity of first episode. METHODS: Data from 4037 patients with bipolar I disorder were collected at 36 collection sites in 23 countries at latitudes spanning 3.2 north (N) to 63.4 N and 38.2 south (S) of the equator. The age of onset of the first episode, onset location, family history of mood disorders, and polarity of first episode were obtained retrospectively, from patient records and/or direct interview. Solar insolation data were obtained for the onset locations. RESULTS: There was a large, significant inverse relationship between maximum monthly increase in solar insolation and age of onset, controlling for the country median age and the birth cohort. The effect was reduced by half if there was no family history. The maximum monthly increase in solar insolation occurred in springtime. The effect was one-third smaller for initial episodes of mania than depression. The largest maximum monthly increase in solar insolation occurred in northern latitudes such as Oslo, Norway, and warm and dry areas such as Los Angeles, California. LIMITATIONS: Recall bias for onset and family history data. CONCLUSIONS: A large springtime increase in sunlight may have an important influence on the onset of bipolar disorder, especially in those with a family history of mood disorders.

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Aripiprazole is a third generation atypical antipsychotic with compelling evidence as a highly effective treatment option in the management of acute manic and mixed episodes of bipolar I disorders. It has a unique mode of action, acting as a partial agonist at dopamine D2 and D3, and serotonin 5-HT1A; and exhibiting antagonistic action at the 5-HT2A and H1 receptors. Overall, it has a favorable safety and tolerability profile, with low potential for clinically significant weight gain and metabolic effects, especially compared to other well-established treatments. It also has a superior tolerability profile when used as maintenance treatment. Side effects like headache, insomnia, and extrapyramidal side effects (EPSEs), such as tremor and akathisia may be treatment limiting in some cases. It is efficacious in both acute mania and mixed states, and in the long-term prevention of manic relapses. Aripiprazole therefore, is a significant player in the current portfolio of anti-manic pharmacological treatments. The data sources for this article are from EMBASE, MEDLINE, and the clinical trial database searches for all the literature published between January 2003 and September 2013. The key search terms were "aripiprazole" combined with "bipolar disorder", "mania", "antipsychotics", "mood stabilizer", "randomized controlled trial", and "pharmacology". Abstracts and proceedings from national and international psychiatric meetings were also reviewed, along with reviews of the reference lists of relevant articles.

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The main objective of this study was to examine the rate of three dimensions of depressive symptoms in medical student population in Serbia, and to find out whether this rate had changed over the period often years. This cross-sectional study included 615 medical students (F = 61% and M = 39%), mean age = 23.60 (SD = 1.541), who were tested in five non-consecutive surveys between 2002 and 2012. Depressive symptoms were measured by the Beck Depression Inventory (BDI). The mean BDI score for the entire sample was 6.26 +/- 6.175. There was no significant difference in total BDI score among the values obtained during the ten years of testing. The greatest portion of the examined sample (77.24%) had no signs of depressive symptoms, and there was no difference in symptom intensity between medical students and other educational profiles. Similar to previous results, females had higher scores on all depressive dimensions except for one tested year, whereas a weak correlation was found between BDI scores and student age (r = 0.104; p = 0.010). Since there are still discrepancies among studies that do (not) report that medical students have typical depressive symptoms, potential explanations for the mentioned discrepancies may be found in individual characteristics of the members of the student population. Our suggestions for future studies are that they should include the stress factor, stress coping strategies, estimated life satisfaction, and the impact of these factors on the potential mental disorders.

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Despite the high morbidity and mortality associated with bipolar depression, the optimal treatment for this phase is still a matter of debate. The aim of the current review was to provide updated evidence about the efficacy and tolerability of anticonvulsants in the treatment of acute bipolar depression. A comprehensive review of randomized controlled trials (RCTs) evaluating the use of anticonvulsants for the treatment of acute bipolar depression up to June 2011 was conducted by means of the PubMed-Medline database. Eligibility criteria included active comparator-controlled or placebo-controlled randomized studies involving monotherapy or combination therapy. A total of 18 RCTs fulfilled the inclusion criteria. Studies supported the efficacy of divalproex as monotherapy in acute bipolar depression but small sample size was a common methodological limitation. Findings were inconclusive for lamotrigine and carbamazepine although overall lamotrigine may have a beneficial but modest effect. Negative results were found for levetiracetam and gabapentin but the evidence base on these agents is scant. All anticonvulsants were generally well tolerated. No double-blind RCTs were found for the use of other anticonvulsants such as oxcarbazepine, licarbazepine, zonisamide, retigabine, pregabalin, tiagabine, felbamate and vigabatrine in the acute treatment of bipolar depression. To sum up, taking into consideration the efficacy and tolerability profiles of anticonvulsants, current evidence supports the use of divalproex and lamotrigine in the treatment of acute bipolar depression. However, available data for most other anticonvulsants are inconclusive and further RCTs with larger sample sizes are needed before drawing firm conclusions.

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Current gold standard in the treatment of depression includes pharmacotherapeutic and psychotherapeutic strategies together with social support. Due to the actually discussed controversies concerning the differential efficacy of antidepressants, a contribution to a comprehensive clarification seems to be necessary to avert further deterioration and uncertainty from patients, relatives, and their treating psychiatrists and general practitioners. Both efficacy and clinical effectiveness of antidepressants in the treatment of depressive disorders can be confirmed. Clinically meaningful antidepressant treatment effects were confirmed in different types of studies. Methodological issues of randomized controlled studies, meta-analyses, and effectiveness studies will be discussed. Furthermore, actual data about the differential efficacy and effectiveness of antidepressants with distinct pharmacodynamic properties and about outcome differences in studies using antidepressants and/or psychotherapy are discussed. This is followed by a clinically oriented depiction-the differential clinical effectiveness of different pharmacodynamic modes of action of antidepressants in different subtypes of depressive disorders. It can be summarized that the spectrum of different antidepressant treatments has broadened during the last decades. The efficacy and clinical effectiveness of antidepressants is statistically significant and clinically relevant and proven repeatedly. For further optimizing antidepressant treatment plans, clearly structured treatment algorithms and the implementation of psychotherapy seem to be useful. A modern individualized antidepressant treatment in most cases is a well-tolerated and efficacious tool to minimize the negative impact of the otherwise devastating and life-threatening outcome of depressive disorders.

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Current gold standard approaches to the treatment of depression include pharmacotherapeutic and psychotherapeutic interventions with social support. Due to current controversies concerning the efficacy of antidepressants in randomized controlled trials, the generalizability of study findings to wider clinical practice and the increasing importance of socioeconomic considerations, it seems timely to address the uncertainty of concerned patients and relatives, and their treating psychiatrists and general practitioners. We therefore discuss both the efficacy and clinical effectiveness of antidepressants in the treatment of depressive disorders. We explain and clarify useful measures for assessing clinically meaningful antidepressant treatment effects and the types of studies that are useful for addressing uncertainties. This includes considerations of methodological issues in randomized controlled studies, meta-analyses, and effectiveness studies. Furthermore, we summarize the differential efficacy and effectiveness of antidepressants with distinct pharmacodynamic properties, and differences between studies using antidepressants and/or psychotherapy. We also address the differential effectiveness of antidepressant drugs with differing modes of action and in varying subtypes of depressive disorder. After highlighting the clinical usefulness of treatment algorithms and the divergent biological, psychological, and clinical efforts to predict the effectiveness of antidepressant treatments, we conclude that the spectrum of different antidepressant treatments has broadened over the last few decades. The efficacy and clinical effectiveness of antidepressants is statistically significant, clinically relevant, and proven repeatedly. Further optimization of treatment can be helped by clearly structured treatment algorithms and the implementation of psychotherapeutic interventions. Modern individualized antidepressant treatment is in most cases a well-tolerated and efficacious approach to minimize the negative impact of otherwise potentially devastating and life-threatening outcomes in depressive disorders.

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INTRODUCTION: Bipolar depression poses a great burden on patients and their families due to its duration, associated functional impairment, and limited treatment options. Given the complexity of the disorder and the advances in treatment, a number of clinical guidelines, consensus statements and expert opinions were developed with the aim to standardize treatment and provide clinicians with treatment algorithms for every-day clinical practice. Unfortunately, they often led to conflicting conclusions and recommendations due to limitations of the available literature. As findings emerge from research literature, guidelines quickly become obsolete and need to be updated or revised. Many guidelines have been updated in the last 5 years, after the last review of bipolar disorder (BD) treatment guidelines. OBJECTIVE: The purpose of this work is to systematically review guidelines, consensus meetings and treatment algorithms on the acute treatment of bipolar depression updated or published since 2005, to critically underline common and critical points, highlight limits and strengths, and provide a starting point for future research MATERIALS AND METHODS: The MEDLINe/PubMed/Index Medicus, PsycINFO/PsycLIT, Excerpta Medica/EMBASE, databases were searched using "depression", "bipolar", "manic-depression", "manic-depressive" and "treatment guidelines" as key words RESULTS: The search returned 204 articles. Amongst them, there were 28 papers concerning structured treatment algorithms and/or guidelines suggested by official panels. After excluding those guidelines that were not performed by scientific societies or international groups and those published before 2005, the final selection yielded 7 papers When looking into guidelines content, the results indicate a trend to the gradual acceptance of the use of the atypical antipsychotic quetiapine as monotherapy as first-line treatment. Antidepressant monotherapy is discouraged in most of them, although some support the use of antidepressants in combination with antimanic agents for a limited period of time. Lamotrigine has become a highly controversial option. CONCLUSION: The management of bipolar depression is complex and should be differentiated from management of unipolar depression. Guidelines may be useful instruments for helping clinicians to choose and plan bipolar depression treatment by integrating the more updated scientific knowledge with every-day clinical practice and patient-specific factors; however, a further effort is needed in order to improve guidelines implementation in clinical practice. The latest updates on treatment guidelines for bipolar depression give priority to novel treatment approaches, such as quetiapine, over more traditional ones, such as lithium or antidepressants. Lamotrigine is a controversial option.

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Although suicide is very complex, multicausal human behaviour, untreated major mood disorders, particularly in combination with adverse life situations, carry the highest risk for it. As medical contact before suicide is quite frequent healthcare workers, particularly general practitioners, play important role in suicide prevention. This paper summarizes the healthcare-based educational programmes that have been shown effective in reducing suicide morbidity and mortality even in this high-risk population.

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PURPOSE OF REVIEW: Although excess rates of medical comorbidities in people with mental disorders have been known for years, concrete steps undertaken to fight this unsatisfactory situation have not been undertaken yet. Therefore, in this issue of Current Opinion in Psychiatry, recent findings in five major areas are summarized. RECENT FINDINGS: All major psychiatric disorders seem to be affected with physical comorbidities, but the issue has attracted attention only recently. SUMMARY: Reasons for the excess rates of physical comorbidities in mental illnesses are diverse. They are in part inherent in psychiatric disorders, are related to the problems of the health system and have to do with stigma and the insufficient training of psychiatrists.

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UNLABELLED: The aim of the present study was to search for differences between subtypes of major depression with the use of single photon emission tomography. MATERIALS AND METHODS: Fifty (50) patients aged 21-60 years suffering from Major Depression according to DSM-IV took part in the study. The SCAN v 2.0 was used to assist clinical diagnosis. The psychometric assessment included the HDRS, the HAS, the GAF, the Newcastle scales and the Diagnostic Melancholia Scale (DMS). Single Photon Emission Computerized Tomography (HMPAO SPECT) was used to assess regional cerebral blood flow. The methods of analysis included chi-square test, ANCOVA, and Discriminant Function Analysis. RESULTS: Forty one (82%) depressed patients had abnormal SPECT findings. The most consistent finding in all patients across all subtypes was a global brain hypoperfusion, which did not include the frontal lobes. The most impressive finding was the relative increase of right frontal lobe perfusion in atypicals, in contrast to the relative decrease of perfusion in both the melancholic and the 'undifferentiated' patients in that particular region. The reverse was true for the right occipital lobe. CONCLUSION: The results of the current study provide support for the old hypothesis on the existence of two distinct types of depression, characterized by different underlying psychopathologies, but also provide strong evidence for a neurobiological abnormality underlying atypical depression, the subtype closer to the old concept of 'neurotic' depression, which was considered to be psychological or reactive in origin.

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