Joshua T. Kantrowitz

N-methyl-D-aspartate (NMDA) receptor dysfunction or dysregulation: the final common pathway on the road to schizophrenia?

Schizophrenia is a severe mental disorder associated with a characteristic constellation of symptoms and neurocognitive deficits. At present, etiological mechanisms remain relatively unknown, although multiple points of convergence have been identified over recent years. One of the primary convergence points is dysfunction of N-methyl-d-aspartate (NMDAR)-type glutamate receptors. Antagonists of NMDAR produce a clinical syndrome that closely resembles, and uniquely incorporates negative and cognitive symptoms of schizophrenia, along with the specific pattern of neurocognitive dysfunction seen in schizophrenia. Genetic polymorphisms involving NMDAR subunits, particularly the GRIN2B subunit have been described. In addition, polymorphisms have been described in modulatory systems involving the NMDAR, including the enzymes serine racemase and d-amino acid oxidase/G72 that regulate brain d-serine synthesis. Reductions in plasma and brain glycine, d-serine and glutathione levels have been described as well, providing potential mechanisms underlying NMDAR dysfunction. Unique characteristics of the NMDAR are described that may explain the characteristic pattern of symptoms and neurocognitive deficits observed in schizophrenia. Finally, the NMDAR complex represents a convergence point for potential new treatment approaches in schizophrenia aimed at correcting underlying abnormalities in synthesis and regulation of allosteric modulators, as well as more general potentiation of pre- and post-synaptic glutamatergic and NMDAR function.

High dose D-serine in the treatment of schizophrenia

BACKGROUND D-serine is an allosteric modulator of the brain N-methyl-d-aspartate (NMDA) receptor and a potential novel treatment of schizophrenia. Double-blind studies have been performed at 30 mg/kg/day (approximately 2 g/day) with encouraging results, but no formal dose escalation studies have been performed. We describe the first evaluation of the efficacy and safety of d-serine at doses >30 mg/kg/day; a 4-week, open-label trial of adjunctive D-serine (30, 60 or 120 mg/kg/day). METHODS 42 antipsychotic-stabilized patients with schizophrenia or schizoaffective disorder participated. PANSS was obtained bi-weekly and neuropsychological (MATRICS) was obtained pre- and post medication phase. The pharmacokinetics/pharmacodynamics (PK/PD), and safety of doses> or =30 mg/kg was also evaluated. RESULTS Significant improvement in symptoms and neuropsychological measures was noted across doses. On the PANSS, improvement was observed for positive (p=0.006;d=0.46), negative (p<0.001;d=0.68), general (p=0.001;d=0.53), and total (p<0.0001;d=0.74) symptoms. On MATRICS, while only non-significant improvement was noted at 30 mg/kg, highly significant, large effect size improvement was noted on the composite score (p<0.01;d=1.0) for doses> or =60 mg/kg, leading to a significant dose-by-time interaction (p<0.01). In PK analyses, significant dose-dependent increases in plasma D-serine levels were seen during the study, predictive of significantly increased brain levels. Furthermore, increases in plasma levels correlated with improved symptomatic and neuropsychological function. DISCUSSION These findings support double-blind investigation of D-serine at doses> or =60 mg/kg/d, and suggest effectiveness in treatment of both persistent symptoms and neurocognitive dysfunction.

Glutamatergic transmission in schizophrenia: from basic research to clinical practice.

Purpose of review The past 20 years have seen the glutamatergic hypothesis go from theory to phase III trials of novel mechanism antipsychotics. Recent findings We review the recent literature on glutamatergic theory, covering assessment and genetic studies, as well as drug development in animals and humans. Summary Although evidence continues to accumulate in support of glutamate hypotheses, further research continues to be required and interactions with other key systems need to be explored.

Glutamatergic Abnormalities In Schizophrenia: a review of proton MRS findings

The last fifteen years have seen a great increase in our understanding of the role of glutamate in schizophrenia (SCZ). The glutamate hypothesis focuses on disturbances in brain glutamatergic pathways and impairment in signaling at glutamate receptors. Proton Magnetic Resonance Spectroscopy ((1)H-MRS) is an MR-based technique that affords investigators the ability to study glutamate function by measuring in vivo glutamatergic indices in the brains of individuals with SCZ. (1)H-MRS studies have been performed comparing glutamatergic levels of individuals with SCZ and healthy control subjects or studying the effect of antipsychotic medications on glutamatergic levels. In this article we summarize the results of these studies by brain region. We will review the contribution of (1)H-MRS studies to our knowledge about glutamatergic abnormalities in the brains of individuals with SCZ and discuss the implications for future research and clinical care.

Auditory Emotion Recognition Impairments in Schizophrenia: Relationship to Acoustic Features and Cognition

OBJECTIVE Schizophrenia is associated with deficits in the ability to perceive emotion based on tone of voice. The basis for this deficit remains unclear, however, and relevant assessment batteries remain limited. The authors evaluated performance in schizophrenia on a novel voice emotion recognition battery with well-characterized physical features, relative to impairments in more general emotional and cognitive functioning. METHOD The authors studied a primary sample of 92 patients and 73 comparison subjects. Stimuli were characterized according to both intended emotion and acoustic features (e.g., pitch, intensity) that contributed to the emotional percept. Parallel measures of visual emotion recognition, pitch perception, general cognition, and overall outcome were obtained. More limited measures were obtained in an independent replication sample of 36 patients, 31 age-matched comparison subjects, and 188 general comparison subjects. RESULTS Patients showed statistically significant large-effect-size deficits in voice emotion recognition (d=1.1) and were preferentially impaired in recognition of emotion based on pitch features but not intensity features. Emotion recognition deficits were significantly correlated with pitch perception impairments both across (r=0.56) and within (r=0.47) groups. Path analysis showed both sensory-specific and general cognitive contributions to auditory emotion recognition deficits in schizophrenia. Similar patterns of results were observed in the replication sample. CONCLUSIONS The results demonstrate that patients with schizophrenia show a significant deficit in the ability to recognize emotion based on tone of voice and that this deficit is related to impairment in detecting the underlying acoustic features, such as change in pitch, required for auditory emotion recognition. This study provides tools for, and highlights the need for, greater attention to physical features of stimuli used in studying social cognition in neuropsychiatric disorders.

Seeing the World Dimly: The Impact of Early Visual Deficits on Visual Experience in Schizophrenia

Deficits in early visual processing are well documented in schizophrenia, using methods such as contrast sensitivity. Higher, integrative stages of functioning, such as susceptibility to visual illusions, have been evaluated less extensively. For example, patients show increased susceptibility to (ie, are more easily affected by) the Muller-Lyer illusion but decreased susceptibility (ie, are less easily affected by) to stereopsis based upon binocular disparity. The basis for pattern of illusion response and interaction between sensory and integrative stages of processing, however, is unclear. We tested a group of 38 patients and 28 control subjects in contrast sensitivity, the Muller-Lyer and Poggendorff illusions, as well as a subgroup in stereopsis and the Ponzo illusion, Sander parallelogram, and Hermann grid illusions. We predicted that patients would be more susceptible to tests that become more apparent with increased contrast (Muller-Lyer illusion), less susceptible to tests that become less apparent with increased contrast (stereopsis, Ponzo illusion, Hermann grid), and equally susceptible to contrast-insensitive tests (Poggendorff illusion). Additionally, the Hermann grid was tested at varying levels of contrast. Patients demonstrated significant deficits in contrast sensitivity, especially to brief, low spatial frequency stimuli, and the predicted differential response to the tested illusions. Additionally, poor performance on stereopsis and the Hermann grid significantly correlated with decreased contrast sensitivity (all Ps <.01). Muller-Lyer illusion and stereopsis performance were also inversely related (P < .01). This study replicates and expands upon previous findings with visual illusions. Our results offer a unifying explanation for disparate studies and suggest that deficits in early sensory gain affect subsequent integrative processes.

D-serine for the treatment of negative symptoms in individuals at clinical high risk of schizophrenia: a pilot, double-blind, placebo-controlled, randomised parallel group mechanistic proof-of-concept trial

BACKGROUND Antagonists of N-methyl-D-aspartate-type glutamate receptors (NMDAR) induce symptoms that closely resemble those of schizophrenia, including negative symptoms. D-serine is a naturally occurring NMDAR modulator that reverses the effects of NMDAR antagonists in animal models of schizophrenia. D-serine effects have been assessed previously for treatment of established schizophrenia, but not in the early stages of the disorder. We aimed to assess effects of D-serine on negative symptoms in at risk individuals. METHODS We did a double-blind, placebo-controlled, parallel-group randomised clinical trial at four academic US centres. Individuals were eligible for inclusion in the study if they were at clinical high risk of schizophrenia, aged between 13-35 years, had a total score of more than 20 on the Scale of Prodromal Symptoms (SOPS), and had an interest in participation in the clinical trial. Exclusion criteria included a history of suprathreshold psychosis symptoms (ie, no longer qualifying as prodromal) or clinical judgment that the reported symptoms from the SOPS were accounted for better by another disorder (eg, depression). Randomisation was done using a generated list with block sizes of four. Participants were stratified by site, with participants, investigators, and assessors all masked through use of identical looking placebos and centralised drug dispensation to study assignment. D-serine (60 mg/kg) was given orally in divided daily doses for 16 weeks. The primary endpoint was for negative SOPS, measured weekly for the first 6 weeks, then every 2 weeks. Participants who received at least one post-baseline assessment were included in analysis. Serum cytokine concentrations were collected at baseline, midpoint, and endpoint to assess the mechanism of action. Safety outcomes including laboratory assessments were obtained for all individuals. This trial is registered with ClinicalTrials.gov, number NCT0082620. FINDINGS We enrolled participants between April 2, 2009, and July 23, 2012. 44 participants were randomly assigned to receive either D-serine (n=20) or placebo (n=24); 35 had assessable data (15 D-serine, 20 placebo). D-serine induced a 35·7% (SD 17·8) improvement in negative symptoms, which was significant compared with placebo (mean final SOPS negative score 7·6 [SEM 1·4] for D-serine group vs 11·3 [1·2] for placebo group; d=0·68, p=0·03). Five participants who received D-serine and nine participants who received placebo discontinued the study early because of withdrawn consent or loss to follow-up (n=8), conversion to psychosis (n=2), laboratory-confirmed adverse events (n=2), or protocol deviations (n=2). INTERPRETATION This study supports use of NMDAR-based interventions, such as D-serine, for treatment of prodromal symptoms of schizophrenia. On the basis of observed effect sizes, future studies with sample sizes of about 40 per treatment group would be needed for confirmation of beneficial effects on symptoms and NMDAR-related inflammatory changes. Long-term studies are needed to assess effects on psychosis conversion in individuals at clinical high risk of schizophrenia. FUNDING National Institutes of Health.

Olanzapine: review of safety 2008.

Background: Olanzapine is a second-generation antipsychotic approved for the treatment of schizophrenia, bipolar mania and associated agitation. Objective: To assess the safety profile of olanzapine, including its propensity to be associated with weight gain, diabetes mellitus and dyslipidemias. Methods: Review of English-language reports located through PubMed and information available on regulatory agency websites. Results/conclusion: The use of olanzapine can pose a therapeutic dilemma in that on one hand, a number of large scale studies have found effectiveness advantages for olanzapine in comparison to other first-line second-generation medications. On the other hand, olanzapine is associated with substantial weight gain and the development of dyslipidemia. Regarding other important safety concerns, olanzapine has a favorable profile in terms of extra-pyramidal side effects and is also relatively prolactin-sparing. The effectiveness benefits may outweigh the risks, particularly in patients with low baseline risk for metabolic syndrome but monitoring for untoward metabolic effects is crucial. Switch-or-stay and other intervention decisions need to be made early before substantial weight gain has occurred.

Reduction in Tonal Discriminations Predicts Receptive Emotion Processing Deficits in Schizophrenia and Schizoaffective Disorder

INTRODUCTION Schizophrenia patients show decreased ability to identify emotion based upon tone of voice (voice emotion recognition), along with deficits in basic auditory processing. Interrelationship among these measures is poorly understood. METHODS Forty-one patients with schizophrenia/schizoaffective disorder and 41 controls were asked to identify the emotional valence (happy, sad, angry, fear, or neutral) of 38 synthesized frequency-modulated (FM) tones designed to mimic key acoustic features of human vocal expressions. The mean (F0M) and variability (F0SD) of fundamental frequency (pitch) and absence or presence of high frequency energy (HF500) of the tones were independently manipulated to assess contributions on emotion identification. Forty patients and 39 controls also completed tone-matching and voice emotion recognition tasks. RESULTS Both groups showed a nonrandom response pattern (P < .0001). Stimuli with highest and lowest F0M/F0SD were preferentially identified as happy and sad, respectively. Stimuli with low F0M and midrange F0SD values were identified as angry. Addition of HF500 increased rates of angry and decreased rates of sad identifications. Patients showed less differentiation of response across frequency changes, leading to a highly significant between-group difference in response pattern to maximally identifiable stimuli (d = 1.4). The differential identification pattern for FM tones correlated with deficits in basic tone-matching ability (P = .01), voice emotion recognition (P < .001), and negative symptoms (P < .001). CONCLUSIONS Specific FM tones conveyed reliable emotional percepts in both patients and controls and correlated highly with deficits in ability to recognize information based upon tone of voice, suggesting significant bottom-up contributions to social cognition and negative symptom impairments in schizophrenia.

GABAB Receptors, Schizophrenia and Sleep Dysfunction: A Review of the Relationship and its Potential Clinical and Therapeutic Implications

Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABAB receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia.At the phenotypic level, sleep disturbance occurs in 16–30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with anti-psychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABAA receptor modulators, such as ben-zodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia.GABAB receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABAB receptor deficits result in a sustained hyper-dopaminergic state and can be reversed by a GABAB receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABAB receptors with schizophrenia.While studies thus far have not shown significant effects, prior focus on the use of GABAB receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABAB receptor agonists such as baclofen or γ-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.Evidence for an intrinsic relationship between sleep, cognition and the symptomatic manifestations of schizophrenia is accumulating. This review presents evidence for the possible utility of GABA(B) receptor agonists for the treatment of subjective and objective sleep abnormalities related to schizophrenia. At the phenotypic level, sleep disturbance occurs in 16-30% of patients with schizophrenia and is related to reduced quality of life and poor coping skills. On the neurophysiological level, studies suggest that sleep deficits reflect a core component of schizophrenia. Specifically, slow-wave sleep deficits, which are inversely correlated with cognition scores, are seen. Moreover, sleep plays an increasingly well documented role in memory consolidation in schizophrenia. Correlations of slow-wave sleep deficits with impaired reaction time and declarative memory have also been reported. Thus, both behavioural insomnia and sleep architecture are critical therapeutic targets in patients with schizophrenia. However, long-term treatment with antipsychotics often results in residual sleep dysfunction and does not improve slow-wave sleep, and adjunctive GABA(A) receptor modulators, such as benzodiazepines and zolpidem, can impair sleep architecture and cognition in schizophrenia. GABA(B) receptor agonists have therapeutic potential in schizophrenia. These agents have minimal effect on rapid eye movement sleep while increasing slow-wave sleep. Preclinical associations with increased expression of genes related to slow-wave sleep production and circadian rhythm function have also been reported. GABA(B) receptor deficits result in a sustained hyperdopaminergic state and can be reversed by a GABA(B) receptor agonist. Genetic, postmortem and electrophysiological studies also associate GABA(B) receptors with schizophrenia. While studies thus far have not shown significant effects, prior focus on the use of GABA(B) receptor agonists has been on the positive symptoms of schizophrenia, with minimal investigation of GABA(B) receptor agonists such as baclofen or gamma-hydroxybutyric acid and their effects on sleep architecture, cognition and negative symptoms in patients with schizophrenia. Further study is needed.