Douglas L. Boggs

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.

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.

Lack of beneficial galantamine effect for smoking behavior: A double-blind randomized trial in people with schizophrenia

Cigarette smoking is in schizophrenia is prevalent and may be due to self-medicating attempts to improve cognitive deficits related to alpha7 and alpha4beta2 nicotinic receptor dysregulation. Galantamine is an acetylcholinesterase inhibitor that acts as a positive allosteric modulator of nicotine acetylcholine receptors including both the alpha4beta2 and alpha7 subunits. In a double-blind randomized clinical trial galantamine was compared to placebo for its effects on cognitive functioning in people with schizophrenia. This manuscript reports findings for galantamines effect on smoking behavior in people from this 12-week trial who were smokers (18 galantamine, 25 placebo). Expired CO was measured every 2 weeks and the Fagerström Test for Nicotine Dependence (FTND) was administered at baseline and endpoint. Expired CO measures in galantamine subjects were 23.0+/-9.7 ppm and 21.1+/-10.3 ppm at baseline and Week 12, respectively, compared to 20.1+/-8.5 ppm and 21.0+/-10.3 ppm at baseline and Week 12 in placebo subjects. The mean tau-b correlation between expired CO level and visit was -0.05+/-0.41 in the galantamine group and 0.13+/-0.42 in the placebo group (F=0.73, df=1,38, p=0.40), suggesting that there were no trends toward increased or decreased smoking in either group. Mean FTND scores in the galantamine group were 4.9+/-2.5 at baseline and 5.2+/-2.2 at Week 12, compared to 4.1+/-2.6 at baseline and 3.7+/-2.6 at Week 12 in the placebo group (Mantel-Haenszel chi2=5.53, df=1, p=0.019), for an effect size of 0.4. These results suggest that galantamine has no effect on cigarette smoking and that during galantamine treatment nicotine dependency scores worsen.

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.

The role of antihistaminic effects in the misuse of quetiapine: a case report and review of the literature.

Recent case reports and case series suggest that the atypical antipsychotic quetiapine has the potential for misuse. This includes drug-seeking behaviors motivated by quetiapine as well as inappropriate (intranasal or intravenous) administration. We present an additional case of quetiapine misuse and review other published cases. In general, quetiapine misuse is associated with prior CNS depressant use and is more common in forensic settings. The mechanism of reinforcement for this misuse is unknown, but we hypothesize that it is related to quetiapines pharmacological profile as an antihistamine with a relative low affinity for dopamine receptors. The risks to individuals and society of exaggerating/simulating symptoms to obtain high-dose quetiapine in the absence of a clinical indication are discussed. This includes the unwelcome possibility of restricting access to this effective medication.

Feasibility of Reducing the Duration of Placebo-Controlled Trials in Schizophrenia Research

Use of placebo-controlled trials in medical and psychiatric research has been controversial, although a consensus is emerging about conditions under which placebo-controlled trials are ethical. In schizophrenia research, the paradigm of slow onset of antipsychotic effects has led to a model in which placebo-controlled trials of 6-8 weeks duration have been used to demonstrate efficacy. Recent evidence that the largest symptom reductions are typically seen in the first weeks of treatment suggests that shorter placebo-controlled studies to demonstrate antipsychotic efficacy are possible. In a pilot study of the feasibility of shortening placebo-controlled studies, we reanalyzed data from placebo-controlled registry trials of olanzapine and risperidone and found that trials as short as 4 weeks could have similar power to longer term 6-8 week studies, given the estimated time course of treatment effects. Although fuller evaluation is required, the results suggest future antipsychotic trials could be shortened from 6-8 weeks to 3-4 weeks with a relatively low increase in sample size requirements. Shortening placebo-controlled trials would reduce patient burden and ethical objections to prolonged administration of placebo and reduce potential bias due to high dropout rates in longer clinical trials.

Clinical and Preclinical Evidence for Functional Interactions of Cannabidiol and Δ 9 -Tetrahydrocannabinol

The plant Cannabis sativa, commonly called cannabis or marijuana, has been used for its psychotropic and mind-altering side effects for millennia. There has been growing attention in recent years on its potential therapeutic efficacy as municipalities and legislative bodies in the United States, Canada, and other countries grapple with enacting policy to facilitate the use of cannabis or its constituents for medical purposes. There are >550 chemical compounds and >100 phytocannabinoids isolated from cannabis, including Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). THC is thought to produce the main psychoactive effects of cannabis, while CBD does not appear to have similar effects. Studies conflict as to whether CBD attenuates or exacerbates the behavioral and cognitive effects of THC. This includes effects of CBD on THC-induced anxiety, psychosis, and cognitive deficits. In this article, we review the available evidence on the pharmacology and behavioral interactions of THC and CBD from preclinical and human studies, particularly with reference to anxiety and psychosis-like symptoms. Both THC and CBD, as well as other cannabinoid molecules, are currently being evaluated for medicinal purposes, separately and in combination. Future cannabis-related policy decisions should include consideration of scientific findings, including the individual and interactive effects of CBD and THC.

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.

Nonresponse to clozapine and premorbid functioning in treatment refractory schizophrenia

INTRODUCTION It is recognized that early treatment can improve outcomes and generally improve recovery potential for those with schizophrenia. Data suggest that poor premorbid functioning has been found to be related to more severe symptoms and poor antipsychotic response; however, little is known about premorbid functioning in patients who have no response to clozapine treatment. METHODS This study compares the premorbid functioning among patients who responded to clozapine treatment (20% decrease in total Brief Psychiatric Rating Scale [BPRS] score; n = 35) and those who did not respond (n = 50) to 8 weeks of clozapine treatment. Premorbid functioning was assessed using the Cannon-Spoor Premorbid Adjustment Scale. RESULTS Patients who did not respond to clozapine had significantly lower total BPRS scores (P = .01) at baseline, driven primarily by lower ratings in hostility (P = .007) and activation (P = .02), compared with those who responded to clozapine. Responders and nonresponders did not differ in their age, race, level of education, marital status, age of onset, characterization of the deficit syndrome, and positive or negative symptoms. Nonresponders to clozapine did not improve in any area of symptoms or global functioning, whereas there were significant improvements in BPRS total scores (analysis of covariance) and all symptom domains in the responder groups (P < .0001). Level of functioning scores in those who responded to clozapine was significantly higher at end point (P = .02). As for premorbid functioning, there were no differences in scores between responders and nonresponders at the time of early and late adolescence; however, there was a trend toward lower premorbid functioning in the clozapine nonresponders on most childhood measures (before the age of 11 years). Clozapine nonresponders tended to be less social and more withdrawn as compared with those who responded to clozapine (P = .08), as well as tended to have poorer adaptation to school (P = .06) and fewer peer relationships (P = .08). These results did not reach significance. Work and/or school performance changed more insidiously in the nonresponders group before illness onset (P = .045). DISCUSSION Clozapine is beneficial to many patients with treatment-resistant symptoms; however, nonresponse to this medication may represent a subtype of patients who may present differently with symptoms. These findings should encourage further examination of early childhood indicators and opportunities for appropriate and effective intervention.

Treatment of Hyperprolactinemia and Gynecomastia With Adjunctive Aripiprazole in 2 Men Receiving Long-Acting Injectable Antipsychotics

To the Editor: Hyperprolactinemia and its consequences, including sexual dysfunction, osteoporosis, pituitary tumors, and gynecomastia, are potential side effects of many antipsychotics.1 Treatment recommendations include decreasing the dose of the antipsychotic, switching to a prolactin-sparing antipsychotic, or adding medications such as direct-acting dopamine agonists1; however, options are limited with long-acting injectable antipsychotics. A series of reports and clinical trials have shown that the antipsychotic aripiprazole, a partial dopamine D2 receptor agonist, can lower prolactin concentrations and potentially reduce prolactin-related effects (eg, sexual dysfunction) when given with oral antipsychotics.2–5 We report, for the first time, the adjunctive use of aripiprazole for the treatment of hyperprolactinemia and associated gynecomastia related to long-acting injectable antipsychotics. Case 1. Mr A, a 29-year-old man of Indian ancestry with DSM-IV schizophrenia and nicotine dependence, was hospitalized for a suicide attempt in late 2009. Risperidone microspheres 25 mg intramuscularly every 2 weeks and oral risperidone 1 mg twice daily were started. He responded to treatment and continued on this regimen; however, prolactin levels were elevated (21.9 ng/mL; reference, 2–14 ng/mL) 3 months later. Oral risperidone was discontinued, but intramuscular risperidone was continued; about 10 months later, prolactin levels were higher, (29.8 ng/mL; reference, 2–14 ng/mL) Two months after this finding, Mr A reported sexual dysfunction and left breast tenderness and redness, with no galactorrhea evident on physical examination. He was prescribed oral aripiprazole 2.5 mg daily, and, after a month, breast tenderness and redness resolved, with no worsening of psychotic symptoms. Prolactin level dropped to 18.6 and 16.3 ng/mL (reference, 3.5–19.4; new reference standards were reported due to a change by the laboratory in the assay to measure prolactin levels) 2 months and 5 months later, respectively. Risperidone 25 mg intramuscularly every 2 weeks and oral aripiprazole 2.5 mg daily were continued with no reported symptoms of breast tenderness and with an improvement in sexual function. Case 2. Mr B, a 58-year-old African American man diagnosed with DSM-IV schizophrenia and cocaine abuse in remission, was treated with fluphenazine decanoate 25 mg intramuscularly every 2 weeks starting in 1991 and then with 15 mg intramuscularly every 2 weeks starting in 2002. In 2009, he first reported breast tenderness and enlargement with no galactorrhea. He reported worsening of these symptoms in early 2011. Prolactin level in the middle of 2011 was 9.9 ng/mL (reference, 2–14 ng/mL) and then 12.2 ng/mL a week later. Bilateral tender gynecomastia, 3 cm on the left and 2 cm on the right, without galactorrhea was noted after about a month. Serum estradiol, testosterone, human chorionic gonadotropin β, and luteinizing hormone levels were all within normal limits. A trial of oral tamoxifen 10 mg daily was initiated by the endocrinologist, but despite 4 weeks of treatment, the patient reported continued breast tenderness and had a significantly elevated prolactin level (33.2 ng/mL; reference, 3.5–19.4 ng/mL). Four months later, tamoxifen was stopped; prolactin level decreased to 19.9 ng/mL (reference, 3.5–19.4), but breast tenderness continued. That same month, oral aripiprazole 5 mg daily was added to treatment with fluphenazine decanoate. A month later, Mr B reported resolution of breast tenderness and improvement in psychiatric symptoms; serum prolactin level was 12.7 ng/mL (reference, 3.5–19.4 ng/mL). Over the next few months, Mr B reported well-controlled psychotic symptoms without breast tenderness; prolactin concentration was 5.2 and 5.6 ng/mL (reference, 3.5–19.4 ng/mL) after 2 months and 4 months, respectively. However, after 4 months, he reported new breast swelling and tenderness, and the dosage of oral aripiprazole was increased to 10 mg daily. Complete resolution of breast soreness was seen after 1 month. The majority of reported cases to date have shown that aripiprazole can reverse hyperprolactinemia and related side effects associated with other oral antipsychotics.2–5 A recently published open-label study by van Kooten and colleagues6 found, similar to this report, that aripiprazole given adjunctively with long-acting injectable risperidone can decrease prolactin concentrations.6 However, in that report, none of the participants had symptoms related to hyperprolactinemia. While several studies have shown that aripiprazole can decrease serum prolactin level, serum prolactin level does not correlate with related side effects in men.7 Therefore, it is important to determine if addition of aripiprazole can reverse hyperprolactinemia-induced side effects in addition to causing decreases in serum prolactin. We report, for the first time, that low-to-moderate adjunctive doses of aripiprazole can reverse gynecomastia associated with hyperprolactinemia caused by long-acting injectable antipsychotics.