Henry Nasrallah

Decreased BDNF levels in CSF of drug-naive first-episode psychotic subjects: Correlation with plasma BDNF and psychopathology

Brain-derived neurotrophic factor (BDNF), which plays an important role in neurodevelopmental plasticity and cognitive performance, has been implicated in neuropsychopathology of schizophrenia. We examined the levels of both cerebrospinal fluid (CSF) and plasma BDNF concomitantly in drug-naive first-episode psychotic (FEP) subjects with ELISA to determine if these levels were different from control values and if any correlation exists between CSF and plasma BDNF levels. A significant reduction in BDNF protein levels was observed in both plasma and CSF of FEP subjects compared to controls. BDNF levels showed significant negative correlation with the scores of baseline PANSS positive symptom subscales. In addition, there was a significant positive correlation between plasma and CSF BDNF levels in FEP subjects. The parallel changes in BDNF levels in plasma and CSF indicate that plasma BDNF levels reflect the brain changes in BDNF levels in schizophrenia.

Reliability, validity and ability to detect change of the Personal and Social Performance scale in patients with stable schizophrenia

This report describes the measurement properties of the Personal and Social Performance scale (PSP), a clinician-reported measure of severity of personal and social dysfunction, in an outpatient population with stabilized schizophrenia. Pooled data from two similar antipsychotic clinical studies were analyzed (n=411). The PSP showed good test-retest reliability (intraclass correlation coefficient=0.79). The PSP was more highly correlated with the Strauss-Carpenter Level of Function, an instrument measuring a similar construct, than the Positive and Negative Syndrome Scale, an instrument measuring a different construct. There was a statistically significant difference between mean PSP scores in subjects grouped by their severity rating on the Clinical Global Impression-Severity (CGI-S) (mild or less versus at least moderate), indicating the ability to discriminate between known groups. Effect sizes for mean change in the PSP based on 1-category improvement (0.72) or worsening (-0.88) versus no change in the CGI-S were moderate to large, demonstrating the ability to detect change. Estimates of between-group minimum important difference suggest that a 7-point improvement in the PSP may be clinically meaningful in a clinical trial setting. Initial reliability and validity assessments suggest the PSP may be a useful measure of social functioning in patients with stable schizophrenia.

Remission in schizophrenia: applying recent consensus criteria to refine the concept.

Although the concept of remission has been widely accepted and utilized in depression and anxiety disorders, there has been much less emphasis on defining remission in schizophrenia. Recently, an expert consensus definition of remission in schizophrenia was proposed along specific operational criteria for the attainment of remission focusing on the three core dimensions of psychopathology identified within schizophrenia: psychoticism, disorganization and negative symptoms. To date, the criteria have been applied retrospectively to several clinical studies, and these have demonstrated that the proposed definition of remission correlates significantly with established measures of symptom severity, functioning and quality of life, and appears achievable for a significant proportion of patients receiving at least 3 months of pharmacotherapy. In this article we extend the notion of remission to include an examination of the possible association of several modifiable and unmodifiable factors and co-morbidities on remission status. We also propose an investigation into the likelihood of different patient populations in achieving remission as well as assessing the impact of remission on health care costs and family burden. Since cognitive dysfunction and negative symptoms may be strongly correlated with a lower likelihood of achieving remission, we recommend retrospective and/or prospective studies to determine the relationship between neurocognitive status and the predominance of negative symptoms at treatment start and the probability of achieving remission. Taken together, these studies should help identify key predictors of remission, further define the remitted state, reduce therapeutic pessimism, raise treatment expectations and chart a strategy for further research in this important area.

A systematic review of psychostimulant treatment of negative symptoms of schizophrenia: challenges and therapeutic opportunities.

BACKGROUND Primary negative symptoms of schizophrenia (NSS) contribute heavily to functional disability and treatment of these symptoms continues to be a major unmet need even when the positive (psychotic) symptoms are controlled. The modified dopamine (DA) hypothesis posits that positive symptoms are associated with increased DA activity in the mesolimbic tract whereas NSS and cognitive symptoms are associated with decreased DA activity in the mesocortical (frontal) region. Several studies have reported improvement in NSS with DA agonist use, but with varying degrees of risk for triggering psychotic symptoms, especially in the absence of concurrent antipsychotic drug treatment. This article aims to examine older and newer evidence suggesting that psychostimulants may have a potential therapeutic role in the treatment of NSS together with a thorough review of the potential risks and benefits of psychostimulant administration in individuals with schizophrenia. METHODS A systematic search of relevant literature using electronic databases, reference lists, and data presented at recent meetings was conducted. RESULTS Improvement of NSS after psychostimulant administration is reviewed both in challenge and treatment paradigms with various agents such as methylphenidate, amphetamine, and modafinil or armodafinil. The literature points to evidence that, used adjunctively, DA agonists may improve NSS without worsening of positive symptoms in selected patients who are stable and treated with effective antipsychotic medications. Several areas of inadequate study and limitations are identified including small study samples, single-site trials, varying rigor of bias control, the dose and the duration of adjunctive psychostimulant administration, and the potential for development of tolerance. CONCLUSION Large, controlled clinical trials to further characterize effects of psychostimulants on NSS in carefully selected patients are warranted.

Opposite changes in predominantly docosahexaenoic acid (DHA) in cerebrospinal fluid and red blood cells from never-medicated first-episode psychotic patients.

Variable levels of essential polyunsaturated fatty acids (EPUFAs) reported in schizophrenia are likely due to differences in age, sex, ethnicity, diet, life style and treatments. The present study examined the EPUFAs levels in plasma, RBC and CSF in never-medicated first-episode psychotic patients and normal controls matched for ethnicity, diet and life style. The plasma EPUFAs levels were similar in both groups. Among the EPUFAs enriched in the brain, predominantly docosahexaenoic acid (DHA) levels were lower in RBC (p=<0.01) whereas higher in CSF (p=<0.01) in male>female patients. This altered DHA metabolism may provide clues for neuropathology and treatment of schizophrenia.

Impaired plasmalogens in patients with schizophrenia

Plasmalogens are a subclass of glycerophospholipids and ubiquitous constituents of cellular membranes and serum lipoproteins. Several neurological disorders show decreased level of plasmogens. An earlier study found differences in plasma phospholipids between unmedicated patients with schizophrenia and matched healthy control subjects. We here report a comparison of plasma plasmalogen levels across 20 drug-naïve patients experiencing first psychotic episodes, 20 recently unmedicated patients experiencing psychotic relapses after failing to comply with prescribed medications, and 17 matched healthy control subjects. Multiple plasma phosphatidylcholine and phosphatidylethanolamine plasmalogen levels were significantly lower in first episode patients and patients with recurrent disease compared to healthy controls. Reduced plasmalogen levels appear to be a trait evident at the onset of psychotic illness and after multiple psychotic relapses. It is implied that reductions in plasmalogen levels are not related to antipsychotic treatment but due to the illness itself. Reduced plasmalogen levels suggest impairments in membrane structure and function in patients with schizophrenia that might happen early in development. This may serve as a clue to the neurobiology of schizophrenia and should be studied as a potential biomarker for individuals at risk for schizophrenia.

The association between weight change and symptom reduction in the CATIE schizophrenia trial

BACKGROUND Weight gain and changes in metabolic indicators associated with some antipsychotics may be related to symptom improvement and thus an unavoidable correlate of clinical benefit. METHODS Data from the CATIE schizophrenia trial comparing the effectiveness of perphenazine, olanzapine, risperidone, quetiapine and ziprasidone in a randomized, double-blind, trial over 18 months were used to evaluate the relationship between percent change in body mass index (BMI) and change in total serum cholesterol and triglycerides with the Positive and Negative Syndrome Scale (PANSS) score. Analysis of covariance for observations at 3 months and a mixed effects model for all observations up to 18 months adjusted for potentially confounding variables were used to examine these associations. RESULTS In both models, there was a significant association (p = 0.001) between change in PANSS total score and percent change in BMI, equating to a 0.28 and 0.21 point decrease in PANSS total score (range 30-210) per 1% increase in BMI respectively. Change in BMI accounted for 3% or less of variance for change in PANSS scores. There was no evidence that the association of symptoms and weight gain differed across medications in spite of substantial differences in weight gain and other metabolic measures. Neither total serum cholesterol nor triglyceride levels displayed a significant association with change in PANSS. CONCLUSION The magnitude of the relationship between change in BMI and PANSS was too small to be clinically important, indicating that switching medications to one with less metabolic risk is unlikely to result in meaningful loss of clinical benefit.

Risk of diabetic ketoacidosis after exposure to risperidone or olanzapine.

AbstractBackground: Atypical antipsychotics have been associated with metabolic abnormalities including impaired glucose metabolism, exacerbation of existing diabetes mellitus and new-onset type 2 diabetes. Not all atypical antipsychotic agents appear to have the same propensity to cause these complications. Objective: To assess diabetic ketoacidosis risk in patients receiving risperidone or olanzapine. Methods: California Medicaid data were evaluated for the presence of a diabetic ketoacidosis hospital claim (9th Edition of the International Classification of Diseases code 2501x) for patients receiving an atypical antipsychotic agent between July 1997 and September 2000. Initial prescription claims were identified for risperidone, olanzapine, clozapine, quetiapine and multiple atypical medications; however, the final analysis was restricted to risperidone and olanzapine owing to sample size challenges in the clozapine and quetiapine groups. Cases were specified if a claim occurred within 45 days after antipsychotic dispensation. Potential confounding variables and duration of antipsychotic exposure were included. Results: Initial users of risperidone (n = 51 330; 31 diabetic ketoacidosis) and olanzapine (n = 51 302; 55 diabetic ketoacidosis) were identified between July 1997 and September 2000. The adjusted risk of diabetic ketoacidosis for olanzapine versus risperidone was 1.62 (p = 0.033). The risk of diabetic ketoacidosis was associated with a longer duration of drug exposure. A progressive and statistically significant divergence in risk was observed between the two treatment groups after the first 30 days of therapy. For risperidone patients, diabetic ketoacidosis risk stabilised after the first 90 days; for olanzapine patients, diabetic ketoacidosis risk continued to increase until 360 days (study duration). For exposures of >30 days, >90 days and >180 days, diabetic ketoacidosis risk was 1.7 (p = 0.026), 2.4 (p = 0.004) and 3.5 (p = 0.001) times greater for olanzapine than risperidone. Treatment group, age, African American race and the presence of schizophrenia or diabetes were significant predictors of diabetic ketoacidosis. Conclusion: The risk of diabetic ketoacidosis appears to be greater for patients exposed to olanzapine compared with risperidone after adjusting for confounding factors. This risk appears to increase with longer duration of exposure to olanzapine.

Adjunctive Lisdexamfetamine Dimesylate Therapy in Adult Outpatients With Predominant Negative Symptoms of Schizophrenia: Open-Label and Randomized-Withdrawal Phases

Negative symptoms of schizophrenia (NSS), related to hypodopaminergic activity in the mesocortical pathway and prefrontal cortex, are predictive of poor outcomes and have no effective treatment. Use of dopamine-enhancing drugs (eg, psychostimulants) has been limited by potential adverse effects. This multicenter study examined lisdexamfetamine dimesylate (LDX), a d-amphetamine prodrug, as adjunctive therapy to antipsychotics in adults with clinically stable schizophrenia and predominant NSS. Outpatients with stable schizophrenia, predominant NSS, limited positive symptoms, and maintained on stable atypical antipsychotic therapy underwent a 3-week screening, 10-week open-label adjunctive LDX (20–70 mg/day), and 4-week, double-blind, randomized, placebo-controlled withdrawal. Efficacy measures included a modified Scale for the Assessment of Negative Symptoms (SANS-18) and Positive and Negative Syndrome Scale (PANSS) total and subscale scores. Ninety-two participants received open-label LDX; 69 received double-blind therapy with placebo (n=35) or LDX (n=34). At week 10 (last observation carried forward; last open-label visit), mean (95% confidence interval) change in SANS-18 scores was −12.9 (−15.0, −10.8; P<0.0001). At week 10, 52.9% of participants demonstrated a minimum of 20% reduction from baseline in SANS-18 score. Open-label LDX was also associated with significant improvement in PANSS total and subscale scores. During the double-blind/randomized-withdrawal phase, no significant differences (change from randomization baseline) were found between placebo and LDX in SANS-18 or PANSS subscale scores. In adults with clinically stable schizophrenia, open-label LDX appeared to be associated with significant improvements in negative symptoms without positive symptom worsening. Abrupt LDX discontinuation was not associated with positive or negative symptom worsening. Confirmation with larger controlled trials is warranted.

Reduced cerebrospinal fluid and plasma nerve growth factor in drug-naïve psychotic patients

Impaired expression and function of several major neurotrophic factors such as nerve growth factor (NGF) has been proposed to contribute to the neurodevelopmental pathology of schizophrenia. However, the evidence in the majority of studies is based on variable and inconsistent levels of plasma NGF in diverse populations of early psychosis or medicated patients with chronic schizophrenia. We report here the first study comparing NGF levels in cerebrospinal fluid (CSF) and plasma from a unique patient cohort (unmedicated, early psychotic patients with similar racial and dietary patterns) and matched healthy controls. Significantly lower levels of NGF in both CSF (p=0.038) and plasma (p=0.002) were observed in drug-naïve first-episode psychosis patients as compared to controls. The levels of NGF in the CSF correlated (p=0.05) to the plasma values in controls. The data on plasma NGF confirm the reported deficits of NGF in drug-naïve first-episode psychosis. The reduced levels first time observed here may have important implications to repeatedly reported neurobiological and clinical deficits which are discussed.