Decreased leucocyte telomere length in male patients with chronic bipolar disorder: lack of effect of long-term lithium treatment.

OBJECTIVES: Bipolar disorder (BD) may be connected with accelerated aging, the marker of this can be shorter telomere length (TL). Some data suggest that lithium may exert a protective effect against telomere shortening. The study aimed to compare the TL between patients with BD and control subjects. The effect of long-term lithium treatment was also assessed. METHODS: The study group comprised 41 patients with BD, including 29 patients treated longitudinally with lithium (mean 16.5 years) and 20 healthy people. TL was assessed by the quantitative polymerase chain reaction (qPCR). RESULTS: In the control group, the TL was significantly longer in males than in females. Male bipolar patients had significantly shorter TL compared with the control male group. In bipolar patients, there was no correlation between TL and duration of treatment. The TL was negatively correlated with age in male bipolar patients. CONCLUSIONS: The study did not confirm the lithium effect on TL in bipolar patients. TL showed gender differences, being shorter in BD males, compared to control males, and longer in healthy males, compared to control females.

Glutamate-Related Antibodies and Peripheral Insulin-Like Growth Factor in Bipolar Disorder and Lithium Prophylaxis.

AIMS: The aim of this study was to evaluate serum levels of the antineuronal antibodies anti-N-methyl-D-aspartate receptor (NMDAR) and anti-glutamic acid decarboxylase (GAD), and insulin-like growth factor 1 (IGF-1), in patients with bipolar disorder (BD), during manic and depressive episodes and in remission compared to euthymic patients receiving long-term lithium therapy. METHODS: Serum levels of anti-NMDAR and anti-GAD 450/620 antibodies, as well as IGF-1, were measured using the ELISA method in 19 manic and 17 depressed patients both in an acute episode and in remission after the episode. All of the subjects were under pharmacological treatment. The control group included 18 euthymic BD patients receiving lithium for 9-44 years (mean 22 ± 11) in whom a single measurement was performed. RESULTS: Serum levels of anti-NMDAR antibodies were higher in acute manic episodes than in lithium-treated patients. Serum levels of anti-GAD 450/620 antibodies were higher in acute manic and depressive episodes compared to remission after the respective episode. Their values in both acute manic and depressive episodes were higher than those in lithium-treated patients. Serum levels of IGF-1 were higher in acute manic episodes and in remission after mania than in lithium-treated patients. CONCLUSION: Higher levels of anti-NMDAR and anti-GAD antibodies during episodes may point to an abnormality in the glutamatergic system in BD. Increased levels of IGF-1 during an acute manic episode and in remission after mania may constitute a compensatory mechanism against excitotoxicity. Lower levels of anti-NMDAR, anti-GAD antibodies, and IGF-1 during long-term lithium treatment may reflect normalization of this processes, contributing to mood stabilization.

Augmentation of Pharmacotherapy by Sleep Deprivation with Sleep Phase Advance in Treatment-Resistant Depression.

INTRODUCTION: The aim was to assess the efficacy of total sleep deprivation (TSD) with sleep phase advance (SPA) in treatment-resistant depression (TRD) and associated biochemical factors. METHODS: We studied nine males and 12 females, aged 49±14 years, with treatment-resistant unipolar or bipolar depression, receiving antidepressant and mood-stabilizing drugs. The four-day schedule included single TSD and three consecutive nights with SPA. Biochemical markers were measured on the day before and on 1st, 7th and 14th day after the TSD. RESULTS: Ten subjects met criteria for response, defined as a reduction of ≥50% in the Hamilton Depression Rating Scale, on the 14th day. Concentrations of cortisol at baseline were lower in responders, and they decreased during therapy in both groups. In responders, there was an increase of interleukin-10 (IL-10) and IL-1ß on the 14th day. DISCUSSION: Our preliminary study demonstrated the efficacy of pharmacotherapy augmentation by TSD and SPA in half of the patients with TRD. The main biochemical factors related to clinical response included status of cortisol and increase in IL-10 and IL-1ß levels.

No Connection between Long-Term Lithium Treatment and Antithyroid Antibodies.

INTRODUCTION: The studies on the effect of lithium treatment on antithyroid antibodies showed either a higher concentration of these antibodies in patients receiving lithium compared to those lithium-naive or no difference between these groups. In lithium-treated bipolar patients, some researchers pointed to an association between antithyroid antibodies and other features of thyroid dysfunction such as hypothyroidism and decrease of glomerular filtration rate. METHODS: We compared antithyroid antibodies in 98 patients (30 male, 68 female) with bipolar disorder, aged 62±13 years, who received lithium for 19±10 years to 39 patients (12 male, 27 female), aged 57±10 years, who were never treated with lithium. The antibodies against thyroid peroxidase (TPOAb), against thyroglobulin (TGAb), and thyroid-stimulating hormone (TSH) receptors (TSHRAb) were estimated. RESULTS: No difference in the percentages of antibodies occurrence was found between groups, although the concentrations of TGAb were higher in patients receiving lithium. In lithium-treated patients, the presence of TPOAb was associated with lower concentrations of free triiodothyronine and the presence of TGAb, with higher concentrations of TSH. In females, the levels of TGAb were associated with lower thyroid volume. The concentrations of TPOAb correlated positively with the duration of lithium therapy in males, and those of TPOAb and TGAb negatively, with such duration, in female patients. CONCLUSION: The results obtained showed no significant connection between long-term lithium treatment and antithyroid antibodies. In bipolar patients receiving lithium longitudinally, antithyroid antibodies can be associated with some indexes of thyroid function. However, they behave differently in male and female patients.

A Study of Biological Rhythm Disturbances in Polish Remitted Bipolar Patients using the BRIAN, CSM, and SWPAQ Scales.

BACKGROUND/AIMS: The Biological Rhythms Interview of Assessment in Neuropsychiatry (BRIAN) is a novel tool allowing for a complex assessment of biological rhythms. We compared patients with bipolar disorder (BD) and healthy control subjects (HC) using the Polish version of the BRIAN scale. METHOD: Fifty-four remitted BD patients (17 males and 37 females aged 52 ± 13 years) and 54 healthy control subjects (25 males and 29 females aged 42 ± 14 years) were studied. In addition to the BRIAN scale, the Composite Scale of Morningness (CSM) and the Sleep-Wake Pattern Assessment Questionnaire (SWPAQ) were employed. RESULTS: The Polish version of the BRIAN scale displayed high feasibility and consistency, showing that the patients had greater biological rhythm disturbances than the controls. After regression analysis, significant differences were obtained for the BRIAN subscales activity and predominant chronotype, and for the SWPAQ items quality of night-time sleep and ability to stay awake. We obtained positive correlations between higher BRIAN scores and morningness and eveningness, but the correlations with vigilance and the ability to stay awake (on the SWPAQ) were negative. CONCLUSIONS: Using the BRIAN scale, we confirmed the greater disturbances of biological rhythm in Polish remitted bipolar patients, compared with healthy controls. The differences between these 2 groups in sleep-awake patterns were also demonstrated by the SWPAQ scores. In contrast to other studies, we were unable to confirm an evening chronotype as a discriminating factor between remitted bipolar patients and healthy subjects. This can be explained by the older age and the use of lithium by a significant proportion of the patients.

Sensory Processing Sensitivity as a trait of temperament - evolutionary, socio-cultural, biological context and relation to mental disorders. / Wrazliwosc Przetwarzania Sensorycznego jako cecha temperamentu ­ kontekst ewolucyjny, spoleczno-kulturowy, biologiczny oraz zwiazek z zaburzeniami psychicznymi.

This article presents the trait of sensory processing sensitivity (SPS), its characteristics, assessment tool and association with psychiatric disorders based on an analysis of the literature on SPS since 1997. An overview of research on SPS in several relevant contexts is presented: evolutionary/adaptive, socio-cultural, temperamental/personality, and biological, taking into account the influence of genetic factors and the activity of specific areas of the central nervous system involved in processing emotional and cognitive stimuli. High sensitivity of sensory processing is an innate trait, biologically determined and modulating developmental processes, occurring in 20-35% of the general population regardless of gender. It is characterized by deeper processing of stimuli, ease of overstimulation, strong emotional reactions and empathic bonds, as well as sensitivity to subtleties in the surrounding world. SPS can be associated with susceptibility to the development of a wide range of psychiatric symptoms and disorders, including depressive and anxiety disorders, social phobia, alexithymia, burnout, internalizing and externalizing disorders and selective mutism in children.

Effectiveness of ultra-long-term lithium treatment: relevant factors and case series.

BACKGROUND: The phenomenon of preventing the recurrences of mood disorders by the long-term lithium administration was discovered sixty years ago. Such a property of lithium has been unequivocally confirmed in subsequent years, and the procedure makes nowadays the gold standard for the pharmacological prophylaxis of bipolar disorder (BD). The efficacy of lithium prophylaxis surpasses other mood stabilizers, and the drug has the longest record as far as the duration of its administration is concerned. The continuation of lithium administration in case of good response could be a lifetime and last for several decades. The stability of lithium prophylactic efficacy in most patients is pretty steady. However, resuming lithium after its discontinuation may, in some patients, be less efficient. MAIN BODY: In the article, the clinical and biological factors connected with the prophylactic efficacy of long-term lithium administration are listed. Next, the adverse and beneficial side effects of such longitudinal treatment are presented. The main problems of long-term lithium therapy, which could make an obstacle to lithium continuation, are connected with lithium's adverse effects on the kidney and, to lesser extent, on thyroid and parathyroid functions. In the paper, the management of these adversities is proposed. Finally, the case reports of three patients who have completed 50 years of lithium therapy are described. CONCLUSIONS: The authors of the paper reckon that in the case of good response, lithium can be given indefinitely. Given the appropriate candidates for such therapy and successful management of the adverse effects, ultra-long term lithium therapy is possible and beneficial for such patients.

Exploring the genetics of lithium response in bipolar disorders.

BACKGROUND: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N = 2064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. RESULTS: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. CONCLUSIONS: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Lithium response in bipolar disorder is associated with focal adhesion and PI3K-Akt networks: a multi-omics replication study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Long-Term Lithium Therapy: Side Effects and Interactions.

Lithium remains the drug of first choice for prophylactic treatment of bipolar disorder, preventing the recurrences of manic and depressive episodes. The longitudinal experiences with lithium administration greatly exceed those with other mood stabilizers. Among the adverse side effects of lithium, renal, gastrointestinal, neurological, thyroid, metabolic, cognitive, dermatological, cardiologic, and sexual are listed. Probably, the most important negative effect of lithium, occurring mostly after 10-20 years of its administration, is interstitial nephropathy. Beneficial side-effects of long-term lithium therapy also occur such as anti-suicidal, antiviral, and anti-dementia ones. Pharmacokinetic and pharmacodynamic interactions of lithium, mostly those with other drugs, may have an impact on the success of long-term lithium treatment. This paper makes the narrative updated review of lithium-induced side-effects and interactions that may influence its prophylactic effect in bipolar disorder. Their description, mechanisms, and management strategies are provided. The papers appearing in recent years focused mainly on the long-term lithium treatment are reviewed in detail, including recent research performed at Department of Psychiatry, Poznan University of Medical Sciences, Poland. Their own observations on ultra-long lithium treatment of patients with bipolar disorder are also presented. The review can help psychiatrists to perform a successful lithium prophylaxis in bipolar patients.

Updated perspectives on how and when lithium should be used in the treatment of mood disorders.

INTRODUCTION: Lithium is one of the most important drugs for the treatment of mood disorders. The appropriate guidelines can ensure that more patients benefit from its use in a personalized way. AREAS COVERED: This manuscript provides an update on the application of lithium in mood disorders, including prophylaxis of bipolar and unipolar mood disorder, treatment of acute manic and depressive episodes, augmentation of antidepressants in treatment-resistant depression, and use of lithium in pregnancy and the postpartum period. EXPERT OPINION: Lithium remains the gold standard for the prevention of recurrences in bipolar mood disorder. For long-term treatment/management of bipolar mood disorder, clinicians should also consider lithium's anti-suicidal effect. Furthermore, after prophylactic treatment, lithium may also be augmented with antidepressants in treatment-resistant depression. There have also been some demonstration of lithium having some efficacy in acute episodes of mania and bipolar depression as well as in the prophylaxis of unipolar depression.

An integrated precision medicine approach in major depressive disorder: a study protocol to create a new algorithm for the prediction of treatment response.

Major depressive disorder (MDD) is the most common psychiatric disease worldwide with a huge socio-economic impact. Pharmacotherapy represents the most common option among the first-line treatment choice; however, only about one third of patients respond to the first trial and about 30% are classified as treatment-resistant depression (TRD). TRD is associated with specific clinical features and genetic/gene expression signatures. To date, single sets of markers have shown limited power in response prediction. Here we describe the methodology of the PROMPT project that aims at the development of a precision medicine algorithm that would help early detection of non-responder patients, who might be more prone to later develop TRD. To address this, the project will be organized in 2 phases. Phase 1 will involve 300 patients with MDD already recruited, comprising 150 TRD and 150 responders, considered as extremes phenotypes of response. A deep clinical stratification will be performed for all patients; moreover, a genomic, transcriptomic and miRNomic profiling will be conducted. The data generated will be exploited to develop an innovative algorithm integrating clinical, omics and sex-related data, in order to predict treatment response and TRD development. In phase 2, a new naturalistic cohort of 300 MDD patients will be recruited to assess, under real-world conditions, the capability of the algorithm to correctly predict the treatment outcomes. Moreover, in this phase we will investigate shared decision making (SDM) in the context of pharmacogenetic testing and evaluate various needs and perspectives of different stakeholders toward the use of predictive tools for MDD treatment to foster active participation and patients' empowerment. This project represents a proof-of-concept study. The obtained results will provide information about the feasibility and usefulness of the proposed approach, with the perspective of designing future clinical trials in which algorithms could be tested as a predictive tool to drive decision making by clinicians, enabling a better prevention and management of MDD resistance.

Immunogenetics of lithium response and psychiatric phenotypes in patients with bipolar disorder.

The link between bipolar disorder (BP) and immune dysfunction remains controversial. While epidemiological studies have long suggested an association, recent research has found only limited evidence of such a relationship. To clarify this, we investigated the contributions of immune-relevant genetic factors to the response to lithium (Li) treatment and the clinical presentation of BP. First, we assessed the association of a large collection of immune-related genes (4,925) with Li response, defined by the Retrospective Assessment of the Lithium Response Phenotype Scale (Alda scale), and clinical characteristics in patients with BP from the International Consortium on Lithium Genetics (ConLi+Gen, N = 2,374). Second, we calculated here previously published polygenic scores (PGSs) for immune-related traits and evaluated their associations with Li response and clinical features. We found several genes associated with Li response at p < 1×10- 4 values, including HAS3, CNTNAP5 and NFIB. Network and functional enrichment analyses uncovered an overrepresentation of pathways involved in cell adhesion and intercellular communication, which appear to converge on the well-known Li-induced inhibition of GSK-3ß. We also found various genes associated with BP's age-at-onset, number of mood episodes, and presence of psychosis, substance abuse and/or suicidal ideation at the exploratory threshold. These included RTN4, XKR4, NRXN1, NRG1/3 and GRK5. Additionally, PGS analyses suggested serum FAS, ECP, TRANCE and cytokine ligands, amongst others, might represent potential circulating biomarkers of Li response and clinical presentation. Taken together, our results support the notion of a relatively weak association between immunity and clinically relevant features of BP at the genetic level.

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.

Exploring the genetics of lithium response in bipolar disorders.

Background: Lithium (Li) remains the treatment of choice for bipolar disorders (BP). Its mood-stabilizing effects help reduce the long-term burden of mania, depression and suicide risk in patients with BP. It also has been shown to have beneficial effects on disease-associated conditions, including sleep and cardiovascular disorders. However, the individual responses to Li treatment vary within and between diagnostic subtypes of BP (e.g. BP-I and BP-II) according to the clinical presentation. Moreover, long-term Li treatment has been linked to adverse side-effects that are a cause of concern and non-adherence, including the risk of developing chronic medical conditions such as thyroid and renal disease. In recent years, studies by the Consortium on Lithium Genetics (ConLiGen) have uncovered a number of genetic factors that contribute to the variability in Li treatment response in patients with BP. Here, we leveraged the ConLiGen cohort (N=2,064) to investigate the genetic basis of Li effects in BP. For this, we studied how Li response and linked genes associate with the psychiatric symptoms and polygenic load for medical comorbidities, placing particular emphasis on identifying differences between BP-I and BP-II. Results: We found that clinical response to Li treatment, measured with the Alda scale, was associated with a diminished burden of mania, depression, substance and alcohol abuse, psychosis and suicidal ideation in patients with BP-I and, in patients with BP-II, of depression only. Our genetic analyses showed that a stronger clinical response to Li was modestly related to lower polygenic load for diabetes and hypertension in BP-I but not BP-II. Moreover, our results suggested that a number of genes that have been previously linked to Li response variability in BP differentially relate to the psychiatric symptomatology, particularly to the numbers of manic and depressive episodes, and to the polygenic load for comorbid conditions, including diabetes, hypertension and hypothyroidism. Conclusions: Taken together, our findings suggest that the effects of Li on symptomatology and comorbidity in BP are partially modulated by common genetic factors, with differential effects between BP-I and BP-II.

Lithium Response in Bipolar Disorder is Associated with Focal Adhesion and PI3K-Akt Networks: A Multi-omics Replication Study.

Lithium is the gold standard treatment for bipolar disorder (BD). However, its mechanism of action is incompletely understood, and prediction of treatment outcomes is limited. In our previous multi-omics study of the Pharmacogenomics of Bipolar Disorder (PGBD) sample combining transcriptomic and genomic data, we found that focal adhesion, the extracellular matrix (ECM), and PI3K-Akt signaling networks were associated with response to lithium. In this study, we replicated the results of our previous study using network propagation methods in a genome-wide association study of an independent sample of 2,039 patients from the International Consortium on Lithium Genetics (ConLiGen) study. We identified functional enrichment in focal adhesion and PI3K-Akt pathways, but we did not find an association with the ECM pathway. Our results suggest that deficits in the neuronal growth cone and PI3K-Akt signaling, but not in ECM proteins, may influence response to lithium in BD.

Mini-review: Anomalous association between lithium data and lithium use.

This mini-review aims to show a discrepancy between favorable data of lithium's therapeutic activity and the decreased use of the drug worldwide. The data point to lithium as the best mood stabilizer in the maintenance treatment of bipolar disorder for the prevention of manic and depressive recurrences. The second most encouraging psychiatric use of lithium is the augmentation of antidepressants in treatment-resistant depression. In addition to its mood-stabilizing properties, lithium is the most efficacious antisuicidal drug among all mood stabilizers. The drug also exerts antiviral, immunomodulatory, and neuroprotective effects which may be of major clinical value. On the other hand, the data of lithium use show that its therapeutic application in many countries has declined. A reason for this can be the introduction and heavy promotion of other mood-stabilizers, while lithium is an "orphan" drug with the minimal interest of any drug company. Probably, very important is also a perception of lithium as a "toxic drug", pointing to its side effects, mainly thyroid, renal and cognitive ones. In recent years, several proposals to turn back this anomalous association appeared, challenging a negative perception of lithium and optimizing its long-term administration. They show the data on lithium superiority over other mood stabilizers and point to the proper management of the lithium-induced side effects. This endeavor aims to allow a larger number of mood disorder patients to become beneficiaries of lithium use.

Studies on candidate genes for lithium prophylaxis performed at the Poznan University of Medical Sciences. / Badania genów kandydujacych profilaktyki litem przeprowadzone na Uniwersytecie Medycznym w Poznaniu.

Lithium is a drug of choice as a mood-stabilizer for the maintenance treatment of bipolar disorder. The prophylactic efficacy of lithium can be determined by genetic factors, partially related to a predisposition to bipolar disorder. In the field of psychiatric genetics, the first decade of the 21st century was dominated by the "candidate gene" research. In this paper, the studies on candidate genes connected with lithium prophylaxis performed at the Poznan University of Medical Sciences in 2005-2018 are presented. During this time, the polymorphisms of multiple genes have been investigated, many of which are also connected with a predisposition to bipolar illness. The associations with lithium prophylactic efficacy were found for the polymorphisms in 5HTT, ACP1, ARNTL, BDNF, COMT, DRD1, FKBP5, FYN, GLCC, NR3C1, and TIM, genes, but not those in 5HT2A, 5HT2C, DRD2, DRD3, DRD4, GRIN2B, GSK-3ß, MMP-9, and NTRK2 genes. The polymorphism of the GSK-3ß gene was found to be associated with the kidney side-effects occurring during lithium therapy. Possible roles for these genes in both the mechanism of lithium prophylactic activity and pathogenesis of bipolar mood disorder were discussed.

Association between polarity of first episode and solar insolation in bipolar I disorder.

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.