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My long day’s journey into sleep began as an adolescent trying to manage my evening chronotype. The relief I felt when my undergraduate finals were scheduled at night and as a medical student being able to select psychiatry over surgery deepened my interest in sleep and chronobiology. That interest was allowed to flourish at the National Institute of Mental Health and then at Yale Medical School in setting up a sleep laboratory. The decision to move to the University of Pittsburgh in 1973 led to a 42-year adventure in which we were able to initiate research efforts on the psychobiology of depression. Our interest in social zeitgebers (daily routines) led directly to the development and testing of a treatment intervention for mood disorders, interpersonal and social rhythm therapy. Our continued emphasis on sleep and circadian rhythms convinced us that sleep and circadian factors were central to all of health, based on the importance of connectivity between sleep and major metabolic and cell functions. This ongoing research motivated to our strong desire to study developmental aspects of sleep. Our success was influenced immensely by the presence of young scientists and a strong subsequent interest in career mentoring. Finally, as we left Pittsburgh in 2015, we became involved in the field of continuous objective monitoring using the commercial smartphone’s behavioral sensing capabilities. Our journey is not over. We hope to explore the potential of these remarkable devices to improve our understanding of sleep/wake and circadian factors across all of health.

Objective At least half of youths with mental disorders are unrecognized and untreated. Rapid, accurate assessment of child mental disorders could facilitate identification and referral and potentially reduce the occurrence of functional disability that stems from early-onset mental disorders. Method Computerized adaptive tests (CATs) based on multidimensional item response theory were developed for depression, anxiety, mania/hypomania, attention-deficit/hyperactivity disorder, conduct disorder, oppositional defiant disorder, and suicidality, based on parent and child ratings of 1,060 items each. In phase 1, CATs were developed from 801 participants. In phase 2, predictive, discriminant, and convergent validity were tested against semi-structured research interviews for diagnoses and suicidality in 497 patients and 104 healthy controls. Overall strength of association was determined by area under the receiver operating characteristic curve (AUC). Results The child and parent independently completed the Kiddie−Computerized Adaptive Tests (K-CATs) in a median time of 7.56 and 5.03 minutes, respectively, with an average of 7 items per domain. The K-CATs accurately captured the presence of diagnoses (AUCs from 0.83 for generalized anxiety disorder to 0.92 for major depressive disorder) and suicidal ideation (AUC = 0.996). Strong correlations with extant measures were found (r ≥ 0.60). Test−retest reliability averaged r = 0.80. Conclusion These K-CATs provide a new approach to child psychopathology screening and measurement. Testing can be completed by child and parent in less than 8 minutes and yields results that are highly convergent with much more time-consuming structured clinical interviews and dimensional severity assessment and measurement. Testing of the implementation of the K-CAT is now indicated.

In clinical practice, differentiating Bipolar Disorder (BD) from unipolar depression is a challenge due to the depressive symptoms, which are the core presentations of both disorders. This misdiagnosis during depressive episodes results in a delay in proper treatment and a poor management of their condition. In a first step, using A-to-I RNA editome analysis, we discovered 646 variants (366 genes) differentially edited between depressed patients and healthy volunteers in a discovery cohort of 57 participants. After using stringent criteria and biological pathway analysis, candidate biomarkers from 8 genes were singled out and tested in a validation cohort of 410 participants. Combining the selected biomarkers with a machine learning approach achieved to discriminate depressed patients (n = 267) versus controls (n = 143) with an AUC of 0.930 (CI 95% [0.879–0.982]), a sensitivity of 84.0% and a specificity of 87.1%. In a second step by selecting among the depressed patients those with unipolar depression (n = 160) or BD (n = 95), we identified a combination of 6 biomarkers which allowed a differential diagnosis of bipolar disorder with an AUC of 0.935 and high specificity (Sp = 84.6%) and sensitivity (Se = 90.9%). The association of RNA editing variants modifications with depression subtypes and the use of artificial intelligence allowed developing a new tool to identify, among depressed patients, those suffering from BD. This test will help to reduce the misdiagnosis delay of bipolar patients, leading to an earlier implementation of a proper treatment.

We thank Kaufman et al.1 for their comprehensive review of the many commendable features of the Kiddie-Computerized Adaptive Test (K-CAT). We do wish to clarify what may be a misunderstanding of the intent of the K-CAT and our view of its role in treatment planning.

The World Health Organization classification of psychotropic drugs is unsatisfactory. It employs the so-called ATC (Anatomical Therapeutic Chemical) approach. It has allowed a mix of terminology which recognizes treatment indication, drug chemistry, or pharmacology. An international consortium has now developed the neuroscience-based nomenclature (NbN), which is a multi-dimensional system for classifying psychotropic drugs. It emphasizes their pharmacological profile and, as far as possible, mode of action. The NbN provides a contemporary framework for better informed treatment decisions in the form of a downloadable app. The current ideal is for prescribers to match the symptom profile of the patient to a specific and appropriate psychotropic. At present, this is often mediated by a conventional disease-based naming. NbN, as a pharmacologically driven nomenclature, could be adapted to more complicated multi-axial descriptions of symptom dimensions.

Key Points Question Can rapid psychometrically sound adaptive diagnostic screening and dimensional severity measures be developed for posttraumatic stress disorder? Findings In this diagnostic study including 713 US military veterans, the Computerized Adaptive Diagnostic–Posttraumatic Stress Disorder measure was shown to have excellent diagnostic accuracy. The Computerized Adaptive Test–Posttraumatic Stress Disorder also provided valid severity ratings and demonstrated convergent validity with the Post-Traumatic Stress Disorder checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Meaning In this study, the Computerized Adaptive Diagnostic–Posttraumatic Stress Disorder and Computerized Adaptive Test–Posttraumatic Stress Disorder measures appeared to provide valid screening diagnoses and severity scores, with substantial reductions in patient and clinician burden., Importance Veterans from recent and past conflicts have high rates of posttraumatic stress disorder (PTSD). Adaptive testing strategies can increase accuracy of diagnostic screening and symptom severity measurement while decreasing patient and clinician burden. Objective To develop and validate a computerized adaptive diagnostic (CAD) screener and computerized adaptive test (CAT) for PTSD symptom severity. Design, Setting, and Participants A diagnostic study of measure development and validation was conducted at a Veterans Health Administration facility. A total of 713 US military veterans were included. The study was conducted from April 25, 2017, to November 10, 2019. Main Outcomes and Measures The participants completed a PTSD-symptom questionnaire from the item bank and provided responses on the PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (PCL-5). A subsample of 304 participants were interviewed using the Clinician-Administered Scale for PTSD for DSM-5. Results Of the 713 participants, 585 were men; mean (SD) age was 52.8 (15.0) years. The CAD-PTSD reproduced the Clinician-Administered Scale for PTSD for DSM-5 PTSD diagnosis with high sensitivity and specificity as evidenced by an area under the curve of 0.91 (95% CI, 0.87-0.95). The CAT-PTSD demonstrated convergent validity with the PCL-5 (r = 0.88) and also tracked PTSD diagnosis (area under the curve = 0.85; 95% CI, 0.79-0.89). The CAT-PTSD reproduced the final 203-item bank score with a correlation of r = 0.95 with a mean of only 10 adaptively administered items, a 95% reduction in patient burden. Conclusions and Relevance Using a maximum of only 6 items, the CAD-PTSD developed in this study was shown to have excellent diagnostic screening accuracy. Similarly, using a mean of 10 items, the CAT-PTSD provided valid severity ratings with excellent convergent validity with an extant scale containing twice the number of items. The 10-item CAT-PTSD also outperformed the 20-item PCL-5 in terms of diagnostic accuracy. The results suggest that scalable, valid, and rapid PTSD diagnostic screening and severity measurement are possible., This diagnostic study develops and validates a tool for use in diagnostic screening of US military veterans for posttraumatic stress disorder.

Exercise is presumed to be a potentially helpful smoking cessation adjunct reputed to attenuate the negative effects of deprivation. The present study examined the effectiveness of moderate within-session exercise to reduce 4 key symptoms of smoking deprivation during 3 72-hr nicotine abstinence blocks in both male and female smokers. Forty-nine (25 male, 24 female) sedentary smokers abstained from smoking for 3 consecutive days on 3 separate occasions. At each session, smokers' abstinence-induced craving, cue-induced craving, negative mood, and withdrawal symptom severity were assessed prior to and after either exercise (a.m. exercise, p.m. exercise) or a sedentary control activity (magazine reading). Abstinence-induced craving and negative mood differed as a function of condition, F(2, 385) = 21, p < .0001; and, F(2, 385) = 3.38, p = .03. Planned contrasts revealed no difference between a.m. and p.m. exercise, but exercise overall led to greater pre-post reduction in abstinence-induced craving, t(385) = 6.23, p < .0001, effect size Cohen's d = 0.64; and negative mood, t(385) = 2.25, p = .03, d = 0.23. Overall exercise also led to a larger pre-post reduction in cue-induced craving in response to smoking cues, F(2, 387) = 8.94, p = .0002; and withdrawal severity, F(2, 385) = 3.8, p = .02. Unlike the other 3 measures, p.m. exercise reduced withdrawal severity over control, t(385) = 2.64, p = .009, d = 0.27, whereas a.m. exercise did not. The results support the clinical potential of exercise to assist smokers in managing common and robust negative symptoms experienced during the first 3 days of abstinence. (PsycINFO Database Record

BACKGROUND Previous studies have explored the role of stressful life events in the development of mood disorders. We examined the frequency and nature of stressful life events as measured by the Stressful Life Events Schedule (SLES) among 3 groups of adolescent offspring of probands with bipolar (BD), with non-BD psychiatric disorders, and healthy controls. Furthermore, we examined the relationship between stressful life events and the presence of DSM-IV Axis I disorders in these offspring. Stressful life events were characterized as dependent, independent, or uncertain (neither dependent nor independent) and positive, negative, or neutral (neither positive nor negative). METHODS Offspring of probands with BD aged 13-18 years (n = 269), demographically matched offspring of probands with non-BD Axis I disorders (n = 88), and offspring of healthy controls (n = 81) from the Pittsburgh Bipolar Offspring Study were assessed from 2002 to 2007 with standardized instruments at intake. Probands completed the SLES for their offspring for life events within the prior year. Life events were evaluated with regard to current Axis I diagnoses in offspring after adjusting for confounds. RESULTS After adjusting for demographic and clinical between-group differences (in probands and offspring), offspring of probands with BD had greater independent (χ² = 11.96, P < .04) and neutral (χ² = 17.99, P < .003) life events compared with offspring of healthy controls and greater number of more severe stressful life events than offspring of healthy controls, but not offspring of probands with non-BD. Offspring of BD probands with comorbid substance use disorder reported more independent stressful life events compared to those without comorbid substance use disorder (P = .024). Greater frequency and severity of stressful life events were associated with current Axis I disorder in offspring of both probands with BD and probands with other Axis I disorders regardless of dependency or valence. Greater frequency and severity of stressful life events were associated with greater current Axis I disorder in all offspring. CONCLUSIONS Offspring of probands with BD have greater exposure to independent and neutral life events than offspring of healthy controls. Greater frequency and severity of stressful life events were associated with Axis I disorder in offspring of both BD and non-BD affected probands.

We aim to close a methodological gap in analyzing durations of successive events that are subject to induced dependent censoring as well as competing-risk censoring. In the Bipolar Disorder Center for Pennsylvanians study, some patients who managed to recover from their symptomatic entry later developed a new depressive or manic episode. It is of great clinical interest to quantify the association between time to recovery and time to recurrence in patients with bipolar disorder. The estimation of the bivariate distribution of the gap times with independent censoring has been well studied. However, the existing methods cannot be applied to failure times that are censored by competing causes such as in the Bipolar Disorder Center for Pennsylvanians study. Bivariate cumulative incidence function has been used to describe the joint distribution of parallel event times that involve multiple causes. To the best of our knowledge, however, there is no method available for successive events with competing-risk censoring. Therefore, we extend the bivariate cumulative incidence function to successive events data, and propose non-parametric estimators of the bivariate cumulative incidence function and the related conditional cumulative incidence function. Moreover, an odds ratio measure is proposed to describe the cause-specific dependence, leading to the development of a formal test for independence of successive events. Simulation studies demonstrate that the estimators and tests perform well for realistic sample sizes, and our methods can be readily applied to the Bipolar Disorder Center for Pennsylvanians study.

In this Seminar we discuss developments from the past 5 years in the diagnosis, neurobiology, and treatment of major depressive disorder. For diagnosis, psychiatric and medical comorbidity have been emphasised as important factors in improving the appropriate assessment and management of depression. Advances in neurobiology have also increased, and we aim to indicate genetic, molecular, and neuroimaging studies that are relevant for assessment and treatment selection of this disorder. Further studies of depression-specific psychotherapies, the continued application of antidepressants, the development of new treatment compounds, and the status of new somatic treatments are also discussed. We address two treatment-related issues: suicide risk with selective serotonin reuptake inhibitors, and the safety of antidepressants in pregnancy. Although clear advances have been made, no fully satisfactory treatments for major depression are available.(Reprinted with permission from the Lancet 2012; 379: 1045–55)

Objectives Disruptions in sleep and dysregulation in circadian functioning may represent core abnormalities in the pathophysiology of bipolar disorder (BP). However, it is not clear whether these dysfunctions are state or trait markers of BP. This report compared sleep and circadian phenotypes among three groups: offspring of parents with BP diagnosed with BP at intake (BP/OB; n = 47), offspring of parents with BP without BP at intake (non-BP/OB; n = 386), and offspring of matched control parents who did not have BP (controls; n = 301). We also examined the association of baseline sleep parameters with subsequent development of BP among the non-BP/OB group. Methods Pittsburgh Bipolar Offspring Study youth (ages 6–18 years) and their parents completed assessments every two years pertaining to the child's sleep and circadian phenotypes and current psychopathology. Mixed-effects models examined differences in baseline sleep and circadian variables among the three groups. Results BP/OB offspring who were in a mood episode differed significantly on sleep parameters from the non-BP/OB and the offspring of controls, such as having inadequate sleep. Mixed logistic regression procedures showed that baseline sleep and circadian variables, such as frequent waking during the night, significantly predicted the development of BP among non-BP/OB over longitudinal follow-up. Conclusions While lifetime diagnostic status accounted for differences among the groups in sleep and circadian disturbances, psychopathology explained the differences even further. Additionally, sleep disturbance may be a prognostic indicator of the development of BP in high-risk youth. Future studies are required to further disentangle whether sleep and circadian disruption are state or trait features of BP.

Article first published online 27 March 2015., Background: Crohn's disease (CD) is associated with depression. It is unclear if psychosocial interventions offer benefit for depressive symptoms during active CD. In this secondary analysis of a larger study of treating depression in pediatric inflammatory bowel disease, we assessed whether cognitive behavioral therapy (CBT) would differentiate from supportive nondirective therapy in treating depression and disease activity in youth with CD. We also explored whether somatic depressive symptoms showed a different pattern of response in the overall sample and the subset with active inflammatory bowel disease. Methods: Youth with depression and CD (n = 161) were randomized to 3 months of CBT (teaching coping skills) or supportive nondirective therapy (supportive listening). Depressive severity was measured using the Children's Depression Rating Scale-Revised (CDRS-R) with the somatic depressive subtype consisting of those CDRS-R items, which significantly correlated with CD activity. Disease activity was measured by the Pediatric Crohn's disease Activity Index. Given the potential confound of higher dose steroids, subanalyses excluded subjects on >20 mg/d prednisone equivalent (n = 34). Results: Total CDRS-R scores in the overall sample significantly decreased over time after both treatments (P < 0.0001). Treatment with CBT was associated with a significantly greater improvement in the Pediatric Crohn's disease Activity Index (P = 0.05) and somatic depressive subtype (P = 0.03) in those with active inflammatory bowel disease (n = 95) compared with supportive nondirective therapy. After excluding those on steroids (n = 34), there was a significant improvement in total CDRS-R (P = 0.03) and in Pediatric Crohn's disease Activity Index (P = 0.03) after CBT. Conclusions: Psychotherapy may be a useful adjunct to treat depression in the context of CD-related inflammation in youth who are not concurrently on higher dose steroids.

OBJECTIVE There is growing evidence that bipolar disorder (BD) is associated with inflammation, including abnormal levels of acute-phase C-reactive protein (CRP). Our meta-analysis was conducted to estimate the size of the association between CRP levels and BD, accounting also for subgroup differences (mood phases and treatment). DATA SOURCES MEDLINE, EMBASE, PsycINFO, and ISI Web of Science and references of identified articles were searched up to June 2013 using the keywords (bipolar disorder) AND (C-reactive protein OR CRP). STUDY SELECTION English language studies measuring blood levels of CRP in patients with BD and control subjects were selected, 136 abstracts were reviewed, 20 articles retrieved, and 11 studies included. DATA EXTRACTION Two independent reviewers extracted data. All studies were included in the primary analyses, and between-group differences for subanalyses were also reported. This meta-analysis was performed using random-effects models. RESULTS Eleven studies comprising 1,618 subjects were eligible for inclusion. Overall, CRP levels were significantly elevated in patients with BD versus controls (standardized mean difference [SMD] = 0.39; 95% CI, 0.24 to 0.55; P < .0001). CRP levels were significantly higher in manic (SMD = 0.73; 95% CI, 0.44 to 1.02; P < .001) and euthymic (SMD = 0.26; 95% CI, 0.01 to 0.51; P = .04), but not in depressed (SMD = 0.28; 95% CI, -0.17 to 0.73; P = .22) patients with BD compared to controls. CRP levels were unrelated to use of lithium or antipsychotic medication. CONCLUSIONS This meta-analysis supports an association between increased CRP levels and BD. Given that an elevated level of CRP is a marker of low-grade inflammation and a risk factor for cardiovascular and malignant diseases, measurement of CRP level might be relevant to the clinical care of bipolar patients.

We conducted a randomized, controlled trial comparing the efficacy of an Integrated Risk Reduction Intervention (IRRI) to a control condition with the objective of improving mood stability and psychosocial functioning by reducing cardiometabolic risk factors in overweight/obese patients with bipolar I disorder.A total of 122 patients were recruited from our outpatient services and randomly allocated to IRRI (n = 61) or psychiatric care with medical monitoring (n = 61). Individuals allocated to IRRI received psychiatric treatment and assessment, medical monitoring by a nurse, and a healthy lifestyle program from a lifestyle coach. Those allocated to the control condition received psychiatric treatment and assessment and referral, if indicated, for medical problems. A mixed-effects model was used to examine the impact of the interventions on body mass index (BMI). Exploratory moderator analyses were used to characterize those individuals likely to benefit from each treatment approach.Analyses were conducted on data for the IRRI (n = 58) and control (n = 56) participants with ≥ 1 study visit. IRRI was associated with a significantly greater rate of decrease in BMI (d = -0.51, 95% confidence interval: -0.91 to -0.14). Three variables (C-reactive protein, total cholesterol, and instability of total sleep time) contributed to a combined moderator of faster decrease in BMI with IRRI treatment.Overweight/obese patients with bipolar disorder can make modest improvements in BMI, even when taking medications with known potential for weight gain. Our finding that a combination of three baseline variables provides a profile of patients likely to benefit from IRRI will need to be tested further to evaluate its utility in clinical practice.

Background Sleep disturbances are a prominent feature of bipolar disorder (BP). However, it remains unclear how sleep phenotypes may evolve among at-risk youth, and their relevance to BP onset. Methods Pittsburgh Bipolar Offspring Study (BIOS) offspring (ages 10–18) and their parents completed assessments approximately every two years pertaining to current psychopathology and offspring sleep habits. A latent transition analysis (LTA) identified latent sleep groups within offspring based on their ratings of six sleep domains using the School Sleep Habits Survey. Demographic and clinical characteristics were compared between sleep groups. Logistic regression tested links between sleep group and BP onset at the subsequent assessment. Results The LTA model identified latent groups of good, poor, and variable sleepers. We observed an overall trend of good sleep becoming variable, and then poor, as youth age. Offspring in the poor sleep group were more likely to have psychopathology. Adjusting for age and depression, poor sleepers had nearly twice the odds of developing BP relative to good (OR=1.99, CI=0.45–8.91) or variable (OR=2.03, CI=0.72–5.72) sleepers. Limitations Limitations include the use of proximal sleep phenotypes to predict BP onset, and a self-report measure of sleep Conclusions We found three non-overlapping sleep phenotype groups in a large sample of offspring of bipolar probands and offspring of demographically-matched community control parents. Clinicians should consider that youth will likely experience variable and/or poor sleep as they age, and that at-risk youth with poor sleep may be at increased risk of developing MDD and BP at their next assessment.

Study Objectives The mechanisms linking short sleep duration to cardiovascular disease (CVD) are poorly understood. Emerging evidence suggests that endothelial dysregulation may lie along the causal pathway linking sleep duration to cardiovascular risk, although current evidence in humans is based on cross-sectional studies. Our objective was to evaluate the prospective association between objectively assessed sleep duration and clinical indices of endothelial health. Methods A total of 141 medically healthy adults underwent an overnight laboratory sleep study when they were between the ages of 21 and 60 years. Total sleep time was objectively assessed by polysomnography at study entry. Endothelial health, including brachial artery diameter (BAD) and flow-mediated dilation (FMD), was measured 18.9 ± 4.6 years later. Medical health and psychiatric status were assessed at both time points. Approximately half of the sample had a lifetime history of major depressive disorder. Results In univariate analyses, shorter sleep duration was associated with increased BAD (β = -0.24, p = .004) and decreased FMD (β = 0.17, p = .042). BAD, but not FMD, remained significantly associated with sleep duration after adjusting for sex, age, body mass index (BMI), smoking, diabetes, hypertension, and lifetime history of major depressive disorder (MDD) at T2. The association between sleep duration and BAD was stronger than the association between BAD and an aggregate measure of CVD risk including three or more of the following risk factors: male sex, age ≥ 65 years, smoker, BMI ≥ 30, diabetes, hypertension, and MDD. Conclusions Objectively assessed short sleep duration was prospectively associated with increased BAD over a 12- to 30-year period.

Objective Pediatric inflammatory bowel disease (IBD) is associated with high rates of depression. This study compared the efficacy of cognitive behavioral therapy (CBT) to supportive nondirective therapy (SNDT) in treating youth with comorbid IBD and depression. Method Youth (51% female and 49% male; age 9–17 years, mean age 14.3 years) with depression and Crohn's disease (n = 161) or ulcerative colitis (n = 56) were randomly assigned to a 3-month course of CBT or SNDT. The primary outcome was comparative reduction in depressive symptom severity; secondary outcomes were depression remission, increase in depression response, and improved health-related adjustment and IBD activity. Results A total of 178 participants (82%) completed the 3-month intervention. Both psychotherapies resulted in significant reductions in total Children's Depression Rating Scale Revised score (37.3% for CBT and 31.9% for SNDT), but the difference between the 2 treatments was not significant ( p = .16). There were large pre–post effect sizes for each treatment (d = 1.31 for CBT and d = 1.30 for SNDT). More than 65% of youth had a complete remission of depression at 3 months, with no difference between CBT and SNDT (67.8% and 63.2%, respectively). Compared to SNDT, CBT was associated with a greater reduction in IBD activity ( p = .04) but no greater improvement on the Clinical Global Assessment Scale ( p = .06) and health-related quality of life (IMPACT-III scale) ( p = .07). Conclusion This is the first randomized controlled study to suggest improvements in depression severity, global functioning, quality of life, and disease activity in a physically ill pediatric cohort treated with psychotherapy. Clinical trial registration information—Reducing Depressive Symptoms in Physically Ill Youth; http://clinical trials.gov; NCT00534911.

Current psychopharmacological nomenclature remains wedded in an earlier period of scientific understanding, failing to reflect contemporary developments and knowledge, does not aid clinicians in selecting the best medication for a given patient, and tends to confuse patients by prescribing a drug that does not reflect their identified diagnosis (e.g. prescribe “antipsychotics” to depression). Four major colleges of Neuropsychopharmacology (ECNP, ACNP, Asian CNP, and CINP) proposed a new template comprising a multi-axial pharmacologically-driven nomenclature tested by four surveys. The template has five axes: 1—class (primary pharmacological target and relevant mechanism); 2—family (reflecting the relevant neurotransmitter and mechanism); 3—neurobiological activities; 4—efficacy and major side effects; and 5—approved indications. The results of the surveys suggest that the clinicians found the available indication-based nomenclature system dissatisfactory, non-intuitive, confusing, and doubt-inducing for them and the patients. The proposed five-axis template seeks to upend current usage by placing pharmacology rather than indication as the primary axes, with the proposed nomenclature relating primarily to Axis 1—the class, and usage of the other axes would largely depend upon the extent to which the clinician seeks to deepen the scientific and clinical base of his involvement. A significant proportion of the participants in the four surveys were in favour of the proposed system, a similar number wanted to consider the idea further, and only a small proportion (8.6%) were against it. The proposed five-axis pharmacology based nomenclature template is a system which might refresh and reflect the current scientific concepts of neuropsychopharmacology.

International audience; AbstractBackgroundThe diagnostic scheme for psychiatric disorders is currently based purely on descriptive nomenclature given that biomarkers subtypes and clearly defined causal mechanisms are lacking for the vast majority of disorders. The emerging field of “immuno-psychiatry” has the potential to widen the exploration of a mechanism-based nosology, possibly leading to the discovery of more effective personalised treatment strategies.DiscussionDisturbances in immuno-inflammatory and related systems have been implicated in the aetiology, pathophysiology, phenomenology and comorbidity of several psychiatric disorders, including major mood disorders and schizophrenia. A fundamental challenge in their clinical management is to identify bio-signatures that might indicate risk, state, trait, prognosis or theragnosis. Here, we provide the rationale for a clinical and research agenda to refine future clinical practice and conceptual views, and to delineate pathways toward innovative treatment discovery.ConclusionThe development of bio-signatures will allow clinicians to tailor interventions to the abovementioned biomarker subtypes – a major translational goal for research in this field.

BACKGROUND: The purpose of this study is to compare the dimensional psychopathology, as ascertained by parental report, in preschool offspring of parents with bipolar disorder (BP) and offspring of community control parents. METHODS: 122 preschool offspring (mean age 3.3 years) of 84 parents with BP, with 102 offspring of 65 control parents (36 healthy, 29 with non-BP psychopathology), were evaluated using the Child Behavior Checklist (CBCL), the CBCL-Dysregulation Profile (CBCL-DP), the Early Childhood Inventory (ECI-4), and the Emotionality Activity Sociability (EAS) survey. Teachers' Report Forms (TRF) were available for 51 preschoolers. RESULTS: After adjusting for confounders, offspring of parents with BP showed higher scores in the CBCL total, externalizing, somatic, sleep, aggressive, and CBCL-DP subscales; the ECI-4 sleep problem scale; and the EAS total and emotionality scale. The proportion of offspring with CBCL T-scores ≥2 SD above the norm was significantly higher on most CBCL subscales and the CBCL-DP in offspring of parents with BP compared to offspring of controls even after excluding offspring with attention deficit hyperactivity disorder and/or oppositional defiant disorder. Compared to offspring of parents with BP-I, offspring of parents with BP-II showed significantly higher scores in total and most CBCL subscales, the ECI-4 anxiety and sleep scales and the EAS emotionality scale. For both groups of parents, there were significant correlations between CBCL and TRF scores (r = .32-.38, p-values ≤.02). CONCLUSIONS: Independent of categorical axis-I psychopathology and other demographic or clinical factors in both biological parents, preschool offspring of parents with BP have significantly greater aggression, mood dysregulation, sleep disturbances, and somatic complaints compared to offspring of control parents. Interventions to target these symptoms are warranted. Language: en

The goal of this study was to compare five actigraphy scoring methods in a sample of 18 remitted patients with bipolar disorder. Actigraphy records were processed using five different scoring methods relying on the sleep diary; the event-marker; the software-provided automatic algorithm; the automatic algorithm supplemented by the event-marker; visual inspection (VI) only. The Algorithm and the VI methods differed from the other methods for many actigraphy parameters of interest. Particularly, the Algorithm method yielded longer sleep duration, and the VI method yielded shorter sleep latency compared to the others methods. The present findings provide guidance for the selection of signal processing method based on sleep parameters of interest, time-cue sources and availability, and related scoring time costs for the study.

Objective Some reports suggest an increase in suicide ideations and behaviors in patients treated with antidepressants. This is an analysis of the impact of fluoxetine on suicide ideations in outpatients with minor depressive disorder. Methods Research subjects were adult outpatients with minor depressive disorder ( N = 162), who received fluoxetine or placebo in a prospective, 12-week, double-blind randomized trial. The research participants were evaluated weekly with standard rating scales that included four suicide-related items: item 3 of the Hamilton Rating Scale for Depression (HRSD), item 18 of Inventory of Depressive Symptomatology (IDS-C), and items 15 and 59 of the Hopkins Symptom Checklist (SCL-90). Clinically significant intensification of suicide ideation was defined as an increase of ≥2 points on any of these items. Results Overall 60/162 subjects (37%) had an increase of ≥1 point during treatment and 17/162 (10.5%) of ≥2 points on at least one suicide item, with 12/81 (14.8%) placebo and 5/81 (6.2%) fluoxetine-treated subjects having a ≥2 point gain. Of the study participants with baseline suicide ideation, 9/22 (40.9%) placebo and 3/24 (12.5%) fluoxetine treated had ≥2 point increase ( p = 0.04). Survival analysis revealed that subjects on placebo were significantly more likely ( p = 0.050) to experience a ≥2 point increase on one or more item, a difference that emerged early and continued throughout the 12-week trial. Conclusions Compared to placebo, fluoxetine was not associated with a clinically significant increase in suicide ideation among adults with minor depressive disorder during 12 weeks of treatment.

Recent reports demonstrate a link between inflammatory bowel disease (IBD) and sleep disturbance. Increased psychiatric dysfunction is consistently reported in patients with IBD. Our objective is to examine relations among sleep disturbance, inflammation, and psychiatric dysfunction in a pediatric population with Crohn disease (CD) and depression.Pediatric patients with CD with depression (n = 96) and healthy controls (n = 19) completed measures of sleep (Pittsburgh Sleep Quality Index [PSQI]), depression, anxiety, and abdominal pain, and provided blood for inflammatory markers. CD activity was determined by the Pediatric Crohn's Disease Activity Index. Factor analysis was performed on subscales of the PSQI to derive measures of sleep disturbance. Univariate and multivariate regression analyses assessed relations between sleep disturbance, psychosocial, and biological measures of CD and psychiatric dysfunction.Sleep disturbance in depressed youth with CD was significantly greater than healthy controls, and was significantly related to measures of abdominal pain, depression, and anxiety, but not biomarkers of inflammation. Factor analysis of the PSQI demonstrated a 2-factor solution. The first factor, termed "Qualitative," included Subjective Sleep Quality, Daytime Dysfunction, Sleep Disturbance, and Sleep Latency, whereas the second factor, "Quantitative," consisted of Habitual Sleep Efficiency and Sleep Duration. This factor showed a significant relation to inflammatory markers. Multivariate modeling suggested that qualitative sleep disturbance was predicted by disease activity, pain, and anxiety, whereas quantitative sleep disturbance was predicted by disease activity.These results indicate that sleep disturbance in depressed youth with CD differs depending upon illness activity. Patients may require different interventions depending upon the sleep disturbance exhibited.

Objectives Disruption of circadian function has been observed in several human disorders, including bipolar disorder (BD). Research into these disorders can be facilitated by human cellular models that evaluate external factors (zeitgebers) that impact circadian pacemaker activity. Incorporating a firefly luciferase reporter system into human fibroblasts provides a facile, bioluminescent readout that estimates circadian phase, while leaving the cells intact. We evaluated whether this system can be adapted to clinical BD research and whether it can incorporate zeitgeber challenge paradigms. Methods Fibroblasts from patients with bipolar I disorder (BD-I) (n = 13) and controls (n = 12) were infected ex vivo with a lentiviral reporter incorporating the promoter sequences for Bmal1, a circadian gene to drive expression of the firefly luciferase gene. Following synchronization, the bioluminescence was used to estimate period length. Phase response curves (PRCs) were also generated following forskolin challenge and the phase response patterns were characterized. Results Period length and PRCs could be estimated reliably from the constructs. There were no significant case-control differences in period length, with a nonsignificant trend for differences in PRCs following the phase-setting experiments. Conclusions An ex vivo cellular fibroblast-based model can be used to investigate circadian function in BD-I. It can be generated from specific individuals and this could usefully complement ongoing circadian clinical research.

Bipolar disorder refers to a group of affective disorders, which together are characterised by depressive and manic or hypomanic episodes. These disorders include: bipolar disorder type I (depressive and manic episodes: this disorder can be diagnosed on the basis of one manic episode); bipolar disorder type II (depressive and hypomanic episodes); cyclothymic disorder (hypomanic and depressive symptoms that do not meet criteria for depressive episodes); and bipolar disorder not otherwise specified (depressive and hypomanic-like symptoms that do not meet the diagnostic criteria for any of the aforementioned disorders). Bipolar disorder type II is especially difficult to diagnose accurately because of the difficulty in differentiation of this disorder from recurrent unipolar depression (recurrent depressive episodes) in depressed patients. The identification of objective biomarkers that represent pathophysiologic processes that differ between bipolar disorder and unipolar depression can both inform bipolar disorder diagnosis and provide biological targets for the development of new and personalised treatments. Neuroimaging studies could help the identification of biomarkers that differentiate bipolar disorder from unipolar depression, but the problem in detection of a clear boundary between these disorders suggests that they might be better represented as a continuum of affective disorders. Innovative combinations of neuroimaging and pattern recognition approaches can identify individual patterns of neural structure and function that accurately ascertain where a patient might lie on a behavioural scale. Ultimately, an integrative approach, with several biological measurements using different scales, could yield patterns of biomarkers (biosignatures) to help identify biological targets for personalised and new treatments for all affective disorders.

Bipolar disorder (BP) is a recurrent illness that usually has its onset during adolescence and is associated with substantial morbidity and impairment (1). Nonetheless, there is often a delay of up to a decade from the onset of the mood symptoms until proper diagnosis and treatment of BP (1, 2) increasing the risk of worse outcomes (2–4). Therefore, identification of early BP symptomatology could aid in earlier treatment and better psychosocial outcome. Retrospective studies of youth and adults with BP consistently indicate increased irritability, mood lability, subclinical mood and anxiety symptomatology, and behavior and sleep problems may be potential prodromal symptoms of BP (5–12). Of these symptoms, mood lability, defined as sudden, exaggerated, unpredictable and developmentally inappropriate changes in mood, is one of the strongest potential prodromal symptoms for BP. However, it is important to note that as used in the literature, mood lability is an umbrella term that captures pathological changes across several mood states including irritability. Among the studies that reported mood lability (or irritability) as a prodromal for BP, Angst and colleagues (7) in a large prospective adult community study reported that, independent of family history, unstable mood regulation was the strongest risk factor for BP. Also, Egeland and colleagues (13) in a well-characterized sample of 58 Amish bipolar I disorder (BP-I) adults whose medical records from childhood were available, reported that the most frequently symptoms included episodic changes in depressed, irritable, anger, and increased energy. In this study, there was a 9–12-year time interval between appearance of the first symptoms and the onset of the BP-I. Finally, Correll and colleagues (14) also reported a long symptomatic prodromal phase prior to the first manic episode manifested by mood lability (including anger outbursts), subclinical manic and depressed symptoms, anxiety, and social isolation. To obviate the biases encountered with retrospective investigations, and since the single most significant vulnerability factor for the development of BP is a family history of BP, studies have evaluated the prevalence of psychopathology in child and adolescent offspring of parents with BP. Using categorical as well as dimensional measurements, cross-sectional studies have reported higher levels of mood lability (including irritability and other rapid mood fluctuations), negative affect, depressed mood, anxiety, aggressive behaviors, and attention and sleep problems in offspring of parents with BP when compared with offspring of controls (8, 9, 12, 15–22). In the Pittsburgh Bipolar Offspring Study (BIOS) (18), from which the sample for the present study is derived, the offspring of parents with BP, particularly those offspring who already developed BP, had higher scores in the Total, Internalizing, Anxious/Depressed, Withdrawn/Depressed, and Aggressive Behavior scales of the Children Behavior Checklist (CBCL), the CBCL–Dysregulation Profile (CBCL-DP), and a sum of CBCL items associated with mood lability than the offspring of the control parents (17), independent of child and parental non-BP psychopathology. Using the Child Hostility Inventory, Farchione and colleagues (23) also reported high levels of irritability and hostility in the BIOS offspring of parents with BP when compared with offspring of the controls. The above literature suggest that mood lability and its components (e.g., irritability) as well the presence of subclinical mood and anxiety symptoms are a potential prodromal phenotype for BP. However, these symptoms, and in particular mood lability, are ubiquitous among psychiatric disorders (24–28). In fact, whereas some have found mood lability to be associated with the development of BP (5, 11, 14, 29–32), others have reported that it increases the risk for anxiety and depressive disorders, antisocial behaviors, and suicidality, but not BP (33–38). Thus, further investigations with more clear definitions or instruments to ascertain mood lability and its components are warranted to clarify the association of these symptoms with pediatric BP in high-risk populations without full-blown BP. Different methods have been used to ascertain mood lability such as single items and a composite of symptoms derived from instruments not specifically designed to ascertain mood lability, like the CBCL (e.g., 24, 26, 39–41). We therefore decided to use a parent-report (about their children) scale specifically developed to assess mood lability in youth, the Children’s Affective Lability Scale (CALS) (42). To compare and expand the original factor analysis of the CALS which was carried out with school children among whom there is less likelihood of mood symptomatology, and because the primary aim of our study was to identify prodromal symptoms of mania, a new factor analysis was performed. In this study, we sought to investigate the prevalence of mood lability and its components in non-BP offspring of BP parents, BP offspring of BP parents, and offspring of community control parents. These comparisons will help to clarify whether excessive mood lability only exists in the BP offspring of BP parents or is also increased in the non-BP offspring of parents with BP. Moreover, since some control parents are healthy whereas others have non-BP psychopathology, we will be able to evaluate if excessive mood lability is associated with having a parent with BP or is non-specifically associated parental overall psychopathology. Based on the literature and prior BIOS results it was hypothesized that after adjusting for confounding factors (e.g., effect of parental and offspring non-BP psychopathology) non-BP offspring of BP parents will have significantly higher scores on the parent and child CALS and its subscales than the offspring of community control parents. In addition, after adjusting for confounding factors, BP offspring of BP parents will show higher CALS scores than the non-BP offspring of BP parents and the offspring of the control parents.

Cardiovascular risk factors, such as abdominal obesity and obesity in general, are very prevalent among patients with bipolar disorder (BD). Although long-term use of psychotropic medications is an important determinant of these risk factors, other evidence suggests that early development may interact with the mood disorder diathesis to exponentially increase the risk of obesity. The goal of our study was to test whether season of birth is associated with adult body mass index (BMI) and abdominal obesity in individuals with bipolar disorder. We compared season of birth effects on BMI in 375 adult patients with bipolar disorder and 196 adult patients with unipolar major depression. We found a significant season of birth effect on BMI in patients with bipolar disorder, but not unipolar. In patients with bipolar disorder, season of birth was also associated with waist circumference, with a stronger effect in males. Season of birth affects adult BMI and waist circumference in patients with bipolar disorder, but not in patients with unipolar depression. Our results suggest that early environmental factors, yet to be identified, interact with specific neurobiological features of bipolar disorder to determine stable traits and disease risk factors in adult life.

The DSM-5 Field Trials were designed to obtain precise (standard error,0.1) estimates of the intraclass kappa asa measure of the degree to which two clinicians could independently agree on the presence or absence of selected DSM-5 diagnoses when the same patient was interviewed on separate occasions, in clinical settings, and evaluated with usual clinical interview methods.Eleven academic centers in the United States and Canada were selected,and each was assigned several target diagnoses frequently treated in that setting.Consecutive patients visiting a site during the study were screened and stratified on the basis of DSM-IV diagnoses or symptomatic presentations. Patients were randomly assigned to two clinicians for a diagnostic interview; clinicians were blind to any previous diagnosis. All data were entered directly via an Internet-based software system to a secure central server. Detailed research design and statistical methods are presented in an accompanying article.There were a total of 15 adult and eight child/adolescent diagnoses for which adequate sample sizes were obtained to report adequately precise estimates of the intraclass kappa. Overall, five diagnoses were in the very good range(kappa=0.60–0.79), nine in the good range(kappa=0.40–0.59), six in the questionable range (kappa = 0.20–0.39), and three in the unacceptable range (kappa values,0.20). Eight diagnoses had insufficient sample sizes to generate precise kappa estimates at any site.Most diagnoses adequately tested had good to very good reliability with these representative clinical populations assessed with usual clinical interview methods. Some diagnoses that were revised to encompass a broader spectrum of symptom expression or had a more dimensional approach tested in the good to very good range.

Background Patients with bipolar disorder are known to be at high risk of premature death. Comorbid cardio-vascular diseases are a leading cause of excess mortality, well above the risk associated with suicide. In this review, we explore comorbid medical disorders, highlighting evidence that bipolar disorder can be effectively conceptualized as a multi-systemic inflammatory disease. Methods We conducted a systematic PubMed search of all English-language articles recently published with bipolar disorder cross-referenced with the following terms: mortality and morbidity, cardio-vascular, diabetes, obesity, metabolic syndrome, inflammation, auto-antibody, retro-virus, stress, sleep and circadian rhythm. Results Evidence gathered so far suggests that the multi-system involvement is present from the early stages, and therefore requires proactive screening and diagnostic procedures, as well as comprehensive treatment to reduce progression and premature mortality. Exploring the biological pathways that could account for the observed link show that dysregulated inflammatory background could be a common factor underlying cardio-vascular and bipolar disorders. Viewing bipolar disorder as a multi-system disorder should help us to re-conceptualize disorders of the mind as “disorders of the brain and the body”. Limitations The current literature substantially lacks longitudinal and mechanistic studies, as well as comparison studies to explore the magnitude of the medical burden in bipolar disorder compared to major mood disorders as well as psychotic disorders. It is also necessary to look for subgroups of bipolar disorder based on their rates of comorbid disorders. Conclusions Comorbid medical illnesses in bipolar disorder might be viewed not only as the consequence of health behaviors and of psychotropic medications, but rather as an early manifestation of a multi-systemic disorder. Medical monitoring is thus a critical component of case assessment. Exploring common biological pathways of inflammation should help biomarkers discovery, ultimately leading to innovative diagnostic tools, new methods of prevention and personalized treatments.

Background: Few studies have prospectively examined the relationships of sleep with symptoms and functioning in bipolar disorder. Methods: The present study examined concurrent and prospective associations between total sleep time (TST) and sleep variability (SV) with symptom severity and functioning in a cohort of DSM-IV bipolar patients (N = 468) participating in the National Institute of Mental Health Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), all of whom were recovered at study entry. Results: Concurrent associations at study entry indicated that shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity. Mixed-effects regression modeling was used to examine prospective associations in the 196 patients for whom follow-up data were available. Consistent with findings at study entry, shorter TST was associated with increased mania severity, and greater SV was associated with increased mania and depression severity over 12 months. Discussion: These findings highlight the importance of disrupted sleep patterns in the course of bipolar illness. © 2011 Elsevier B.V. All rights reserved.

The pathogenesis of bipolar disorder may involve, at least in part, aberrations in serotonergic neurotransmission. Hence, serotonergic genes are attractive targets for association studies of bipolar disorder. We have reviewed the literature in this field. It is difficult to synthesize results as only one polymorphism per gene was typically investigated in relatively small samples. Nevertheless, suggestive associations are available for the 5HT2A receptor and the serotonin transporter genes. With the availability of extensive polymorphism data and high throughput genotyping techniques, comprehensive evaluation of these genes using adequately powered samples is warranted. We also report on our investigations of the serotonin transporter, SLC6A4 (17q11.1-q12). An insertion/deletion polymorphism (5HTTLPR) in the promoter region of this gene has been investigated intensively. However, the results have been inconsistent. We reasoned that other polymorphism/s may contribute to the associations and the inconsistencies may be due to variations in linkage disequilibrium (LD) patterns between samples. Therefore, we conducted LD analyses, as well as association and linkage using 12 polymorphisms, including 5HTTLPR. We evaluated two samples. The first sample consisted of 135 US Caucasian nuclear families having a proband with bipolar I disorder (BDI, DSM IV criteria) and available parents. For case-control analyses, the patients from these families were compared with cord blood samples from local Caucasian live births (n = 182). Our second, independent sample was recruited through the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD, 545 cases, 548 controls). No significant associations were detected at the individual polymorphism or haplotype level using the case-control or family-based analyses. Our analyses do not support association between SLC6A4 and BDI families. Further studies using sub-groups of BDI are worthwhile.

Background Individuals diagnosed with bipolar 1 disorder (BP1), bipolar 2 disorder (BP2), or major depressive disorder (MDD) experience varying levels of depressive and (hypo)manic symptoms. Clarifying symptom heterogeneity is meaningful, as even subthreshold symptoms may impact quality of life and treatment outcome. The MOODS Lifetime self-report instrument was designed to capture the full range of depressive and (hypo)manic characteristics. Methods This study applied clustering methods to 347 currently depressed adults with MDD, BP2, or BP1 to reveal naturally occurring MOODS subgroups. Subgroups were then compared on baseline clinical and demographic characteristics and as well as depressive and (hypo)manic symptoms over twenty weeks of treatment. Results Four subgroups were identified: (1) high depressive and (hypo)manic symptoms (N=77, 22%), (2) moderate depressive and (hypo)manic symptoms (N=115, 33%), (3) low depressive and moderate (hypo)manic symptoms (N=82, 24%), and (4) low depressive and (hypo)manic symptoms (N=73, 21%). Individuals in the low depressive/moderate (hypo)manic subgroup had poorer quality of life and greater depressive symptoms over the course of treatment. Individuals in the high and moderate severity subgroups had greater substance use, longer duration of illness, and greater (hypo)manic symptoms throughout treatment. Treatment outcomes were primarily driven by individuals diagnosed with MDD. Limitations The sample was drawn from three randomized clinical trials. Validation is required for this exploratory study. Conclusions After validation, these subgroups may inform classification and personalized treatment beyond categorical diagnosis.

The authors sought to assess dimensional symptomatic predictors of new-onset bipolar spectrum disorders in youths at familial risk of bipolar disorder ("at-risk" youths).Offspring 6-18 years old of parents with bipolar I or II disorder (N=359) and community comparison offspring (N=220) were recruited. At baseline, 8.4% of the offspring of bipolar parents had a bipolar spectrum disorder. Over 8 years, 14.7% of offspring for whom follow-up data were available (44/299) developed a new-onset bipolar spectrum disorder (15 with bipolar I or II disorder). Measures collected at baseline and follow-up were reduced using factor analyses, and factors (both at baseline and at the visit prior to conversion or last contact) were assessed as predictors of new-onset bipolar spectrum disorders.Relative to comparison offspring, at-risk and bipolar offspring had higher baseline levels of anxiety/depression, inattention/disinhibition, externalizing, subsyndromal manic, and affective lability symptoms. The strongest predictors of new-onset bipolar spectrum disorders were baseline anxiety/depression, baseline and proximal affective lability, and proximal subsyndromal manic symptoms (p0.05). While affective lability and anxiety/depression were elevated throughout follow-up in those who later developed a bipolar spectrum disorder, manic symptoms increased up to the point of conversion. A path analysis supported the hypothesis that affective lability at baseline predicts a new-onset bipolar spectrum disorder in part through increased manic symptoms at the visit prior to conversion; earlier parental age at mood disorder onset was also significantly associated with an increased risk of conversion. While youths without anxiety/depression, affective lability, and mania (and with a parent with older age at mood disorder onset) had a 2% predicted chance of conversion to a bipolar spectrum disorder, those with all risk factors had a 49% predicted chance of conversion.Dimensional measures of anxiety/depression, affective lability, and mania are important predictors of new-onset bipolar spectrum disorders in at-risk youths. These symptoms emerged from among numerous other candidates, underscoring the potential clinical and research utility of these findings.

Bipolar disorder (BD) is often associated with high levels of general medical burden, high rates of cardiovascular diseases and a high mortality rate from medical causes (1–5). In spite of the high prevalence of well-documented risk factors for obstructive sleep apnea (OSA) (6), the actual prevalence of sleep-related disordered breathing in BD has not been systematically investigated beyond small case series and anecdotal reports (7). The clinical presentation of OSA may overlap substantially with that of major depression, including report of poor sleep quality, daytime fatigue, difficulty concentrating, cognitive deficits and somatic symptoms such as headaches. Since the depressive phase of BD is often chronic and difficult to treat, and undiagnosed underlying medical conditions may greatly contribute to its unfavorable outcome, it is reasonable to speculate that sleep-disordered breathing may play a role in this clinical picture. Indeed, the presence of medical comorbidities that constitute risk factors for OSA has been associated with a worse outcome of BD (8). For example, obesity has been linked to a higher number of lifetime depressive episodes and to a shorter time to recurrence (9). Abdominal obesity, particularly, is associated with increased suicidality (3). Part of the detrimental effect of these conditions on mood regulation may be ascribed to underlying sleep-related breathing problems. Patients who develop OSA as a result of cumulative risk factors may be over-represented among those who present a history of chronic and treatment-resistant depressive symptoms. Therefore, we sought to determine the risk for OSA in a population of 72 patients with bipolar I disorder who were currently engaged in an outpatient maintenance treatment protocol. We asked participants to complete a validated instrument that determines risk for sleep apnea. We then compared the demographic and clinical characteristics of patients at high risk and low risk for sleep apnea. Our goal was to explore whether the age and gender distribution of the apnea risk would reflect the age and gender distribution reported in the general population. We also tested the hypothesis that being at high risk for sleep apnea would be associated with greater severity of the mood disorder, independent of sleep disturbance.

Objective To document the investments made in research on mental disorders by both government and nonprofit nongovernmental organizations in France, the United Kingdom, and the United States. Data sources An exhaustive survey was conducted of primary sources of public and nonprofit organization funding for mental health research for the year 2007 in France and the United Kingdom and for fiscal year 2007-2008 in the United States, augmented with an examination of relevant Web sites and publications. In France, all universities and research institutions were identified using the Public Finance Act. In the United Kingdom, we scrutinized Web sites and hand searched annual reports and grant lists for the public sector and nonprofit charitable medical research awarding bodies. In the United States, we included the following sources: the National Institutes of Health, other administrative entities within the Department of Health and Human Services (eg, Centers for Disease Control and Prevention), the Department of Education, the Department of Veterans Affairs, the Department of Defense, and the National Science Foundation and, for nonprofit funding, The Foundation Center. Data extraction We included research on all mental disorders and substance-related disorders using the same keywords. We excluded research on mental retardation and dementia and on the promotion of mental well-being. We used the same algorithm in each country to obtain data for only mental health funding in situations in which funding had a broader scope. Results France spent $27.6 million (2%) of its health research budget on mental disorders, the United Kingdom spent $172.6 million (7%), and the United States spent $5.2 billion (16%). Nongovernmental funding ranged from 1% of total funding for mental health research in France and the United States to 14% in the United Kingdom. Conclusions Funding for research on mental disorders accounts for low proportions of research budgets compared with funding levels for research on other major health problems, whereas the expected return on investment is potentially high.