Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial.

CONTEXT: Serotonin reuptake-inhibiting (SRI) antidepressants are the only FDA-approved pharmacotherapies for the treatment of posttraumatic stress disorder (PTSD). OBJECTIVE: To determine efficacy of the second-generation antipsychotic risperidone as an adjunct to ongoing pharmacologic and psychosocial treatments for veterans with chronic military-related PTSD. DESIGN, SETTING, AND PARTICIPANTS: A 6-month, randomized, double-blind, placebo-controlled multicenter trial conducted between February 2007 and February 2010 at 23 Veterans Administration outpatient medical centers. Of the 367 patients screened, 296 were diagnosed with military-related PTSD and had ongoing symptoms despite at least 2 adequate SRI treatments, and 247 contributed to analysis of the primary outcome measure. INTERVENTION: Risperidone (up to 4 mg once daily) or placebo. MAIN OUTCOME MEASURES: The Clinician-Administered PTSD Scale (CAPS) (range, 0-136). Other measures included the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Scale (HAMA), Clinical Global Impression scale (CGI), and Veterans RAND 36-Item Health Survey (SF-36V). RESULTS: Change in CAPS scores from baseline to 24 weeks in the risperidone group was -16.3 (95% CI, -19.7 to -12.9) and in the placebo group, -12.5 (95% CI, -15.7 to -9.4); the mean difference was 3.74 (95% CI, -0.86 to 8.35; t = 1.6; P = .11). Mixed model analysis of all time points also showed no significant difference in CAPS score (risperidone: mean, 64.43; 95% CI, 61.98 to 66.89, vs placebo: mean, 67.16; 95% CI, 64.71 to 69.62; mean difference, 2.73; 95% CI, -0.74 to 6.20; P = .12). Risperidone did not reduce symptoms of depression (MADRS mean difference, 1.19; 95% CI, -0.29 to 2.68; P = .11) or anxiety (HAMA mean difference, 1.16; 95% CI, -0.18 to 2.51; P = .09; patient-rated CGI mean difference, 0.20; 95% CI, -0.06 to 0.45; P = .14; observer-rated CGI mean difference, 0.18; 95% CI, 0.01 to 0.34; P = .04), or increase quality of life (SF-36V physical component mean difference, -1.13, 95% CI, -2.58 to 0.32; P = .13; SF-36V mental component mean difference, -0.26; 95% CI, -2.13 to 1.61; P = .79). Adverse events were more common with risperidone vs placebo, including self-reported weight gain (15.3% vs 2.3%), fatigue (13.7% vs 0.0%), somnolence (9.9% vs 1.5%), and hypersalivation (9.9% vs 0.8%), respectively. CONCLUSION: Among patients with military-related PTSD with SRI-resistant symptoms, 6-month treatment with risperidone compared with placebo did not reduce PTSD symptoms. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00099983.

Design of the National Adaptive Trial for PTSD-related Insomnia (NAP Study), VA Cooperative Study Program (CSP) #2016.

There are currently no validated pharmacotherapies for posttraumatic stress disorder (PTSD)-related insomnia. The purpose of the National Adaptive Trial for PTSD-Related Insomnia (NAP Study) is to efficiently compare to placebo the effects of three insomnia medications with different mechanisms of action that are already prescribed widely to veterans diagnosed with PTSD within U.S. Department of Veterans Affairs (VA) Medical Centers. This study plans to enroll 1224 patients from 34 VA Medical Centers into a 12- week prospective, randomized placebo-controlled clinical trial comparing trazodone, eszopiclone, and gabapentin. The primary outcome measure is insomnia, assessed with the Insomnia Severity Index. A novel aspect of this study is its adaptive design. At the recruitment midpoint, an interim analysis will be conducted to inform a decision to close recruitment to any "futile" arms (i.e. arms where further recruitment is very unlikely to yield a significant result) while maintaining the overall study recruitment target. This step could result in the enrichment of the remaining study arms, enhancing statistical power for the remaining comparisons to placebo. This study will also explore clinical, actigraphic, and biochemical predictors of treatment response that may guide future biomarker development. Lastly, due to the COVID-19 pandemic, this study will allow the consenting process and follow-up visits to be conducted via video or phone contact if in-person meetings are not possible. Overall, this study aims to identify at least one effective pharmacotherapy for PTSD-related insomnia, and, perhaps, to generate definitive negative data to reduce the use of ineffective insomnia medications. NATIONAL CLINICAL TRIAL (NCT) IDENTIFIED NUMBER: NCT03668041.

A tobacco reconceptualization in psychiatry: toward the development of tobacco-free psychiatric facilities.

Tobacco dependence is the leading cause of death in persons with psychiatric and substance use disorders. This has lead to interest in the development of pharmacological and behavioral treatments for tobacco dependence in this subset of smokers. However, there has been little attention paid to the development of tobacco-free environments in psychiatric institutions despite the creation of smoke-free psychiatric hospitals mandated by the Joint Commission for Accreditation of Health Organizations (JCAHO) in 1992. This review article addresses the reasons why tobacco should be excluded from psychiatric and addictions treatment settings, and strategies that can be employed to initiate and maintain tobacco-free psychiatric settings. Finally, questions for further research in this field are delineated. This Tobacco Reconceptualization in Psychiatry is long overdue, given the clear and compelling benefits of tobacco-free environments in psychiatric institutions.

Survey of clinician attitudes toward smoking cessation for psychiatric and substance abusing clients.

The current study examined mental health clinician attitudes regarding smoking cessation for psychiatric and substance abusing patients. Participants included n = 15 never smokers, n = 12 former smokers, and n = 7 current smokers. There was a trend (p = 0.08) for current smokers as compared to former and never smokers to be less likely to encourage their clients to stop smoking. Overall, clinicians strongly agreed that an individual's motivation is the most important determinant of success in quitting. Clinicians were concerned that smoking cessation would initiate a relapse to substance abuse. We suggest that mental health clinicians can be instrumental in providing information, encouragement, and opportunities for their patients to attempt smoking cessation.

Effects of acute abstinence, reinstatement, and mecamylamine on biochemical and behavioral measures of cigarette smoking in schizophrenia.

BACKGROUND: Schizophrenics have higher rates of smoking than the general population, and more difficulty with smoking cessation. However, there has been little study of differences between schizophrenics and controls with respect to biochemical and behavioral indices of smoking. We compared smokers with schizophrenia (SS; n=27) and control smokers (CS; n=26) on smoking and psychiatric outcomes at baseline, during acute smoking abstinence and reinstatement, and with pre-treatment using the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC) in a human laboratory setting. METHODS: Biochemical (e.g., plasma nicotine) and behavioral (e.g., craving, withdrawal) outcomes were assessed at baseline, after overnight abstinence, and after smoking reinstatement during three consecutive test weeks. Each week, participants received one of three doses of MEC (0.0, 5.0, or 10.0 mg/dayx3 days) in a randomized, counterbalanced manner. RESULTS: Compared to CS, SS displayed similar levels of craving and withdrawal, but higher plasma nicotine and cotinine levels, and cotinine/CPD ratio. During reinstatement, SS consumed significantly more cigarettes than CS, but MEC did not significantly alter indices of smoking, psychiatric symptoms, or cigarette consumption during reinstatement. CONCLUSIONS: 1) The reinforcing effects of smoking may be increased in SS versus CS after overnight abstinence; 2) the lack of effects of nAChR antagonism may suggest that non-nicotinic components of cigarettes may contribute to the behavioral effects of smoking in both SS and CS; and 3) consistent with previous studies, SS may exhibit higher baseline levels of nicotine and cotinine, and greater extraction of nicotine per cigarette than CS.

Reliability of the Fagerström Test for Nicotine Dependence, Minnesota Nicotine Withdrawal Scale, and Tiffany Questionnaire for Smoking Urges in smokers with and without schizophrenia.

Few studies have examined the psychometrics of smoking-related behavioral measures in schizophrenia and questions have been raised about the applicability to smokers with schizophrenia. We examined the reliability of the Fagerström Test for Nicotine Dependence (FTND), Minnesota Nicotine Withdrawal Scale (M-NWS), and the Tiffany Questionnaire for Smoking Urges (TQSU) for smokers with schizophrenia (SS; n=151) and nonpsychiatric smokers (CS; n=181) recruited into three studies with similar inclusion criteria. SS and CS did not differ on a number of demographic and smoking variables (e.g., age). SS reported higher carbon monoxide (CO) levels, plasma cotinine levels, FTND, M-NWS, and TQSU Factor 1 scores. The internal consistencies (Cronbach's alpha) of the smoking measures were found to be high and comparable between diagnostic groups for the FTND, M-NWS total scores, and TQSU Factor 2 (all alpha's>0.70) but higher for the CS than SS for the TQSU Factor 1 (0.86 versus 0.79). Test-retest correlations were lower for SS than CS on the FTND (0.65 versus 0.82), TQSU Factor 1 (0.65 versus 0.79), and TQSU Factor 2 (0.69 versus 0.81), but did not differ between diagnostic groups for M-NWS (0.58 versus 0.64). Our findings suggest that these measures may be reliable for use in smokers with schizophrenia.

Neuropsychological deficits in nonsmokers with schizophrenia: effects of a nicotinic antagonist.

BACKGROUND: Biochemical, physiological and genetic evidence suggests dysregulation of central nicotinic acetylcholine receptor (nAChR) systems in schizophrenia, which may contribute to neuropsychological dysfunction and the high rates of smoking in this disorder. To evaluate the effects of nAChR blockade on neuropsychological performance in schizophrenia without the confounding effects of cigarette smoking, we compared neuropsychological performance in schizophrenia and healthy control nonsmokers after pre-treatment with the centrally-acting nAChR antagonist mecamylamine (MEC). METHODS: Using a within-subjects, counterbalanced design, schizophrenia (n = 14) and control (n = 15) nonsmokers were pre-treated for 3 days with MEC (0.0, 5.0, and 10.0 mg/day). Subjects performed repeated neuropsychological assessments including visuospatial working memory (VSWM), Continuous Performance Test (CPT), Wisconsin Card Sorting Test (WCST), Word Serial Position Test (WSPT) and Stroop Color Word Test (SCWT) during three sequential test sessions per week over three test weeks. RESULTS: We found significant main effects of schizophrenia diagnosis on: VSWM 30 and 60 delays (p's < 0.01), CPT (% Hit Rate, Reaction Time, Variability Index; p < 0.01 for all outcomes), WCST (p < 0.01 for all outcomes) and Word Serial Position Test (p < 0.01). However, there were no main effects of repeated test administration (Session) or MEC dose on any of these outcomes, and no significant 3-way (DiagnosisxSessionxMEC dose) interactions. CONCLUSIONS: Our results suggest that there are a broad range of neuropsychological deficits in nonsmokers with schizophrenia. Furthermore, pretreatment with a centrally-acting nAChR antagonist did not alter neuropsychological performance in either nonsmoking patients with schizophrenia or controls.

A preliminary study of the effects of cigarette smoking on prepulse inhibition in schizophrenia: involvement of nicotinic receptor mechanisms.

BACKGROUND: Schizophrenics exhibit deficits in prepulse inhibition (PPI) of the startle response, and have high rates of cigarette smoking. We evaluated the effects of cigarette smoking on PPI deficits in schizophrenia, and the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related PPI enhancement. METHODS: PPI was assessed at baseline, after overnight abstinence, and after smoking reinstatement during three separate test weeks in nicotine-dependent schizophrenia (n=15) and control (n=14) smokers pre-treated with the nAChR antagonist mecamylamine (MEC; 0.0, 5.0 or 10.0 mg/day). RESULTS: PPI was comparable between schizophrenia and control smokers after ad lib cigarette smoking. Overnight smoking abstinence significantly reduced PPI, while smoking reinstatement reversed abstinence-induced worsening of PPI deficits in schizophrenia. However, acute abstinence and reinstatement did not alter PPI in controls. PPI enhancement by smoking reinstatement in schizophrenia was dose-dependently blocked by MEC, whereas MEC had no effect on PPI in control smokers. CONCLUSIONS: These results suggest that: 1) Non-deprived smokers with schizophrenia have comparable levels of PPI to non-deprived smoking controls; 2) In schizophrenia, PPI is impaired by smoking abstinence and improved by acute smoking reinstatement, and; 3) enhancement of PPI by cigarette smoking in schizophrenia is mediated by stimulation of central nAChRs. Our findings may contribute to understanding the increased vulnerability to nicotine dependence in schizophrenia, with implications for treatment of PPI deficits in this disorder.

Effects of cigarette smoking on spatial working memory and attentional deficits in schizophrenia: involvement of nicotinic receptor mechanisms.

BACKGROUND: Cigarette smoking rates in schizophrenia are higher than in the general population. OBJECTIVES: To determine whether cigarette smoking modifies cognitive deficits in schizophrenia and to establish the role of nicotinic acetylcholine receptors (nAChRs) in mediating cigarette smoking-related cognitive enhancement. DESIGN: Neuropsychological assessments were performed at smoking baseline, after overnight abstinence, and after smoking reinstatement across 3 separate test weeks during which subjects were pretreated in a counterbalanced manner with the nonselective nAChR antagonist mecamylamine hydrochloride (0, 5, or 10 mg/d). PARTICIPANTS: Twenty-five smokers with schizophrenia and 25 control smokers. SETTING: Outpatient mental health center. MAIN OUTCOME MEASURES: Visuospatial working memory (VSWM) and Continuous Performance Test (CPT) scores. RESULTS: In smokers with schizophrenia and control smokers, overnight abstinence led to undetectable plasma nicotine levels and an increase in tobacco craving. While abstinence reduced CPT hit rate in both groups, VSWM was only impaired in smokers with schizophrenia. Smoking reinstatement reversed abstinence-induced cognitive impairment. Enhancement of VSWM and CPT performance by smoking reinstatement in smokers with schizophrenia, but not the subjective effects of smoking, was blocked by mecamylamine treatment. CONCLUSIONS: Cigarette smoking may selectively enhance VSWM and attentional deficits in smokers with schizophrenia, which may depend on nAChR stimulation. These findings may have implications for understanding the high rates of smoking in schizophrenia and for developing pharmacotherapies for cognitive deficits and nicotine dependence in schizophrenia.

Sleep disturbance in chronic military-related PTSD: clinical impact and response to adjunctive risperidone in the Veterans Affairs cooperative study #504.

OBJECTIVE: Sleep disturbances are common among veterans with chronic military-related posttraumatic stress disorder (PTSD). This article reports the results of a multicenter clinical trial that explored the clinical correlates of reported sleep impairment in these veterans and tested the impact of the second-generation antipsychotic risperidone upon these symptoms. METHOD: This article reports secondary analyses of a 24-week multicenter randomized placebo-controlled trial of adjunctive risperidone in patients with chronic military-related PTSD symptoms (n = 267, 97% male) who were symptomatic despite treatment with antidepressants and other medications. The study was conducted between February 2007 and February 2010. DSM-IV PTSD diagnoses were made by using the Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Nonpatient Edition. Sleep disturbances were assessed principally by using the Pittsburgh Sleep Quality Index (PSQI) (primary outcome measure). Analyses were conducted using bivariate correlations and longitudinal mixed model regressions. RESULTS: Eighty-eight percent of the patients in this study had clinically significantly impaired sleep on the PSQI. Severity of sleep disturbances correlated with PTSD symptom severity as measured by the Clinician-Administered PTSD Scale (CAPS) and reductions in multiple measures of quality of life (Veterans RAND 36-item Health Survey [SF-36 V] subscales, Boston Life Satisfaction Index). Risperidone produced small but statistically significant effects on total PSQI scores (main effect of drug: F1,228 = 4.57, P = .034; drug-by-time interaction: F2,421 = 4.32, P = .014) and severity of nightmares as assessed by the CAPS (main effect of drug: F1,248 = 4.60, P = .033). The improvements in sleep quality produced by risperidone correlated with reductions in PTSD symptom severity and improvement in the mental health subscale of the SF-36 V. CONCLUSIONS: This study highlighted the near universality and significant negative impact of severe disturbances in sleep quality in veterans with chronic military-related PTSD who were partial responders to standard pharmacotherapies. The modest improvements in sleep quality produced by adjunctive risperidone were correlated with limited reductions in PTSD severity and improvements in quality of life. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00099983.

Smoking cue reactivity in schizophrenia: effects of a nicotinic receptor antagonist.

BACKGROUND: Rates of cigarette smoking in schizophrenia are higher than in the general population. To investigate differences in sensitivity to smoking cues between schizophrenia and control subjects, we compared smoking cue reactivity (CR) in schizophrenia versus control smokers with and without pretreatment with the nicotinic acetylcholine receptor (nAChR) antagonist mecamylamine (MEC). METHODS: Smoking CR in schizophrenia (n = 22) and nonpsychiatric control (n = 20) smokers was determined using exposure to smoking pictures. Three doses of MEC (0, 5, and 10 mg/day) were administered during the 3 test weeks to determine the role of nAChRs in mediating the smoking CR response. RESULTS: Eleven of 22 (50%) schizophrenia and 10 of 20 (50%) control smokers displayed smoking CR. Smoking CR was not significantly different between schizophrenia and control smokers in the placebo (0 mg/day) condition. However, MEC pretreatment produced a dose-dependent reduction of CR in schizophrenia smokers compared with placebo. There was no significant effect of MEC on CR in control smokers. CONCLUSIONS: Our findings suggest that blockade of CR by MEC may be more robust in schizophrenia versus control smokers, possibly due to reduced nAChR levels in the brains of patients with schizophrenia.

A placebo controlled trial of bupropion for smoking cessation in schizophrenia.

BACKGROUND: Schizophrenic patients have high rates of cigarette smoking compared with the general population. We compared sustained-release (SR) bupropion with placebo for smoking cessation in patients with schizophrenic disorders. We also examined how antipsychotic class predicts smoking cessation outcomes with bupropion. METHODS: Thirty-two subjects meeting DSM-IV criteria for schizophrenia or schizoaffective disorder and nicotine dependence were randomized to bupropion SR (BUP, 300 mg/day) or placebo (PLA). Outcomes included treatment retention, smoking abstinence rates, expired breath carbon monoxide (CO) levels, psychotic symptoms, and medication side effects. RESULTS: Bupropion significantly increased trial endpoint 7-day point prevalence smoking abstinence rates compared with placebo [BUP, 8/16 (50.0%), PLA, 2/16 (12.5%); chi(2) = 5.24, df = 1, p <.05], and reduced CO levels during the trial [Medication x Time interaction; Z = 3.09, p <.01]. Positive schizophrenia symptoms were not altered by BUP, but negative symptoms were significantly reduced. Atypical antipsychotic drug treatment enhanced smoking cessation responses to BUP. Major side effects were dry mouth, gastrointestinal symptoms, headache, and insomnia. CONCLUSIONS: Our results suggest that 1) BUP enhances smoking abstinence rates compared with PLA in nicotine-dependent schizophrenic smokers; 2) BUP is well-tolerated and safe for use in these patients; and 3) atypical antipsychotics may enhance smoking cessation outcomes with BUP.

A preliminary placebo-controlled trial of selegiline hydrochloride for smoking cessation.

BACKGROUND: Since dopaminergic mechanisms appear to be involved in nicotine dependence, we studied the safety and efficacy of the monoamine oxidase B inhibitor selegiline hydrochloride compared with placebo for smoking cessation in nicotine-dependent cigarette smokers. METHODS: Forty subjects with DSM-IV nicotine dependence were randomized to: 1) selegiline hydrochloride (5 mg p.o. twice daily) or 2) placebo in an 8-week trial. Outcome measures included smoking cessation rates, treatment retention, and medication side effects. RESULTS: Selegiline hydrochloride increased trial end point (week 8) 7-day point prevalence smoking cessation rates (selegiline hydrochloride, 9/20 [45.0%]; placebo, 3/20 [15.0%], odds ratio = 4.64, 95% CI, 1.02-21.00, p <.05), and smoking cessation rates during the last 4 weeks of the trial (selegiline hydrochloride, 6/20 [30.0%]; placebo, 1/20 [5.0%], odds ratio = 8.14, 95% CI, 0.88-75.48, p =.07) in comparison with placebo. Six-month follow-up 7-day point prevalence smoking cessation rates were reduced compared with trial end point (selegiline hydrochloride, 4/20 [20.0%]; placebo, 1/20 [5.0%], odds ratio = 4.75, 95% CI, 0.48-46.91, p =.18). Treatment retention was similar between drug and placebo groups (p =.13), and selegiline hydrochloride was well tolerated in cigarette smokers. CONCLUSION: This preliminary study suggests that selegiline (10 mg/day) is safe for use and enhances smoking cessation rates compared with placebo in nicotine-dependent cigarette smokers.

Effects of smoking abstinence on visuospatial working memory function in schizophrenia.

Schizophrenic patients have impairments in cognitive function, including deficits in visuospatial working memory (VSWM). VSWM is mediated, in part, by prefrontal cortical dopamine (DA) function, and dysregulation of prefrontal cortical DA systems may contribute to the pathophysiology of schizophrenia. Nicotine has complex effects on spatial working memory (SWM) in animal studies, with most studies demonstrating enhancement of SWM. Cigarette smoking is highly prevalent in schizophrenia, and these patients may smoke cigarettes to remediate cognitive deficits. The present study examined the effects of acute (<1 week) and prolonged (8-10 weeks) smoking abstinence on VSWM in schizophrenic (n = 23) and control (n = 29) nicotine-dependent cigarette smokers during placebo-controlled smoking cessation trials. Schizophrenic and control smoking patients had significant impairments in VSWM compared to non-smoking controls, after adjusting for differences in age, education and depressive symptoms. Schizophrenic smokers who quit smoking had further impairments in VSWM, and control quitters had improvements in VSWM. Abstinence-induced changes in VSWM varied as a function of gender in controls, but not in schizophrenics. These changes in VSWM appeared to be independent of study medications, and smoking abstinence did not significantly alter performance on the Stroop Color Word Test in either group. These results suggest that smoking abstinence differentially alters VSWM in schizophrenic vs. control smokers, and that cigarette smoking has beneficial effects on VSWM in schizophrenic, but not control, smokers.

Neuropsychological deficits are associated with smoking cessation treatment failure in patients with schizophrenia.

Schizophrenics have deficits in neuropsychological performance, some of which are modified by cigarette smoking. These patients also have high rates of smoking and resistance to smoking cessation interventions. We examined whether the presence of neuropsychological deficits prior to smoking cessation treatment was associated with smoking cessation treatment failure in schizophrenic as compared to non-psychiatric control smokers. Neuropsychological assessments were performed prior to treatment with pharmacological agents during the course of placebo-controlled trials in schizophrenic and non-psychiatric control smokers, and included the Wisconsin Card Sorting Test (WCST), a Visuospatial Working Memory (VSWM) task, the Stroop Color Word Test (SCWT) and the Continuous Performance Test (CPT). In schizophrenics (n=32), subjects who had greater deficits in VSWM and WCST performance were significantly less likely to quit smoking, but this association was not observed in controls (n=40). Differences between quitters and non-quitters were not likely related to atypical antipsychotic treatment or differences in depressive symptoms. No associations between baseline performance on CPT or SCWT and quit status were found in either group. These preliminary data suggest that in schizophrenics, neuropsychological deficits are associated with smoking cessation treatment failure.