Ragy R. Girgis

Elevated prefrontal cortex γ-aminobutyric acid and glutamate-glutamine levels in schizophrenia measured in vivo with proton magnetic resonance spectroscopy.

CONTEXT Postmortem studies have found evidence of γ-aminobutyric acid (GABA) deficits in fast-spiking, parvalbumin-positive interneurons in the prefrontal cortex in schizophrenia. Magnetic resonance spectroscopy studies in unmedicated patients have reported glutamine or glutamate-glutamine (Glx) elevations in this region. Abnormalities in these transmitters are thought to play a role in cognitive impairments in the illness. OBJECTIVE To measure GABA and Glx levels in vivo in 2 prefrontal brain regions in unmedicated and medicated patients with schizophrenia and healthy controls. DESIGN Case-control study. SETTING Inpatient psychiatric research unit and associated outpatient clinic. PARTICIPANTS Sixteen unmedicated patients with schizophrenia, 16 medicated patients, and 22 healthy controls matched for age, sex, ethnicity, parental socioeconomic status, and cigarette smoking. METHODS Proton magnetic resonance spectroscopy with a 3-T system and the J-edited spin-echo difference method. The GABA and Glx levels were measured in the dorsolateral and medial prefrontal cortex and normalized to the simultaneously acquired water signal. Working memory performance was assessed in all subjects. MAIN OUTCOME MEASURES The GABA and Glx concentrations determined by proton magnetic resonance spectroscopy. RESULTS In the medial prefrontal cortex region, 30% elevations were found in GABA (P = .02) and Glx (P = .03) levels in unmedicated patients compared with controls. There were no alterations in the medicated patients or in either group in the dorsolateral prefrontal cortex. Both regions showed correlations between GABA and Glx levels in patients and controls. No correlations with working memory performance were found. CONCLUSIONS To our knowledge, this study presents the first GABA concentration measurements in unmedicated patients with schizophrenia, who showed elevations in both GABA and Glx levels in the medial prefrontal cortex but not the dorsolateral prefrontal cortex. Medicated patients did not show these elevations, suggesting possible normalization of levels with antipsychotic medication. The Glx elevations agree with prior magnetic resonance spectroscopy literature, but GABA elevations were unexpected and suggest possible involvement of classes of interneurons not found to show impairments in postmortem studies.

Deficits in Prefrontal Cortical and Extrastriatal Dopamine Release in Schizophrenia: A Positron Emission Tomographic Functional Magnetic Resonance Imaging Study

IMPORTANCE Multiple lines of evidence suggest a deficit in dopamine release in the prefrontal cortex (PFC) in schizophrenia. Despite the prevalence of the concept of prefrontal cortical hypodopaminergia in schizophrenia, in vivo imaging of dopamine release in the PFC has not been possible until now, when the validity of using the positron emission tomographic D2/3 radiotracer carbon 11-labeled FLB457 in combination with the amphetamine paradigm was clearly established. OBJECTIVES To (1) test amphetamine-induced dopamine release in the dorsolateral PFC (DLPFC) in drug-free or drug-naive patients with schizophrenia (SCZ) and healthy control (HC) individuals matched for age, sex, race/ethnicity, and familial socioeconomic status;(2) test blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging activation during a working memory task in the same participants; and (3) examine the relationship between positron emission tomographic and functional magnetic resonance imaging outcome measures. DESIGN, SETTING AND PARTICIPANTS Positron emission tomographic imaging with carbon 11-labeled FLB457 before and following 0.5 mg/kg of amphetamine by mouth. Blood oxygenation level-dependent functional magnetic resonance imaging during the self-ordered working memory task. Twenty patients with schizophrenia recruited from the inpatient and outpatient research facilities at New York State Psychiatric Institute and 21 healthy control individuals participated, and data were acquired between June 16, 2011, and February 25, 2014. MAIN OUTCOMES AND MEASURE The percentage change in binding potential (∆BPND) in the DLPFC following amphetamine, BOLD activation during the self-ordered working memory task compared with the control task, and the correlation between these 2 outcome measures. RESULTS We observed significant differences in the effect of amphetamine on DLPFC BPND (mean [SD], ∆BPND in HC: -7.5% [11%]; SCZ: +1.8% [11%]; P = .01); a generalized blunting in dopamine release in SCZ involving most extrastriatal regions and the midbrain; and a significant association between ∆BPND and BOLD activation in the DLPFC in the overall sample including patients with SCZ and HC individuals. CONCLUSIONS AND RELEVANCE To our knowledge, these results provide the first in vivo evidence for a deficit in the capacity for dopamine release in the DLPFC in SCZ and suggest a more widespread deficit extending to many cortical and extrastriatal regions including the midbrain. This contrasts with the well-replicated excess in dopamine release in the associative striatum in SCZ and suggests a differential regulation of striatal dopamine release in associative striatum vs extrastriatal regions. Furthermore, dopamine release in the DLPFC relates to working memory-related activation of this region, suggesting that blunted release may affect frontal cortical function.

A Randomized Exploratory Trial of an Alpha-7 Nicotinic Receptor Agonist (TC-5619) for Cognitive Enhancement in Schizophrenia

This exploratory trial was conducted to test the effects of an alpha7 nicotinic receptor partial agonist, TC-5619, on cognitive dysfunction and negative symptoms in subjects with schizophrenia. In the United States and India, 185 outpatients (18–60 years; male 69%; 46% tobacco users) with schizophrenia treated with quetiapine or risperidone monotherapy were randomized to 12 weeks of placebo (n=91) or TC-5619 (n=94; orally once daily 1 mg day 1 to week 4, 5 mg week 4 to 8, and 25 mg week 8 to 12). The primary efficacy outcome measure was the Groton Maze Learning Task (GMLT; executive function) of the CogState Schizophrenia Battery (CSB). Secondary outcome measures included: CSB composite score; Scale for Assessment of Negative Symptoms (SANS); Clinical Global Impression-Global Improvement (CGI-I); CGI-severity (CGI-S); and Subject Global Impression-Cognition. GMLT statistically favored TC-5619 (P=0.036) in this exploratory trial. SANS also statistically favored TC-5619 (P=0.030). No other secondary outcome measure demonstrated a drug effect in the total population; there was a statistically significant drug effect on working memory in tobacco users. The results were typically stronger in favor of TC-5619 in tobacco users and occasionally better in the United States than in India. TC-5619 was generally well tolerated with no clinically noteworthy safety findings. These results support the potential benefits of TC-5619 and alpha7 nicotinic receptor partial agonists for cognitive dysfunction and negative symptoms in schizophrenia.

Imaging glutamate in schizophrenia: review of findings and implications for drug discovery

Currently, all treatments for schizophrenia (SCZ) function primarily by blocking D2-type dopamine receptors. Given the limitations of these medications, substantial efforts have been made to identify alternative neurochemical targets for treatment development in SCZ. One such target is brain glutamate. The objective of this article is to review and synthesize the proton magnetic resonance spectroscopy (1H MRS) and positron emission tomography (PET)/single-photon emission computed tomography (SPECT) investigations that have examined glutamatergic indices in SCZ, including those of modulatory compounds such as glutathione (GSH) and glycine, as well as data from ketamine challenge studies. The reviewed 1H MRS and PET/SPECT studies support the theory of hypofunction of the N-methyl-D-aspartate receptor (NMDAR) in SCZ, as well as the convergence between the dopamine and glutamate models of SCZ. We also review several advances in MRS and PET technologies that have opened the door for new opportunities to investigate the glutamate system in SCZ and discuss some ways in which these imaging tools can be used to facilitate a greater understanding of the glutamate system in SCZ and the successful and efficient development of new glutamate-based treatments for SCZ.

Signaling pathways in schizophrenia: emerging targets and therapeutic strategies

Dopamine D(2) receptor antagonism is a unifying property of all antipsychotic drugs in use for schizophrenia. While often effective at ameliorating psychosis, these drugs are largely ineffective at treating negative and cognitive symptoms. Increasing attention is being focused on the complex genetics of the illness and the signaling pathways implicated in its pathophysiology. We review targeted approaches for pharmacotherapy involving the glutamatergic, GABAergic and cholinergic pathways. We also describe several of the major genetic findings that identify signaling pathways representing potential targets for novel pharmacological intervention. These include genes in the 22q11 locus, DISC1, Neuregulin 1/ErbB4, and components of the Akt/GSK-3 pathway.

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.

Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway.

The exact therapeutic mechanism of action of antipsychotic drugs remains unclear. Recent evidence has shown that second-generation antipsychotic drugs (SGAs) are differentially associated with metabolic side effects compared to first-generation antipsychotic drugs (FGAs). Their proclivity to cause metabolic disturbances correlates, to some degree, with their comparative efficacy. This is particularly the case for clozapine and olanzapine. In addition, the insulin signaling pathway is vital for normal brain development and function. Abnormalities of this pathway have been found in persons with schizophrenia and antipsychotic drugs may ameliorate some of these alterations. This prompted us to hypothesize that the therapeutic antipsychotic and adverse metabolic effects of antipsychotic drugs might be related to a common pharmacologic mechanism. This article reviews insulin metabolism in the brain and related abnormalities associated with schizophrenia with the goals of gaining insight into antipsychotic drug effects and possibly also into the pathophysiology of schizophrenia. Finally, we speculate about one potential mechanism of action (that is, functional selectivity) that would be consistent with the data reviewed herein and make suggestions for the future investigation that is required before a therapeutic agent based on these data can be realized.

Dopamine release in chronic cannabis users: a [11c]raclopride positron emission tomography study.

BACKGROUND Low striatal dopamine 2/3 receptor (D(2/3)) availability and low ventrostriatal dopamine (DA) release have been observed in alcoholism and cocaine and heroin dependence. Less is known about the dopaminergic system in cannabis dependence. We assessed D(2/3) availability and DA release in abstinent cannabis users compared with control subjects and explored relationships to cannabis use history using [(11)C]raclopride positron emission tomography and an amphetamine challenge paradigm. METHODS Sixteen recently abstinent, psychiatrically healthy cannabis-using participants (27.3 ± 6.1 years, 1 woman, 15 men) and 16 matched control subjects (28.1 ± 6.7 years, 2 women, 14 men) completed two positron emission tomography scans, before and after injection of intravenous d-amphetamine (.3 mg/kg). Percent change in [(11)C]raclopride binding after amphetamine (change in nondisplaceable binding potential, ΔBP(ND)) in subregions of the striatum was compared between groups. Correlations with clinical parameters were examined. RESULTS Cannabis users had an average consumption of 517 ± 465 estimated puffs per month, indicating mild to moderate cannabis dependence. Neither baseline BP(ND) nor ΔBP(ND) differed from control subjects in any region of interest, including ventral striatum. In cannabis-dependent subjects, earlier age of onset of use correlated with lower [ΔBP(ND)] in the associative striatum when controlling for current age. CONCLUSIONS Unlike other addictions, cannabis dependence of mild to moderate severity is not associated with striatal DA alterations. However, earlier or longer duration of use is related to lower DA release in the associative striatum. These observations suggest a more harmful effect of use during adolescence; more research is needed to distinguish effects of chronicity versus onset.

The cytokine model of schizophrenia: emerging therapeutic strategies.

We discuss the rationale for a trial of a novel biological immunotherapy in schizophrenia (SCZ). Available antipsychotic treatments for SCZ are often limited by partial effectiveness and significant side effects. The search for novel medications is of high priority. All current antipsychotics function primarily by blocking D2-type dopamine receptors. An emerging theory of SCZ postulates disturbances of cytokines and inflammatory mediators (i.e., the cytokine model), possibly originating in part from infectious exposures. Cytokines are one of the most important components of the immune system that orchestrate the response to infectious and other exogenous insults. Preclinical models of SCZ support a convergence between a role for certain cytokines in the pathophysiology of SCZ and major neurochemical postulates of the disorder, including the dopamine and glutamate hypotheses. Several cytokines are elevated in plasma in SCZ, and positron emission tomography studies have shown active inflammation in the brains of patients with psychosis. Treatment studies of anti-inflammatory agents, such as celecoxib and aspirin, in patients with SCZ have provided further support for neuroinflammation in this disorder. The development of approved biological therapies for autoimmune diseases provides new opportunities to target cytokine signaling directly as a novel treatment strategy in SCZ. In addition, advances in imaging, immunology, and psychopharmacology have paved the way for using measures of target engagement of neuroimmune components that would facilitate the identification of patient subgroups who are most likely to benefit from cytokine modulation.

Risperidone in first-episode psychosis: A longitudinal, exploratory voxel-based morphometric study

Previous studies have provided evidence supporting a neuroplastic effect of atypical antipsychotics. The present investigation explores the short-term effects of risperidone on brain parenchyma by performing voxel-based morphometry on baseline and 6-week follow-up MRI scans obtained from 15 neuroleptic-naïve individuals with first-episode psychosis treated with risperidone and 15 healthy controls. The risperidone-treated subjects demonstrated changes in grey matter and white matter in several brain regions, including superior temporal gyrus. No areas of change were found in controls. The results of this exploratory investigation support the possibility that risperidone has short-term effects on brain parenchyma in individuals with first-episode psychosis.