Antipsychotics and the risk of diabetes and death among adults with serious mental illnesses.

BACKGROUND: Individuals with schizophrenia exposed to second-generation antipsychotics (SGA) have an increased risk for diabetes, with aripiprazole purportedly a safer drug. Less is known about the drugs' mortality risk or whether serious mental illness (SMI) diagnosis or race/ethnicity modify these effects. METHODS: Authors created a retrospective cohort of non-elderly adults with SMI initiating monotherapy with an SGA (olanzapine, quetiapine, risperidone, and ziprasidone, aripiprazole) or haloperidol during 2008-2013. Three-year diabetes incidence or all-cause death risk differences were estimated between each drug and aripiprazole, the comparator, as well as effects within SMI diagnosis and race/ethnicity. Sensitivity analyses evaluated potential confounding by indication. RESULTS: 38 762 adults, 65% White and 55% with schizophrenia, initiated monotherapy, with haloperidol least (6%) and quetiapine most (26·5%) frequent. Three-year mortality was 5% and diabetes incidence 9.3%. Compared with aripiprazole, haloperidol and olanzapine reduced diabetes risk by 1.9 (95% CI 1.2-2.6) percentage points, or a 18.6 percentage point reduction relative to aripiprazole users' unadjusted risk (10.2%), with risperidone having a smaller advantage. Relative to aripiprazole users' unadjusted risk (3.4%), all antipsychotics increased mortality risk by 1.1-2.2 percentage points, representing 32.4-64.7 percentage point increases. Findings within diagnosis and race/ethnicity were generally consistent with overall findings. Only quetiapine's higher mortality risk held in sensitivity analyses. CONCLUSIONS: Haloperidol's, olanzapine's, and risperidone's lower diabetes risks relative to aripiprazole were not robust in sensitivity analyses but quetiapine's higher mortality risk proved robust. Findings expand the evidence on antipsychotics' risks, suggesting a need for caution in the use of quetiapine among individuals with SMI.

Lurasidone and risk of metabolic syndrome: results from short and long-term studies in patients with bipolar depression.

OBJECTIVE: The elevated prevalence of metabolic syndrome (MetS) in patients with depression has been associated with increased mortality. This post hoc analysis assessed the effect of treatment with lurasidone on risk of MetS in patients with bipolar depression. METHODS: Data used in the current analyses consisted of 3 double-blind (DB), placebo-controlled, 6-week studies in adults with bipolar I depression (N = 1192), consisting of 1 monotherapy, and 2 adjunctive trials (lithium or valproate). Also analyzed was a 6-month open-label (OL) extension study (monotherapy, N = 316; adjunctive therapy, N = 497); and a 5-month, OL, stabilization phase followed by randomization to a 28-week DB, placebo-controlled, adjunctive therapy study with lurasidone (N = 490). MetS was defined based on NCEP ATP III criteria (2005 revision). RESULTS: The proportion of patients with new-onset MetS was similar for lurasidone vs placebo in the short-term studies (monotherapy, 13.9% vs 15.3%; adjunctive therapy, 13.6% vs 11.0%); and remained stable during both the 6-month extension phase study (monotherapy, 15.2%; adjunctive therapy, 16.9%), and the 5-month stabilization study (adjunctive therapy, 12.2%). After 28 weeks of DB treatment (following 5-month treatment in the stabilization study), new onset MetS was observed at endpoint (OC) in 26.2% of the lurasidone group, and 30.8% of the placebo group. CONCLUSIONS: This post hoc analysis found that both short and long-term treatment with lurasidone was associated with a relatively low risk for the development of MetS in patients with bipolar I disorder. These findings are consistent with similar analyses in patients with schizophrenia.

CRANIUM: a quasi-experimental study to improve metabolic screening and HIV testing in community mental health clinics compared to usual care.

BACKGROUND: Individuals with serious mental illness often do not receive guideline-concordant metabolic screening and human immunodeficiency virus (HIV) testing, contributing to increased morbidity and premature mortality. This study evaluates the effectiveness of CRANIUM (Cardiometabolic Risk Assessment and treatment through a Novel Integration model for Underserved populations with Mental illness), an intervention to increase metabolic screening and HIV testing among patients with serious mental illness in a community mental health clinic compared to usual care. METHODS: The study used a quasi-experimental design, prospectively comparing a preventive care screening intervention at one community mental health clinic (n = 536 patients) to usual care at the remaining clinics within an urban behavioural health system (n = 4,847 patients). Psychiatrists at the intervention site received training in preventive health screening and had access to a primary care consultant, screening and treatment algorithms, patient registries, and a peer support specialist. Outcomes were the change in screening rates of A1c, lipid, and HIV testing post-intervention at the intervention site compared to usual care sites. RESULTS: Rates of lipid screening and HIV testing increased significantly at the intervention site compared to usual care, with and without multivariable adjustment [Lipid: aOR 1.90, 95% CI 1.32-2.75, P = .001; HIV: aOR 23.42, 95% CI 5.94-92.41, P < .001]. While we observed a significant increase in A1c screening rates at the intervention site, this increase did not persist after multivariable adjustment (aOR 1.37, 95% CI .95-1.99, P = .09). CONCLUSIONS: This low-cost, reverse integrated care model targeting community psychiatrist practices had modest effects on increasing preventive care screenings, with the biggest effect seen for HIV testing rates. Additional incentives and structural supports may be needed to further promote screening practices for individuals with serious mental illness.

Comorbid Diabetes and Severe Mental Illness: Outcomes in an Integrated Health Care Delivery System.

BACKGROUND: Diabetes prevalence is twice as high among people with severe mental illness (SMI) when compared to the general population. Despite high prevalence, care outcomes are not well understood. OBJECTIVE: To compare diabetes health outcomes received by people with and without comorbid SMI, and to understand demographic factors associated with poor diabetes control among those with SMI. DESIGN: Retrospective cohort study PARTICIPANTS: 269,243 adults with diabetes MAIN MEASURES: Primary outcomes included optimal glycemic control (A1c < 7) or poor diabetes control (A1c > 9) in 2014. Secondary outcomes included control of other cardiometabolic risk factors (hypertension, dyslipidemia, smoking) and recommended diabetes monitoring. KEY RESULTS: Among this cohort, people with SMI (N = 4,399), compared to those without SMI (N = 264,844), were more likely to have optimal glycemic control, adjusting for various covariates (adjusted relative risk (aRR) 1.25, 95% CI 1.21-1.28, p < .001) and less likely to have poor control (aRR 0.92, 95% CI 0.87-0.98, p = 0.012). Better blood pressure and lipid control was more prevalent among people with SMI when compared to those without SMI (aRR 1.03; 95% CI 1.02-1.05, p < .001; aRR 1.02; 95% CI 1.00-1.05, p = 0.044, respectively). No differences were observed in recommended A1c or LDL testing, but people with SMI were more likely to have blood pressure checked (aRR 1.02, 95% CI 1.02-1.03, p < .001) and less likely to receive retinopathy screening (aRR 0.80, 95% CI 0.71-0.91, p < .001) than those without SMI. Among people with diabetes and comorbid SMI, younger adults and Hispanics were more likely to have poor diabetes control. CONCLUSIONS: Adults with diabetes and comorbid SMI had better cardiometabolic control than people with diabetes who did not have SMI, despite lower rates of retinopathy screening. Among those with comorbid SMI, younger adults and Hispanics were more vulnerable to poor A1c control.

Lurasidone and risk for metabolic syndrome: results from short- and long-term clinical studies in patients with schizophrenia.

OBJECTIVE: To assess the effects of treatment with lurasidone on risk for metabolic syndrome (MetS) in patients with schizophrenia. METHODS: Rates of metabolic syndrome during treatment with lurasidone (40-160 mg/d) were analyzed using pooled, short-term data from three randomized, double-blind, placebo-controlled studies (vs olanzapine and quetiapine XR); long-term data from two active-comparator-controlled studies (vs risperidone and quetiapine XR); and data from two open-label studies in which patients were switched from olanzapine or risperidone to lurasidone. RESULTS: MetS was defined based on the National Cholesterol Education Program criteria. In short-term studies, the odds of meeting criteria for MetS at week 6 LOCF (adjusted for baseline metabolic syndrome status) was similar for the lurasidone and placebo groups (OR = 1.18; [95% CI, 0.81-1.71]; P = .39), but the odds (vs placebo) were significantly greater for olanzapine (OR = 2.81; [95% CI, 1.53-5.15]; P < .001) and quetiapine (OR = 3.49; [95% CI, 1.93-6.29]; P < .0001). No dose effect was observed for lurasidone across the dose range of 40-160 mg/d. In long-term studies, the odds of MetS after 12 months of treatment was significantly higher for risperidone compared with lurasidone (OR = 2.12; 95% CI, 1.15-3.90; P = .016) and for quetiapine XR compared with lurasidone (OR = 3.92; 95% CI, 1.15-13.40; P = .029). In open-label extension studies, the rate of MetS decreased in patients switched to lurasidone after 6 weeks of treatment with olanzapine or 12 months of treatment with risperidone. CONCLUSION: In this analysis of lurasidone clinical trials, the odds of developing metabolic syndrome were minimal during short- and long-term treatment with lurasidone (40-160 mg/d).

Association of C-reactive protein and metabolic risk with cognitive effects of lurasidone in patients with schizophrenia.

BACKGROUND: Accumulating evidence has implicated insulin resistance and inflammation in the pathophysiology of cognitive impairments associated with neuropsychiatric disorders. This post-hoc analysis based on a placebo-controlled trial investigated the effect of inflammation (indexed by CRP) and metabolic risk factors on cognitive performance in patients with schizophrenia treated with lurasidone. METHODS: Acutely exacerbated patients with schizophrenia were randomized to lurasidone (80 or 160 mg/day), quetiapine XR 600 mg/day, or placebo. A wide range CRP test and a cognitive assessment using the CogState computerized battery were performed at baseline and week 6 study endpoint. Associations between log-transformed CRP, high density lipoprotein (HDL), homeostatic model assessment of insulin resistance (HOMA-IR) and treatment response were evaluated. RESULTS: CRP combined with HDL, triglyceride-to-HDL (TG/HDL) ratio, or HOMA-IR at study baseline were significant moderators of the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment (p < .05). Greater placebo-corrected treatment effect size on the CogState composite score was observed for patients in the lurasidone 160 mg/day treatment group who had either low CRP and high HDL (d = 0.43), or low CRP and low HOMA-IR (d = 0.46). Interactive relationships between CRP, HDL, TG/HDL, HOMA-IR and the antipsychotic efficacy of lurasidone or quetiapine XR were not significant. There were no significant associations between antipsychotic treatment and changes in CRP level at study endpoint. CONCLUSIONS: Findings of this post-hoc analysis based on a placebo-controlled trial in patients with schizophrenia suggest that baseline CRP level combined with measures of metabolic risk significantly moderated the improvement in cognitive performance associated with lurasidone 160 mg/day (vs. placebo) treatment. Our findings underscore the importance of maintaining a low metabolic risk profile in patients with schizophrenia.

Monthly Extended-Release Risperidone (RBP-7000) in the Treatment of Schizophrenia: Results From the Phase 3 Program.

PURPOSE/BACKGROUND: The Phase 3 program for RBP-7000, a once-monthly subcutaneous (SC) extended-release risperidone formulation approved for treatment of schizophrenia, consisted of a double-blind placebo-controlled trial (previously reported) and a 52-week open-label study of monthly RBP-7000 120 mg. The primary objective of the open-label study was to evaluate the long-term safety and tolerability of RBP-7000 in adults with schizophrenia. A secondary objective was to assess long-term maintenance of effectiveness. METHODS/PROCEDURES: The 52-week Phase 3 open-label study (NCT02203838) enrolled 92 rollover participants from the double-blind trial (NCT02109562) and 408 stable (Positive and Negative Syndrome Scale [PANSS] total score, ≤70) de novo participants. Participants received up to 13 monthly SC injections of RBP-7000 120 mg. Safety assessments included treatment-emergent adverse events, injection-site assessments, vital signs, laboratory and ECG parameters, extrapyramidal symptoms, and suicidality. Clinical outcomes included the PANSS and Clinical Global Impression-Severity. FINDINGS/RESULTS: Overall, 367 participants (73.4%) reported 1 or more treatment-emergent adverse event; the most common were injection-site pain (13.0%) and weight increase (12.8%). Most participants (>80%) experienced no injection-site reactions. No clinically meaningful changes were observed in laboratory or electrocardiogram values, vital signs, extrapyramidal symptoms, or suicidality. Over 12 months of exposure, mean PANSS scores continued to improve in rollover participants and remained stable among de novo participants. Mean Clinical Global Impression-Severity scores remained stable among all participants. IMPLICATIONS/CONCLUSIONS: Except for anticipated injection-site reactions, RBP-7000 demonstrated a favorable safety and tolerability profile similar to oral risperidone. Notably, PANSS scores continued to improve for participants from the pivotal study and remained stable for de novo participants.

Diabetes Screening among Antipsychotic-Treated Adults with Severe Mental Illness in an Integrated Delivery System: A Retrospective Cohort Study.

BACKGROUND: Severe mental illness (SMI) is associated with increased risk for type 2 diabetes, partly due to adverse metabolic effects of antipsychotic medications. In public health care settings, annual screening rates are 30%. We measured adherence to national diabetes screening guidelines for patients taking antipsychotic medications. OBJECTIVE: To estimate diabetes screening prevalence among patients with SMI within an integrated health care system, and to assess characteristics associated with lack of screening. DESIGN: Retrospective cohort study. PARTICIPANTS: Antipsychotic-treated adults with SMI. We excluded participants with known diabetes. MAIN MEASURES: Primary outcome was screening via fasting glucose test or hemoglobin A1c during a 1-year period. KEY RESULTS: In 2014, 16,754 patients with SMI diagnoses were receiving antipsychotics. Seventy-four percent of these patients' providers ordered diabetes screening tests that year, but only 55% (9247/16,754) received screening. When the observation time frame was extended to 2 years, 73% (12,250/16,754) were screened. Adjusting for sex and race/ethnicity, young adults (aged 18-29 years) were less likely to receive screening than older age groups [adjusted RR (aRR) 1.23-1.57, p < 0.0001]. Compared to whites, screening was more common for Asians (aRR 1.141, 95% CI 1.089-1.195, p < 0.0001), less common for blacks (aRR 0.946, 95% CI 0.898-0.997, p < 0.0375), and no different for Hispanics (aRR 1.030, 95% CI 0.988-1.074, p = 0.165). Smokers were less likely to be screened than non-smokers (aRR 0.93, 95% CI 0.89-0.97, p < 0.0008). Utilization of either mental health or primary care services increased the likelihood of screening. CONCLUSIONS: While almost three-fourths of adults with SMI taking antipsychotic medications received a lab order for diabetes screening, only 55% received screening within a 12-month period. Young adults and smokers were less likely to be screened, despite their disproportionate metabolic risk. Future studies should assess the barriers and facilitators with regard to diabetes screening in this vulnerable population at the patient, provider, and system levels.

Hospitalization outcomes in patients with schizophrenia after switching to lurasidone or quetiapine: a US claims database analysis.

BACKGROUND: This study compared hospital admission rates among adult patients with schizophrenia who switched to antipsychotic monotherapy with lurasidone or quetiapine. METHODS: This retrospective cohort study used U.S.-based Truven Health MarketScan® Medicaid Multi-State Database (April 2010 through December 2012) and MarketScan® Commercial Claims and Encounters Database (April 2010 through October 2013). Continuous enrollment for 6-months before and after medication initiation was required. Treatment episodes ended after 6-months post lurasidone or quetiapine initiation, a 60-day treatment gap, or initiation of another antipsychotic. Length of treatment episodes (i.e., treatment duration) was compared using a t-test. All-cause, mental-health, and schizophrenia-related hospitalization rates, as well as costs, were compared between lurasidone- and quetiapine-treated patients using multivariable generalized linear models that adjusted for background characteristics. RESULTS: Quetiapine (n = 435) compared to lurasidone (n = 238) treatment was associated with increased all-cause (21% vs 13%, p < 0.05) and mental health-related hospitalizations (20% vs 12%, p < 0.05), but similar rates of schizophrenia-related hospitalizations (14% vs. 10%, p = 0.14). After adjusting for baseline covariates, quetiapine had 64% higher likelihood of all-cause hospitalizations (OR [odds ratio] = 1.64, 95% confidence interval [CI] 1.05-2.57, p = 0.03), 74% higher likelihood of mental health-related hospitalizations (OR = 1.74, 95% CI 1.11-2.75, p = 0.02), and a similar likelihood of schizophrenia-related hospitalization (OR = 1.35, 95% CI 0.82-2.22, p = 0.24). For those with hospital admissions, adjusted all-cause admission costs were higher for quetiapine when compared with lurasidone in both the Medicaid ($22,036 vs. $15,424, p = 0.17) and commercial populations ($23,490 vs. $20,049, p = 0.61). These differences were not significant. The length of treatment episodes was significantly shorter for quetiapine than lurasidone (115.4 vs 123.1 days, p < 0.05). CONCLUSIONS: In this retrospective claims database study, patients with schizophrenia who were switched to lurasidone had significantly fewer all-cause and mental health-related hospitalizations and similar rates of schizophrenia-related hospitalization compared with those switched to quetiapine. Patients switching to lurasidone had a significantly longer treatment duration rate than those switching to quetiapine. These results may reflect differences in efficacy or tolerability between lurasidone and quetiapine.

A Doctor is in the House: Stakeholder Focus Groups About Expanded Scope of Practice of Community Psychiatrists.

We sought to understand stakeholder perspectives on barriers to metabolic screening for people with severe mental illness. We additionally assessed the feasibility of expanding psychiatrists' scope of practice to include treatment of cardiometabolic abnormalities. We conducted four focus groups among patients with severe mental illness, community psychiatrists, primary care providers, and public health administrators. Focus group transcripts were thematically analyzed. Three domains emerged: challenges with patient navigation of the complex health care system, problem list prioritization difficulties, and concern that treatment of cardiometabolic abnormalities were beyond the scope of practice of psychiatrists. Stakeholders agreed that navigating the health care system was challenging for this population and led to undertreatment of cardiometabolic risk factors. Expansion of psychiatrists' scope of practice within community mental health appears acceptable to patients and may be a mechanism to improve cardiometabolic care among people with severe mental illness.

Efficacy, safety, and tolerability of augmentation pharmacotherapy with aripiprazole for treatment-resistant depression in late life: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Treatment-resistant major depression is common and potentially life-threatening in elderly people, in whom little is known about the benefits and risks of augmentation pharmacotherapy. We aimed to assess whether aripiprazole is associated with a higher probability of remission than is placebo. METHODS: We did a randomised, double-blind, placebo-controlled trial at three centres in the USA and Canada to test the efficacy and safety of aripiprazole augmentation for adults aged older than 60 years with treatment-resistant depression (Montgomery Asberg Depression Rating Scale [MADRS] score of ≥15). Patients who did not achieve remission during a pre-trial with venlafaxine extended-release (150-300 mg/day) were randomly assigned (1:1) to the addition of aripiprazole (target dose 10 mg [maximum 15 mg] daily) daily or placebo for 12 weeks. The computer-generated randomisation was done in blocks and stratified by site. Only the database administrator and research pharmacists had knowledge of treatment assignment. The primary endpoint was remission, defined as an MADRS score of 10 or less (and at least 2 points below the score at the start of the randomised phase) at both of the final two consecutive visits, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00892047. FINDINGS: From July 20, 2009, to Dec 30, 2013, we recruited 468 eligible participants, 181 (39%) of whom did not remit and were randomly assigned to aripiprazole (n=91) or placebo (n=90). A greater proportion of participants in the aripiprazole group achieved remission than did those in the placebo group (40 [44%] vs 26 [29%] participants; odds ratio [OR] 2·0 [95% CI 1·1-3·7], p=0·03; number needed to treat [NNT] 6·6 [95% CI 3·5-81·8]). Akathisia was the most common adverse effect of aripiprazole (reported in 24 [26%] of 91 participants on aripiprazole vs 11 [12%] of 90 on placebo). Compared with placebo, aripiprazole was also associated with more Parkinsonism (15 [17%] of 86 vs two [2%] of 81 participants), but not with treatment-emergent suicidal ideation (13 [21%] of 61 vs 19 [29%] of 65 participants) or other measured safety variables. INTERPRETATION: In adults aged 60 years or older who do not achieve remission from depression with a first-line antidepressant, the addition of aripiprazole is effective in achieving and sustaining remission. Tolerability concerns include the potential for akathisia and Parkinsonism. FUNDING: National Institute of Mental Health, UPMC Endowment in Geriatric Psychiatry, Taylor Family Institute for Innovative Psychiatric Research, National Center for Advancing Translational Sciences, and the Campbell Family Mental Health Research Institute.

Diabetes and Cardiovascular Care Among People with Severe Mental Illness: A Literature Review.

Close to 19 million US adults have severe mental illnesses (SMI), and they die, on average, 25 years earlier than the general population, most often from cardiovascular disease (CVD). Many of the antipsychotic medications used to treat SMI contribute to CVD risk by increasing risk for obesity, type 2 diabetes, dyslipidemia, and hypertension. Based on compelling evidence, the American Diabetes Association and the American Psychiatric Association developed guidelines for metabolic screening and monitoring during use of these medications.In this manuscript, we have reviewed the evidence on diabetes and other CVD risk screening, prevalence, and management among populations with SMI. We also review differences in screening among subpopulations with SMI (e.g., racial/ethnic minorities, women, and children). We found that despite national guidelines for screening for diabetes and other cardiovascular risk factors, up to 70 % of people taking antipsychotics remain unscreened and untreated. Based on estimates that 20 % of the 19 million US adults with SMI have diabetes and 70 % of them are not screened; it is likely that over 2 million Americans with SMI have unidentified diabetes. Given that undiagnosed diabetes costs over $4,000 per person, this failure to identify diabetes among people with SMI represents a missed opportunity to prevent morbidity and translates to over $8 billion in annual preventable costs to our healthcare system.Given the high burden of disease and significant evidence of suboptimal medical care received by people with SMI, we propose several clinical and policy recommendations to improve diabetes and other CVD risk screening and care for this highly vulnerable population. These recommendations include reducing antipsychotic medication dose or switching antipsychotic medications, enhancing smoking cessation efforts, sharing electronic health records between physical and mental health care systems, and promoting integration of care.

Association of anxiety disorders and depression with incident heart failure.

OBJECTIVE: Depression has been associated with increased risk of heart failure (HF). Because anxiety is highly comorbid with depression, we sought to establish if anxiety, depression, or their co-occurrence is associated with incident HF. METHODS: A retrospective cohort (N = 236,079) including Veteran's Administration patients (age, 50-80 years) free of cardiovascular disease (CVD) at baseline was followed up between 2001 and 2007. Cox proportional hazards models were computed to estimate the association between anxiety disorders alone, major depressive disorder (MDD) alone, and the combination of anxiety and MDD, with incident HF before and after adjusting for sociodemographics, CVD risk factors (Type 2 diabetes, hypertension, hyperlipidemia, obesity), nicotine dependence/personal history of tobacco use, substance use disorders (alcohol and illicit drug abuse/dependence), and psychotropic medication. RESULTS: Compared with unaffected patients, those with anxiety only, MDD only, and both disorders were at increased risk for incident HF in age-adjusted models (hazard ratio [HR] = 1.19 [ 95% confidence interval {CI} = 1.10-1.28], HR = 1.21 [95% CI = 1.13-1.28], and HR = 1.24 [95% CI = 1.17-1.32], respectively). After controlling for psychotropics in a full model, the association between anxiety only, MDD only, and both disorders and incident HF increased (HRs = 1.46, 1.56, and 1.74, respectively). CONCLUSIONS: Anxiety disorders, MDD, and co-occurring anxiety and MDD are associated with incident HF in this large cohort of Veteran's Administration patients free of CVD at baseline. This risk of HF is greater after accounting for protective effects of psychotropic medications. Prospective studies are needed to clarify the role of depression and anxiety and their pharmacological treatment in the etiology of HF.

Antiglucocorticoid therapy for older adults with anxiety and co-occurring cognitive dysfunction: results from a pilot study with mifepristone.

OBJECTIVES: In older adults with anxiety disorders, chronically elevated cortisol may contribute to cognitive impairment and elevated anxiety. We conducted a pilot study with mifepristone, a glucocorticoid receptor antagonist, as a potential treatment for late-life anxiety disorders and co-occurring cognitive dysfunction. METHODS: Fifteen individuals 60 years and older with an anxiety disorder plus cognitive dysfunction participated in the 12-week study. In the first week, participants were randomly assigned to mifepristone 300 mg daily or placebo. In the subsequent 3 weeks, all participants received mifepristone 300 mg. Mifepristone was then discontinued, and the participants were reassessed 8 weeks later. We examined the following: (1) cognitive changes; (2) worry symptom severity; (3) safety and tolerability; and (4) salivary cortisol before, during, and after mifepristone exposure. RESULTS: Overall safety, tolerability, and high retention supported the feasibility of this research. Participants with higher baseline cortisol levels (peak cortisol >6.0 ng/ml, n = 5) showed improvements in memory, executive function, and worry severity after 3-4 weeks of mifepristone with persistent memory and worry improvements 8 weeks after mifepristone discontinuation. Individuals with low-to-normal baseline cortisol (n = 8) showed little to no improvement. As expected, cortisol levels rose during mifepristone exposure and returned to pretreatment levels 8 weeks after mifepristone discontinuation. In the first week of treatment, there were no differences between placebo-treated and mifepristone-treated participants. CONCLUSION: The results of this pilot study warrant further testing of antiglucocorticoid agents in late-life anxiety disorders with co-occurring cognitive dysfunction. Mifepristone is hypothesized to have benefits in patients with evidence of glucocorticoid excess. Directions for further study are discussed.

Revisiting diabetes risk of olanzapine versus aripiprazole in serious mental illness care.

BACKGROUND: Exposure to second-generation antipsychotics (SGAs) carries a risk of type 2 diabetes, but questions remain about the diabetogenic effects of SGAs. AIMS: To assess the diabetes risk associated with two frequently used SGAs. METHOD: This was a retrospective cohort study of adults with schizophrenia, bipolar I disorder or severe major depressive disorder (MDD) exposed during 2008-2013 to continuous monotherapy with aripiprazole or olanzapine for up to 24 months, with no pre-period exposure to other antipsychotics. Newly diagnosed type 2 diabetes was quantified with targeted minimum loss-based estimation; risk was summarised as the restricted mean survival time (RMST), the average number of diabetes-free months. Sensitivity analyses were used to evaluate potential confounding by indication. RESULTS: Aripiprazole-treated patients had fewer diabetes-free months compared with olanzapine-treated patients. RMSTs were longer in olanzapine-treated patients, by 0.25 months [95% CI: 0.14, 0.36], 0.16 months [0.02, 0.31] and 0.22 months [0.01, 0.44] among patients with schizophrenia, bipolar I disorder and severe MDD, respectively. Although some sensitivity analyses suggest a risk of unobserved confounding, E-values indicate that this risk is not severe. CONCLUSIONS: Using robust methods and accounting for exposure duration effects, we found a slightly higher risk of type 2 diabetes associated with aripiprazole compared with olanzapine monotherapy regardless of diagnosis. If this result was subject to unmeasured selection despite our methods, it would suggest clinician success in identifying olanzapine candidates with low diabetes risk. Confirmatory research is needed, but this insight suggests a potentially larger role for olanzapine in the treatment of well-selected patients, particularly for those with schizophrenia, given the drug's effectiveness advantage among them.

Metabolic and body mass parameters after treatment with JNJ-37822681, a novel fast-dissociating D2 receptor antagonist, vs olanzapine in patients with schizophrenia.

BACKGROUND: The highly selective and fast dissociating D2 receptor antagonist JNJ-37822681 may be associated with lower risk for weight gain and undesirable metabolic effects compared with available antipsychotics. METHODS: In this double-blind, randomized study, patients were randomly assigned (1:1:1:1:1) to 12 weeks of JNJ-37822681 (10 mg, 20 mg, or 30 mg, twice daily) or olanzapine (10 mg/d during week 1; 15 mg/d after week 1), or 6 weeks of placebo (followed by 6 weeks of olanzapine, 15 mg/d). Metabolic and body mass parameters were assessed at weeks 6 and 12. RESULTS: For metabolic parameters, at week 6 none of the JNJ-37822681 groups demonstrated significant change vs placebo; however, significant changes (P < .05) were observed in the olanzapine vs placebo group in triglycerides, low-density lipoprotein (LDL) and very-LDL cholesterol, and free fatty acids. For all JNJ-37822681 groups, mean weight changes at week 12 (-0.3 [10 mg], + 0.3 [20 mg], + 0.8 kg [30 mg]) were significantly less (P < .001) than for the olanzapine group (+ 2.7 kg). A higher percentage of overweight or obese patients (baseline body mass index: ≥25 kg/m2) receiving olanzapine had ≥7% increase in weight than those receiving JNJ-37822681 (9.8% vs 2.3%, respectively). CONCLUSIONS: JNJ-37822681 treatment was associated with a more favorable outcome on weight and metabolic adverse effects vs olanzapine for treating schizophrenia; the 10 mg twice-daily dose demonstrated minimal to no weight gain.

Implementation of a weight loss program for Latino outpatients with severe mental illness.

To determine feasibility of implementation of a weight loss program for overweight Latinos with severe mental illness. In this quasi-experimental study, a 14-week behavioral weight loss course (extended) was implemented at one clinic. A one-time nutrition class (brief) was given at a sister clinic. Implementation feasibility was assessed by consent and participation rates. Weight was followed for 6 months. Consent rates were high [77 % (49/64) extended; 68 % (39/57) brief], and 88 % (43/49) of extended subjects participated and 88 % (38/43) completed follow-up. Weight loss did not differ between groups. A behavioral weight loss course is feasible to implement for this population.

Changes in Metabolic Parameters and Body Weight in Patients With Prediabetes Treated With Adjunctive Brexpiprazole for Major Depressive Disorder: Pooled Analysis of Short- and Long-Term Clinical Studies.

Objective: Certain atypical antipsychotics, while efficacious as adjunctive treatments in major depressive disorder (MDD), are associated with metabolic adverse effects and weight gain. This analysis determined the effect of adjunctive brexpiprazole on metabolic parameters and body weight in adults with MDD and prediabetes (ie, at risk of developing diabetes) based on pooled data from 3 short-term studies and 1 long-term study.Methods: The short-term studies were 6-week, randomized, double-blind, placebo-controlled studies of adjunctive oral brexpiprazole 1-3 mg/d in outpatients with MDD (DSM-IV-TR criteria) and inadequate response to antidepressant treatment, conducted between June 2011 and May 2016. The long-term study was a 26- to 52-week, open-label extension study conducted between October 2011 and May 2017. Prediabetes was defined based on fasting serum glucose and glycated hemoglobin (HbA1c) levels. Shifts in diabetes status and shifts/changes in fasting metabolic parameters and body weight were determined.Results: Most patients receiving adjunctive brexpiprazole maintained their baseline diabetes status in the short term (568/751; 75.6%) and long term (1,919/2,746; 69.9%). The incidence of categorical shifts in fasting metabolic parameters generally did not differ between treatment groups or between prediabetes and non-diabetes subgroups. Mean changes from baseline in metabolic parameters were small in the short term (all < 5 mg/dL) and long term (all < 6 mg/dL, except < 20 mg/dL for triglycerides). Moderate weight gain was observed in the short term (1.5 kg) and long term (3.4-4.1 kg).Conclusions: Adjunctive brexpiprazole had a limited impact on the metabolic profile of patients with MDD, regardless of diabetes status (prediabetes/non-diabetes).Trial Registration: Data used in this post hoc analysis came from studies with ClinicalTrials.gov identifiers NCT01360645, NCT01360632, NCT02196506, and NCT01360866.

Adaptation of a Mobile Interactive Obesity Treatment Approach for Early Severe Mental Illness: Protocol for a Mixed Methods Implementation and Pilot Randomized Controlled Trial.

BACKGROUND: Obesity is common in individuals with severe mental illness (SMI), contributing to a significantly shortened lifespan when compared to the general population. Available weight loss treatments have attenuated efficacy in this population, underscoring the importance of prevention and early intervention. OBJECTIVE: Here, we describe a type 1 hybrid study design for adapting and pilot-testing an existing mobile health intervention for obesity prevention in individuals with early SMI and Class I or early-stage obesity, defined as a BMI of 30-35. METHODS: An existing, evidence-based interactive obesity treatment approach using low-cost, semiautomated SMS text messaging was selected for adaptation. Community mental health clinics and Clubhouse settings in Eastern Missouri and South Florida were identified to participate. This study has the following 3 aims. First, using the Enhanced Framework for Reporting Adaptations and Modifications to Evidence-based interventions, contextual aspects of the clinical and digital treatment environments are identified for adaptation, considering 5 main stakeholder groups (clinical administrators, prescribing clinicians, case managers, nurses, and patients). Following a 2-week trial of unadapted SMS text messaging, Innovation Corps methods are used to discover needed intervention adaptations by stakeholder group and clinical setting. Second, adaptations to digital functionality and intervention content will be made based on themes identified in aim 1, followed by rapid usability testing with key stakeholders. A process for iterative treatment adaptation will be developed for making unplanned modifications during the aim 3 implementation pilot study. Individuals working in partner community mental health clinics and Clubhouse settings will be trained in intervention delivery. Third, in a randomized pilot and feasibility trial, adults with 5 years or less of treatment for an SMI diagnosis will be randomized 2:1 to 6 months of an adapted interactive obesity treatment approach or to an attentional control condition, followed by a 3-month extension phase of SMS text messages only. Changes in weight, BMI, and behavioral outcomes, as well as implementation challenges, will be evaluated at 6 and 9 months. RESULTS: Institutional review board approval for aims 1 and 2 was granted on August 12, 2018, with 72 focus group participants enrolled; institutional review board approval for aim 3 was granted on May 6, 2020. To date, 52 participants have been enrolled in the study protocol. CONCLUSIONS: In this type 1 hybrid study design, we apply an evidence-based treatment adaptation framework to plan, adapt, and feasibility test a mobile health intervention in real-world treatment settings. Resting at the intersection of community mental health treatment and physical health promotion, this study aims to advance the use of simple technology for obesity prevention in individuals with early-stage mental illness. TRIAL REGISTRATION: ClinicalTrials.gov NCT03980743; https://clinicaltrials.gov/ct2/show/NCT03980743. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/42114.