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Objective: This study assessed costs among patients with bipolar disorder for treatment related to bipolar disorder and to comorbid conditions. Risk factors associated with costs were also assessed.Methods: Data (January 1998 to December 2002) were from a seven-state Medicaid managed care claims database for 13,471 patients who had received a diagnosis of bipolar disorder, most of whom received medications. Each medical claims cost was adjusted by the medical component of the Consumer Price Index as the dollar value in 2002. In a Poisson regression analysis, treatment costs per enrollment month were regressed on patient's age, gender, medications, and clinical comorbidities.Results: Bipolar disorder treatment accounted for 30% of costs and comorbid disorders for 70%. Key cost components were inpatient care (35%), outpatient care (16%), prescriptions (13%), and physician encounters (11%). Patients with bipolar disorder received a variety of medications: lithium, 13%; anticonvulsants, 35%; second-generation antipsychotics, 24%; first-generation antipsychotics, 22%; and antidepressants, 42%. Compared with the costs for patients receiving antidepressants alone or no medication, the high costs for bipolar disorder treatment and overall treatment were associated with use of second-generation antipsychotics (rate ratio [RR]=1.71, 95% confidence interval [CI]=1.58-1.86 and RR=1.26, CI=1.18-1.34, respectively) and use of anticonvulsants (RR=1.37, CI=1.26-1.48 and RR=1.06, CI=1.00-1.12). Higher costs were significantly associated with key comorbidities, such as drug abuse (RR=1.58, CI=1.47-1.70), cerebral-vascular disease (RR=1.72, CI=1.51-1.94), ischemic heart disease (RR=1.47, CI=1.30-1.66), and hypertension (RR=1.44, CI=1.33-1.56).Conclusions: Cost-containment efforts may need to manage or prevent key comorbidities among patients with bipolar disorder and to evaluate the association between antipsychotic use and treatment outcomes and hospital services. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To assess the efficacy and safety of gabapentin in patients with fibromyalgia. METHODS: A 12-week, randomized, double-blind study was designed to compare gabapentin (1,200-2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0-10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of >/=30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent-to-treat sample, with treatment-by-time interaction as the measure of effect. RESULTS: Gabapentin-treated patients displayed a significantly greater improvement in the BPI average pain severity score (P = 0.015; estimated difference between groups at week 12 = -0.92 [95% confidence interval -1.75, -0.71]). A significantly greater proportion of gabapentin-treated patients compared with placebo-treated patients achieved response at end point (51% versus 31%; P = 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated. CONCLUSION: Gabapentin (1,200-2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Bipolar spectrum disorders, which include bipolar I, bipolar II, and bipolar disorder not otherwise specified, frequently go unrecognized, undiagnosed, and untreated. This report describes the validation of a new brief self-report screening instrument for bipolar spectrum disorders called the Mood Disorder Questionnaire. METHOD: A total of 198 patients attending five outpatient clinics that primarily treat patients with mood disorders completed the Mood Disorder Questionnaire. A research professional, blind to the Mood Disorder Questionnaire results, conducted a telephone research diagnostic interview by means of the bipolar module of the Structured Clinical Interview for DSM-IV. RESULTS: A Mood Disorder Questionnaire screening score of 7 or more items yielded good sensitivity (0.73) and very good specificity (0.90). CONCLUSIONS: The Mood Disorder Questionnaire is a useful screening instrument for bipolar spectrum disorder in a psychiatric outpatient population. [ABSTRACT FROM AUTHOR]

Objectives: The authors compared the switch rate into hypomania/mania in depressed patients treated with second-generation antidepressants who had either bipolar I or bipolar II disorder., Methods: In a 10-week trial, 184 outpatients with bipolar depression (134 with bipolar I disorder, 48 with bipolar II disorder, two with bipolar disorder not otherwise specified) were treated with one of three antidepressants as an adjunct to mood stabilizers. The patients' switch rates were assessed. Switch was defined as a Young Mania Rating Scale (YMRS) score >13 or a Clinical Global Impression (CGI) mania score ≥3 (mildly ill)., Results: Depressed subjects with bipolar II disorder had a significantly lower acute switch rate into hypomania/mania when either YMRS or CGI criteria were used to define switch., Conclusions: These data suggest that depressed patients with bipolar II disorder are less vulnerable than those with bipolar I disorder to switch into hypomania/mania when treated with an antidepressant adjunctive to a mood stabilizer.Reprinted from Am J Psychiatry 2006; 163:313-315 , with permission from American Psychiatric Association Publishing. Copyright © 2006., (Copyright © 2023 by the American Psychiatric Association.)

Objective: Bipolar patients in the United States (US) compared to those from the Netherlands and Germany (here abbrev. as "Europe") have more Axis I comorbidities and more poor prognosis factors such as early onset and psychosocial adversity in childhood. We wished to examine whether these differences also extended to Axis II personality disorders (PDs)., Methods: 793 outpatients with bipolar disorder diagnosed by SCID gave informed consent for participating in a prospective longitudinal follow up study with clinician ratings at each visit. They completed detailed patient questionnaires and a 99 item personality disorder inventory (PDQ-4). US versus European differences in PDs were examined in univariate analyses and then logistic regressions, controlling for severity of depression, age, gender, and other poor prognosis factors., Results: In the univariate analysis, 7 PDs were more prevalent in the US than in Europe, including antisocial, avoidant, borderline, depressive, histrionic, obsessive compulsive, and schizoid PDs. In the multivariate analysis, the last 4 of these PDs remained independently greater in the US than Europe., Conclusions: Although limited by use of self report and other potentially confounding factors, multiple PDs were more prevalent in the US than in Europe, but these preliminary findings need to be confirmed using other methodologies. Other poor prognosis factors are prevalent in the US, including early age of onset, more childhood adversity, anxiety and substance abuse comorbidity, and more episodes and rapid cycling. The interactions among these variables in relationship to the more adverse course of illness in the US than in Europe require further study., Competing Interests: Conflict of interest Trisha Suppes, MD, PhD, in the past 36 months has reported grants from Merck, National Institute of Health, National Institute of Mental Health, National Institute on Drug Abuse, Palo Alto Health Sciences, Pathways Genomics, Stanley Medical Research Institute, VA Cooperative Studies Program, and VA OR&D PRIME Care; consulting fees from Allergan, Inc., Impel NeuroPharma Inc., and Sunovion Pharmaceuticals Inc.; honoraria from CME Institute (underwritten by Otsuka), CMEology, Global Medical Education, and Medscape Education; royalties from Jones and Bartlett, Hogrefe Publishing and Wolters Kluwer Health (UpToDate); and travel reimbursement from CMEology, Global Medication Education, and Sunovion Pharmaceuticals, Inc., (Copyright © 2022. Published by Elsevier B.V.)

Background: Depending on the classification system used, 5-40% of manic subjects present with concomitant depressive symptoms. This post-hoc analysis evaluates the hypothesis that (hypo)manic subjects have a higher burden of depression than non-(hypo)manic subjects., Methods: Data from 806 Bipolar I or II participants of the Stanley Foundation Bipolar Network (SFBN) were analyzed, comprising 17,937 visits. A split data approach was used to separate evaluation and verification in independent samples. For verification of our hypotheses, we compared mean IDS-C scores ratings of non-manic, hypomanic and manic patients. Data were stored on an SQL-server and extracted using standard SQL functions. Linear correlation coefficients and pivotal tables were used to characterize patient groups., Results: Mean age of participants was 40 ± 12 years (range 18-81). 460 patients (57.1%) were female and 624 were diagnosed as having bipolar I disorder (77.4%) and 182 with bipolar II (22.6%). Data of 17,937 visits were available for analyses, split into odd and even patient numbers and stratified into three groups by YMRS-scores: not manic < 12, hypomanic < 21, manic < 30. Average IDS-C sum scores in manic or hypomanic states were significantly higher (p < .001) than for non-manic states. (Hypo)manic female patients were likely to show more depressive symptoms than males (p < .001). Similar results were obtained when only the core items of the YMRS or only the number of depressive symptoms were considered. Analyzing the frequency of (hypo)manic mixed states applying a proxy of the DSM-5 mixed features specifier extracted from the IDS-C, we found that almost 50% of the (hypo)manic group visits fulfilled DSM-5 mixed features specifier criteria., Conclusion: Subjects with a higher manic symptom load are also significantly more likely to experience a higher number of depressive symptoms. Mania and depression are not opposing poles of bipolarity but complement each other., (© 2021. The Author(s).)

Background: The Stanley Foundation Bipolar Treatment Outcome Network (SFBN) recruited more than 900 outpatients from 1995 to 2002 from 4 sites in the United States (US) and 3 in the Netherlands and Germany (abbreviated as Europe). When funding was discontinued, the international group of investigators continued to work together as the Bipolar Collaborative Network (BCN), publishing so far 87 peer-reviewed manuscripts. On the 25th year anniversary of its founding, publication of a brief summary of some of the major findings appeared appropriate. Important insights into the course and treatment of adult outpatients with bipolar disorder were revealed and some methodological issues and lessons learned will be discussed., Results: The illness is recurrent and pernicious and difficult to bring to a long-term remission. Virtually all aspects of the illness were more prevalent in the US compared to Europe. This included vastly more patients with early onset illness and those with more psychosocial adversity in childhood; more genetic vulnerability; more anxiety and substance abuse comorbidity; more episodes and rapid cycling; and more treatment non-responsiveness., Conclusions: The findings provide a road map for a new round of much needed clinical treatment research studies. They also emphasize the need for the formation of a new network focusing on child and youth onset of mood disorders with a goal to achieve early precision diagnostics for intervention and prevention in attempting to make the course of bipolar illness more benign.

Background: Evidence is emerging that early onset bipolar disorder and the duration of the delay to first treatment are both risk factors for poor treatment outcome. We report on the incidence and implications of these two risk factors in patients from the United States (US) versus Europe., Methods: Age of onset and age at first treatment for depression or mania was assessed in 967 outpatients with bipolar disorder who gave informed consent for participation and filling out a detailed questionnaire. Age at onset and treatment delay were compared in the 675 patients from the US and 292 from the Netherlands and Germany (abbreviated as Europe). Both were then graphed and analyzed., Results: Age of onset of bipolar disorder was earlier in the US than in Europeans by an average of 6-7 years with similar results in those with first onsets of depression or of mania. Delay to first treatment was strongly inversely related to age of onset and was twice as long in the US than in Europe, and especially different for mania in adolescents. The longer delay to treatment in the US was not solely due to earlier age of onset., Conclusions: Treatment delay is a remedial risk factor and could be shortened with better recognition of the higher incidence of early onset bipolar disorder in the US, which also associated with more genetic and environmental vulnerability factors compared to Europe. New treatment and research initiatives are needed to address these liabilities so that children with bipolar achieve more positive long-term outcomes., (Copyright © 2020. Published by Elsevier B.V.)

The effect of assortative mating on offspring is often not considered. Here, we present data on illness in the spouse and the parents of patients with bipolar disorder as they affect illness in the offspring. A history of psychiatric illness (depression, bipolar disorder, suicide attempt, alcohol abuse, drug abuse, and "other" illness) was elicited for the parents, spouse, and the offspring of 968 patients with bipolar disorder (540 of whom had children) who gave informed consent for participation in a treatment outcome network. Assortative mating for a mood disorder in the spouse and parents in those from the United States (US) was compared to those from the Netherlands and Germany and related to illnesses in the offspring. There was more illness and assortative mating for a mood disorder in both the spouse and patient's parents from the US compared to Europe. In the parents of the US patients, assortative mating for a mood disorder was associated with more depression, bipolar disorder, alcohol, and "other" illness in the offspring. Compared to the Europeans, there was more assortative mating for mood and other disorders in two generations of those from the US. This bilineal positivity for a parental mood disorder was related to more depression a second generation later in the patients' offspring. In clinical assessment of risk of illness in the offspring, the history of psychiatric illness in the spouse and patient's parents might provide additional information.

Objective: According to DSM-IV, criterion (A) for diagnosing a hypomanic/manic episode is mood change (ie, elevated, expansive, or irritable mood). Criterion (A) was redefined in DSM-5, adding increased energy or activity in addition to mood change. We sought to investigate the effect of adding increased energy or activity to criterion (A) for the diagnosis of hypomania/mania and, thus, bipolar disorder., Methods: This analysis of prospectively collected data from the Bipolar Collaborative Network (1995-2002) includes 907 DSM-IV-TR-diagnosed bipolar outpatients (14,306 visits). The Young Mania Rating Scale (YMRS) was administered monthly and used to define DSM-IV and DSM-5 criterion (A) fulfillment during a hypomanic/manic visit., Results: Patients were adults (median age = 40; IQR, 33-49), and over half (56%) were women. Median number of contributed visits was 10 (IQR, 4-23). Applying DSM-5 criterion (A) reduced the number of patients experiencing a hypomanic/manic visit by 34%, compared to DSM-IV. Visits fulfilling DSM-5 criterion (A) had higher odds of experiencing elevated levels of all other mania symptoms, compared to fulfilling DSM-IV criterion (A) only. Association between individual symptoms was strongest with mood elevation and energy or activity (OR [95% CL] = 8.65, [7.91, 9.47])., Conclusions: The 34% reduction in the number of patients being diagnosed with a hypomanic/manic visit shows that the impact of applying DSM-5 criterion (A) is substantial. Fewer hypomanic/manic episodes may be diagnosed by the stricter DSM-5 criterion (A), but the episodes diagnosed are likely to be more severe. The DSM-5 criteria may in general prevent overdiagnosis of bipolar disorder but possibly at the cost of underdiagnosing hypomanic/manic episodes., (© Copyright 2019 Physicians Postgraduate Press, Inc.)

(Reprinted with permission from Am J Psychiatry 2006; 163:313-315)., (Copyright © 2019 by the American Psychiatric Association.)

Objective: Bipolar disorder has a wide range of clinical manifestations which may progress over time. The aim of this study was to test the applicability of a clinical staging model for bipolar disorder and to gain insight into the nature of the variables influencing progression through consecutive stages., Methods: Using retrospectively reported longitudinal life chart data of 99 subjects from the Stanley Foundation Bipolar Network Naturalistic Follow-up Study, the occurrence, duration and timely sequence of stages 2-4 were determined per month. A multi-state model was used to calculate progression rates and identify determinants of illness progression. Stages 0, 1 and several other variables were added to the multi-state model to determine their influence on the progression rates., Results: Five years after onset of BD (stage 2), 72% reached stage 3 (recurrent episodes) and 21% had reached stage 4 (continuous episodes), of whom 8% recovered back to stage 3. The progression from stage 2 to 3 was increased by a biphasic onset for both the depression-mania and the mania-depression course and by male sex., Conclusions: Staging is a useful model to determine illness progression in longitudinal life chart data. Variables influencing transition rates were successfully identified., (© 2018 The Authors. Bipolar Disorders Published by John Wiley & Sons Ltd.)

Introduction: Instead of the typical assessment of risk of illness in the offspring based on a parent with bipolar disorder, we explored the potential multigenerational conveyance across several disorders of the vulnerability to illness in the offspring of a patient with bipolar disorder., Methods: A total of 968 outpatients (average age 41 years) with bipolar illness gave informed consent and filled out a detailed questionnaire about a family history in their parents, grandparents, and offspring of: depression; bipolar disorder; alcohol abuse; substance abuse; suicide attempt; or "other" illness. Of those with children, 346 were from the USA and 132 were from Europe. Amount and type of illness in progenitors in two and three previous generations were related to offspring illness., Results: The type of illness seen in both prior generations was associated with the same type of illness in the offspring of a bipolar patient, including depression, bipolar disorder, alcohol and substance abuse and "other" illness, but not suicide attempts. There was an impact of multiple generations, such that depression in grandparents and/or great-grandparents increased the risk of depression in the offspring from 12.6% to 41.4%., Conclusions: A family history of illness burden in prior generations was previously related to an earlier age of onset of bipolar illness in our adult patients with bipolar disorder and is now also found to be related to the incidence of multiple psychiatric illnesses in their offspring. Genetic and epigenetic mechanisms deserve consideration for this multigenerational conveyance of illness vulnerability, and clinical and public health attempts to prevent or slow this transmission are indicated., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Binge eating, eating an abnormally large amount of food in a discrete period of time with a sense of loss of control over eating, is a defining feature of the eating disorders binge eating disorder (BED) and bulimia nervosa (BN). Both BED and BN are important public health problems for which there are few medical treatments. However, almost all drugs with central nervous system-mediated weight loss properties studied thus far in randomized, placebo-controlled trials in persons with BED or BN have been efficacious for reducing binge eating behavior. Glucagon-like peptide-1 (GLP-1) receptor agonists, marketed for type 2 diabetes and chronic weight management, produce weight loss in a dose dependent manner and have favorable psychiatric adverse event profiles. We hypothesize that GLP-1 receptor agonists will safely reduce binge eating behavior in individuals with BED or BN, including those with co-occurring psychiatric disorders, and propose that randomized, placebo-controlled clinical trials of GLP-1 receptor agonists be conducted in persons with BED and those with BN. To support this hypothesis, we review studies of GLP-1 and GLP-1 receptor agonists in preclinical models of binge eating, studies of GLP-1 levels in individuals with BED or BN, and preliminary data of GLP-1 receptor agonists in humans with abnormal eating behavior., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Although bipolar disorder (BD) and borderline personality disorder (BPD) share clinical characteristics and frequently co-occur, their interrelationship is controversial. Especially, the differentiation of rapid cycling BD and BPD can be troublesome. This study investigates the relationship between borderline personality features (BPF) and prospective illness course in patients with BD, and explores the effects of current mood state on self-reported BPF profiles., Methods: The study included 375 patients who participated in the former Stanley Foundation Bipolar Network. All patients met DSM-IV criteria for bipolar-I disorder (n = 294), bipolar-II disorder (n = 72) or bipolar disorder NOS (n = 9). BPF were assessed with the self-rated Personality Diagnostic Questionnaire. Illness course was based on 1-year clinician rated prospective daily mood ratings with the life chart methodology. Regression analyses were used to estimate the relationships among these variables., Results: Although correlations were weak, results showed that having more BPF at baseline is associated with a higher episode frequency during subsequent 1-year follow-up. Of the nine BPF, affective instability, impulsivity, and self-mutilation/suicidality showed a relationship to full-duration as well as brief episode frequency. In contrast all other BPF were not related to episode frequency., Conclusions: Having more BPF was associated with an unfavorable illness course of BD. Affective instability, impulsivity, and self-mutilation/suicidality are associated with both rapid cycling BD and BPD. Still, many core features of BPD show no relationship to rapid cycling BD and can help in the differential diagnosis.

A significant minority of people presenting with a major depressive episode (MDE) experience co-occurring subsyndromal hypo/manic symptoms. As this presentation may have important prognostic and treatment implications, the DSM-5 codified a new nosological entity, the "mixed features specifier," referring to individuals meeting threshold criteria for an MDE and subthreshold symptoms of (hypo)mania or to individuals with syndromal mania and subthreshold depressive symptoms. The mixed features specifier adds to a growing list of monikers that have been put forward to describe phenotypes characterized by the admixture of depressive and hypomanic symptoms (e.g., mixed depression, depression with mixed features, or depressive mixed states [DMX]). Current treatment guidelines, regulatory approvals, as well the current evidentiary base provide insufficient decision support to practitioners who provide care to individuals presenting with an MDE with mixed features. In addition, all existing psychotropic agents evaluated in mixed patients have largely been confined to patient populations meeting the DSM-IV definition of "mixed states" wherein the co-occurrence of threshold-level mania and threshold-level MDE was required. Toward the aim of assisting clinicians providing care to adults with MDE and mixed features, we have assembled a panel of experts on mood disorders to develop these guidelines on the recognition and treatment of mixed depression, based on the few studies that have focused specifically on DMX as well as decades of cumulated clinical experience.

Various terms have been used to describe mania when it is accompanied by depressive symptoms. In this article, we attempt to define and discuss 3 of these terms: dysphoric mania, mixed state, and mania with mixed features specifier. We conclude that whatever term is used, it is important to be aware that mania is more often unpleasant than pleasant, and that the unpleasantness is not limited to depression.

Evidence of a high or increasing incidence of childhood onset bipolar disorder in the United States (US) has been viewed skeptically. Here we review evidence that childhood onsets of bipolar disorder are more common in the US than in Europe, treatment delays are longer, and illness course is more adverse and difficult. Epidemiological data and studies of offspring at high risk also support these findings. In our cohort of outpatients with bipolar disorder, two of the major vulnerability factors for early onset - genetics and environmental adversity in childhood - were also greater in the US than in Europe. An increased familial loading for multiple psychiatric disorders was apparent in 4 generations of the family members of the patients from the US, and that familial burden was linked to early onset bipolar disorder. Since both early onset and treatment delay are risk factors for a poor outcome in adulthood, new clinical, research, and public health initiatives are needed to begin to address and ameliorate this ongoing and potentially devastating clinical situation., (Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: The authors compared medication-induced mood switch risk (primary outcome), as well as treatment response and side effects (secondary outcomes) with three acute-phase treatments for bipolar II depression., Method: In a 16-week, double-blind, multisite comparison study, 142 participants with bipolar II depression were randomly assigned to receive lithium monotherapy (N=49), sertraline monotherapy (N=45), or combination treatment with lithium and sertraline (N=48). At each visit, mood was assessed using standardized rating scales. Rates of switch were compared, as were rates of treatment response and the presence and severity of treatment-emergent side effects., Results: Twenty participants (14%) experienced a switch during the study period (hypomania, N=17; severe hypomania, N=3). Switch rates did not differ among the three treatment groups, even after accounting for dropout. No patient had a manic switch or was hospitalized for a switch. Most switches occurred within the first 5 weeks of treatment. The treatment response rate for the overall sample was 62.7% (N=89), without significant differences between groups after accounting for dropout. The lithium/sertraline combination group had a significantly higher overall dropout rate than the monotherapy groups but did not have an accelerated time to response., Conclusions: Lithium monotherapy, sertraline monotherapy, and lithium/sertraline combination therapy were associated with similar switch and treatment response rates in participants with bipolar II depression. The dropout rate was higher in the lithium/sertraline combination treatment group, without any treatment acceleration advantage.

Background: Patients with bipolar disorder from the US have more early-onset illness and a greater familial loading for psychiatric problems than those from the Netherlands or Germany (abbreviated here as Europe). We hypothesized that these regional differences in illness burden would extend to the patients siblings., Methods: Outpatients with bipolar disorder gave consent for participation in a treatment outcome network and for filling out detailed questionnaires. This included a family history of unipolar depression, bipolar disorder, suicide attempt, alcohol abuse/dependence, drug abuse/dependence, and "other" illness elicited for the patients' grandparents, parents, spouses, offspring, and siblings. Problems in the siblings were examined as a function of parental and grandparental problems and the patients' adverse illness characteristics or poor prognosis factors (PPFs)., Results: Each problem in the siblings was significantly (p<0.001) more prevalent in those from the US than in those from Europe. In the US, problems in the parents and grandparents were almost uniformly associated with the same problems in the siblings, and sibling problems were related to the number of PPFs observed in the patients., Limitations: Family history was based on patient report., Conclusions: Increased familial loading for psychiatric problems extends through 4 generations of patients with bipolar disorder from the US compared to Europe, and appears to "breed true" into the siblings of the patients. In addition to early onset, a variety of PPFs are associated with the burden of psychiatric problems in the patients' siblings and offspring. Greater attention to the multigenerational prevalence of illness in patients from the US is indicated., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: DSM-5 introduced the "with mixed features" specifier for major depressive episodes. The authors assessed the prevalence and phenomenology of mixed depression among bipolar disorder patients and qualitatively compared a range of diagnostic thresholds for mixed depression., Method: In a naturalistic study, 907 adult outpatients with bipolar disorder participating in the Stanley Foundation Bipolar Network were followed longitudinally across 14,310 visits from 1995 to 2002. The Inventory of Depressive Symptomatology-Clinician-Rated Version (IDS-C) and the Young Mania Rating Scale (YMRS) were administered at each visit., Results: Mixed depression, defined as an IDS-C score ≥15 and a YMRS score >2 and <12 at the same visit, was observed in 2,139 visits (14.9% of total visits, and 43.5% of visits with depression) by 584 patients (64.4% of all patients). Women were significantly more likely than men to experience subthreshold hypomania during visits with depression (40.7% compared with 34.4%). Patients with one or more mixed depression visits had more symptomatic visits and fewer euthymic visits compared with those with no mixed depression visits. DSM-5-based definitions of mixed depression (ranging from narrower definitions requiring ≥3 nonoverlapping YMRS items concurrent with an IDS-C score ≥15, to broader definitions requiring ≥2 nonoverlapping YMRS items) yielded lower mixed depression prevalence rates (6.3% and 10.8% of visits, respectively) but were found to have similar relationships to gender and longitudinal symptom severity., Conclusions: Among outpatients with bipolar disorder, concurrent hypomanic symptoms observed during visits with depression were common, particularly in women. The DSM-5 diagnostic criteria for depression with mixed features may yield inadequate sensitivity to detect patients with mixed depression.

Background: Family history and adversity in childhood are two replicated risk factors for early onset bipolar disorder. However, their combined impact has not been adequately studied., Methods: Based on questionnaire data from 968 outpatients with bipolar disorder who gave informed consent, the relationship and interaction of: 1) parental and grandparental total burden of psychiatric illness; and 2) the degree of adversity the patient experienced in childhood on their age of onset of bipolar disorder was examined with multiple regression and illustrated with a heat map., Results: The familial loading and child adversity vulnerability factors were significantly related to age of onset of bipolar and their combined effect was even larger. A heat map showed that at the extremes (none of each factor vs high amounts of both) the average age of onset differed by almost 20 years (mean = 25.8 vs 5.9 years of age)., Limitations: The data were not based on interviews of family members and came from unverified answers on a patient questionnaire., Conclusions: Family loading for psychiatric illness and adversity in childhood combine to have a very large influence on age of onset of bipolar disorder. These variables should be considered in assessment of risk for illness onset in different populations, the need for early intervention, and in the design of studies of primary and secondary prevention., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Objective: The age at onset of bipolar disorder varies greatly in different countries and continents. The association between load of family history of psychiatric illness and age at onset has not been adequately explored., Methods: 979 outpatients with bipolar disorder (from 4 sites in the United States and 3 in the Netherlands and Germany) gave informed consent and completed a questionnaire about their demographics, age at onset of illness, and family history of unipolar and bipolar disorder, alcohol and substance abuse comorbidity, suicide attempts, and "other" illnesses in their parents, 4 grandparents, and any offspring. We examined how the parental and grandparental burden of these illnesses related to the age at onset of the patients' bipolar disorder., Results: The burden of family psychiatric history was strongly related to an earlier age at onset of illness in both US and European patients (F₃,₉₀₆ = 35.42, P < .0001). However, compared to the Europeans, patients in the United States had both more family history of most difficulties and notably earlier age at onset. Earlier age at onset was associated with a greater illness burden in the patient's offspring (t₅₆₈ = 4.1, P < .0001)., Conclusions: More parental and grandparental psychiatric illness was associated with an earlier age at onset of bipolar disorder, which is earlier in the United States compared with Europe and is strongly related to a poor long-term prognosis. This apparent polygenic contribution to early onset deserves further study and therapeutic attempts at ameliorating the transgenerational impact., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Objective: To evaluate lisdexamfetamine dimesylate (LDX) in the treatment of binge eating disorder (BED)., Method: Fifty participants with BED received LDX (20-70 mg/day) (n = 25) or placebo (n = 25) for up to 12 weeks in a single-center, randomized, double-blind, and flexible-dose trial. The primary outcome measure was binge eating (BE) days/week., Results: In the primary longitudinal analysis, compared with placebo, LDX was not associated with a significantly greater rate of reduction in BE days/week, as well as BE episodes/week, and scores on the Clinical Global Impression-Severity or Yale-Brown Obsessive-Compulsive Scale modified for binge eating scales. It was, however, associated with significantly decreased weight, body mass index, and fasting triglyceride level. In the secondary last observation carried forward analyses, LDX was associated with statistically significant reductions in BE days/week, BE episodes/week, weight, and BMI, as well as a statistically significant greater level of categorical response and global improvement. The mean (standard deviation) LDX daily dose at endpoint evaluation was 59.6 (14.9) mg. One participant discontinued LDX for a serious adverse cardiovascular event, which resolved fully., Conclusion: Lisdexamfetamine dimesylate may have clinical utility for BED but further studies of its efficacy, tolerability, and safety in this population are needed. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Objective: Given that a cohort effect is rarely mentioned as one of the possible contributors to the increased incidence of childhood-onset bipolar disorder in the United States, we reexamined evidence for the phenomenon within our outpatient Bipolar Collaborative Network., Methods: 968 outpatients (mean age, 41 years) with DSM bipolar disorder from 1995 to 2002 from 4 sites in the United States and 3 in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic, illness, and family history information on a patient questionnaire. Family history of bipolar disorder, depression, suicide attempt, alcohol abuse, substance abuse, and "other" illness was collected for each parent and the 4 grandparents. Age at onset and family history of illness burden were then assessed as a function of the age of the patient at network entry., Results: Data for patients aged 35 years or older (n = 613) were included in the first analysis. Compared to older patients, those who were younger when they entered the network had an earlier age at onset of their bipolar disorder (r = 0.33, P < .001). Similarly, the youngest patients at entry (representing the most recent cohorts) had parents and grandparents with more psychiatric illness than patients born in earlier cohorts (n = 968)., Conclusions: These preliminary data, taken with the substantial literature, suggest a cohort effect for earlier age at onset of bipolar disorder and greater burden of psychiatric disorders in 2 generations of direct progenitors of our patients. The resulting likely increase in severity of bipolar illness in future generations based on this earlier age at onset and increased familial loading, particularly in the United States, deserves focused clinical and public health attention and attempts at amelioration., (© Copyright 2016 Physicians Postgraduate Press, Inc.)

Introduction: Obesity and mood disorders co-occur more often than expected by chance alone. As no randomized, controlled pharmacotherapy trials have been conducted in obese patients with an active mood disorder, it is unclear how to use medication to treat this patient group., Areas Covered: We briefly overview the relationship between obesity and mood disorders; the effects of psychotropic medications commonly used in mood disorders on body weight; the psychiatric effects of available anti-obesity medications; and highlight the few treatment studies of medications in obese patients with mood disorders or depressive symptoms. As binge eating and psychotropic-induced weight gain are common correlates of obese patients with mood disorders, we also provide brief overviews of the pharmacotherapy of these conditions., Expert Opinion: When treating a patient with a mood disorder and obesity, both conditions need to be a focus of clinical attention. Psychotropic medications that have minimal weight gain effects should be used if possible. Weight-loss agents can probably be used in some mood disorder patients, but must be done so cautiously and with a full understanding of their potential psychiatric effects and interactions with psychotropic medications. Knowledge of the pharmacotherapy of binge eating and psychotropic-induced weight gain is also crucial.

Objective: To report use and treatment success rates of medications for bipolar disorder as a function of patients' clinical characteristics., Method: Outpatients with bipolar illness diagnosed by SCID were rated by research assistants on the NIMH-LCM and those who had an good response for at least 6months (much or very much improved on the CGI-BP) were considered responders (treatment "success"). Clinical characteristics associated with treatment response in the literature were examined for how often a drug was in a successful regimen when a given characteristic was either present or absent., Results: Lithium was less successful in those with histories of rapid cycling, substance abuse, or (surprisingly) a positive parental history of mood disorders. Valproate was less successful in those with ≥20 prior episodes. Lamotrigine (LTG) was less successful in those with a parental history of mood disorders or in BP-I compared to BP-II disorder. Antidepressants (ADs) had low success rates, especially in those with a history of anxiety disorders. Benzodiazepines had low success rates in those with child abuse, substance use, or ≥20 episodes. Atypical antipsychotics were less successful in the presence of rapid cycling, ≥20 prior episodes, or a greater number of poor prognosis factors., Conclusion: Success rates reflect medications used in combination with an average of two other drugs during naturalistic treatment and thus should be considered exploratory. However, the low long-term success rates of drugs (even when used in combination with others) that occurred in the presence of many very common clinical characteristics of bipolar illness speak to the need for the development of alternative treatment strategies., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Evidence suggests that patients with bipolar disorder from the United States have an earlier age of onset and a more difficult course of illness than those from Germany and the Netherlands. These characteristics were related to a greater family burden of psychiatric illness and the experience of more psychosocial adversity in childhood. We hypothesized that this greater illness burden would extend to the offspring of the US patients., Methods: 968 outpatients (average age 41) with bipolar illness gave informed consent for participation in a treatment outcome network and filled out a detailed questionnaire about their illness and family history of illness, including whether their offspring had a diagnosis of depression, bipolar disorder, alcohol or substance abuse, suicide attempt or "other" illness. Of those with children, 356 were from the US and 132 were from Europe., Results: Compared to the Europeans, offspring of patients from the US had significantly (p<0.001) more depression, bipolar disorder, drug abuse, and "other" illnesses. The number of illnesses in the offspring was related to the bipolar parent being from the US, having had childhood adversity, more than 20 prior episodes, and more parental psychiatric illness., Conclusions: While the findings are limited by their basis on self report, the distribution of the percentages in the US offspring are similar to those of Axelson et al. (2015) who used direct interviews. The higher burden of illness in the offspring and their in direct progenitors from the US compared to Europe warrant new attempts at better treatment and prevention., (Copyright © 2016 The Authors. Published by Elsevier B.V. All rights reserved.)

We performed a qualitative review of treatment studies of binge eating disorder (BED), focusing on randomized clinical trials (RCTs). Limited effectiveness has been demonstrated for self-help strategies, and substantial effectiveness has been shown for cognitive behavioral therapy (CBT) and interpersonal therapy (IPT). CBT and IPT may each be more effective than behavior weight loss therapy (BWLT) for reducing binge eating over the long term. The stimulant pro-drug lisdexamfetamine dimesylate (LDX) is the only drug approved by the FDA for the treatment of BED in adults based on 2 pivotal RCTs. Topiramate also decreases binge eating behavior, but its use is limited by its adverse event profile. Antidepressants may be modestly effective over the short term for reducing binge eating behavior and comorbid depressive symptoms, but are not associated with clinically significant weight loss. A RCT presented in abstract form suggests that intranasal naloxone may decrease time spent binge eating. There is no RCT of obesity surgery in BED, but many patients with BED seek and receive such surgery. While some studies suggest patients with BED and obesity do just as well as patients with obesity alone, other studies suggest that patients with BED have more post-operative complications, less weight loss, and more weight regain. This evidence suggests that patients with BED would benefit from receiving highly individualized treatment.

Objective: We previously found that compared with Europe more parents of the USA patients were positive for a mood disorder, and that this was associated with early onset bipolar disorder. Here we examine family history of psychiatric illness in more detail across several generations., Methods: A total of 968 outpatients (average age 41) with bipolar disorder from four sites in the USA and three in the Netherlands and Germany (abbreviated as Europe) gave informed consent and provided detailed demographic and family history information on a patient questionnaire. Family history of psychiatric illness (bipolar disorder, unipolar depression, suicide attempt, alcohol abuse, substance abuse, and other illness) was collected for each parent, four grandparents, siblings, and children., Results: Parents of the probands with bipolar disorder from the USA compared with Europe had a significantly higher incidence of both unipolar and bipolar mood disorders, as well as each of the other psychiatric conditions listed above. With a few exceptions, this burden of psychiatric disorders was also significantly greater in the grandparents, siblings, and children of the USA versus European patients., Conclusion: The increased complexity of psychiatric illness and its occurrence over several generations in the families of patients with bipolar disorder from the USA versus Europe could be contributing to the higher incidence of childhood onsets and greater virulence of illness in the USA compared with Europe. These data are convergent with others suggesting increased both genetic and environmental risk in the USA, but require replication in epidemiologically-derived populations with data based on interviews of the family members.

The authors assessed how family history loading affected the course of illness in patients from the United States. A total of 676 outpatients with bipolar disorder from the United States rated their illness and provided a parental and grandparental history of mood disorder, substance abuse, and other clinical conditions. A positive family history for each illness was associated with almost all of the seven poor prognosis factors established in the study (abuse in childhood, early onset, anxiety and substance abuse comorbidity, rapid cycling, multiple episodes, and worsening of severity or frequency of episodes). Family history for psychiatric difficulties in parents and grandparents was associated with a more complex and difficult course of bipolar illness.

This study evaluated the efficacy, tolerability, and safety of armodafinil in the treatment of binge eating disorder (BED). Sixty participants with BED were randomized to receive armodafinil (150-250 mg/day) (N = 30) or placebo (N = 30) in a 10-week, prospective, parallel-group, double-blind, flexible-dose, single-center trial. In the primary longitudinal analysis, armodafinil and placebo produced similar rates of improvement in binge eating day frequency (the primary outcome measure); however, armodafinil was associated with a statistically significantly higher rate of decrease in binge eating episode frequency. In the secondary baseline-to-endpoint analyses, armodafinil was associated with statistically significant reductions in obsessive-compulsive features of binge eating and BMI. The mean (SD) armodafinil daily dose at endpoint evaluation was 216.7 (43.9) mg. There were no serious adverse events, although one armodafinil recipient developed markedly increased blood pressure that resolved upon drug discontinuation. The small sample size may have limited the detection of important drug-placebo differences. As some of the observed effect sizes appeared clinically meaningful, larger studies of armodafinil in the treatment of BED are warranted.

Psychopharmacologic treatment is playing a greater role in the management of patients with eating disorders. In this paper, we review randomized, placebo-controlled trials (RCTs) conducted in anorexia nervosa (AN), bulimia nervosa (BN), binge eating disorder (BED), and other eating disorders over the past 3 years. Fluoxetine remains the only medication approved for an eating disorder, that being BN. RCTs of antipsychotics in AN have had mixed results; the only agent with some evidence of efficacy is olanzapine. One study suggests dronabinol may induce weight gain in AN. Preliminary studies suggest lack of efficacy of alprazolam, dehydroepiandrosterone, or physiologic estrogen replacement in AN; erythromycin in BN; and the opioid antagonist ALKS-33 in BED. In BED with obesity or overweight, bupropion may cause mild weight loss without seizures, and chromium may improve glucose regulation. Also in BED, three RCTs suggest the stimulant prodrug lisdexamfetamine may reduce binge eating episodes, and another RCT suggests intranasal naloxone may decrease time spent binge eating. There remains a disconnection between the size of eating disorders as a public health problem and the lack of pharmacotherapy research of these conditions.

Objectives: Physical or sexual abuse in childhood is known to have an adverse effect on the course of bipolar disorder, but the impact of verbal abuse has not been well elucidated., Methods: We examined the occurrence and frequency (never to frequently) of each type of abuse in childhood in 634 US adult outpatients (average age 40 years). Patients gave informed consent and provided information about their age of onset and course of illness prior to study entry., Results: Verbal abuse alone occurred in 24% of the patients. Similar to a history of physical or sexual abuse, a history of verbal abuse was related to an earlier age of onset of bipolar disorder and other poor prognosis characteristics, including anxiety and substance abuse comorbidity, rapid cycling, and a deteriorating illness course as reflected in ratings of increasing frequency or severity of mania and depression., Conclusions: A lasting adverse impact of the experience of verbal abuse in childhood is suggested by its relationship to an earlier age of onset of bipolar disorder, other poor prognosis factors, and a deteriorating course of illness. Verbal abuse is a common confound in comparison groups defined by a lack of physical or sexual abuse. Ameliorating the impact of verbal abuse on the unfolding course of bipolar disorder appears to be an important target of therapeutics and worthy of attempts at primary and secondary prophylaxis. Family-based treatments that focus on psychoeducation, enhancing intra-family communication, and coping skills may be particularly helpful., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: This phase 3 trial evaluated the efficacy, safety, and tolerability of low- and high-dose cariprazine in patients meeting DSM-IV-TR criteria for acute manic or mixed episodes associated with bipolar I disorder., Method: This multicenter, randomized, double-blind, placebo-controlled, parallel-group, fixed/flexible-dose study was conducted from February 2010 to December 2011. Patients were randomly assigned to placebo, cariprazine 3-6 mg/d, or cariprazine 6-12 mg/d for 3 weeks of double-blind treatment. Primary and secondary efficacy parameters were change from baseline to week 3 in Young Mania Rating Scale (YMRS) total score and Clinical Global Impressions-Severity of Illness (CGI-S) score, respectively. Post hoc analysis examined change from baseline to week 3 in YMRS single items., Results: A total of 497 patients were randomized; 74% completed the study. The least squares mean difference (LSMD) for change from baseline to week 3 in YMRS total score was statistically significant in favor of both cariprazine groups versus placebo (LSMD [95% CI]: 3-6 mg/d, -6.1 [-8.4 to -3.8]; 6-12 mg/d, -5.9 [-8.2, -3.6]; P < .001 [both]). Both cariprazine treatment groups showed statistically significant superiority to placebo on all 11 YMRS single items (all comparisons, P < .05). Change from baseline in CGI-S scores was statistically significantly greater in both cariprazine groups compared with placebo (LSMD [95% CI]: 3-6 mg/d, -0.6 [-0.9 to -0.4]; 6-12 mg/d, -0.6 [-0.9 to -0.3]; P < .001 [both]). The most common (≥ 5% and twice the rate of placebo) treatment-related adverse events for cariprazine were akathisia (both groups) and nausea, constipation, and tremor (6-12 mg/d only)., Conclusions: Results of this study demonstrated that both low- and high-dose cariprazine were more effective than placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. Cariprazine was generally well tolerated, although the incidence of akathisia was greater with cariprazine than with placebo., Trial Registration: ClinicalTrials.gov identifier: NCT01058668., (© Copyright 2015 Physicians Postgraduate Press, Inc.)

This study evaluated the efficacy and tolerability of lisdexamfetamine (LDX) in the treatment of bipolar depression. Twenty-five outpatients with bipolar I or II disorder and syndromal depression despite at least 4 weeks of stable mood stabilizer and/or antipsychotic therapy were randomized to receive LDX (N=11) or placebo (N=14) in an 8-week, prospective, parallel-group, double-blind study. In the primary longitudinal analysis, LDX and placebo produced similar rates of improvement in depressive symptoms as assessed by the Montgomery-Asberg Depression Scale. However, LDX was associated with a statistically significantly greater rate of improvement in self-reported depressive symptoms and daytime sleepiness, and with greater reductions in fasting levels of low-density lipoprotein and total cholesterol. In the secondary baseline-to-endpoint analysis, LDX was associated with statistically significant improvements in self-reported measures of depression, daytime sleepiness, fatigue, and binge eating, as well as with improvements in fasting levels of triglycerides and low-density lipoprotein and total cholesterol. LDX was well tolerated and was not associated with any serious adverse events, but there was one case of suspected misuse. The small sample size (because of premature study termination by the funding sponsor) may have limited the detection of important drug-placebo differences. Larger studies on the use of psychostimulants for treatment of bipolar depression seem warranted.

Background: Medical illnesses are highly comorbid with bipolar disorder, but their relationship to illness characteristics has not been previously delineated., Methods: The incidence of 34 medical conditions and 6 poor prognosis factors (PPFs) was derived from answers to a questionnaire in over 900 outpatients with bipolar disorder who gave informed consent. The relationship of PPFs to the number of medical comorbidities was examined by Mann-Whitney U, Pearson r, and logistic regression., Results: When examined individually, each of the 6 PPFs associated with an adverse course of bipolar disorder was significantly related to the number of medical comorbidities patients had. When age, gender, and independence of their relationships to each other were controlled for via regression, 3 of the PPFs remained significant (anxiety disorder, childhood abuse, and age of onset), and having 20 or more prior episodes was a strong trend. The number of PPFs was correlated with the number of comorbidities, although the above 3 PPFs show a similar magnitude of relationship., Conclusion: A history of childhood adversity, early age of onset of bipolar disorder, and an anxiety comorbidity were independently related to the number of medical comorbidities that patients experienced as adults. While the nature and mechanisms of this linkage remain to be further explored, the findings indicate the need for greater attention to and treatment of these 3 PPFs in hopes of ameliorating both the adverse course of bipolar illness and the burden of medical comorbidities with which they are associated., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Physician-patient conversations were examined to identify barriers to effective discussions about binge eating disorder (BED) arising from discrepancies in how physicians and patients communicate about BED., Methods: Conversations between suspected or diagnosed BED patients (n = 38) and psychiatrists (n = 11) were recorded and the transcripts were reviewed for BED-related lexical terms using automated conversation analysis software. Researchers disambiguated multivalent terms and combined similar terms., Results: The results showed that psychiatrists evaluated some diagnostic criteria (e.g., the absence of compensatory behavior) but not others (e.g., eating more rapidly than normal), focused more on symptoms in relation to weight and generally discussed weight-related issues more often than did patients, and asked about the type of food consumed more often than the diagnostic criterion related to the quantity of food consumed. In contrast, patients used terminology that attempted to clarify the relationships between feelings, coping strategies, and compulsion to binge eat when discussing binge eating episodes., Conclusion: These findings suggest that educational materials promoting more effective physician-patient dialogues regarding eating behaviors in general, and BED specifically, may be beneficial. Conversations should highlight the BED diagnostic criteria, assessment of patients' emotions and sense of lack of control, and relationships between body weight and BED.

Objective: Many patients with bipolar disorder in the United States experience a deteriorating course of illness despite naturalistic treatment in the community. We examined a variety of factors associated with this pattern of illness progression., Method: From 1995 to 2002, we studied 634 adult outpatients with bipolar disorder (mean age of 40 years) emanating from 4 sites in the United States. Patients gave informed consent and completed a detailed questionnaire about demographic, vulnerability, and course-of-illness factors and indicated whether their illness had shown a pattern of increasing frequency or severity of manic or depressive episodes. Fifteen factors previously linked in the literature to a poor outcome were examined for their relationship to illness progression using Kruskal-Wallis test, followed by a 2-sample Wilcoxon rank sum (Mann-Whitney) test, χ(2), and logistical regression., Results: All of the putative poor prognosis factors occurred with a high incidence, and, with the exception of obesity, were significantly (P < .05) associated with illness progression. These factors included indicators of genetic and psychosocial risk and loss of social support, early onset, long delay to first treatment, anxiety and substance abuse comorbidity, rapid cycling in any year, and the occurrence of more than 20 prior episodes prior to entering the network. A greater number of factors were linearly associated with the likelihood of a progressively worsening course., Conclusions: Multiple genetic, psychosocial, and illness factors were associated with a deteriorating course of bipolar disorder from onset to study entry in adulthood. The identification of these factors provides important targets for earlier and more effective therapeutic intervention in the hope of achieving a more benign course of bipolar disorder.

Background: There is some controversy but growing evidence that childhood onset bipolar disorder may be more prevalent and run a more difficult course in the United States than some European countries., Methods: We update and synthesize course of illness data from more than 960 outpatients with bipolar disorder (average age 40) from 4 sites in the U.S. and 3 sites in Netherlands and Germany. After giving informed consent, patients reported on parental history, childhood and lifetime stressors, comorbidities, and illness characteristics., Results: Almost all aspects of bipolar disorder were more adverse in patients from the US compared with Europe, including a significantly higher prevalence of: bipolar disorder in one parent and a mood disorder in both parents; childhood verbal, physical, or sexual abuse; stressors in the year prior to illness onset and the last episode; childhood onsets of bipolar illness; delay to first treatment; anxiety disorder, substance abuse, and medical comorbidity; mood episodes and rapid cycling; and nonresponse to prospective naturalistic treatment., Limitations: Selection bias in the recruit of patients cannot be ruled out, but convergent data in the literature suggest that this does not account for the findings. Potential mechanisms for the early onset and more adverse course in the U.S. have not been adequately delineated and require further investigation., Conclusions: The data suggest the need for earlier and more effective long-term treatment intervention in an attempt to ameliorate this adverse course and its associated heavy burden of psychiatric and medical morbidity., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Among patients with bipolar disorder, treatment nonadherence can be triggered by lack of response or by medication-induced adverse effects. To track treatment response, clinicians can have patients complete daily life and mood charts to provide accurate information over time on patients' mood, adherence, side effects, and life events. Rating scales like the CGI-BP are also an option for assessing treatment response. In addition, clinicians should monitor patients for common side effects related to bipolar depression treatments, such as sedation and weight gain/metabolic abnormalities, which lead to increased medical problems and shortened life expectancy. By implementing specific interventions to address these effects, clinicians can help promote optimal outcomes for patients with bipolar disorder., (© Copyright 2014 Physicians Postgraduate Press, Inc.)