Jared Linthicum

Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: Results from a randomized double blind placebo controlled pilot study

BACKGROUND Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfactory identification as well as positive and negative symptoms in people with schizophrenia. METHODS Individuals with schizophrenia or schizoaffective disorder (n=28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. RESULTS All 28 participants completed the clinical trial. Odor identification performance significantly improved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleasant smells. UPSIT score (F=5.20, df=1,23, p=0.032) and subscore for pleasant smells (F=4.56, df=1,23, p=0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxytocin was well tolerated during the three week trial. CONCLUSION Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of positive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov).

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.

Rimonabant for neurocognition in schizophrenia: A 16-week double blind randomized placebo controlled trial

OBJECTIVE To examine the effect of rimonabant on neurocognitive impairments in people with schizophrenia. METHODS Participants entered a 16-week double-blind, placebo-controlled, randomized clinical trial. A neurocognitive battery was administered at baseline and end of study. RESULTS In comparison to rimonabant (20mg/day), placebo-treated participants exhibited a significant improvement on the Repeatable Battery for the Assessment of Neuropsychological Status total score. In contrast, rimonabant was associated with significant improvement on a probabilistic learning task. There were no other significant treatment effects. CONCLUSIONS Rimonabant did not improve global cognitive functioning, but did improve a specific learning deficit based on response to positive feedback.

Cardiac-related findings at autopsy in people with severe mental illness treated with clozapine or risperidone

Clozapine is a superior agent for treatment-refractory patients with schizophrenia, but is underutilized in the US, likely due to the risk of side effects. This study examined all available autopsy data on cardiac disease and risk factors in people with schizophrenia in a sample of deceased persons with severe mental illness who had received clozapine (N=62) or risperidone (N=42). The mean body mass index (BMI) at the time of death was 31.4+/-8.8 kg/m2 and 27.1+/-8.2 kg/m2 in the clozapine and risperidone groups respectively (t=1.98, df=60, p=0.052). Cardiac related measures examined included: abdominal wall thickness, heart weight, left ventricle thickness, right ventricle thickness, presence of notable cardiac involvement (atherosclerosis, fibrosis and hypertrophy) and number of cardiac arteries occluded. No significant differences in any of the cardiac findings were noted between patients in the clozapine and risperidone groups. Independent of treatment, cardiomyopathy deaths were associated with a higher abdominal wall thickness (p=0.042) and a tendency towards higher BMI (p=0.051) as compared to the other causes of death. The results of this study suggest that while clozapine is associated with weight gain and metabolic abnormalities, there does not appear to be an increased occurrence of cardiac abnormalities in deceased persons who were treated with clozapine as compared to risperidone.

Cannabis withdrawal in chronic cannabis users with schizophrenia

BACKGROUND Chronic users of cannabis often report withdrawal symptoms after abstinence from use, but little is known about cannabis withdrawal in people with schizophrenia. METHODS Cannabis use patterns and withdrawal symptoms in adults with schizophrenia who had at least weekly cannabis use before attempting to quit without formal treatment were assessed with the Marijuana Quit Questionnaire (MJQQ), a 176-item, semi-structured questionnaire. RESULTS 120 participants, predominantly African-American (62.5%) and male (76.7%), met inclusion criteria. 20.1% reported that their first regular cannabis use (median age 15 years [range 8-48]) preceded their age at first psychotic symptoms (20 [4-50] years). Twenty (16.7%) participants met lifetime criteria for cannabis abuse; 98 (81.7%) met surrogate criteria for lifetime cannabis dependence. Withdrawal symptoms were reported by 113 (94.2%) participants, with 74.2% reporting ≥4 symptoms. The most frequently reported withdrawal symptoms were craving for cannabis (59.2%), feeling anxious (52.57%), feeling bored (47.5%), feeling sad or depressed (45.8%), feeling irritable or jumpy (45.0%), feeling restless (43.3%), and trouble failing asleep (33.3%). One hundred-and-four (92.0%) participants took some action to relieve at least one of their withdrawal symptoms during their index-quit attempt, including 26 (23.0%) participants who reported resuming cannabis use. CONCLUSION Cannabis withdrawal is a clinically significant feature of cannabis use among people with schizophrenia, may serve as a negative reinforcer for relapse, and deserves greater attention in treatment and research. Clinical Trials registration NCT00679016.

Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia

Several clinical studies have found an inverse relationship between clinical symptoms and peripheral oxytocin (OT) levels in people with schizophrenia. As oxytocin is a putative treatment for schizophrenia, the effect of repeated dosing of OT on OT levels, clinical symptoms and the relationship between the two is of interest. In a, randomized, double blind, parallel group 3 week study (N=28) with daily administration of intranasal OT (20 IU twice daily) or placebo (PBO), we examined the effect of OT administration on the correlation between the change in peripheral OT levels and change in clinical symptoms in patients with schizophrenia. At baseline, there were no significant treatment group differences in OT levels. There were no significant associations between baseline OT levels and any symptom measures. After 3 weeks of OT/PBO dosing, there was no significant difference in the magnitude of change in OT levels between the two treatment groups. Correlations between changes in peripheral OT levels and changes in the BPRS total and negative symptom scores were not different between treatment groups. Larger studies are needed to examine the effect of exogenous OT on peripheral OT levels and the relationship between the latter and clinical symptoms. Clinical Trials.gov=NCT00884897.

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. SUD 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. There 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). Table 1 Psychiatric characteristics of 15 people with schizophrenia without current substance use disorder and with or without substantial lifetime substance use. This 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