Kimberly R. Warren

Cigarette Smoking and Mortality Risk in People With Schizophrenia

This study examined effects of cigarette smoking on mortality risk in 1213 persons aged 19-69 years with schizophrenia-related psychotic disorders admitted to State of Maryland Hospitals between 1994 and 2000. Inpatient medical records from 7 hospitals were reviewed to obtain demographic information, diagnosis, medication use, as well as smoking and other substance use. Social Security Death Index data were used to identify deaths in the study group between 1994 and 2004. Death records were reviewed to obtain manner of death and underlying disorders. Of the 1213, 55% were smokers and 71% abused substances. There was an age × smoking interaction (χ(2) = 14.6, df = 1, P = .0001) for mortality, with estimated hazard ratios (HRs) for smokers vs nonsmokers of 2.1 among 35- to 54-year olds and HR of 0.7 among those aged 55-69 years. Five- and 10-year mortality rates for smokers aged 35-54 years were 7.0% and 14.2%, compared with 3.3% and 10.0% for nonsmokers, respectively (χ(2) = 5.53, df = 1, P = .019). Cardiac causes were identified in 43% of deaths in smokers but only 19% of deaths in nonsmokers (P < .006). For those aged 35-54 years, the odds of cardiac related death was increased by 12 fold in smokers relative to nonsmokers (HR = 12.4, χ(2) = 12.0, df = 1, P = .0005). Among people aged 35-54 years, those smoking greater than one pack daily have a significantly increased total mortality risk (HR = 2.7) vs nonsmokers. Cigarette smoking, particularly in people aged 35-54 years, contributes to an increased risk of death. Greater smoking severity significantly increases this risk. Smoking cessation in people with schizophrenia deserves significant attention.

Anticipatory vs. Consummatory Pleasure: What is the Nature of Hedonic Deficits in Schizophrenia?

Recent research has distinguished between anticipatory and consummatory pleasure. In the current study, we examined the psychometric properties of the Temporal Experience of Pleasure Scale (TEPS) to determine whether reliability and validity findings reported in previous research replicate in an additional sample of schizophrenia patients. Participants included 86 individuals with schizophrenia and 59 demographically matched healthy controls. Inconsistent with previous research, patients differed from controls in their reports of consummatory (TEPS-CON), but not anticipatory (TEPS-ANT) pleasure. We also failed to replicate some important correlational findings reported in previous research indicating relationships between the TEPS-ANT subscale and external validators. Analyses of the stability of the TEPS subscales were conducted in a sub-group of patients (n=19), and indicated excellent stability for the TEPS-CON (ICC (intraclass correlation coefficient)=0.93), but somewhat lower stability for the TEPS-ANT subscale (ICC=0.74). These findings suggest that additional studies are needed using the TEPS, as well as other measures, to determine the nature of anhedonia in individuals with schizophrenia.

Cardiovascular disease mortality in patients with chronic schizophrenia treated with clozapine: a retrospective cohort study.

BACKGROUNDnCardiovascular disease (CVD) mortality in schizophrenia is more frequent than in the general population. Whether second-generation antipsychotics (SGAs) increase risk of CVD morbidity and mortality has yet to be determined.nnnMETHODnWe conducted a retrospective cohort study using an administrative database to identify patients with DSM-III- or DSM-IV-diagnosed schizophrenia, treated in Maryland, who started clozapine treatment (n = 1,084) or were never treated with clozapine (initiated on risperidone; n = 602) between 1994 and 2000. Deaths between 1994 and 2004 were identified by the Social Security Death Index, and death records were obtained.nnnRESULTSnDuring the 6- to 10-year follow-up period, there were 136 deaths, of which 43 were attributed to CVD. Cardiovascular disease mortality in patients aged younger than 55 years at medication start was approximately 1.1% (clozapine, 1.1%; risperidone, 1.0%) in both groups at 5 years and 2.7% (clozapine) and 2.8% (risperidone) at 10 years (chi(2)(1) = 0.12, P = .73). Patients who started treatment at ages >or= 55 years had CVD mortality of 8.5% (clozapine) and 3.6% (risperidone) at 5 years and 16.0% (clozapine) and 5.7% (risperidone) at 10 years (chi(2)(1) = 2.13, P = .144). In a Cox regression model, patients aged >or= 55 years were at greater risk of mortality than younger patients (hazard ratio = 4.6, P < .001); whites were at greater risk than nonwhites (HR = 2.1, P = .046); however, SGA treatment (HR = 1.2; 95% CI, 0.6-2.4; P = .61) and sex (HR = 0.9, P = .69) were not statistically significant predictors of CVD, nor was there a significant age x clozapine interaction (chi(2)(1) = 1.52, P = .22). Age-, race-, and gender-adjusted standardized mortality ratios were significantly elevated (clozapine, 4.70; 95% CI, 3.19-6.67; risperidone, 2.88; 95% CI, 1.38-5.30) compared to year 2000 rates for the Maryland general population but did not differ by antipsychotic group (chi(2)(1) = 1.42, P = .23).nnnCONCLUSIONSnThe risk of CVD mortality in schizophrenia does not differ between clozapine and risperidone in adults despite known differences in risk profiles for weight gain and metabolic side effects. However, we cannot rule out an increased risk of CVD mortality among those starting treatment at ages 55 years or older.

Effects of the Cannabinoid-1 Receptor Antagonist Rimonabant on Psychiatric Symptoms in Overweight People With Schizophrenia: A Randomized, Double-Blind, Pilot Study

Weight gain is a major adverse effect of several second-generation antipsychotic medications. Rimonabant is a cannabinoid-1 receptor antagonist that promotes weight loss in the general population. We conducted a 16-week, double-blind, placebo-controlled study of rimonabant (20 mg/d) in people with schizophrenia or schizoaffective disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria, who were clinically stable on second-generation antipsychotics. Participants had a body mass index of 27 kg/m2 or higher with hyperlipidemia or body mass index of 30 kg/m2 or higher, and no current substance abuse/dependence (except nicotine), more than weekly cannabis use, or recent depressive symptoms/suicidality. An exercise and dietary counseling group was offered weekly. Target enrollment was 60; the trial was terminated early because of withdrawal of rimonabant from the European market. Fifteen participants were randomized (7 rimonabant, 8 placebo); 5 completed in each group. Rimonabant was associated with a greater reduction in Brief Psychiatric Rating Scale total score versus placebo (mean ± SE difference, −1.9 ± 0.8, P = 0.02), driven by differences in the Brief Psychiatric Rating Scale anxiety/depression (−1.4 ± 0.35, P = 0.0004) and hostility (−0.7 ± 0.3, P = 0.02) factors. Group differences were not significant for the Calgary Depression Scale total score (P = 0.24), Scale for the Assessment of Negative Symptoms total score (P = 0.13), weight, blood pressure, or fasting lipids or glucose. Rimonabant was well tolerated with no significant adverse events. No significant weight loss, metabolic effects, or adverse psychiatric effects were associated with the cannabinoid-1 receptor antagonist rimonabant in this small sample of people with schizophrenia. The endocannabinoid system remains a promising target for pharmacotherapy of schizophrenia and obesity.

Role of chronic stress and depression in periodontal diseases

Abstract An extensive body of experimental and clinical evidence documents the negative impact of chronic psychological stress and depression on the immune system and health. Chronic stress and depression can result in general dysregulation of the immune system, of both cellular and humoral pathways, which may contribute to pathogenic infection and concomitant periodontal tissue destruction. In general, the evidence is consistent with the hypothesis that stress can modify the host defense and progression of periodontal infections in patients susceptible to periodontitis. However, substantial evidence also indicates that these conditions can mediate risk for disease, including periodontitis, through changes in health‐related behaviors, such as oral hygiene, smoking and diet. The unequivocal interpretation of studies has also been hampered, in part, by issues related to conceptualization of stress and depression, as well as commonly associated comorbidities, such as diabetes, that can modify the onset and progression of periodontal disease. In addition, stress and depression appear to fall into a spectrum, ranging from mild to severe, involving a complex interaction of genetic background, coping strategies and environment. Differences in the conceptualization of stress and depression are probably important in assessing associations with other biologic and clinical measures. Future studies are necessary to clarify the complex interactions of chronic stress and depression in periodontal diseases.

Alcohol and cannabis use and mortality in people with schizophrenia and related psychotic disorders

The impact of co-morbid substance use on mortality is not well studied in psychotic disorders. The objective of this study was to examine the impact of substance use on mortality in people with psychotic disorders and alcohol and/or drug use. We examined the rate of substance use and the risk of substance use on mortality risk over a 4-10 year period in 762 people with psychotic disorders. Deceased patients were identified from the Social Security Death Index and the Maryland Division of Vital Records. Substance use was defined as regular and heavy use or abuse or dependence. Seventy seven percent had co-morbid lifetime substance use, with co-morbid cannabis and alcohol use occurring most commonly. Out of 762 subjects, 62 died during follow up. In a Cox model, predicted mortality risk was higher in age group 35-55 compared to <35 years and in males, but reduced in cannabis users. Overall five- (3.1% vs 7.5%) and ten-year mortality risk (5.5% vs. 13.6%) was lower in cannabis users than in non-users with psychotic disorders (pxa0=xa00.005) in a survival model. Alcohol use was not predictive of mortality. We observed a lower mortality risk in cannabis-using psychotic disorder patients compared to cannabis non-users despite subjects having similar symptoms and treatments. Future research is warranted to replicate these findings and to shed light on the anti-inflammatory properties of the endocannabinoid system and its role in decreased mortality in people with psychotic disorders.

Exercise Program Adherence Using a 5-Kilometer (5K) Event as an Achievable Goal in People With Schizophrenia

People with schizophrenia have a higher prevalence of obesity than the general population. Many people with this illness struggle with weight gain, due, in part, to medications and other factors that act as obstacles to exercise and healthy eating. Several studies have shown the benefits of behavioral weight loss programs targeting eating and/or exercise in people with schizophrenia. Fewer studies have used competitive events as a goal for an exercise program. The current study tested the feasibility of preparing, using an exercise program, for a 5-kilometer (5K) event in people with schizophrenia. The exercise program was a 10-week training program consisting of three supervised walking/jogging sessions per week and a weekly educational meeting on healthy behaviors. Almost 65% (11/17) of the subjects participated in all of the training sessions, and 82% (14/17) participated in the 5K event. Participants did not gain a significant amount of weight during the exercise program (median weight change = 0.7 kg; 25th percentile 0.5, 75th percentile 3.9, p = .10). This study suggests that using an achievable goal, such as a 5K event, promotes adherence to an exercise program and is feasible in a population of people with chronic schizophrenia.

Placebo-Controlled Trial of Atomoxetine for Weight Reduction in People with Schizophrenia Treated with Clozapine or Olanzapine

BACKGROUNDnIn recent years, several pharmacological and psychosocial interventions have examined ways to prevent or treat weight gain in people receiving second-generation antipsychotics. While there has been some success, in general, results have not been compelling. Atomoxetine is a selective norepinepherine reuptake inhibitor found to be associated with appetite suppression. Therefore, we examined whether atomoxetine may be of benefit for those who have gained weight on either clozapine or olanzapine.nnnMETHODSnThe study was a double-blind, placebo-controlled trial. All participants received the same psychosocial platform: a structured support and exercise group. People with schizophrenia or schizoaffective disorder, on olanzapine or clozapine, who had gained at least 7% of their pre-clozapine or pre-olanzapine weight were eligible for a 24-week, randomized, parallel group, double-blind comparison of adjunctive atomoxetine or placebo.nnnRESULTSnThirty-seven participants (20 atomoxetine, 17 placebo) were randomized and 26 participants (14 atomoxetine, 12 placebo; 70.2%) completed the study. There were no significant group differences in baseline BMI (atomoxetine: 34.5±4.9; placebo: 35.7±7.0) or weight (atomoxetine: 102.2±15.7 kg; placebo: 104.3±17.5 kg). Both treatment groups showed modest, not significant, trends in weight loss, averaging about 2 kg. Gender or baseline antipsychotic treatment did not modify treatment effects on weight. Secondary outcomes included neuropsychological assessments, symptom assessments (BPRS, SANS) and safety assessments. Of these, only the group difference in Gordon distractibility test scores was statistically significant and favored treatment with atomoxetine.nnnCONCLUSIONSnAtomoxetine is not effective for weight loss in this population, but both olanzapine and clozapine participants can lose weight with structured group support and exercise.

Psychiatric symptom differences in people with schizophrenia associated with substantial lifetime substance use but no current substance use disorder

People with schizophrenia who have current substance use disorder (SUD) are generally excluded from clinical trials for the following reasons: safety/side effect risk, concern about adherence to the study protocol (Kreyenbuhl et al., 2011) and avoidance of confounds to efficacy evaluations (Buchanan et al., 2010). Patients with a past history of SUD are generally not excluded, but may represent a population with similar potentially unfavorable characteristics. To evaluate the possible consequences of this differential exclusion practice, we examined baseline symptoms of participants with substantial lifetime substance use and compared to participants with no substantial lifetime substance use in a sample of 15 outpatients with schizophrenia or schizoaffective disorder (DSM-IV criteria) enrolled in a controlled clinical trial of an adjunct weight loss medication (Kelly et al., 2011; Boggs et al., 2012). This analysis includes the full sample of patients enrolled in the clinical trial, which was prematurely terminated because of withdrawal of the experimental compound; thus, within-study sample bias did not influence our findings. Participants were 18–55 years old, with stable psychiatric symptoms, treated with a second generation antipsychotic for ≥eight weeks (same dose for ≥four weeks), overweight or obese, with a Calgary Depression Scale (Addington et al., 1992) total score ≤7, no history of hospitalization for depression or suicidal thoughts or behavior in the prior six months, and no substance dependence (DSM-IV criteria) within the prior six months other than caffeine or nicotine and no substance abuse within the prior month. Current drug use status was confirmed by urine and blood tests and self-report. n nSUD history was evaluated using the Structured Clinical Interview for DSM-IV Disorders, with more detailed information on alcohol, heroin, methadone, barbiturates, cocaine, amphetamines, cannabis, hallucinogens, inhalants, and nicotine use from the modified Addiction Severity Index (ASI) interview (McLellan et al., 1980). The ASI collects information on use in the prior 30 days and number of years of lifetime use. Substantial lifetime substance use was defined as ≥5 years of past use ≥4 times per week or with binging or problematic use in which normal activities are compromised. Current schizophrenia symptoms were assessed with the Brief Psychiatric Rating Scale and Scale for the Assessment of Negative Symptoms. n nThere were no significant differences in participants’ socio-demographic characteristics. Both patient groups were comparable in demographic characteristics and cigarette smoking. The ten participants with substantial lifetime substance use had more severe current positive symptoms and less severe negative symptoms than the five participants without a substantial history of substance use (Table 1). n n n nTable 1 n nPsychiatric characteristics of 15 people with schizophrenia without current substance use disorder and with or without substantial lifetime substance use. n n n nThis study has several limitations, including very small sample size, which precluded any statistical control for potential confounding factors, and substance use based on retrospective self-report without objective corroboration. Future studies are warranted with larger sample sizes, objective assessments of substance use, and clear distinctions between substance use groups to validate our findings. These findings suggest that more attention be given to past history of substance use in people without a current SUD who enroll in clinical trials. Persisting effects from prior substance use may adversely affect response to treatment, leading clinicians to add or change medications, when a more appropriate action might be evaluation of prior substance use. In addition, prior substance use is a risk factor for relapse to present substance use or abuse, with potential adverse effects on current treatment response. Therefore, all clinicians should pay attention to lifetime, not just current, co-occurring SUDs. Future research should consider the inclusion of participants with lifetime substance use, even if substantial, in order to improve the external validity of their studies, and account for lifetime substance use in their analysis plan.

Effects of the Cannabinoid-1 Receptor Antagonist/Inverse Agonist Rimonabant on Satiety Signaling in Overweight People with Schizophrenia: A Randomized, Double-Blind, Pilot Study

To the Editors: People with schizophrenia have an increased risk of comorbid medical conditions, primarily coronary heart disease, resulting in a 15to 20-year shorter life expectancy than those without the diagnosis. Coronary heart disease is induced largely by high rates of obesity, insulin resistance and type 2 diabetes, hyperlipidemia, and hypertension compounded by smoking, reduced access to care, inadequate health screening rates, poor diet, and metabolic adverse effects of antipsychotic medications. Weight gain is a serious adverse effect of several second-generation antipsychotic (SGA) medications possibly caused by several peripheral and central mechanisms including disturbances in glucose, insulin, leptin, ghrelin, H1 and 5HT2C receptor antagonism, other hormone signaling or function or secretion, or disturbances in satiety signaling. In fact, people with schizophrenia taking SGA medications show lower levels of self-reported satiety after a standardized breakfast than do those not taking SGAs. Rats taking the SGA olanzapine show impeded behaviorally measured satiety and hyperphagia is implicated in the SGA induction of body weight gain. Thus, one key mechanism of weight gain with SGAs may involve disruption or interruption of normal satiety signaling after eating. Cannabinoid-1 (CB1) antagonists and agonists affect food intake through binding to cannabinoid receptors. Hyperphagia (overeating) can be induced by injection of anandamide, an endogenous cannabinoid (endocannabinoid) neurotransmitter, into the ventral medial hypothalamus or by peripheral administration of exogenous cannabinoids. In addition, cannabinoids increase rodents’ preference for sucrose solution or other palatable substances. Pretreatment with rimonabant, a CB1 receptor inverse agonist/antagonist, inhibited this hyperphagia and increased food preference in rats, suggesting that cannabinoids are acting via the CB1 receptor. The natural craving of rats for sweet substances is intensified by enhanced endocannabinoid signaling in the nucleus accumbens, suggesting a relationship between endocannabinoid activity and satiety modulation. Furthermore, endocannabinoids inhibit digestion signals mediated by afferent vagus nerve fibers, such as the release of cholecystokinin, leading to increased food consumption. Because of the potential satiety-inducing effects of cannabinoid receptor antagonism, we hypothesized that rimonabant may enhance satiety signaling in peoplewith schizophrenia taking a SGA. The aim of this studywas to directly test the behavioral effects of rimonabant on satiety signaling as measured by a preload-test meal paradigm. Inpatients and outpatients at the Maryland Psychiatric Research Center with a Diagnostic and Statistical Manual of Mental Disorders, Fourth EditionYdefined diagnosis of schizophrenia or schizoaffective disorder who were treated with an SGA for at least eight weeks on a stable dose for at least one month were enrolled in a 16-week, double-blind, randomized, placebo-controlled study of rimonabant (20 mg/d). Full results on psychiatric symptoms and metabolic data are presented elsewhere. Participants were between the ages of 18 and 55 years, had a body mass index (BMI) of 30 kg/m or greater or a BMI of 27 kg/m or greater plus adult treatment panel III hyperlipidemia or hypertriglyceridemia, no recent depressive symptoms/suicidality, no current substance abuse/dependence (with the exception of nicotine), no more than weekly cannabis use, and were clinically stable (baseline characteristics, Table 1). An exercise and dietary counseling group was offered weekly during the study. The participants were assessed at baseline, midpoint, and end of study using a preload-test meal paradigm designed to assess satiety signaling. After an overnight fast, the participants were given a standardized breakfast preload of 12-oz. vanilla Ensure. The preload was consumed, in its entirety, within 5 minutes. A preweighed test meal (Wheat Thins, Nilla Wafers, and 12-oz. water) was served an hour later. After 30 minutes, the test meal was removed and weighed. The amount consumed was considered a behavioral index of satiety. Rimonabant-placebo differences in test meal consumption were evaluated using mixed models for analysis of covariance to combine data across repeated visits and to adjust for observed between-group differences in baseline consumption. The models took the following form: treatment phase measure = baseline measure + treatment + week + treatment week. In this model, week is a categorical indicator of week 7 versus week 16; the main effect of treatment estimates the average of the rimonabant-placebo differences at weeks 7 and 16; and the treatment week interaction term tests whether the magnitude of treatment effects varies significantly between the follow-up 2 weeks. The models were fitted using SAS PROC MIXED (version 9.1.3, SAS Institute, Cary, NC), and degrees of freedom for hypothesis tests were estimated using the KenwardRoger method. Similar models were fitted to evaluate rimonabant effects on body weight and BMI. The target sample size was 60 participants (30 in each group); however, the study was terminated prematurely when rimonabant was withdrawn from worldwide marketing due to concerns over psychiatric symptoms and suicidality. We excluded participants with depressive symptoms or suicidality at baseline and did not see any increase in suicidality or depressive symptoms throughout the trial. In fact, total Brief Psychiatric Rating Scale (BPRS) scores improved in the rimonabant group compared to the placebo group over the 16 weeks. Fifteen participants were randomized to medication (7 participants, rimonabant; and 8 participants, placebo); 5 participants in each group completed the 16-week trial. Because of early study termination, 2 participants on rimonabant (at weeks 11 and 13) and 2 participants on placebo (both at week 13) did not complete the 16-week trial but completed end-of-study assessments. No participant discontinued because of adverse events. One participant on placebo did not complete the satiety paradigm. At baseline, mean (SD) test meal consumption was lower in the participants randomized to rimonabant for total kilocalories (64.4 [68.0]) andWheat Thins (40.6 [53.1]) compared to placebo (101.0 [55.4] and 58.0 [44.4], respectively). After statistically adjusting for these baseline differences, least square mean (SE) rimonabant-placebo differences in test meal consumption were j42.7 (19.7) for total kcal (F = 4.70; df = 1, 10.8; P = 0.053) and j17.8 (9.3) for Wheat Thins kcal, (F = 3.64; df = 1, 8.93; P = 0.089), giving estimated treatment LETTERS TO THE EDITORS