Effects of topiramate therapy on serum bicarbonate concentration in a sample of 10,279 veterans.

BACKGROUND: Topiramate, which is increasingly being used to treat alcohol use disorder (AUD), is commonly associated with reduced serum bicarbonate concentrations. However, estimates of the prevalence and magnitude of this effect are from small samples and do not address whether topiramate's effects on acid-base balance differ in the presence of an AUD or by topiramate dosage. METHODS: Veterans Health Administration electronic health record (EHR) data were used to identify patients with a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched control group. We differentiated patients into two subgroups based on the presence of a diagnosis of AUD in the EHR. Baseline alcohol consumption was determined using Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores in the EHR. Analysis also included a three-level measure representing mean daily dosage. The topiramate-associated changes in serum bicarbonate concentration were estimated in difference-in-differences linear regression models. A serum bicarbonate concentration <17 mEq/L was considered to represent possible clinically significant metabolic acidosis. RESULTS: The cohort comprised 4287 topiramate-treated patients and 5992 propensity score-matched controls with a mean follow-up period of 417 days. The mean topiramate-associated reductions in serum bicarbonate concentration were <2 mEq/L in the low (≤88.75), medium (>88.75 and ≤141.70), and high (>141.70) mg/day dosage tertiles, irrespective of AUD history. Concentrations <17 mEq/L occurred in 1.1% of topiramate-treated patients and 0.3% of controls and were not associated with alcohol consumption or an AUD diagnosis. CONCLUSIONS: The excess prevalence of metabolic acidosis associated with topiramate treatment does not differ with dosage, alcohol consumption, or the presence of an AUD. Baseline and periodic serum bicarbonate concentration measurements are recommended during topiramate therapy. Patients prescribed topiramate should be educated about the symptoms of metabolic acidosis and urged to report their occurrence promptly to a healthcare provider.

Enhancing Implementation of Measurement-Based Mental Health Care in Primary Care: A Mixed-Methods Study.

OBJECTIVE: The complex practice of measurement-based care (MBC) for mental health conditions has proven challenging to implement. This study aimed to evaluate an intensive strategy to implement MBC in U.S. Department of Veterans Affairs (VA) Primary Care Mental Health Integration clinics. METHODS: Ten paired sites were randomly assigned to receive national MBC resources alone or with an intensive implementation strategy (external facilitation plus quality improvement teams) between May 2018 and June 2020. The intervention occurred over 12-18 months; two site pairs completed participation before the COVID-19 pandemic. Using the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework, the authors conducted qualitative interviews and used administrative data to evaluate the implementation, adoption, reach, and effectiveness of MBC. RESULTS: All sites improved during the study, suggesting the effectiveness of the VA's national MBC initiative. Sites with facilitation improved more than comparison sites in implementation, adoption, and reach of MBC. The effectiveness of MBC (i.e., clinician responsiveness to high patient-reported outcome measure [PROM] scores) was demonstrated at all sites both before and after facilitation. After the COVID-19 pandemic began, facilitation sites maintained or improved on their implementation gains, whereas comparison sites uniformly reported decreased emphasis on MBC. CONCLUSIONS: Implementation facilitation resulted in greater gains in outcomes of interest and helped sites retain focus on MBC implementation. Regardless of study condition, clinicians were responsive to elevated PROM scores, but MBC had a larger impact on care at facilitation sites because of increased uptake. Multiple technological and contextual challenges remain, but MBC holds promise for improving routine mental health care.

Association of topiramate prescribed for any indication with reduced alcohol consumption in electronic health record data.

BACKGROUND AND AIMS: Topiramate is a medication that is widely prescribed to treat a variety of conditions, including alcohol use disorder (AUD). We used electronic health record (EHR) data to measure topiramate's effects on drinking in individuals differentiated by a history of AUD. DESIGN: Parallel-groups comparison of patients prescribed topiramate and a propensity score-matched comparison group. SETTING: A large US integrated health-care system. PARTICIPANTS: Patients with Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) scores prior to and after a minimum of 180 days of topiramate prescription for any indication and a propensity score-matched group. The sample included 5918 patients with an electronic health record diagnosis of alcohol use disorder at any time (AUD-hx-pos) (1738 topiramate-exposed and 4180 controls) and 23 614 patients with no EHR diagnosis of AUD (AUD-hx-neg) (6324 topiramate-exposed and 17 290 controls). MEASUREMENTS: Regression analyses compared difference-in-difference (DiD) estimates, separately by AUD history. DiD estimates represent exposure-group (i.e. topiramate versus control) differences on the pre-post difference in AUDIT-C score. Effects of baseline AUDIT-C score and daily topiramate dosage were also tested. FINDINGS: AUD-hx-neg patients who received topiramate had a greater reduction in AUDIT-C score (-0.11) than matched controls (-0.04). This yielded a DiD score of -0.07 [95% confidence interval (CI) = -0.11,-0.03; P = 0.002], with the greatest effect among AUD-hx-neg patients with a baseline AUDIT-C score of 4+ (DiD = -0.35, 95% CI = -0.49, -0.21; P < 0.0001) and those prescribed > 150 mg/day of the medication (DiD = -0.15, 95%CI = -0.23, -0.07; P < 0.001). DISCUSSION: Among individuals with no history of alcohol use disorder, topiramate appears to be associated with reduced drinking. This small effect is most evident among patients with higher baseline drinking levels and at a higher average daily topiramate dosage.

Effect of Varenicline on Tardive Dyskinesia: A Pilot Study.

OBJECTIVE: Although evidence implicates striatal cholinergic impairment as a mechanism underlying tardive dyskinesia, trials of nonspecific cholinergic agents have been inconclusive. As a partial agonist at specific nicotinic receptor subtypes, varenicline reduces drug-induced dyskinesias in animal models suggesting promise as a treatment for tardive dyskinesia. METHODS: Three schizophrenia patients with tardive dyskinesia who were smokers underwent an open trial of varenicline. After a 2-week baseline, subjects received varenicline 1 mg twice daily. Changes from baseline on the Abnormal Involuntary Movement Scale were measured after a 4-week varenicline stabilization period, and 6 weeks after the smoking quit date in one patient. RESULTS: Varenicline had no effect on mean Abnormal Involuntary Movement Scale scores after 4 weeks. Although smoking decreased after 4 weeks on varenicline and diminished further in one patient after 10 weeks, this also appeared to have no effect on ratings of tardive dyskinesia. CONCLUSION: In contrast to animal models, no significant change in tardive dyskinesia occurred in response to varenicline replacement in three schizophrenia patients. Further investigations of cholinergic mechanisms in tardive dyskinesia are worthwhile as agents for specific cholinergic targets become available for treatment. In addition, treatment trials of tardive dyskinesia should control for smoking status, while patients on antipsychotics receiving nicotine replacement therapies for smoking should be studied further for changes in movement.

Correlates of the Abnormal Involuntary Movement Scale in Veterans With Tardive Dyskinesia.

PURPOSE/BACKGROUND: To add to limited evidence on the Abnormal Involuntary Movement Scale (AIMS) as a measure of tardive dyskinesia (TD) in clinical practice settings, the characteristics and correlates of AIMS scores were assessed. METHODS/PROCEDURES: Veterans with schizophrenia/schizoaffective, bipolar, or major depressive disorders receiving antipsychotics and at least 1 AIMS score during October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by the International Classification of Diseases, Ninth Revision, Clinical Modification, codes. Correlates of AIMS scores were examined using χ or t tests. Odds ratios and ß parameters with 95% confidence intervals for categorical and continuous variables associated with AIMS scores were derived from a multivariate logistic and linear regression, respectively. FINDINGS/RESULTS: Among 7985 veterans receiving antipsychotics, only 4706 (58.9%) had at least 1 AIMS examination. Of these, 229 (4.9%) were diagnosed with possible TD. The mean total AIMS scores and AIMS awareness/incapacitation scores were significantly higher for patients with TD (both P < 0.0001). Comparing diagnostic threshold criteria of AIMS ratings, only 17.5% to 37.1% of veterans with TD were successfully identified. Among TD patients, 21.4% had a total score of moderate-severe and 15.3% had ratings of at least mild movements in 2 or more body regions. In the regression analyses, being older, African-American, having schizophrenia/schizoaffective disorder, and receiving antipsychotics or benztropine significantly increased the severity of AIMS scores. Higher AIMS scores were not predictive of outcomes other than marital status in socioeconomic or healthcare domains. IMPLICATIONS/CONCLUSIONS: Although the AIMS is essential for TD research, its value in clinical practice without training and oversight remains unclear. Efforts to adapt screening procedures to clinical needs may be worthwhile.

Cumulative Burden of Illness in Veterans With Tardive Dyskinesia and Serious Mental Disorders.

PURPOSE/BACKGROUND: To inform cost-benefit decisions for veterans, the risk of tardive dyskinesia (TD) and its impact on comorbidities and outcomes were assessed. METHODS/PROCEDURES: In a retrospective study, veterans with schizophrenia/schizoaffective, and bipolar and major depressive disorders receiving antipsychotics during the period October 1, 2014, to September 30, 2015, were identified. Tardive dyskinesia was determined by International Classification of Diseases, Ninth Revision, Clinical Modification codes. Correlates of TD were examined using χ or t tests. Odds ratios (ORs) and ß parameters with 95% confidence intervals (CIs) for categorical and continuous variables associated with TD were derived from a multivariate logistic and linear regression, respectively. FINDINGS/RESULTS: Among 7985 veterans, 332 (4.2%) were diagnosed as having possible TD. The odds of having TD were higher for older veterans (OR, 1.04; 95% CI, 1.03-1.05; P < 0.0001) and veterans with schizophrenia/schizoaffective disorder (OR, 1.54; 95% CI, 1.23-1.91; P < 0.0001) or diabetes (OR, 1.64; 95% CI, 1.30-2.06; P < 0.0001). Veterans with TD received more antipsychotic prescriptions (mean ± SD, 18.4 ± 30.3 vs 13.3 ± 26.4; P = 0.003) and days of supply (233.9 ± 95.4 vs 211.4 ± 102.0; P < 0.0001). They were more likely to have received 2 or more antipsychotics (27.1% vs 19.7%, P = 0.0009) and benztropine (OR, 2.25: 95% CI 1.73-2.91; P < 0.0001). Veterans with TD had a higher Charlson Comorbidity Index score (ß = 0.32; SE, 0.09; 95% CI, 0.14-0.49; P = 0.0003) and higher odds of any medical hospitalization (OR, 1.45; 95% CI, 1.07-1.95; P = 0.001). IMPLICATIONS/CONCLUSIONS: The diagnosis of possible TD was associated with older age, schizophrenia/schizoaffective disorder, medical comorbidity, and hospitalization. Tardive dyskinesia may be a marker for patients at risk of adverse health care outcomes and diminished quality of life.

Preliminary support for the role of reward relevant effort and chronotype in the depression/insomnia comorbidity.

BACKGROUND: The presence of insomnia in the context of depression is linked to a number of poor outcomes including reduced treatment response, increased likelihood of relapse, and greater functional impairment. Given the frequent co-occurrence of depression and insomnia, research into systems and processes relevant to both disorders, specifically reward processing and circadian rhythm disruption, may help parse this complex comorbidity. METHODS: A pilot study was conducted on a sample of 10 veterans with clinically significant depression and insomnia symptoms. Participants completed objective (actigraphy) and subjective (sleep diary) assessments of sleep, self-reports of chronotype, and behavioral tasks assessing reward relevant effort before and after 6 sessions of Cognitive Behavioral Therapy for Insomnia. RESULTS: Insomnia and depression significantly improved following CBT-I. Subjective sleep parameters significantly improved with large effect sizes. Actigraphy results were nonsignificant, but effect sizes for sleep efficiency and onset latency were in the medium range. Chronotype shifted significantly toward morningness following CBT-I, and an earlier chronotype at baseline was associated with increased reward effort following treatment. Changes in chronotype, depression and insomnia were not associated with changes in effort. LIMITATIONS: Findings are limited by small sample size and lack of randomized control group. CONCLUSIONS: Findings should be interpreted as hypothesis generating in the service of furthering research aimed at uncovering potential mechanisms underlying the depression/insomnia comorbidity. Analyses of sleep data in extant datasets of reward processing impairments in depression as well as original projects aimed at exploring potential sleep, circadian rhythm, and reward interactions in depression are encouraged.

The associations between suicidality and mental health factors and pain interference in veterans being referred to primary care mental health integration.

In veterans being referred to a primary care-mental health integration (PCMHI) program, the Behavioral Health Laboratory, we sought to identify correlates of suicidal ideation severity and suicide attempts using the ideation-to-action framework among pain interference, psychiatric disorders, and treatment factors. Veterans (n = 17,176) referred to the Behavioral Health Laboratory received a structured assessment that included past-year suicidal thoughts and behaviors, psychiatric symptoms, substance use, psychotropic medication use, and mental health treatment utilization. Nearly 50% of participants reported at least passive suicidal ideation. While psychiatric symptoms differentiated passive ideators, active ideators, and suicide attempters from non-suicide ideators, there were no significant differences among active ideators and attempters. Additionally, attempters differed from passive ideators in terms of drug use, mental health treatment, psychotropic medication use, mania, and psychosis. Pain interference was significantly associated with suicidal ideation severity in bivariate analyses, but not for the adjusted analyses. PCMHI is a setting seeing a high rate of suicidal ideation and may serve as a critical setting to implement suicide prevention efforts.

Socioeconomic Disparities and Metabolic Risk in Veterans with Serious Mental Illness.

Socioeconomic disparities were assessed in predicting metabolic risk among veterans with serious mental illness. Veterans with schizophrenia, schizoaffective, or bipolar disorders were identified in VISN 4 facilities from 10/1/2010 to 9/30/2012. Differences between patients with and without metabolic syndrome were compared using t-tests, Chi square tests and multivariate logistic regressions. Among 10,132 veterans with mental illness, 48.8% had metabolic syndrome. Multivariate logistic regression analysis confirmed that patients with metabolic syndrome were significantly more likely to be older, male, African-American, married, and receiving disability pensions but less likely to be homeless. They were more likely to receive antipsychotics, antidepressants, or anticonvulsants. Bivariate cross-sectional analysis revealed that patients with metabolic syndrome had higher rates of coronary artery disease, cerebrovascular disease, and mortality, and that metabolic syndrome was more often associated with emergency visits and psychiatric or medical hospitalizations. Demographics, socioeconomic status and medications are independent predictors of metabolic syndrome and should be considered in broader screening of risk factors in order to provide preventive interventions for metabolic syndrome.

Prevalence and correlates of suicidal ideation and suicide attempts among veterans in primary care referred for a mental health evaluation.

BACKGROUND: The Veterans Health Administration has made concerted efforts to increase mental health services offered in primary care. However, few studies have evaluated correlates of suicidal ideation and suicide attempt in veterans in primary care-mental health integration (PCMHI). The purpose of the present study is to examine associations between suicidal ideation and suicide attempts as dependent variables and demographic and clinical factors as the independent variables. METHODS: Veterans (n=3004) referred from primary care to PCMHI were contacted for further assessment, which included past-year severity of suicidal thoughts (none, low, high) and attempts using the Paykel Suicide Scale, mental health disorders, and illicit drug use. Multinomial logistic regression models were used to identify correlates of suicidal ideation and suicide attempts. RESULTS: Thoughts of taking one's life was endorsed by 24% of participants and suicide attempts were reported in 2%. In adjusted models, depression, psychosis, mania, PTSD and generalized anxiety disorder were associated with high severity suicidal ideation, but not suicide attempt. Illicit drug use was not associated with suicidal ideation, but was the only variable associated with suicide attempt. LIMITATIONS: The study was cross-sectional, focused on one clinical setting, and the suicide attempt analyses had limited power. CONCLUSIONS: PCMHI is a critical setting to assess suicidal ideation and suicide attempt and researchers and clinicians should be aware that the differential correlates of these suicide-related factors. Future research is needed to identify prospective risk factors and assess the utility of follow-up care in preventing suicide.

Dimensions of distress tolerance and the moderating effects on mindfulness-based stress reduction.

BACKGROUND AND OBJECTIVES: This study examined the relationship between distress tolerance and psychosocial changes among individuals participating in Mindfulness-Based Stress Reduction (MBSR). The objective of the analysis was to discern whether individuals with lower distress tolerance measured before MBSR showed larger reductions in perceived stress following MBSR. DESIGN AND METHODS: Data were collected from a sample of convenience (n = 372) using a quasi-experimental design. Participants completed self-report measures immediately prior to course enrollment and following course completion. RESULTS: Perceived stress, distress tolerance, and mood states showed favorable changes from pre- to post-MBSR in the current study. Baseline distress tolerance significantly moderated reductions on perceived stress, supporting the primary hypothesis that individuals with lower baseline distress tolerance evidenced a greater decline in perceived stress following MBSR. For a one-unit increase on the self-reported baseline Distress Tolerance Scale, reported perceived stress scores decreased by 2.5 units (p < .0001). CONCLUSIONS: The finding that individuals with lower baseline distress tolerance evidenced a greater decline in perceived stress may offer hints about who is most likely to benefit from MBSR and other mindfulness-based treatments. Identifying moderators of treatment outcomes may yield important benefits in matching individuals to treatments that are most likely to work for them.

Naltrexone vs Placebo for the Treatment of Alcohol Dependence: A Randomized Clinical Trial.

IMPORTANCE: Alcohol use disorder is one of the leading causes of disability worldwide. While effective pharmacological treatments exist, they are efficacious only in certain individuals, contributing to their limited use. Secondary analysis of clinical trial data suggests that a functional polymorphism (rs1799971, Asn40Asp) of the µ-opioid receptor gene (OPRM1) is associated with the risk of relapse to heavy drinking following treatment with the opioid antagonist naltrexone. OBJECTIVE: To prospectively examine whether rs1799971 is predictive of naltrexone treatment response. DESIGN, SETTING, AND PARTICIPANTS: We conducted a 12-week, double-blind, randomized clinical trial of naltrexone vs placebo in individuals with alcohol dependence (intent-to-treat analysis). Participants were randomly assigned to study treatment based on the presence of 1 or 2 copies of the Asp40 allele compared with those homozygous for the Asn40 allele (2 × 2 cell design). Recruitment occurred between January 2009 and September 2013. All participants were seen in an outpatient clinical setting. A convenience sample of participants (n = 221) was recruited from 5 sites. All participants met DSM-IV criteria for alcohol dependence, with no concurrent psychotic or manic symptoms, no use of concurrent psychotropic medications, and no current dependence on illicit substances. INTERVENTIONS: The study drug was naltrexone (50 mg) given once daily or corresponding placebo. MAIN OUTCOMES AND MEASURES: The primary study outcome measure was relapse to heavy drinking measured using the timeline follow-back method. RESULTS: There was no evidence of a genotype × treatment interaction on the primary outcome of heavy drinking (P = .32). In the Asn40 group, the observed effect of naltrexone was similar to that in previous trials (odds ratio, 0.69; 95% CI, 0.41-1.18; P = .17), with a very small naltrexone effect in the Asp40 group (odds ratio, 1.10; 95% CI, 0.52-2.31; P = .80), contrary to the pattern expected a priori. A significant reduction in heavy drinking occurred across all groups (P = .001). Other drinking outcomes, and all secondary outcomes, demonstrated similar time effects, with no genotype × treatment interaction. CONCLUSIONS AND RELEVANCE: The results of this study do not support the hypothesis that the Asp40 allele moderates the response to naltrexone treatment. It is premature to use the Asn40Asp polymorphism as a biomarker to predict the response to naltrexone treatment of alcohol dependence. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00831272.

Boundaries of schizoaffective disorder: revisiting Kraepelin.

IMPORTANCE: Established nosology identifies schizoaffective disorder as a distinct category with boundaries separating it from mood disorders with psychosis and from schizophrenia. Alternative models argue for a single boundary distinguishing mood disorders with psychosis from schizophrenia (kraepelinian dichotomy) or a continuous spectrum from affective to nonaffective psychosis. OBJECTIVE: To identify natural boundaries within psychotic disorders by evaluating associations between symptom course and long-term outcome. DESIGN, SETTING, AND PARTICIPANTS: The Suffolk County Mental Health Project cohort consists of first-admission patients with psychosis recruited from all inpatient units of Suffolk County, New York (72% response rate). In an inception cohort design, participants were monitored closely for 4 years after admission, and their symptom course was charted for 526 individuals; 10-year outcome was obtained for 413. MAIN OUTCOMES AND MEASURES: Global Assessment of Functioning (GAF) and other consensus ratings of study psychiatrists. RESULTS: We used nonlinear modeling (locally weighted scatterplot smoothing and spline regression) to examine links between 4-year symptom variables (ratio of nonaffective psychosis to mood disturbance, duration of mania/hypomania, depression, and psychosis) and 10-year outcomes. Nonaffective psychosis ratio exhibited a sharp discontinuity-10 days or more of psychosis outside mood episodes predicted an 11-point decrement in GAF-consistent with the kraepelinian dichotomy. Duration of mania/hypomania showed 2 discontinuities demarcating 3 groups: mania absent, episodic mania, and chronic mania (manic/hypomanic >1 year). The episodic group had a better outcome compared with the mania absent and chronic mania groups (12-point and 8-point difference on GAF). Duration of depression and psychosis had linear associations with worse outcome. CONCLUSIONS AND RELEVANCE: Our data support the kraepelinian dichotomy, although the study requires replication. A boundary between schizoaffective disorder and schizophrenia was not observed, which casts further doubt on schizoaffective diagnosis. Co-occurring schizophrenia and mood disorder may be better coded as separate diagnoses, an approach that could simplify diagnosis, improve its reliability, and align it with the natural taxonomy.