Faculty Bibliography

BACKGROUND: Dysregulation of N-methyl D-aspartate (NMDA) receptor signaling is strongly implicated in schizophrenia. Based on the ketamine model of NMDA receptor hypoactivity, therapeutic approaches designed to maintain a sustained increase in agonist activity at the glycine site of the NMDA receptor have produced promising, although inconsistent, efficacy for negative symptoms. METHODS: A review of the published literature on D-cycloserine (DCS) pharmacology in animal models and in clinical studies was performed. Findings relevant to DCS effects on memory and plasticity and their potential clinical application to schizophrenia were summarized. RESULTS: Studies in animals and clinical trials in patients with anxiety disorders have demonstrated that single or intermittent dosing with DCS enhances memory consolidation. Preliminary trials in patients with schizophrenia suggest that intermittent dosing with DCS may produce persistent improvement of negative symptoms and enhance learning when combined with cognitive behavioral therapy for delusions or with cognitive remediation. The pharmacology of DCS is complex, since it acts as a "super agonist" at NMDA receptors containing GluN2C subunits and, under certain conditions, it may act as an antagonist at NMDA receptors containing GluN2B subunits. CONCLUSIONS: There are preliminary findings that support a role for D-cycloserine in schizophrenia as a strategy to enhance neuroplasticity and memory. However, additional studies with DCS are needed to confirm these findings. In addition, clinical trials with positive and negative allosteric modulators with greater specificity for NMDA receptor subtypes are needed to identify the optimal strategy for enhancing neuroplasticity in schizophrenia.

Social attachment is a biological and affective need. When this need is not met, people experience loneliness. Loneliness is associated with impaired social cognition, and is a risk factor for broad based morbidity across the adult lifespan even after controlling for multiple factors. However, little is known about loneliness in schizophrenia. Eighty-seven non-depressed individuals with schizophrenia or schizoaffective disorder (including 51 inpatients) and 58 control subjects completed the revised UCLA Loneliness scale. Social cognition was assessed with a self-report questionnaire and a performance-based task. Social trait perception was assessed with a facial task. Comorbid medical diagnoses were available for all inpatients. Patients reported greater loneliness levels than controls, while in- and out-patients did not significantly differ. In patients, loneliness was associated with self-report measures of social cognition. Patients' loneliness scores predicted a diagnosis of drug abuse/dependence, number of drugs used, hypertension and abnormal hemoglobin A1c levels. Patients experienced higher levels of loneliness than controls, independently of their objective social isolation. Loneliness did not rely on the same psychological processes in patients than in controls. Loneliness in schizophrenia is a symptom that deserves more scrutiny, particularly as it relates to the high prevalence of metabolic syndrome in this population.

OBJECTIVE: In a pragmatic clinical trial, this study sought to compare relapses among patients receiving either long-acting injectable or oral second-generation antipsychotics. METHODS: PROACTIVE (Preventing Relapse Oral Antipsychotics Compared to Injectables Evaluating Efficacy), a prior 30-month relapse prevention study, compared use of a long-acting injectable second-generation antipsychotic with use of an oral second-generation antipsychotic by 305 patients with schizophrenia or schizoaffective disorder and found similar rates of first relapse between groups (42% with injectable medication, 32% with oral medication). This study examined subsequent relapses among patients who had relapsed in PROACTIVE and who continued in treatment, follow-up, or both. RESULTS: Thirty-two patients (11%) experienced two relapses, and 13 patients (4%) had three relapses. Neither rate of relapse nor time to successive relapses differed between treatment groups. CONCLUSIONS: There was an impressively low rate of subsequent relapses in this pragmatic clinical trial. Because all patients had a clinic visit according to the biweekly long-acting injectable medication administration schedule, frequent contact may have contributed to low relapse rates. Maintaining frequent clinical contact may be a valid psychosocial relapse prevention treatment.

Working memory (WM) impairment, a core feature of schizophrenia, is often associated with aberrant dorsolateral prefrontal cortex (dlPFC) activation. Reduced resting-state connectivity within the frontoparietal control network (FPCN) has also been reported in schizophrenia. However, interpretation of WM-related dlPFC dysfunction has been limited by performance differences between patients and controls, and by uncertainty over the relevance of resting-state connectivity to network engagement during task. We contrasted brain activation in 40 schizophrenia patients and 40 controls during verbal WM performance, and evaluated underlying functional connectivity during rest and task. During correct trials, patients demonstrated normal FPCN activation, despite an inverse relationship between positive symptoms and activation. FPCN activation differed between groups only during error trials (controls>patients). In contrast, controls demonstrated stronger deactivation of ventromedial prefrontal cortex (vmPFC) during correct and error trials. Functional connectivity analysis indicated impaired resting-state FPCN connectivity in patients, but normal connectivity during task. However, patients showed abnormal connectivity among regions such as vmPFC, lateral orbitofrontal cortex, and parahippocampal gyrus (PHG) during both rest and task. During task, patients also exhibited altered thalamic connectivity to PHG and FPCN. Activation and connectivity patterns that were more characteristic of controls generally correlated with better performance. In summary, patients demonstrated normal FPCN activation when they remained on-task, and exhibited normal FPCN connectivity during WM, whereas vmPFC deactivation differences persisted regardless of WM performance. Our findings suggest that altered FPCN activation in patients reflects performance difference, and that limbic and thalamic dysfunction are critically involved in WM deficits in schizophrenia.Neuropsychopharmacology accepted article preview online, 22 April 2016. doi:10.1038/npp.2016.55.

BACKGROUND: An urgent need exists for new treatments of schizophrenia that are effective against a broad range of symptoms and free of limiting safety issues. ITI-007 is a new molecular entity with a pharmacologic profile that combines dose-related monoamine modulation with phosphorylation of intracellular signaling proteins. METHODS: A phase II randomized, double-blind, placebo-controlled, and active-controlled trial was conducted at eight sites in the United States with randomization of 335 acutely psychotic adults with schizophrenia. ITI-007 (60 mg and 120 mg), placebo, and risperidone, included for assay sensitivity, were evaluated as monotherapy for 4 weeks. The primary outcome measure was the Positive and Negative Syndrome Scale total score, with secondary analyses conducted on symptom subscales. RESULTS: ITI-007 60 mg (p = .017, effect size = .4) and risperidone (p = .013, effect size = .4) demonstrated antipsychotic efficacy superiority over placebo on the primary end point. The results of secondary analyses reflected improvements in negative and depressive symptoms by ITI-007 60 mg. ITI-007 120 mg did not separate from placebo. However, both doses of ITI-007 were well tolerated in this patient population, as evidenced by low discontinuation and adverse event rates, and were associated with a benign metabolic profile as evidenced by significantly lower levels of prolactin, fasting glucose, total cholesterol, and triglycerides than risperidone. CONCLUSIONS: The mechanistically novel investigational drug ITI-007 was effective for the treatment of schizophrenia and comparable with placebo on safety measures in this trial. Secondary analyses indicated that ITI-007 improved negative and depression symptoms and might have expanded therapeutic efficacy in comparison with current antipsychotic drugs.

A major goal of current research in schizophrenia is to understand the biology underlying onset and early progression and to develop interventions that modify these processes. Biomarkers can play a critical role in identifying disease state, factors contributing to underlying progression, as well as predicting and monitoring response to treatment. Once biomarker-based therapeutics are established, biomarkers can guide treatment selection. It is increasingly clear that a wide range of potential biomarkers should be examined in schizophrenia, given the large number of genetic and environmental factors that have been identified as risk factors. New models for analysis of biomarkers are needed that represent the central nervous system as a highly complex, dynamic, and interactive system. Many tools are available with which to study relevant brain chemistry, but most are indirect measures and represent only a small fraction of the potential etiologic factors contributing to the molecular, structural and functional components of schizophrenia. This review represents the work of the International Society for CNS Clinical Trials and Methodology (ISCTM) Biomarkers Working Group. It discusses advantages and disadvantages of different categories of biomarkers and provides a summary of evidence that biomarkers representing inflammation, oxidative stress, endocannabinoids, glucocorticoid, and biogenic amines systems are dysregulated and potentially interactive in early phase schizophrenia. As has been recently demonstrated in several neurodevelopmental and neurodegenerative disorders, a multi-modal, longitudinal strategy involving a diverse array of biomarkers and new approaches to statistical modeling are needed to improve early interventions based on the fuller understanding.

BACKGROUND: Abnormal white matter integrity has been reported among first episode schizophrenia patients. However, findings on whether it can be reversed by short-term antipsychotic medications are inconsistent. METHOD: Diffusion tensor imaging (DTI) was obtained from 55 drug-naive first episode schizophrenia patients and 61 healthy controls, and was repeated among 25 patients and 31 controls after 8weeks during which patients were medicated with antipsychotics. White matter integrity is measured using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD). These measures showing a group difference by Tract-based spatial statistics (TBSS) at baseline were extracted for longitudinal comparisons. RESULTS: At baseline, patients exhibited lower FA, higher MD and higher RD versus controls in forceps, left superior longitudinal fasciculus, inferior fronto-occipital fasciculus, left corticospinal tract, left uncinate fasciculus, left anterior thalamic radiation, and bilateral inferior longitudinal fasciculi. FA values of schizophrenia patients correlated with their negative symptoms (r=-0.412, P=0.002), working memory (r=0.377, P=0.005) and visual learning (r=0.281, P=0.038). The longitudinal changes in DTI indices in these tracts did not differ between patients and controls. However, among the patients the longitudinal changes in FA values in left superior longitudinal fasciculus correlated with the change of positive symptoms (r=-0.560, p=0.004), and the change of processing speed (r=0.469, p=0.018). CONCLUSIONS: White matter deficits were validated in the present study by a relatively large sample of medication naive and first episode schizophrenia patients. They could be associated with negative symptoms and cognitive impairment, whereas improvement in white matter integrity of left superior longitudinal fasciculus correlated with improvement in psychosis and processing speed. Further examination of treatment-related changes in white matter integrity may provide clues to the mechanism of antipsychotic response and provide a biomarker for clinical studies.

If treatments for cognitive impairment are to be utilized successfully, clinicians must be able to determine whether they are effective and which patients should receive them. In order to develop consensus on these issues, the International Society for CNS Clinical Trials and Methodology (ISCTM) held a meeting of experts on March 20, 2014, in Washington, DC. Consensus was reached on several important issues. Cognitive impairment and functional disability were viewed as equally important treatment targets. The group supported the notion that sufficient data are not available to exclude patients from available treatments on the basis of age, severity of cognitive impairment, severity of positive symptoms, or the potential to benefit functionally from treatment. The group reached consensus that cognitive remediation is likely to provide substantial benefits in combination with procognitive medications, although a substantial minority believed that medications can be administered without nonpharmacological therapy. There was little consensus on the best methods for assessing cognitive change in clinical practice. Some participants supported the view that performance-based measures are essential for measurement of cognitive change; others pointed to their cost and time requirements as evidence of impracticality. Interview-based measures of cognitive and functional change were viewed as more practical, but lacking validity without informant involvement or frequent contact from clinicians. The lack of consensus on assessment methods was viewed as attributable to differences in experience and education among key stakeholders and significant gaps in available empirical data. Research on the reliability, validity, sensitivity, and practicality of competing methods will facilitate consensus.