Deanna L. Kelly

Prevalence of Celiac Disease and Gluten Sensitivity in the United States Clinical Antipsychotic Trials of Intervention Effectiveness Study Population

Celiac disease (CD) and schizophrenia have approximately the same prevalence, but epidemiologic data show higher prevalence of CD among schizophrenia patients. The reason for this higher co-occurrence is not known, but the clinical knowledge about the presence of immunologic markers for CD or gluten intolerance in schizophrenia patients may have implications for treatment. Our goal was to evaluate antibody prevalence to gliadin (AGA), transglutaminase (tTG), and endomysium (EMA) in a group of individuals with schizophrenia and a comparison group. AGA, tTG, and EMA antibodies were assayed in 1401 schizophrenia patients who were part of the Clinical Antipsychotic Trials of Intervention Effectiveness study and 900 controls. Psychopathology in schizophrenia patients was assessed using the Positive and Negative Symptoms Scale (PANSS). Logistic regression was used to assess the difference in the frequency of AGA, immunoglobulin A (IgA), and tTG antibodies, adjusting for age, sex, and race. Linear regression was used to predict PANSS scores from AGA and tTG antibodies adjusting for age, gender, and race. Among schizophrenia patients, 23.1% had moderate to high levels of IgA-AGA compared with 3.1% of the comparison group (χ(2) = 1885, df = 2, P < .001.) Moderate to high levels of tTG antibodies were present in 5.4% of schizophrenia patients vs 0.80% of the comparison group (χ(2) = 392.0, df = 2, P < .001). Adjustments for sex, age, and race had trivial effects on the differences. Regression analyses failed to predict PANSS scores from AGA and tTG antibodies. Persons with schizophrenia have higher than expected titers of antibodies related to CD and gluten sensitivity.

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.

Neurologic and Psychiatric Manifestations of Celiac Disease and Gluten Sensitivity

Celiac Disease (CD) is an immune-mediated disease dependent on gluten (a protein present in wheat, rye or barley) that occurs in about 1% of the population and is generally characterized by gastrointestinal complaints. More recently the understanding and knowledge of gluten sensitivity (GS), has emerged as an illness distinct from celiac disease with an estimated prevalence 6 times that of CD. Gluten sensitive people do not have villous atrophy or antibodies that are present in celiac disease, but rather they can test positive for antibodies to gliadin. Both CD and GS may present with a variety of neurologic and psychiatric co-morbidities, however, extraintestinal symptoms may be the prime presentation in those with GS. However, gluten sensitivity remains undertreated and underrecognized as a contributing factor to psychiatric and neurologic manifestiations. This review focuses on neurologic and psychiatric manifestations implicated with gluten sensitivity, reviews the emergence of gluten sensitivity distinct from celiac disease, and summarizes the potential mechanisms related to this immune reaction.

Treatment-resistant schizophrenic patients respond to clozapine after olanzapine non-response

BACKGROUND Treatment-resistance in schizophrenia remains a public health problem. Clozapine has been shown to be effective in about one third of this population, but carries with it medical risks and weekly blood draws. As olanzapine is a drug with a very similar biochemical profile to clozapine, it is important to evaluate whether non-response to olanzapine predicts clozapine non-response. METHODS Forty-four treatment-resistant patients received eight weeks of olanzapine, either in a double-blind trial or subsequent open treatment at a mean daily dose of 25 mg/day. Two of 44 patients (5%) responded to olanzapine treatment. Patients who did not respond could then receive clozapine. Twenty-seven subsequently received an 8-week open trial of clozapine. RESULTS Patients who did and did not receive clozapine did not differ demographically or in psychopathology. Eleven of 27 (41%) met a priori response criteria during clozapine treatment (mean dose 693 mg/day) after failing to respond to olanzapine. CONCLUSIONS This study demonstrates that failure to respond to olanzapine treatment does not predict failure to clozapine. Treatment-resistant patients who fail on olanzapine may benefit from a subsequent trial of clozapine.

First-episode schizophrenia: a focus on pharmacological treatment and safety considerations.

Schizophrenia is a debilitating disorder, which is usually chronic, and is one of the most devastating medical illnesses. Early and appropriate treatment with antipsychotics is an important strategy for patients with first-episode schizophrenia. However, there are many possible safety issues for patients with schizophrenia that should be considered and properly addressed.Depressive symptoms and suicidal behaviour commonly occur in first-episode schizophrenic patients, and every effort should be made to treat and minimise these symptoms. There are also important issues and considerations in young and first-episode patients that should also be considered in the emergency treatment setting and for minimising medication nonadherence in this population. Most importantly, adverse effects should be considered, minimised and addressed. While first- and second-generation antipsychotics (SGAs) both appear to offer similar efficacy for amelioration of positive symptoms in first-episode patients, SGAs may offer better tolerability, specifically regarding extrapyramidal symptoms (EPS) and tardive dyskinesia risk, and some prolactin-sparing benefits. However, these medications do cause a host of adverse effects, including weight gain, metabolic disturbances, corrected QT interval prolongation and prolactin-related adverse effects, which are important considerations relating to both the short- and long-term safety of patients with schizophrenia being treated with SGAs. Clozapine and olanzapine are most likely to cause weight gain and metabolic effects, while risperidone is more likely to cause EPS and prolactin elevations. Most antipsychotics should be used in low doses to minimise adverse effects and each medication should be optimised in a highly individualised way to maximise adherence and treatment outcomes and minimise tolerability and safety concerns. At some point in their lives, these patients will most probably experience periods of depression, suicidal behaviours, adverse effects and nonadherence, and every effort should be made to minimise or prevent these from occurring. Thus, safety concerns in this group of young patients, in the beginning of their first psychotic episode, are a major issue as they are starting a journey of antipsychotic treatment that is likely to last for the remainder of their lives.

Adjunctive varenicline treatment with antipsychotic medications for cognitive impairments in people with schizophrenia: a randomized double-blind placebo-controlled trial.

The aim of this study is to examine the effects of treatment with varenicline, a partial agonist at the α4β2 and full agonist at the α7 nicotine acetylcholine receptor, on cognitive impairments in people with schizophrenia. In all, 120 clinically stable people with schizophrenia participated in randomized, double-blind, placebo-controlled 8-week trial. Antipsychotic and concomitant medication doses remained fixed throughout the study. Varenicline was titrated up to 1 mg twice daily for weeks 2–8. Neuropsychological, clinical, and safety assessments were administered at baseline and weeks 1, 2, 4, and 8. In the primary analyses of neurocognitive differences at week 8, no varenicline–placebo differences were significant. In secondary longitudinal analyses, varenicline improved compared with placebo on the Digital Symbol Substitution Test (p=0.013) and the Wisconsin Card Sorting Test non-perseverative errors (p=0.043). Some treatment effects were different between smokers and non-smokers. In smokers, Continuous Performance Test hit reaction time (p=0.008) and Stroop Interference (p=0.004) were reduced for varenicline compared with placebo, while there were no treatment differences in non-smokers. No significant treatment main effects or interactions were noted for total scores on the Positive and Negative Syndrome Scale or the Scale for the Assessment for Negative Symptoms. Our findings suggest beneficial effects of adjunctive varenicline treatment with antipsychotics for some cognitive impairments in people with schizophrenia. In some cases, effects of treatment varied between smokers and non-smokers. Further study is required to assess the functional significance of these changes.

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing. We find that two loci in the major histocompatibility complex are independently associated with CIAG: a single amino acid in HLA-DQB1 (126Q) (P=4.7×10−14, odds ratio, OR=0.19, 95% CI 0.12–0.29) and an amino acid change in the extracellular binding pocket of HLA-B (158T) (P=6.4×10−10, OR=3.3, 95% CI 2.3–4.9). These associations dovetail with the roles of these genes in immunogenetic phenotypes and adverse drug responses for other medications, and provide insight into the pathophysiology of CIAG.

A randomized double-blind 12-week study of quetiapine, risperidone or fluphenazine on sexual functioning in people with schizophrenia

Sexual dysfunction is common in people suffering from schizophrenia and is reported by patients to be a significant reason for medication nonadherence. This report contains data for 27 people with schizophrenia who participated in a randomized double-blind 12-week trial of risperidone (4 mg/day), quetiapine (400 mg/day) or fluphenazine (12.5 mg/day). At baseline and endpoint, subjects were rated on the Changes in Sexual Function Questionnaire (CSFQ), the Prolactin-Related Adverse Event Questionnaire (PRAEQ) and had prolactin levels drawn. Endpoint prolactin levels were 50.6 +/- 40.4, 24.4 +/- 18.5, and 8.2 +/- 4.4 mg/dl for risperidone (N = 12), fluphenazine (N = 9) and quetiapine (N=6), respectively (F = 7.5,df = 2, p = 0.005, controlling for sex). Orgasm quality/ability improved significantly for quetiapine as compared to fluphenazine and risperidone (F = 4.41, df = 2, p = 0.033). Seventy-eight percent of patients on fluphenazine reported sexual dysfunction whereas did only 42 and 50% of those on risperidone and quetiapine. Forty percent of quetiapine patients reported they felt better about their sexuality as compared to previous treatment, as did 55% on risperidone. Conversely, only 13% of fluphenazine subjects reported any improvement. Hormonal problems (menstrual problems, gynecomastia, galactorrhea) were predominately observed in risperidone-treated subjects. Overall, quetiapine was associated with a normalization of prolactin levels and had the greatest benefits among these drugs regarding sexual functioning.

Olanzapine response in treatment-refractory schizophrenic patients with a history of substance abuse

As many as half of all schizophrenic patients have abused alcohol or illicit drugs. This study determines the extent of substance abuse in a treatment-resistant population and assesses the response of this population to olanzapine treatment. Sixty patients with a DSM-III-R diagnosis of schizophrenia were included in an open 7-week trial of up to 25 mg/day of olanzapine. A history of substance abuse was present in 23 (38%) of the patients. At baseline evaluation, patients with a history of substance abuse had lower CGI scores and less negative symptomatology while having a higher rate of tardive dyskinesia. The overall group improved significantly over time. There were no differences in response between the substance-abusing (SA) and non-substance-abusing (NSA) patients as measured by the total BPRS, GGI and SANS ratings. The NSA group had significantly greater improvement in negative symptoms as measured by the BPRS negative symptom factor. Sixty-nine per cent (16/23) of the SA group and 60% (22/37) of the NSA were considered olanzapine responders by a priori criteria (p = NS). Extrapyramidal symptoms declined significantly in the overall group, but did not significantly differ between the SA and NSA groups. Treatment-refractory patients with prior substance abuse had a comparable outcome on olanzapine therapy to those with no history of abuse, as well as no increase in adverse effects. This suggests that olanzapine may be of benefit to SA patients who have a greater tendency for antipsychotic side effects and tardive dyskinesia.

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

BACKGROUND Cardiovascular 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. METHOD We 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. RESULTS During 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). CONCLUSIONS The 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.