A double-blind, randomized, placebo-controlled plus open trial of adjunctive suvorexant for treatment-resistant insomnia in patients with bipolar disorder.

BACKGROUND: Sleep pattern alteration is a core feature of bipolar disorder (BD), often challenging to treat and affecting clinical outcomes. Suvorexant, a hypnotic agent that decreases wakefulness, has shown promising results in treating primary insomnia. To date, data on its use in BD are lacking. This study evaluated the efficacy and tolerability of adjunctive suvorexant for treatment-resistant insomnia in BD patients. METHODS: Thirty-six BD outpatients (19 BDI, 69.4% female, 48.9 [±15.2] years) were randomized for 1 week to double-blind suvorexant (10-20 mg/day) versus placebo. Then, all subjects who completed the randomized phase were offered open suvorexant for 3 months. Subjective total sleep time (sTST) and objective total sleep time (oTST) were assessed. RESULTS: During the randomized control trial (RCT) phase, an overall increase in the oTST emerged, which was statistically significant for the Cole-Kripke algorithm (p = 0.035). The comparison between the suvorexant and placebo groups was limited by significant differences between measurements at baseline. During the open phase, no significant improvement was detected relative to either sTST and oTST. No adverse events nor major intolerances were reported. DISCUSSION: Efficacy results are inconsistent. During the RCT phase, only a small increase in the objective oTST emerged, while during the open phase, no significant improvement was detected. While this is the first ever study of suvorexant in BD-related insomnia, the limitation of the small sample and the high rate of dropouts limits the generalizability of these findings. Larger studies are needed to assess suvorexant in treating BD-related insomnia.

Treatment of Refractory Bipolar Depression With Stereotactic Radiosurgery Targeting the Subgenual Cingulate Cortex.

Background The subgenual cingulate cortex (SGC) has been identified as a key structure within multiple neural circuits whose dysfunction is implicated in the neurobiology of depression. Deep brain stimulation in the SGC is thought to reduce and normalize local metabolism, causing normalization of circuit behavior and an improvement in depressive symptoms. We hypothesized that nonablative stereotactic radiosurgery (SRS) to the SGC would reduce local metabolism and reduce the severity of depression in patients with treatment-resistant bipolar depression. Methods Under the FDA's Humanitarian Device Exemption program, patients were screened for inclusion and exclusion criteria. Three volunteers meeting the criteria provided informed consent. Bilateral SGC targets were irradiated to a maximum dose of 75 Gy in one fraction. Subjects were followed for one year following the procedure with mood assessments (Hamilton Depression Rating Scale (HDRS), Clinical Global Impression-Improvement, Clinical Global Impression-Severity, and Young Mania Rating Scale), neurocognitive testing (Delis-Kaplan Executive Function System, Wechsler Adult Intelligence Scale III digit span, and California Verbal Learning Test II), and imaging. Further imaging was completed approximately two years after the procedure. Clinical improvement was defined as a ≥50% reduction in HDRS. Results Two of the three subjects showed clinical improvement in depressive symptoms during the follow-up period, while one subject showed no change in symptom severity. One of three subjects was hospitalized for the emergence of an episode of psychotic mania after discontinuing antipsychotic medications against medical advice but promptly recovered with the reinstitution of an antipsychotic. Sequential assessments did not reveal impairment in any cognitive domain assessed. For one of the three subjects, MRI imaging showed evidence of edema at 12 months post-SRS, which resolved at 22 months post-procedure. In a second of three patients, there was evidence of local edema at the target site at long-term follow-up. All imaging changes were asymptomatic. Conclusion Radiosurgical targeting of the SGC may be a noninvasive strategy for the reduction of severe depression in treatment-resistant bipolar disorder. Two out of three patients showed clinical improvement. While these results are promising, further study, including improvements in target selection and dosing considerations, is needed.

Ketogenic Diet Intervention on Metabolic and Psychiatric Health in Bipolar and Schizophrenia: A Pilot Trial.

The ketogenic diet (KD, also known as metabolic therapy) has been successful in the treatment of obesity, type 2 diabetes, and epilepsy. More recently, this treatment has shown promise in the treatment of psychiatric illness. We conducted a 4-month pilot study to investigate the effects of a KD on individuals with schizophrenia or bipolar disorder with existing metabolic abnormalities. Twenty-three participants were enrolled in a single-arm trial. Results showcased improvements in metabolic health, with no participants meeting metabolic syndrome criteria by study conclusion. Adherent individuals experienced significant reduction in weight (12 %), BMI (12 %), waist circumference (13 %), and visceral adipose tissue (36 %). Observed biomarker enhancements in this population include a 27 % decrease in HOMA-IR, and a 25 % drop in triglyceride levels. In psychiatric measurements, participants with schizophrenia showed a 32 % reduction in Brief Psychiatric Rating Scale scores. Overall Clinical Global Impression (CGI) severity improved by an average of 31 %, and the proportion of participants that started with elevated symptomatology improved at least 1-point on CGI (79 %). Psychiatric outcomes across the cohort encompassed increased life satisfaction (17 %) and enhanced sleep quality (19 %). This pilot trial underscores the potential advantages of adjunctive ketogenic dietary treatment in individuals grappling with serious mental illness.

Lithium plus antipsychotics or anticonvulsants for bipolar disorder: Comparing clinical response and metabolic changes.

OBJECTIVE: Patients with bipolar disorder treated with lithium often require additional antipsychotics or anticonvulsants. However, the comparative effectiveness and safety of these agents as add-on to lithium has not been studied. METHODS: This secondary analysis combined two similar 24-week trials on outpatients with bipolar disorder randomized to lithium (target serum level 0.4-0.6 mEq/L). Guideline-based adjunctive antipsychotics (Li+AP) and anticonvulsants (Li+AC) could be used if clinically indicated and was assessed at every study visit. Response was measured on the Clinical Global Impression scale and we performed adjusted mixed effects linear regression analyses. Analysis of variance tests compared metabolic measures including a binary diagnosis of metabolic syndrome before and after 24 weeks of treatment. RESULTS: Among 379 outpatients (57% female, mean age 38 years, mean Clinical Global Impression 4.4), users of Li+AP (N = 50, primarily quetiapine and aripiprazole) improved to a similar degree (mean Clinical Global Impression improvement = 1.6, standard deviation = 1.5) as those using lithium-only (i.e. without adjunctive antipsychotics or anticonvulsants, N = 149, mean Clinical Global Impression improvement = 1.7, standard deviation = 1.4) (p = 0.59). Users of Li+AC (N = 107, primarily lamotrigine and valproate, mean Clinical Global Impression improvement = 1.2, standard deviation = 1.3) and users of Li+AP+AC (N = 73, mean Clinical Global Impression improvement = 1.1, standard deviation = 1.3) showed worse response compared to lithium-only users (all p < 0.01). When comparing Li+AP to Li+AC, users of Li+AP improved slightly better on general (p = 0.05) and manic symptoms (p = 0.01), but showed a worse development of glucose, triglycerides, and metabolic syndrome. CONCLUSION: Despite treatment-by-indication confounding, these findings are relevant for real-world treatment settings and emphasize the need for randomized trials on this clinically important topic.

Staging models applied in a sample of patients with bipolar disorder: Results from a retrospective cohort study.

BACKGROUND: Bipolar Disorder (BD) is a life-long illness with compelling evidence of progression. Although different staging models have been proposed to evaluate its course, clinical data remain limited. The aim of the present study was to retrospectively assess applicability of available staging approaches and their pattern of progression in a sample of bipolar patients. METHODS: In a naturalistic sample of 100 BD patients, retrospective assessment of clinical stages was performed at four time points over 10 years, according to four staging models. Staging progression with potential associations between stages and unfavourable illness characteristics were analyzed. RESULTS: A pattern of stage worsening emerged for each model, with a significant increase at every time point. Greater stage increases emerged in patients with lower educational level, age at first elevated episode ≤35 years, duration of illness ≤25 years, and duration of untreated illness ≤5 years. Lower stage values were associated with BD II, no psychiatric hospitalization, depressive onset and predominant polarity, ≤three lifetime episodes, age at first mood stabilizer >40 years, duration of illness ≤25 years, and engaged/employed status. Higher stage values were associated with lower age at first elevated episode and mood stabilizing treatment instead. LIMITATIONS: Naturalistic and retrospective design, recruitment at a 2nd level specialistic clinic. CONCLUSIONS: Reported findings support the progressive nature of BD and the application of staging models for early intervention, suggesting a conceptualization of a standardized approach to better characterize patients, predict their clinical course, and deliver tailored treatment options.

Expert consensus recommendations on the use of randomized clinical trials for drug approval in psychiatry- comparing trial designs.

The use of randomized clinical trials, in particular placebo-controlled trials, for drug approval, is the subject of long-standing debate in the scientific community and beyond. This study offers consensus recommendations from clinical and academic experts to guide the selection of clinical trial design in psychiatry. Forty-one highly cited clinical psychiatrists and/or researchers participated in a Delphi survey. Consensus statements were developed based on the findings of a published, peer-reviewed systematic review. Participants evaluated statements in two survey rounds, following the Delphi method. The expert panel achieved consensus on 7 of 21 recommendations regarding the use of randomized clinical trials. The endorsed recommendations were: (i) Results from placebo-controlled trials are the most reliable and (ii) are necessary despite the growing placebo-effect; (iii) it is ethical to enroll patients in placebo-arms when established treatment is available, if there is no evidence of increased health risk; (iv) There is a need to approve new drugs with the same efficacy as existing treatments, but with different side-effect profiles; (v) Non-inferiority trials incur an increased risk of approving ineffective medications; (vi) The risk of approving an ineffective drug justifies trial designs that incur higher costs, and (vii) superiority trials incur the risk of rejecting potentially efficacious treatments. The endorsed recommendations inform the choice of trial-design appropriate for approval of psychopharmacological drugs. The recommendations strongly support the use of randomized clinical trials in general, and the use of placebo-controlled trials in particular.

Childhood trauma and treatment outcomes during mood-stabilising treatment with lithium or quetiapine among outpatients with bipolar disorder.

BACKGROUND: Childhood trauma affects the course of mood disorders. Researchers are now considering childhood trauma as an influential factor in the treatment of mood disorders. However, the role of childhood trauma in the treatment of bipolar disorder remains understudied. METHODS: The effect of childhood trauma on treatment outcomes was evaluated among participants randomised to treatment with lithium or quetiapine in the Clinical and Health Outcomes Initiatives in Comparative Effectiveness for Bipolar Disorder (Bipolar CHOICE) study by clinician assessment. Mixed effects linear regression models were used to analyse rates of improvement in symptom severity (assessed with the Bipolar Inventory of Symptoms Scale and the Clinical Global Impression Scale for Bipolar Disorder) and functional impairment (assessed with the Longitudinal Interval Follow-up Evaluation-Range of Impaired Functioning Tool). RESULTS: A history of any childhood trauma was reported by 52.7% of the sample (N = 476). Although participants with a history of any childhood trauma presented with greater symptom severity and functional impairment at most study visits, participants with and without a history of any childhood trauma showed similar rates of improvement in symptom severity and functional impairment over the 24 weeks of treatment. CONCLUSION: This is the first study to explore the association between childhood trauma and treatment outcomes during treatment with lithium or quetiapine in the context of a randomised trial. In Bipolar CHOICE, a history of childhood trauma did not inhibit improvement in symptom severity or functional impairment. Nevertheless, these findings need replication across different settings.

Cardiometabolic risk markers during mood-stabilizing treatment: Correlation with drug-specific effects, depressive symptoms and treatment response.

BACKGROUND: Patients with bipolar disorder have higher rates of cardiometabolic comorbidities and mortality. Although guidelines emphasize the importance of cardiovascular monitoring, few studies characterized the cardiometabolic risk profile during treatment and their relation to symptomatology and treatment response. METHODS: We analyzed data from two similar 24-weeks comparative effectiveness trials, with a combined sample of 770 participants randomized to two different lithium doses, quetiapine (300 mg/day), or standard treatment without lithium. Glucose, lipids and vital signs were measured before and after 24 weeks of treatment. We calculated several cardiovascular risk scores, assessed baseline correlations and compared the four treatment arms via multiple linear regression models. RESULTS: Higher cholesterol and LDL levels were associated with greater depression severity, showing differential correlations to specific symptoms, particularly agitation, low energy and suicidality. Those randomized to quetiapine showed a significant worsening of cardiometabolic markers during the 24-week trial. Neither baseline nor change in lipid levels correlated with differential treatment response. LIMITATIONS: Study duration was short from the perspective of cardiometabolic risk markers, and all treatment arms included patients taking adjunct antipsychotics. The trials compared quetiapine to lithium, but not to other medications known to affect similar risk factors. CONCLUSIONS: Treatment with 300 mg/day quetiapine for 24 weeks, representing a short and common dose course, resulted in increased cardiometabolic risk markers, emphasizing the importance of monitoring during mood-stabilizing treatment. The symptom-specific associations are in line with previous studies in unipolar depression, suggesting a cardiometabolic-depression link that needs to be further studied in bipolar depression.

Response and remission rates during 24 weeks of mood-stabilizing treatment for bipolar depression depending on early non-response.

BACKGROUND: We aimed to study the probability of bipolar depression response at 24 weeks given initial non-response. METHODS: We combined two multi-site, 24-week trials including similar populations following the same evidence-based guidelines randomizing patients to lithium or quetiapine. Additional mood-stabilizing treatment was possible if clinically indicated. We report cumulative proportions of response (>50% improvement in MADRS) and remission (MADRS<10). RESULTS: We included 592 participants with bipolar depression (mean 39 years, 59% female, mean MADRS 25). Among 393 (66%) participants without response after 2 weeks, 46% responded by 24 weeks; for 291 (49%) without response at 4 weeks, 40% responded and 33% remitted by 24 weeks; for 222 (38%) without a response at 6 weeks, 36% responded and 29% remitted by 24 weeks; for 185 (31%) without a response at 8 weeks, 29% responded and 24% remitted by 24 weeks. Rates were similar for participants who had started an additional mood-stabilizing drug during the first 6 or 8 weeks. CONCLUSIONS: Among patients with bipolar depression and non-response after 6 weeks treatment, representing an adequate bipolar depression trial, only one-third responded by 24 weeks. These results highlight the need for better treatment alternatives for non-responders to evidence-based treatments for bipolar depression.

Expanding bipolar outreach during college.

OBJECTIVES: To assess feasibility and clinical significance of tracking mania and depression in community college students before and after early identification and intervention. METHODS: From Affective Illness to Recovery: STudent Access to Rapid Treatment (FAIRSTART) is an early intervention program to provide diagnostic therapeutic consultation, short-term care, and community ongoing care referral for 18-28 year-old outpatient community college students (mean age 22.9±4.0 years) experiencing manic symptoms. Over three years, 54 FAIRSTART participants (70% with DSM-IV bipolar I/II/not otherwise specified disorder, BDI/II/NOS) were assessed with the Systematic Treatment Enhancement Program for BD (STEP-BD) Affective Disorders Evaluation (ADE) and followed (range: one-time consult to 4.3±3.6 visits over 3-6 month follow-up) with the STEP-BD Clinical Monitoring Form. RESULTS: 38/54 patients (70%) had BDI/II/NOS, 11 unipolar depression (20%), 1 psychosis spectrum disorder (2%), 2 dysthymia/persistent depressive disorder (4%), and 2 incomplete intake with mood disorder diagnosis undetermined (4%). Average illness duration was 9.1±5.3 years. Among the 38 BD I/II/NOS patients, depression (SUM-D, t(30)=6.5; p<0.001) and mania (SUM-M, t(30)=4.7; p<0.001) scores improved significantly from baseline to last visit, with 17 (44.7%) reporting recovery by time transitioned from FAIRSTART to community care (after 4.3±3.6 visits). CONCLUSIONS: Short-term, early intervention in community college students with mood symptoms appeared feasible and yielded significant improvements in depression and mania scores. However, additional studies, with longer-term follow-ups, larger sample sizes, and comparison to current care standards, are needed to determine this early intervention program's impact on trajectory of mania symptoms in transitional age young adult populations.

Antidepressants in bipolar disorder: Analysis of correlates overall, and in BD-I and BD-II subsamples.

BACKGROUND: Clinical therapeutic approaches to Bipolar Disorders (BDs) include diverse pharmacotherapies, targeting different symptomatic BD presentations. To date, guidelines about pharmacological treatment of BDs have focused on short-term treatment of mood episodes, at the expense of longer-term treatment, especially for (the most common) predominantly depressive polarity patients. METHODS: A database of BD-I and BD-II patients was collected between 2013 and 2019 at the University Psychiatric Clinic of Ospedale Policlinico and Ospedale Luigi Sacco of Milan. Only patients in euthymic phases (no current mood episode) were included in the study. We then analyzed socio-demographic and clinical characteristic overall and in the subgroup BD-I and BD-II, comparing patients taking vs. not taking ADs. RESULTS: Our results showed that approximately 1/3 of BD patients between acute episodes took ADs, also among patients from the subgroup with BD-I, especially those first presenting with a depressive episodes, and those with a most recent depressive (as opposed to elevated, irritable, or mixed) polarity episode. LIMITATIONS: Although patients included in our study were primarily in follow up for Bipolar Disorder, use of ADs could be explained by other comorbidities, such as Anxiety or Eating Disorders. CONCLUSIONS: These data shed light on how managing depressive symptoms is a very important aspect of treating BDs, highlighting the need for wider and more specific studies on the use of ADs in BDs.

Illness stage and predominant polarity in bipolar disorder: Correlation with burden of illness and moderation of treatment outcome.

Bipolar disorder often follows a set progression best described in stages where advanced stages are associated with poorer outcomes. Bipolar disorder is also often characterized by a predominance of episode polarity, where some individuals experience more depressive episodes (termed predominant depressive polarity) while others experience more hypo/manic episodes (termed predominant hypo/manic polarity). We examined the associations between staging and predominant polarity with measures of illness burden and treatment outcome utilizing data from a six-month comparative effectiveness trial of lithium and quetiapine in bipolar disorder (Bipolar CHOICE). We used number of self-reported lifetime mood (depressive and hypo/manic) episodes as a proxy for staging and ratio of depressive to manic episodes to define predominant polarity. Polarity and staging were correlated with several measures of burden of illness. Childhood abuse was correlated with more lifetime mood episodes, while more depressive episodes and depressive polarity were correlated with more anxiety disorder comorbidity. Depressive polarity was also correlated with more past trials of psychotropics, particularly antidepressants. However, neither staging nor predominant polarity moderated the randomized treatment effect of lithium vs. quetiapine. Number of depressive episodes in the past year was identified as a potential predictor of overall worse treatment outcome, regardless of medication condition. In conclusion, though staging and predominant episode polarity correlated with several measures of illness burden, they were not associated with differential treatment outcomes. This could be because many of our patients presented for treatment at advanced stages of illness and further highlights the need for early intervention in bipolar disorder.

Has Bipolar Disorder become a predominantly female gender related condition? Analysis of recently published large sample studies.

Bipolar Disorders (BD) are disabling and severe psychiatric disorders, commonly perceived as equally affecting both men and women. The prevalence of BD in the general population has been growing over the last decade, however, few epidemiological studies are available regarding BD gender distribution, leaving unanswered the question whether the often reported increment of BD diagnosis could be gender specific. In fact, BD in female patients can often be misdiagnosed as MDD, leaving such women non correctly treated for longer times than their male counterparts. From this perspective, we searched literature for large sample (> 1000 subjects) studies published in the last decade (2010 onward) on BD patients. We included ten large sample studies that reported the gender distribution of their samples, and we therefore analysed them. Our results show a higher preponderance of female patients in every sample and sub-sample of BDI and BDII, supporting our hypothesis of an increase in BD diagnosis in females. BD in women presents with higher rates of rapid cycling, depressive polarity and suicide attempts, characteristics of non inferior severity compared to males; prompt recognition and adequate treatment of BD is therefore crucial to reduce risks and improve quality of life of affected women. In this regard, our results could lead the way for national or international epidemiological studies with the aim of more accurately assessing gender-specific prevalence of BD.

Adjunctive antidepressant treatment among 763 outpatients with bipolar disorder: Findings from the Bipolar CHOICE and LiTMUS trials.

BACKGROUND: Adjunctive antidepressants are frequently used for bipolar depression but their clinical efficacy has been studied in few trials and little is known about how co-occurring manic symptoms affect treatment response. METHODS: Bipolar Clinical Health Outcomes Initiative in Comparative Effectiveness (N = 482) and Lithium Treatment Moderate-Dose Use Study (N = 281) were similar comparative effectiveness trials on outpatients with bipolar disorder comparing four different randomized treatment arms with adjunctive personalized guideline-based treatment for 24 weeks. Adjunctive antidepressant treatment could be used if clinically indicated and was assessed at every study visit. Adjusted mixed effects linear regression analyses compared users of antidepressants to nonusers overall and in different subcohorts. RESULTS: Of the 763 patients, 282 (37.0%) used antidepressant drugs during the study. Antidepressant users had less improvement compared to nonusers on the Clinical Global Impression Scale for Bipolar Disorder and on measures of depression. This was particularly true among patients with co-occurring manic symptoms. Exclusion of individuals begun on antidepressants late in the study (potentially due to overall worse response) resulted in no differences between users and nonusers. We found no differences in treatment effects on mania scales. CONCLUSIONS: In this large cohort of outpatients with bipolar disorder, clinically indicated and guideline-based adjunctive antidepressant treatment was not associated with lower depressive symptoms or higher mania symptoms. The treatment-by-indication confounding due to the nonrandomized design of the trials complicates causal interpretations, but no analyses indicated better treatment effects of adjunctive antidepressants.

Familial severe psychiatric history in bipolar disorder and correlation with disease severity and treatment response.

BACKGROUND: Bipolar disorder is a heritable disorder, and we aimed to assess the impact of family history of mental disorders in first-degree relatives on the severity and course of bipolar disorder. METHODS: The Bipolar CHOICE (lithium versus quetiapine) and LiTMUS (optimized treatment with versus without lithium) comparative effectiveness studies were similar trials among bipolar disorder outpatients studying four different randomized treatment arms for 24 weeks. Patients self-reported on six severe mental disorders among first-degree relatives. We performed ANOVA and linear regression regarding disease severity measures, sociodemographic and cardiometabolic markers and mixed effects linear regression to evaluate treatment response. RESULTS: Among 757 patients, 644 (85.1%) reported at least one first-degree relative with a severe mental disorder (mean=2.8; standard deviation=2.2; range=0-13). Depression (67.1%), alcohol abuse (51.0%) and bipolar disorder (47.0%) were the most frequently reported disorders. Familial psychiatric history correlated with several disease severity measures (hospitalizations, suicide attempts, and earlier onset) and sociodemographic markers (lower education and household income) but not with cardiometabolic markers (e.g. cholesterol or waist circumference) or cardiovascular risk scores, e.g. the Framingham risk score. Patients with familial psychiatric history tended to require more psychopharmacological treatment (p=0.054) but responded similarly (all p>0.1) to all four treatment arms. CONCLUSIONS: Our findings indicate that familial psychiatric history is common among outpatients with bipolar disorder and correlates with disease severity and sociodemographic measures. Patients with a greater familial psychiatric load required more intense treatment but achieved similar treatment responses compared to patients without familial psychiatric history.

A Modified Delphi Consensus Study of the Screening, Diagnosis, and Treatment of Tardive Dyskinesia.

OBJECTIVE: A nominal group process followed by a modified Delphi method was used to survey expert opinions on best practices for tardive dyskinesia (TD) screening, diagnosis, and treatment and to identify areas lacking in clinical evidence. PARTICIPANTS: A steering committee of 11 TD experts met in nominal group format to prioritize questions to be addressed and identify core bibliographic materials and criteria for survey panelists. Of 60 invited experts, 29 (23 psychiatrists and 6 neurologists) agreed to participate. EVIDENCE: A targeted literature search of PubMed (search term: tardive dyskinesia) and recommendations of the steering committee were used to generate core bibliographic material. Inclusion criteria were as follows: (1) review articles, meta-analyses, guidelines, or clinical trials; (2) publication in English between 2007 and 2017; (3) > 3 pages in length; and (4) publication in key clinical journals with impact factors ≥ 2.0. Of 29 references that met these criteria, 18 achieved a score ≥ 5 (calculated as the number of steering committee votes multiplied by journal impact factor and number of citations divided by years since publication) and were included. CONSENSUS PROCESS: Two survey rounds were conducted anonymously through electronic media from November 2017 to January 2018; responses were collected, collated, and analyzed. Respondent agreement was defined a priori as unanimous (100%), consensus (75%-99%), or majority (50%-74%). For questions using a 5-point Likert scale, agreement was based on percentage of respondents choosing ≥ 4 ("agree completely" or "agree"). Round 1 survey included questions on TD screening, diagnosis, and treatment. Round 2 questions were refined per panelist feedback and excluded Round 1 questions with < 25% agreement and > 75% agreement (unless feedback suggested further investigation). CONCLUSIONS: Consensus was reached that (1) a brief, clinical assessment for TD should be performed at every clinical encounter in patients taking antipsychotics; (2) even mild movements in 1 body area may represent possible TD; (3) management requires an overall evaluation of treatment, including reassessment of antipsychotics and anticholinergics as well as consideration of vesicular monoamine transporter 2 (VMAT2) inhibitors; and (4) informed discussions with patients/caregivers are essential.

Differential core pharmacotherapy in bipolar I versus bipolar II disorder and European versus American patients not in a syndromal episode.

Assess bipolar disorder subtype and treatment location effects on bipolar disorder core pharmacotherapy. Outpatients not in a syndromal episode referred to the University of Milan and Stanford University Bipolar Disorder Clinics were assessed with SCID for the fourth Edition of the Diagnostic and Statistical Manual of Mood Disorders, and the Systematic Treatment Enhancement Program for Bipolar Disorder Affective Disorders Evaluation, respectively. Prevalence and clinical correlates of antidepressant, antipsychotic, and mood stabilizer use, in aggregate and individually, were compared in bipolar I (BDI) versus II (BDII) patients in Milan/Stanford and in Milan versus Stanford patients, stratified by subtype. Milan/Stanford pooled BDI versus BDII patients significantly more often took antipsychotic (69.8 versus 44.8%), mood stabilizers (68.6 versus 57.7%), and valproate (40.1 versus 17.5%), and less often took antidepressants (23.1 versus 55.6%) and lamotrigine (9.9 versus 25.2%). Milan versus Stanford patients (stratified by bipolar disorder subtype) significantly more often took antipsychotic (BDI and BDII), antidepressants (BDII), and valproate (BDII), and less often took lamotrigine (BDI). Research regarding bipolar disorder core pharmacotherapy relationships with bipolar subtype and treatment location is warranted to enhance clinical management.

Clinical features and patterns of psychopharmacological prescription in bipolar patients with vs without anxiety disorders at onset.

AIM: Up to just over half of bipolar disorder (BD) patients report at least one-lifetime anxiety disorder (AD). In some, anxiety represents the earliest psychiatric manifestation, prior to any mood episode. We sought to investigate prevalence of AD subtypes as first psychiatric manifestations and AD's relations with duration of untreated illness (DUI) and treatment among BD outpatients. METHODS: We recruited patients referred to the Centre for the Treatment of Depressive Disorders in Milan, diagnosed with BD-I, BD-II, BD not otherwise specified (BD-NOS) and cyclothymia according to Diagnostic and Statistical Manual fourth edition-text revision criteria. Several clinical characteristics were assessed through retrospective chart review and/or direct patient interviews. Based on presence/absence of an AD at psychiatric onset, eligible subjects were stratified into two groups (A+ and A-) and clinical features were compared between these groups and between BD subtypes. RESULTS: We analysed 260 BD patients (77 BD-I, 122 BD-II, 45 BD-NOS and 16 cyclothymia). An AD was the first psychiatric manifestation in 69 patients (26.5%). BD-II and BD-NOS more frequently had an AD at psychiatric onset, with panic disorder being the most common AD. Among A+ vs A-, age at BD onset was younger, duration of untreated BD illness (DUI) was longer, and a mood stabilizer/antipsychotic was less often prescribed at psychiatric onset. CONCLUSIONS: Considering BD in its longitudinal course, over one in four BD patients presenting with an AD at psychiatric onset belatedly access adequate treatment, with subsequent prolonged DUI and prospective worse outcome compared to patients with a mood episode at psychiatric onset.

The impact of binge eating behavior on lithium- and quetiapine-associated changes in body weight, body mass index, and waist circumference during 6 months of treatment: Findings from the bipolar CHOICE study.

BACKGROUND: Lithium and quetiapine can cause weight gain, but their comparative longer term anthropometric effects are unknown, as are the potential moderating effects of baseline binge-eating (BE) behavior. METHODS: We assessed 6 month changes in body weight, body mass index (BMI) and waist circumference in 482 adults with DSM-IV bipolar disorders who participated in a comparative effectiveness study of lithium and quetiapine with evidence-based adjunctive treatment (Bipolar CHOICE). Anthropometric measurements were obtained at baseline, and at 2, 4, 6, 8, 12, 16, 20, and 24 weeks. BE behavior was defined as affirmative responses to MINI items M1 and M3 at baseline. Data were analyzed using a mixed model repeated measures approach, adjusted for baseline values of dependent measures. RESULTS: On average, body weight and BMI increased over 6 months with lithium and quetiapine. However, those treated with quetiapine experienced greater increases from baseline in body weight (peak change, + 3.6 lbs. vs. + 1.4 lbs.) and BMI (peak change, + 0.6 kg/m2 vs. + 0.3 kg/m2), starting at 2 weeks (group x time, F8,3052 = 2.9, p = 0.003 for body weight, F8,3052 = 3.0, p = 0.002 for BMI). Significant increases in waist circumference were observed only with quetiapine. The relationship between drug treatment and changes in body weight (group x time x binge eating status, F1,2770 = 2.0, p = 0.002), BMI (F1,2767 = 2.0, p = 0.002), and waist circumference (women only, F25,1621 = 2.9, p < 0.0001) were moderated by BE behavior. The largest increases over 24 weeks in body weight and BMI, and waist circumference in women, occurred for quetiapine-treated patients with baseline binge-eating, relative to quetiapine-treated patients without binge eating and lithium-treated patients with or without baseline binge-eating. LIMITATIONS: Bipolar CHOICE was not designed to study anthropometric outcomes. CONCLUSIONS: Greater changes in body weight, BMI, and waist circumference occurred with quetiapine- versus lithium-based treatment over 6 months of treatment. The effects of study drugs on these anthropometric measures were moderated by BE behavior at baseline.

Antipsychotic use in Northern Italian inter-episode bipolar disorder patients: considering both second- and first-generation agents.

Evidence supports increasing antipsychotic use in bipolar disorder, especially second-generation antipsychotics. However, data regarding first-generation antipsychotic contemporary use are limited. We studied 380 Northern Italian bipolar disorder inter-episode patients, grouped according to current antipsychotic use, stratified by bipolar subtype (BDI vs. BDII). Furthermore, we compared first-generation antipsychotic users vs. non-users. In our sample (n = 357), 81.8% were taking antipsychotics (74% second-generation antipsychotics, 24.1% first-generation antipsychotics), with antipsychotic use in BDI significantly more prevalent than in BDII (85.2% vs. 72.0%). Overall, antipsychotic users vs. non-users had higher rates of hypo/manic last episode, lifetime psychiatric hospitalization, psychosis, and current psychotropic use, but lower rates of anxiety disorder main comorbidity and current antidepressant use. First-generation antipsychotic use rates (30.3% in BDI vs. 6.5% in BDII) were associated with more frequently being unpartnered, having elevated first/last episodes, higher lifetime hospitalization, involuntary commitment, psychosis, and psychosocial rehabilitation rates, and more current psychotropic use, but lower Global Assessment Functioning scores and less current antidepressant use. Bipolar disorder patients had robust antipsychotic (second-generation antipsychotic > first-generation antipsychotic) use, consistently with previous reports. FGAs were still prescribed for a substantial group of patients, likely suffering from severe bipolar disorder. Prescriptions need to be monitored to assess their appropriateness and adherence to evidence-based recommendations.