Faculty Bibliography

BACKGROUND:The increased mutational burden for rare structural genomic variants in schizophrenia and other neurodevelopmental disorders has so far not yielded therapies targeting the biological effects of specific mutations. We identified two carriers (mother and son) of a triplication of the gene encoding glycine decarboxylase, GLDC, presumably resulting in reduced availability of the N-methyl-D-aspartate receptor coagonists glycine and D-serine and N-methyl-D-aspartate receptor hypofunction. Both carriers had a diagnosis of a psychotic disorder. METHODS:We carried out two double-blind, placebo-controlled clinical trials of N-methyl-D-aspartate receptor augmentation of psychotropic drug treatment in these two individuals. Glycine was used in the first clinical trial, and D-cycloserine was used in the second one. RESULTS:Glycine or D-cycloserine augmentation of psychotropic drug treatment each improved psychotic and mood symptoms in placebo-controlled trials. CONCLUSIONS:These results provide two independent proof-of-principle demonstrations of symptom relief by targeting a specific genotype and explicitly link an individual mutation to the pathophysiology of psychosis and treatment response.

Prior postmortem studies have shown gray matter (GM) microstructural abnormalities in schizophrenia. However, few studies to date have examined GM microstructural integrity in schizophrenia in vivo. Here, we employed diffusion kurtosis imaging (DKI) to test for differences in GM microstructure in eighteen schizophrenia (SZ) patients versus nineteen healthy controls (HC). GM microstructure was characterized in each participant using DKI-derived metrics of mean kurtosis (MK) and mean diffusivity (MD). Individual T1-weighted images were used to create subject-specific cortically-labelled regions of interest (ROIs) of the four cortical lobes and sixty-eight cortical GM regions delineated by the Desikan-Killiany atlas, and to derive the associated cortical thickness and area measures. The derived ROIs were also registered to the diffusion space of each subject and used to generate region-specific mean MK and MD values. We additionally administered the Wisconsin Card Sorting Test (WCST), Stroop test, and Trail Making Test part B (Trails-B) to test the relationship between GM metrics and executive function in SZ. We found significantly increased MK and MD in SZ compared to HC participants in the temporal lobe, sub-lobar temporal cortical regions (fusiform, inferior temporal, middle temporal and temporal pole), and posterior cingulate cortex after correcting for multiple comparisons. Correlational analyses revealed significant associations of MK and MD with executive function scores derived from the WCST, Stroop, and Trails-B tests, along with an inverse relationship between MK and MD and cortical thickness and area. A hierarchical multiple linear regression analysis showed that up to 85% of the inter-subject variability in cognitive function in schizophrenia measured by the WCST could be explained by MK in combination with either GM thickness or area. MK and MD appear to be sensitive to GM microstructural pathology in schizophrenia and may provide useful biomarkers of abnormal cortical microstructure in this disorder.

Importance/UNASSIGNED:Antipsychotic medications for the treatment of schizophrenia have limitations, and new treatments are needed. A prior pilot investigation suggested that adjunctive sodium nitroprusside (SNP) administered intravenously had rapid efficacy in the treatment of patients with schizophrenia. Objective/UNASSIGNED:To determine the efficacy and tolerability of intravenous SNP infused at a rate of 0.5 μg/kg/min for 4 hours in patients with schizophrenia with some degree of treatment resistance. Design, Setting, and Participants/UNASSIGNED:Multicenter, randomized, double-blind acute treatment study using a sequential parallel comparison design conducted in two 2-week phases at 4 academic medical centers beginning May 20, 2015, and ending March 31, 2017. Participants were adults 18 to 65 years of age with a diagnosis of schizophrenia as confirmed by the Structured Clinical Interview for DSM-IV, taking antipsychotic medication for at least 8 weeks, and had at least 1 failed trial of an antipsychotic medication within the past year. A total of 90 participants consented, 60 participants enrolled, and 52 participants were included in the analyses. A modified intent-to-treat analysis was used. Interventions/UNASSIGNED:Participants were randomized in a 1:1:1 ratio to 1 of 3 treatment sequences: SNP and SNP, placebo and SNP, and placebo and placebo. The SNP and SNP group received SNP in phase 1 and SNP in phase 2 for the purpose of blinding, but the data from phase 2 were not included in the results. The placebo and SNP group received placebo in phase 1 and SNP in phase 2. If there was no response to placebo in phase 1, data from phase 2 were included in the analyses. The placebo and placebo group received placebo in both phases; if there was no response to placebo in phase 1, data from phase 2 were included in the analyses. Main Outcomes and Measures/UNASSIGNED:Effectiveness of SNP compared with placebo in improving Positive and Negative Syndrome Scale (PANSS) total, positive, and negative scores across each 2-week phase. Results/UNASSIGNED:Fifty-two participants (12 women and 40 men) were included in the study. In the SNP and SNP group, the mean (SD) age was 47.1 (10.5) years. In the placebo and SNP group, the mean (SD) age was 45.9 (12.3) years. In the placebo and placebo group, the mean (SD) age was 40.4 (11.0) years. There were no significant differences between the SNP and placebo groups at baseline or in change from baseline for PANSS-total (weighted β = -1.04; z = -0.59; P = .57), PANSS-positive (weighted β = -0.62; z = -0.93; P = .35), or PANSS-negative (weighted β = -0.12; z = -0.19; P = .85) scores. No significant differences in safety or tolerability measures were identified. Conclusions and Relevance/UNASSIGNED:Although intravenous SNP is well tolerated, it was not an efficacious adjunctive treatment of positive or negative symptoms of psychosis among outpatients with schizophrenia with prior history of treatment resistance. Trial Registration/UNASSIGNED:ClinicalTrials.gov identifier: NCT02164981.

OBJECTIVE:This study examined the effect of adjunctive telmisartan on body metabolism in clozapine- or olanzapine-treated patients with schizophrenia. METHOD/METHODS:Each subject had been on stable dose of olanzapine or clozapine for at least 1 month. In a 12-week randomized, double-blind, placebo-controlled study, subjects received either telmisartan (80 mg once per day) or placebo. The homeostasis model of assessment of insulin resistance (HOMA-IR) was calculated based on fasting blood levels of insulin and glucose. Fasting blood levels of triglycerides and cholesterols, as well as serum levels of high-sensitivity C-reactive protein (hsCRP) and interleukin-6 (IL-6) were measured. The whole-body dual-energy X-ray absorptiometry (DXA) was used to assess body composition. Lipid particles were assessed using nuclear magnetic resonance (NMR) spectroscopy. All assessments were conducted at baseline and repeated at week 12. RESULTS:Fifty-four subjects were randomized and 43 completed the study (22 in the telmisartan group, 21 in the placebo group). There were no significant differences between the two groups in week 12 changes for HOMA-IR or fasting triglycerides (- 0.18 ± 1.24 vs 0.39 ± 1.39, p = 0.181; - 26 ± 76 vs - 10 ± 81 mg/dL, p = 0.679, respectively) (telmisartan vs placebo). Further, there were no significant between group differences in week 12 changes for other fasting lipids, body weight, body mass index, waist circumference, as well as various measures of lipid particles (p's > 0.100). The DXA assessment showed no significant differences between the two groups in week 12 changes for fat mass, lean mass, or total mass (p's > 0.100). CONCLUSION/CONCLUSIONS:In the present study, adjunctive treatment of telmisartan did not seem to improve body metabolism in schizophrenia patients receiving olanzapine or clozapine. The implications for future studies were discussed. CLINICALTRIALS. GOV IDENTIFIER/UNASSIGNED:NCT00981526.

Antidepressants are frequently prescribed in first episode schizophrenia (FES) patients for negative symptoms or for subsyndromal depressive symptoms, but therapeutic benefit has not been established, despite evidence of efficacy in later-stage schizophrenia. We conducted a 52 week, placebo-controlled add-on trial of citalopram in patients with FES who did not meet criteria for major depression to determine whether maintenance therapy with citalopram would improve outcomes by preventing or improving negative and depressive symptoms. Primary outcomes were negative symptoms measured by the Scale for Assessment of Negative Symptoms and depressive symptoms measured by the Calgary Depression Scale for Schizophrenia; both were analyzed by an intent-to-treat, mixed effects, area-under-the-curve analysis to assess the cumulative effects of symptom improvement and symptom prevention over a one-year period. Ninety-five patients were randomized and 52 (54%) completed the trial. Negative symptoms were reduced with citalopram compared to placebo (p = .04); the effect size of citalopram versus placebo was 0.32 for participants with a duration of untreated psychosis (DUP) of <18 weeks (median split) and 0.52 with a DUP >18 weeks. Rates of new-onset depression did not differ between groups; improvement in depressive symptoms was greater with placebo than citalopram (p = .02). Sexual side effects were more common with citalopram, but overall treatment-emergent side effects were not increased compared to placebo. In conclusion, citalopram may reduce levels of negative symptoms, particularly in patients with longer DUP, but we found no evidence of benefit for subsyndromal depressive symptoms.