Yael Ratner

Is the G72/G30 locus associated with schizophrenia? single nucleotide polymorphisms, haplotypes, and gene expression analysis

BACKGROUND The genes G72/G30 were recently implicated in schizophrenia in both Canadian and Russian populations. We hypothesized that 1) polymorphic changes in this gene region might be associated with schizophrenia in the Ashkenazi Jewish population and that 2) changes in G72/G30 gene expression might be expected in schizophrenic patients compared with control subjects. METHODS Eleven single nucleotide polymorphisms (SNPs) encompassing the G72/G30 genes were typed in the genomic deoxyribonucleic acid (DNA) from 60 schizophrenic patients and 130 matched control subjects of Ashkenazi ethnic origin. Case-control comparisons were based on linkage disequilibrium (LD) and haplotype frequency estimations. Gene expression analysis of G72 and G30 was performed on 88 postmortem dorsolateral prefrontal cortex samples. RESULTS Linkage disequilibrium analysis revealed two main SNP blocks. Haplotype analysis on block II, containing three SNPs external to the genes, demonstrated an association with schizophrenia. Gene expression analysis exhibited correlations between expression levels of the G72 and G30 genes, as well as a tendency toward overexpression of the G72 gene in schizophrenic brain samples of 44 schizophrenic patients compared with 44 control subjects. CONCLUSIONS It is likely that the G72/G30 region is involved in susceptibility to schizophrenia in the Ashkenazi population. The elevation in expression of the G72 gene coincides with the glutamatergic theory of schizophrenia.

Validity of an abbreviated Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-18) for schizophrenia, schizoaffective,and mood disorder patients

We sought to identify a core subset of Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q) items that maintains the validity and psychometric properties of the basic version. A parsimonious subset of items from the Q-LES-Q that can accurately predict the basic Q-LES-Q domain mean scores was sought and evaluated in 339 inpatients meeting DSM-IV criteria for schizophrenia, schizoaffective, and mood disorders. Three additional data sets were used for validation. Assessments included Q-LES-Q, Quality of Life Scale, Lancashire Quality of Life Profile, rating scales for psychopathology, medication side effects, and self-reported emotional distress, self-esteem, self-efficacy, and social support. We found that 18-items predicted basic Q-LES-Q domains (physical health, subjective feelings, leisure time activities, social relationships) and general index scores with high accuracy. Q-LES-Q-18 showed high reliability, validity, and stability of test-retest ratings. Thus, Q-LES-Q-18, a brief, self-administered questionnaire may aid in monitoring quality of life outcomes of schizophrenia, schizoaffective, and mood disorder patients.

Improvement of Sustained Attention and Visual and Movement Skills, but Not Clinical Symptoms, After Dehydroepiandrosterone Augmentation in Schizophrenia A Randomized, Double-blind, Placebo-controlled, Crossover Trial

Background: Dehydroepiandrosterone (DHEA) augmentation has been reported, in a preliminary fashion, to be useful in the management of schizophrenia symptoms and side effects. In this study, the intention was to investigate the efficacy and safety of DHEA administration to ongoing antipsychotic medication in a multicenter, 12-week, double-blind, randomized, placebo-controlled, crossover trial. Methods: Fifty-five of 62 inpatients and outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, diagnosis of schizophrenia completed the trial. Patients were randomly allocated to 2 treatment groups receiving either DHEA (200 mg/d) or placebo for 6 weeks with the crossover between DHEA and placebo occurring after 6 weeks. Patients continued to receive their regular antipsychotic medication for the duration of the study. Results: Compared with placebo, DHEA administration did not produce significant improvement in clinical symptoms, side effects, and quality-of-life scores. However, 6 weeks of DHEA administration (but not placebo) was associated with a significant improvement in Positive and Negative Symptom Scale ratings compared with baseline. Furthermore, 6 weeks of DHEA treatment was associated with significant improvement in cognitive functions of visual sustained attention and visual and movement skills compared with placebo conditions. The DHEA augmentation was associated with elevations of serum concentrations of both DHEA and its sulfate ester. The DHEA treatment was well tolerated without any serious adverse effects. Conclusion: This short-term study does not support DHEAs value as an effective adjunct in the treatment of symptoms, side effects, and quality-of-life impairment in schizophrenia, while suggesting that DHEA improves sustained attention and visual and movement skills. A long-term, large-scale study with a broader dose range is warranted to further investigate DHEAs role in the management of schizophrenia.

Quality of life outcomes of risperidone, olanzapine, and typical antipsychotics among schizophrenia patients treated in routine clinical practice: A naturalistic comparative study

Abstract: Findings in previous studies investigating the beneficial effect of risperidone and olanzapine versus typical antipsychotics on quality of life (QOL) are controversial since they did not adjust for various factors contributing to QOL. To test this assumption in a naturalistic cross-sectional design, we evaluated general and domain-specific QOL scores for baseline data of schizophrenia outpatients stabilized on atypical (N = 78, risperidone or olanzapine) and typical (N = 55) agents. Self-report and observer-rated QOL outcomes of both risperidone and olanzapine with typical antipsychotic therapy were compared across demographic, illness-related, and treatment-related factors using analysis of variance, multivariate analysis of variance, and correlation analysis. No significant differences were found in QOL outcomes of risperidone-treated and olanzapine-treated patients. Both self-report and rater-observed QOL measures indicated superiority of atypical over typical antipsychotic agents after adjusting for daily doses, duration of treatment, subjective tolerability, and adjuvant antidepressants. Lower daily doses and longer antipsychotic treatment were associated with better QOL. Self-report and observer-rated QOL scores correlated positively (r = 0.64, P < 0.001). Gender, marital status, age, education, living arrangement and employment status, age of onset, illness duration, symptom severity, emotional distress, subtypes of schizophrenia, and side effects did not affect QOL outcomes in either group. Risperidone and olanzapine revealed an advantage over typical agents in terms of QOL. Findings suggest that when calculating the beneficial effects of atypical antipsychotic therapy on QOL outcomes, daily doses, duration of treatment, and subjective tolerability may be intervening variables and should be adjusted accordingly to clearly appreciate benefits of atypical antipsychotics.

Cortisol/Dehydroepiandrosterone Ratio and Responses to Antipsychotic Treatment in Schizophrenia

Dehydroepiandrosterone (DHEA) or their sulfate conjugate (DHEAS) (together abbreviated DHEA(S)) exert multiple effects in the central nervous system, and may be involved in the pathophysiological processes in schizophrenia. This prospective study aimed to investigate whether serum cortisol/DHEA(S) molar ratios are associated with response to antipsychotic treatment during the exacerbation of schizophrenia. Serum DHEA(S) and cortisol were determined at baseline, and 2 and 4 weeks later for 43 medicated schizophrenia inpatients with acute exacerbation. The patients were treated with stable doses of antipsychotic agents up to 2 weeks prior to entering the study and for the 4-week duration of the study after which they were classified as either responders or nonresponders to treatment. Findings suggest that responders had significantly higher serum cortisol levels and cortisol/DHEA(S) ratios compared with nonresponders. These differences remained significant at three time points controlling for gender, age, severity of symptoms and emotional distress, benzodiazepines, type or dosage of antipsychotic agents, and background variables. The logistic regression model shows advantages of both cortisol/DHEA(S) molar ratios vs serum cortisol and DHEA(S) concentrations for prediction of responsivity to antipsychotic treatment. No significant canonical correlations were observed between changes from baseline through end-of-study in hormonal values and severity of symptoms and emotional distress among responders and nonresponders. Thus, these data provide evidence that elevated serum cortisol and cortisol/DHEA(S) ratios may serve as markers of biological mechanisms that are involved in responsivity of schizophrenia patients to antipsychotic treatment.

Coping patterns as a valid presentation of the diversity of coping responses in schizophrenia patients.

This study aimed to identify coping patterns used by schizophrenia inpatients in comparison with those used by healthy individuals, and to explore their association with selected clinical and psychosocial variables. The Coping Inventory for Stressful Situations (CISS) was used to assess coping strategies among 237 inpatients who met DSM-IV criteria for schizophrenia and 175 healthy individuals. Severity of psychopathology and distress, insight into illness, feelings of self-efficacy and self-esteem (self-construct variables), social support, and quality of life were also examined. Factor analysis, analysis of covariance and correlations were used to examine the relationships between the parameters of interest. Using dimensional measures, we found that emotion-oriented coping style and emotional distress were significantly higher in the schizophrenia group, whereas the task-oriented coping style, self-efficacy, perceived social support and satisfaction with quality of life were lower compared with controls. When eight CISS coping patterns were defined, the results revealed that patients used emotion coping patterns 5.5 times more frequently, and task and task-avoidance coping patterns significantly less often than healthy subjects. Coping patterns have different associations with current levels of dysphoric mood and emotional distress, self-construct variables, and satisfaction with quality of life. Thus, the identified coping patterns may be an additional useful presentation of the diversity of coping strategies used by schizophrenia patients. Coping patterns may be considered an important source of knowledge for patients who struggle with the illness and for mental health professionals who work with schizophrenia patients.

L-theanine relieves positive, activation, and anxiety symptoms in patients with schizophrenia and schizoaffective disorder: an 8-week, randomized, double-blind, placebo-controlled, 2-center study.

OBJECTIVE L-theanine is a unique amino acid present almost exclusively in the tea plant. It possesses neuroprotective, mood-enhancing, and relaxation properties. This is a first study designed to evaluate the efficacy and tolerability of L-theanine augmentation of antipsychotic treatment of patients with chronic schizophrenia and schizoaffective disorder. METHOD 60 patients with DSM-IV schizophrenia or schizoaffective disorder participated in an 8-week, double-blind, randomized, placebo-controlled study. 400 mg/d of L-theanine was added to ongoing antipsychotic treatment from February 2006 until October 2008. The outcome measures were the Positive and Negative Syndrome Scale (PANSS), the Hamilton Anxiety Rating Scale (HARS), the Cambridge Neuropsychological Test Automated Battery (CANTAB) for neurocognitive functioning, and additional measures of general functioning, side effects, and quality of life. RESULTS 40 patients completed the study protocol. Compared with placebo, L-theanine augmentation was associated with reduction of anxiety (P = .015; measured by the HARS scale) and positive (P = .009) and general psychopathology (P < .001) scores (measured by the PANSS 3-dimensional model). According to the 5-dimension model of psychopathology, L-theanine produced significant reductions on PANSS positive (P = .004) and activation factor (P = .006) scores compared to placebo. The effect sizes (Cohen d) for these differences ranged from modest to moderate (0.09-0.39). PANSS negative and CANTAB task scores, general functioning, side effect, and quality of life measures were not affected by L-theanine augmentation. L-theanine was found to be a safe and well-tolerated medication. CONCLUSIONS L-theanine augmentation of antipsychotic therapy can ameliorate positive, activation, and anxiety symptoms in schizophrenia and schizoaffective disorder patients. Further long-term studies of L-theanine are needed to substantiate the clinically significant benefits of L-theanine augmentation.

Improvement of aggressive behavior and quality of life impairment following S-Adenosyl-Methionine (SAM-e) augmentation in schizophrenia

S-adenosyl-methionine (SAM-e), functions as a primary methyl group donor for several metabolic compounds. Since SAM-e is involved in several metabolic processes, its administration may have a role in the amelioration of several disorders. In addition, SAM-e increases catechol-O-methyltransferase (COMT) enzyme activity, which may ameliorate aggressive symptoms in certain patients. We have therefore investigated the efficacy of SAM-e in managing schizophrenia symptomatology in patients with the low activity COMT polymorphism. Eighteen patients with chronic schizophrenia were randomly assigned to receive either SAM-e (800 mg) or placebo for 8 weeks in double-blind fashion. Results indicated some reduction in aggressive behavior and improved quality of life following SAM-e administration. Female patients showed improvement of depressive symptoms. Clinical improvement did not correlate with serum SAM-e levels. Two patients receiving SAM-e exhibited some exacerbation of irritability. This preliminary pilot short-term study cautiously supports SAM-e as an adjunct in management of aggressive behavior and quality of life impairment in schizophrenia.

Familiality in a five-factor model of schizophrenia psychopathology: Findings from a 16-month follow-up study

We sought to examine stability associations between family history and variability of schizophrenia symptoms repeatedly examined during a naturalistic follow-up study. The Positive and Negative Syndrome Scale, the Insight and Treatment Attitudes Questionnaire, and the Abnormal Involuntary Movement Scale were administered to 69 patients with familial and 79 patients with sporadic schizophrenia, at hospital admission and at stabilization stage (about 16 months later). Analysis of covariance was applied to identify the association of symptom factors with familiality of schizophrenia. We found that schizophrenia patients with positive family histories had significantly higher dysphoric, activation and negative factors. However, familiality of activation and negative factors were dependent on additional variables such as age of onset (both factors), baseline ratings, insight, and side effects (negative factor). No significant association of family history with intensity of positive and autistic preoccupation factors was found. Familial schizophrenia is characterized by higher severity of dysphoric mood factors that may represent impaired emotional reactivity. It is suggested that dysphoric mood may be a useful phenotype for molecular genetic studies of schizophrenia with positive family history.

The Long-term Changes in Coping Strategies in Schizophrenia: Temporal Coping Types

This prospective study aimed to define the long-term changes in coping strategies used by schizophrenia patients and their relation to clinical and psychosocial factors. The Coping Inventory for Stressful Situations, psychiatric scales, and self-report questionnaires were administered to 148 schizophrenia patients at admission and 16 months thereafter. Based on trends of individual coping patterns to show change over time, four temporal coping types were distinguished: stable favorable and unfavorable, and becoming favorable and unfavorable. We found that coping patterns of 62.2% of patients remained stable over time, became unfavorable among 19.6% of patients, and became favorable among 18.2% of patients. Each temporal coping type is associated with a specific pattern of changes in clinical and psychosocial variables. The findings underscore the clinical relevance of temporal coping types and corroborate the appropriateness of focusing on aspects of coping behavior in treatment and rehabilitation of schizophrenia patients.