Faculty Bibliography

To investigate the immediate and lasting effects of transcranial electrical stimulation (tES) on working memory (WM) in schizophrenia. We performed a literature search to identify randomized controlled trials (RCTs) evaluating the ability of tES to ameliorate WM. Twelve studies were included: 215 patients in the active stimulation group and 214 in the sham stimulation group. Meta-analysis demonstrated a significant efficacy of tES on WM in follow up, a summary of one or more assessments weeks after the last tES session (standardized mean difference (SMD) 0.33, 95% confidence interval (CI) 0.04 to 0.62; p = 0.02; n = 190, 4 studies; I²Â = 33%) compared to sham tES, while non-significant results were observed for WM assessed immediately after the last tES session (SMD 0.14, 95% CI -0.12 to 0.41; p = 0.30; n = 417, 11 studies; I²Â = 41%) in schizophrenia. There was no significant difference between the two groups in tolerability and dropouts. Evidence of low quality indicates that effects of tES on WM in schizophrenia may appear a few weeks after the last tES session, but not always be present when tested immediately after the last tES session. Further large-scale RCTs with a parallel-group design, sample size estimation and a longer follow-up period are needed.

Schizophrenia is a severe neuropsychiatric disorder associated with a wide array of transcriptomic and neurobiochemical changes. Genome-wide transcriptomic profiling conducted in postmortem brain have provided novel insights into the pathophysiology of this disorder, and identified biological processes including immune/inflammatory-related responses, metabolic, endocrine, and synaptic function. However, few studies have investigated whether similar changes are present in peripheral tissue. Here, we used RNA-sequencing to characterize transcriptomic profiles of lymphocytes in 18 nonpsychotic controls and 19 individuals with schizophrenia. We identified 2819 differentially expressed transcripts (P_nominal < .05) in the schizophrenia group when compared to controls. Bioinformatic analyses conducted on a subset of 293 genes (P_nominal < .01 and |log₂ FC| > 0.5) highlighted immune/inflammatory responses as key biological processes in our dataset. Differentially expressed genes in lymphocytes were highly enriched in gene expression profiles associated with cortex layer 5a and immune cells. Thus, we investigated whether the changes in transcripts levels observed in lymphocytes could also be detected in the prefrontal cortex (PFC, BA10) in a second replication cohort of schizophrenia subjects. Remarkably, mRNA levels detected in the PFC and lymphocytes were in strong agreement, and measurements obtained using RNA-sequencing positively correlated with data obtained by reverse transcriptase-quantitative polymerase chain reaction analysis. Collectively, our work supports a role for immune dysfunction in the pathogenesis of schizophrenia and suggests that peripheral markers can be used as accessible surrogates to investigate putative central nervous system disruptions.

There is preliminary evidence that transcranial direct current stimulation(tDCS) may improve symptoms and cognitive function in schizophrenia, but the generalizability of these results needs further investigation. We present a study of the effects of active vs. sham tDCS on cognition and symptoms in a sample of 45 Chinese patients with schizophrenia who showed significant cognitive deficits and were treated for 10 sessions with active or sham tDCS. Psychiatric symptoms were assessed by PANSS scores, and cognitive symptoms assessed by MATRICS battery and other tests. There were no differences between cognitive or symptom scores between subjects treated with active vs. sham tDCS tested within 1-2 days after the end of the 10th session. However, two weeks later subjects treated with active tDCS showed significantly more improvements on MATRICS Speed of Processing domain. MATRICS Overall Composite and a CogState measure related to accuracy on a 1-back working memory task were improved at two weeks in statistical tests without multiple corrections. The improvement in cognitive test scores 2 weeks after the last tDCS session, suggests longer term effects may be related to changes in neuroplasticity induced by 10 sessions of tDCS. The lack of significant changes in cognition shortly after the completion of 10 tDCS sessions contrasts with our earlier positive findings in U.S. patients with schizophrenia.

Background: Transcranial Direct Current Stimulation (TDCS)is a brain stimulation technique which some studies have suggested may improve cognition and decrease auditory hallucinations in patients with schizophrenia. We conducted a study of a study of effects of tDCS on cognition, symptoms, and brain connectivity in inpatients with relatively stable chronic schizophrenics in China who had substantial cognitive deficits but were not chosen for prominent auditory hallucinations. Method(s): Patients participated in a double blind study of 10 sessions of active or sham tDCS and followed up lasting up to 1 month. Patient were evaluated for cognitive changes by MATRICS, PASAT and COGSTATE, for symptoms on the PANSS scale, and for brain changes with fMRI for resting state and during active n-back task. Result(s): There were no significant (P<.05) changes in cognitive scores in active vs sham patients after 10 tDCS sessions compared to baseline, but MATRICS Speed of Processing scores and 1 back memory improved over testing times in the active tDCS group over several weeks (P<.05) and there were trends for improvement in other measures. The were no significant change in psychiatric symptoms. fMRI scans showed significant increases in brain activation in R and L middle frontal gurus and differences in activation on a n-back task after 10 sessions of active vs sham tDCS. Conclusion(s): Effects of tDCS in this Chinese sample did not replicate the marked cognitive improvement seen in our earlier U.S. study, but there were selective improvements in speed of processing and n-back. 10 sessions of tDCS produced significant effects on increasing brain activation in selected areas differentially in active vs sham treated subjects in resting state and during an active n-back task. 2 Introduction: Transcranial Direct Current Stimulation (tDCS) is a non-invasive brain stimulation technique which has shown cognitive and clinical effects in patients with schizophrenia and depression as well as controls, and there is preliminary evidence it may also effect brain networks. Its comparatively lower cost, low-side effects, and ease of administration may make it a more easily administered therapy to a wide population of patients, if efficacy can be consistently demonstrated. In an earlier study (Smith et al. 2015), in schizophrenic outpatients in the United States, we presented evidence from a double-blind study that 5 sessions of active 2 ma tDCS compared to Sham, produced statistically significant improvement in MATRICS battery scores. 3 Methods: We now report results from a larger double-blind study of active vs sham tDCS stimulation in 45 relatively stable inpatients with schizophrenia studied at the Shanghai Mental Health Center in China. Active and sham tDCS administration followed the procedures with placement of electrodes, current and other procedures described in detail in our previous published research (Smith et al. 2015). Placement of electrodes for tDCS had the anode placed over LDLPFC (F3) and the cathode over the contralateral supraorbital ridge (Fp2). The active tDCS group was stimulated with a 2 mA current for 20minutes. The sham group had stimulation with 2 mA lasting only 45 seconds, though the electrodes remained in place for 20 minutes. The main cognitive outcome measures were the composite and domain scores on the Chinese version of the MATRIC (MCCB) battery (Nuechterlein et al. 2008), which was administered at baseline, after 10 sessions of tDCS, and 2 and 4 weeks after completion of the 10^th session. Because the Chinese version of the MCCB does not contain the verbal working memory test (LNS), we used an additional task to test for verbal working memory, the Paced Auditory Serial Addition Task (PASAT)(Gronwall 1977), using the 3 second presentation module, which was evaluated at the same time points as the MATRICS battery. Additionally, we used components of the CogState battery (CS) using CS tasks - identification task, n-back (1-back/2-back). Patients were evaluated for changes in psychopathology with the PANSS scale at baseline and after completion of 10 tDCS sessions and 2 weeks and 4 weeks later. Changes in brain activation were evaluated with fMRI Brain Scans at baseline and after 10 sessions using a Siemens Trio 3.0 Tesla MRI scanner with a standard 32-channel head coil. fMRI data was evaluated for: a) Changes on resting state intensity activation, and b) Before and after 10 sessions of tDCS, participants perform 0 back and 2 back tasks while scanned in fMRI. Cortical activation during 0 back and 2 back tasks were analyzed to check the difference between low and high load tasks. For (a) resting state fMRI data were preprocessed by Configurable Pipeline for the Analysis of Connectomes. Group analysis was conducted by FMRIB's Software Library (FSL) proprietary mixed effects analysis (FLAMEO). Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. For (b) fMRI data processing was carried out using FEAT (FMRI Expert Analysis Tool) Version 6.00, part of FSL. Z (Gaussianised T/F) statistic images were thresholded using clusters determined by Z>2.3 and a corrected cluster significance threshold of P=0.05. 1 Results: Behavioral measures: There were no significant differences (P<=.05) in effect of Active vs. Sham tDCS on any cognitive measure tested shortly after completion of 10 sessions of stimulation. However, the active tDCS group showed trends for better improvement vs. sham group, on testing done at two and/or 4 weeks after 10 tDCS session. At the two-week time point the difference from baseline improvement scores of the MATRICS Overall Composite Score and Speed of Processing Domain score, as well as a measure of accuracy on CogState 1-back was significantly better in active than sham groups at uncorrected significance levels (P<.05). Brain Activation: In testing with the n-back during fMRI scans, in active tDCS group, we found significant improvement in accuracy of 0 back condition after 10 sessions of tDCS (p<0.01). In the active tDCS vs. sham group task activation decreased in right middle frontal gyrus after 10 sessions of tDCS for the 0 back condition. No changes were found under the 2 back condition. Comparing the 2 back and 0 back conditions, increased activation in bilateral middle frontal gyrus was evident after 10 sessions of active tDCS vs sham. In resting state brain scans, the active tDCS group vs sham showed significantly increased activation in the R middle frontal and superior gyrus and L middle frontal gyrus. [Figure presented] N=45, Active tDcs-24, sham tDCS=2. Analysis is result of mixed-model analysis including all subjects who had value for in the at baseline and after 10 sessions tDCS. Significance of difference between the active vs sham values at specific time point by t-test from mixed-model output: *P<=05 **P<=01. Benjamini-Hochberg corrected significance levels taking into account the three time-point comparisons: ^Asignificant at (a=.05) [Figure presented] 2 Discussion and Conclusion(s): The results of this study in Chinese schizophrenics did not replicate the immediate pro-cognitive effects directly after a series to tDCS sessions that we found in the U.S. sample but suggest possible pro-cognitive effects 2 or 4 weeks after treatment. The long term effects to tDCS on cognitive function reported in this and some other studies suggest that some of the positive effects of tDCS may require a consolidation period to improve some aspects of cognitive functions. The fMRI data show that the tDCS treatment had significant effects on brain activation, and the changes in n-back performance in the active tDCS group during fMRI scans suggest increased capacity for working memory performance. References: Gronwall DM (1977) Paced auditory serial-addition task: a measure of recovery from concussion. Percept Mot Skills 44: 367-73. Nuechterlein K, Green M, Kern R, Baade L, Barch D, Cohen J, Essock S, Fenton W, Frese F, Gold J, Goldberg T, Heaton R, Keefe R, Kraemer H, Seidman L, Stover E, Weinberger D, Young A, Zalcan S, Mardder S (2008) The MATRICS Consensus Cognitive Battery, Part 1: Test Selection, Reliability, and Validity. The American journal of psychiatry. Smith RC, Boules S, Mattiuz S, Youssef M, Tobe RH, Sershen H, Lajtha A, Nolan K, Amiaz R, Davis JM (2015) Effects of transcranial direct current stimulation (tDCS) on cognition, symptoms, and smoking in schizophrenia: A randomized controlled study. Schizophrenia research 168: 260-266.

BACKGROUND:Identifying the types and characteristics of cognitive deficits before the onset of schizophrenia and during its subsequent course could improve early detection and contribute to our understanding of the evolution of the core behavioral deficits underlying this disorder. METHODS:This study used the Measurement and Treatment Research to Improve Cognition In Schizophrenia (MATRICS) battery to identify cognitive deficits and their progression during the course of schizophrenia from genetic high risk (HRF) subjects, subjects with prodromal symptoms (prodromal), and patients with first episode (FSCZ) and multi-episode (CSCZ) schizophrenia, compared to controls, in a Chinese Han population of 267 subjects. RESULTS:There were statistically significant cognitive deficits which first appeared in prodromal subjects which were also present in FSCZ and CSCZ. There were no statistically significant differences between controls and HRF on any cognitive measure. Deficits in Visual Learning, Speed of Processing, and Overall Cognition were significantly correlated with some symptom measures on PANSS or SIPS. There were no statistically significant differences in cognitive deficits between FSCZ and CSCZ, and on most measures the patients with schizophrenia did not show a progression to more severe cognitive deficits than the prodromal subjects. CONCLUSIONS:In this sample of Chinese subjects, prodromal subjects showed significant cognitive deficits which were similar in most domains to those found in patients with schizophrenia. Whether the pattern of cognitive deficits on the MATRICS battery found in prodromal subjects will help predict conversion to diagnosed schizophrenia or other psychotic disorders would help determine how useful this profile of cognitive deficits is as a potential endophenotype for schizophrenia.

RATIONALE/BACKGROUND:There are many psychotropic drugs available for treatment of schizophrenia. The clinician's choice of the most effective first-line antipsychotic treatment for patients with schizophrenia should balance considerations of differential efficacy of antipsychotics against the relative risk of different side effects. METHOD/METHODS:We reviewed recent studies using meta-analytic techniques and additional studies of new antipsychotics which quantitatively evaluate the efficacy of side effects of first- and second-generation antipsychotics and studies of the efficacy on add-on secondary medications. We present an integrated summary of these results to guide a clinician's decision-making. RESULTS:Recent meta-analyses have suggested that antipsychotics are not equivalent in efficacy. Clozapine (effect size [SMD] 0.88 vs. placebo), amisulpride (effect size 0.6 vs placebo), olanzapine (effect size 0.59 vs. placebo), and risperidone (effect size 0.56 vs placebo) show small but statistically significant differences compared to a number of other antipsychotics on measures of overall efficacy (effect sizes 0.33-0.50). However, increasing placebo response remains a concern in interpreting these data. Amisulpride (effect size 0.47 vs placebo) and cariprazine (effect size in one trial compared to risperidone 0.29) have the strongest evidence indicating greater efficacy for treating primary negative symptoms relative to other antipsychotics. In terms of side effects, clozapine and olanzapine have among the highest weight gain potential and sertindole and amisulpride have more effects on QTc prolongation than other commonly used antipsychotics. Prolactin elevation is highest with paliperidone, risperidone, and amisulpride. Adjunctive treatment with an antidepressant drug may improve response in patients with schizophrenia who also have severe depressive or negative symptoms. For multi-episode patients with an inadequate response to an adequate dose and duration of the initial antipsychotic choice, switching to another antipsychotic, with a different receptor profile, may improve response, although evidence is very limited. In first-episode patients, a recent study on switching to another antipsychotic, with a different receptor profile after 4 weeks demonstrated no beneficial effects. There is little evidence to support using doses above the therapeutic range other than in exceptional circumstances. CONCLUSIONS:Our review of recent studies using meta-analytic techniques has provided evidence that all antipsychotics are not equal in the severity of different side effects and in some measures of clinical efficacy. Comparative analysis and rankings from network meta-analyses can provide guidance to clinicians in choosing the most appropriate antipsychotic for first-line treatment, if used in conjunction with available information of the patient's history of previous clinical response or higher risks for specific side effects.

Elderly patients with schizophrenia are a particularly vulnerable group often excluded from clinical trials. Currently there is no evidence-synthesis about the efficacy and safety of antipsychotics in this subgroup. We reviewed all randomized-controlled-trials, about antipsychotics in elderly schizophrenics (last search Dec 12, 2017). Pairwise meta-analyses were conducted. The primary outcome was overall symptoms. Secondary outcomes included positive symptoms, negative symptoms, response, dropouts, quality of life, social functioning and side-effects. We included 29 references from 18 unique randomized-controlled-trials with 1225 participants published from 1958 to 2009. The definition of "elderly" was very heterogeneous across the studies (minimum age 46-65, mean age 57-73). There were evidence gaps for most drugs in many outcomes. In terms of efficacy paliperidone was associated with fewer dropouts due to inefficacy than placebo in the only placebo-controlled-trial. Olanzapine was superior to haloperidol in overall symptoms, negative symptoms and response, and it was associated with fewer dropouts than risperidone. Risperidone and haloperidol produced more prolactin increase than olanzapine, and olanzapine was associated with less use of antiparkinson medication than haloperidol. Although we found no marked differences of the effects of these drugs in the elderly, the evidence presented was based on very few usually small studies. To examine specifically whether there are differences in efficacy and side-effects in elderly, which differs in meaningful ways from the general population, studies in patients who are defined by critiera as truly geriatric, which incorporates older age together with multimorbidity and fraility dimensions, may be more informative.

RATIONALE/BACKGROUND:Weight gain during treatment with antipsychotics is a prominent side-effect, especially with some second-generation antipsychotics, such as olanzapine and clozapine, and pharmacological treatments which ameliorate this side-effect are important to investigate. Decreases in histaminergic transmission in the brain induced by antipsychotics may be one of the mechanisms contributing to weight gain. Since betahistine is a histaminergic agonist, it may potentially counteract the weight gain effects of antipsychotics. METHOD/METHODS:We conducted a double-blind placebo-controlled study to evaluate the effects of 12 weeks of treatment with betahistine (N = 29) or placebo (N = 22) in adolescents and adults on anthropomorphically measured weight-related parameters, appetite, and fasting glucose-lipid and leptin levels in 51 patients treated with first and/or second-generation antipsychotics who had gained weight during treatment or had high body-mass-index (BMI). Psychopathology and side-effects were also assessed with relevant scales. RESULTS:In a sub-group of patients being treated with olanzapine or clozapine (n = 26), betahistine was significantly (P < .05) better than placebo in preventing increases in weight (3.1 kg less weight gain than placebo), BMI, and waist circumference. Betahistine did not decrease weight or BMI in patients treated with other antipsychotics. There was also no effect of betahistine on preventing weight or BMI gain in the total combined sample of all subjects. Betahistine did not significantly improve appetite or glucose-lipid measures in either subgroup. There were no significant differences in side-effects or psychopathology changes in the betahistine- vs. placebo-treated patients. CONCLUSIONS:These results suggest that betahistine may potentially be a useful adjunctive drug for decreasing weight gain in patients treated with antipsychotics that are potent histamine antagonists, such as olanzapine or clozapine, but may not be useful for this purpose in patients on other antipsychotic medications. The results justify larger placebo-controlled studies to further confirm these effects before specific recommendations can be made for routine use.