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ICOSR 2011—Neurotransmitters and Neuromodulators in Schizophrenia

As part of our ongoing coverage of the 2011 International Congress on Schizophrenia Research (ICOSR), 2-6 April, in Colorado Springs, Colorado, we bring you session summaries from some of the Young Investigator travel award winners. For this report, we thank Caroline Wass of the Centre for Addiction and Mental Health, Toronto, Canada.

6 May 2011. On Monday afternoon, April 4, at the International Congress on Schizophrenia Research, Anthony Grace of the University of Pittsburgh, Pennsylvania, chaired a very full slate of talks on glutamate, GABA, and neuromodulation in the pathophysiology of schizophrenia.

The first speaker, Yan Fang, and coworkers at the University of Texas Southwestern in Dallas conduct work on the glutamatergic and GABAergic systems of the hippocampus in schizophrenia, as these systems have been implicated in the pathophysiology of the disorder. Using proton magnetic resonance spectroscopy (1H-MRS) measuring glutamate, GABA, and N-acetylaspartate (N-AA, a marker of neuronal integrity found to be reduced in the hippocampus and prefrontal cortex in patients with schizophrenia), the researchers found a decrease in N-AA and glutamate, but no deviations in GABA tissue levels in the hippocampus of patients with schizophrenia compared with control subjects. In addition, the glutamate levels correlated with symptom severity, more specifically, with negative symptoms. Fang and coworkers are planning futures studies using a higher resolution imaging method to assess glutamatergic and GABAergic transmission in other pivotal brain regions, such as the anterior cingulate and prefrontal cortex in patients with schizophrenia.

Laura Rowland of the University of Maryland, Baltimore, continued the discussion of pathophysiology of the glutamatergic and GABAergic systems in schizophrenia by telling us about the inconsistencies in previous findings. In order to move past these inconsistencies, the researchers employed a 1H-MRS scan measuring glutamate, GABA, and N-acetylaspartylglutamate (NAAG, a mGLURr3 agonist and weak NMDAR antagonist) in the medial prefrontal cortex and centrum semiovale of patients and controls. The findings show that there was no significant difference in GABA or NAAG levels between patients with schizophrenia and controls, and there was a trend towards a reduction in glutamate levels in the medial prefrontal cortex of patients versus controls. Interestingly, Rowland pointed out, in patients with schizophrenia a higher level of NAAG in the centrum semiovale was correlated with more negative symptoms, while low levels of GABA in the same region were associated with increased positive symptoms. In addition, higher medial prefrontal cortex glutamate/GABA ratios correlated with better attention in control subjects, while the same ratio was negatively correlated with attention in patients with schizophrenia. Rowland concluded that these findings are consistent with the notion of a hypoglutamatergic tone being associated with negative symptomatology and a GABAergic deficiency signaling inhibitory alterations that may lead to positive symptoms in schizophrenia.

Third up was Paola Dazzan of the Institute of Psychiatry, London, presenting a study evaluating the relationship between childhood trauma and inflammation-induced reductions of BDNF as a proposed mechanism for reduced hippocampal volume. To address this hypothesis, the cross-sectional study of first-episode psychosis (FEP) patients measured cortisol, BDNF, interleukin-6, and tumor necrosis factor α (TNFα) mRNA measured in leukocytes, in addition to measuring hippocampal volume using MRI. The results showed that there was an increased incidence of childhood trauma in FEP patients compared with controls, in addition to a stressful event preceding the onset of psychosis, which was accompanied by increased levels of cortisol. Furthermore, FEP persons had decreased levels of leukocyte BDNF and increased cytokine levels, which together with cortisol levels and childhood traumas correlated with hippocampal volume in a way that suggests that stress, inflammatory processes, and lack of neurotrophic factors may contribute to reduced hippocampal volume in patients experiencing first-episode psychosis.

Thalia F van der Doef and colleagues at the University Medical Center Utrecht, The Netherlands, are investigating the pathophysiological mechanism underlying gray matter loss in schizophrenia. They used a PET tracer for microglial activation to look for regional differences between patients with schizophrenia and healthy controls. Microglial activation was found in the temporal region in patients with schizophrenia, but not in controls. Van der Doef proposed a joint neuroinflammatory and neurodegenerative hypothesis by which the microglial activation could lead to a release of nitric oxide, which in high levels acts as a neurotoxic compound, that could result in a potentially neurodegenerative process and, consequently, gray matter loss. This hypothesis is appealing, as previous studies have consistently found reduced volumes of the hippocampus in schizophrenia.

Elisabeth Thomas of the Scripps Research Institute, La Jolla, California, and colleagues have previously shown that there are alterations in the expression of inflammation-associated genes in the prefrontal cortex of patients with schizophrenia compared to controls. Recently, they investigated the expression of the inflammatory prostaglandin pathway in the prefrontal cortex of schizophrenia patients and age-matched controls. They found alterations in the genetic expression of the prostaglandin pathway in patients versus controls, and these changes varied with age and duration of illness. Thomas pointed out that these findings further support a neuroinflammatory process in schizophrenia. In addition, they open up the possibility of tailoring treatment according to age and stage of illness. As an example, COX-2 inhibitors may be particularly effective in non-chronic patients.

To assess the relationship between inflammatory markers—interleukin (IL) 1 and 6, tumor necrosis factor α (TNFα), Von Willebrand factor (vWF), and osteoprotegerin—and disease or symptom severity, Sigrun Hope of Ostfold Hospital, Fredrikstad, Norway, and coworkers collected serum from 322 patients. The researchers measured serum soluble IL-6, interleukin-1 receptor antagonist (IL-1Ra), TNF receptor 1 (TNF-R1), and vWF, and found that IL-1Ra and TNF-R1 correlate with both functioning and symptom severity. Several other correlations between inflammatory markers and hospitalizations and premorbid adjustment were found. Taken together, these results support a role of immune activation in the pathological mechanisms of psychiatric disorders.

An elegant study presented by Camilo de la Fuente of the National Institute of Neurology and Neurosurgery in Mexico City used proton magnetic resonance spectroscopy imaging to measure brain glutamate levels in persons at ultra high risk for schizophrenia, as well as in drug-naïve first-episode patients and healthy controls. They found increased levels of glutamate in the dorsal caudate nucleus in ultra high-risk persons as well as first-episode patients compared with controls. The researchers also report increased glutamate in the associative striatum of subjects with prodromal symptoms of schizophrenia and patients with first-episode psychosis. Thus, glutamate abnormalities appear to be independent of antipsychotic treatment and constitute part of the pathophysiology, as they precede the onset of schizophrenia.

Anissa Abi-Dargham, Columbia University, New York City, reported on the use of N-acetylcysteine (NAC) and the metabotropic glutamate receptor 5 radioligand [11C]ABP688 to measure in vivo glutamate levels in anesthetized baboons. Because NAC treatment has been proved to increase glutamate levels by affecting the glial cysteine-glutamate pump, it was hypothesized that NAC treatment would shift the metabotropic glutamate receptor 5 tracer occupancy visualized by PET. Abi-Dargham found that [11C]ABP688 binding was significantly decreased following treatment with NAC in nearly every brain region. These findings are likely due to the increase in glutamate release after NAC treatment and are also non-region specific and not due to test-retest artifacts. Thus, if the glutamate mechanism can be confirmed, imaging using [11C]ABP688 may be applied to assess in vivo glutamate transmission.

Schizophrenia stems in part from a genetic vulnerability thought to be carried by first-degree relatives; however, the extent of the neurobiological vulnerabilities and the clinical impact of such aberrations in relatives are largely unknown. To investigate stress-induced dopamine changes in the mesocortical system in first-degree relatives of patients with schizophrenia and how these relate to psychotic experiences, Johan Lataster of the Maastricht University Medical Center, The Netherlands, and coworkers conducted a PET study. Psychotic experiences were self-reported daily using an electronic device, and social stress was induced using the Montreal Imaging Stress Task 100 minutes after injection of the dopamine (D2/D3) receptor ligand, fallypride. The results demonstrated that first-degree relatives had a lower dopamine response to stress in their prefrontal cortex (frontal gyrus) in comparison with control subjects. In addition, first-degree relatives also reported more psychotic experiences than did controls. The results also showed that higher stress-induced dopamine release in the prefrontal cortex was associated with fewer psychotic experiences. Taken together, these findings suggest that there may be a genetic vulnerability for abnormal processing of stress, manifested by hypodopaminergia in the prefrontal cortex, associated with schizophrenia.

Cognitive deficits coupled to a dysfunctional dorsolateral prefrontal cortex (DLPFC) constitute a core feature of schizophrenia. During a working memory test, γ band power in the DLPFC is increased. However, in patients with schizophrenia, this increase is attenuated. To investigate the underlying neurochemical basis for the working memory deficits and the DLPFC γ band abnormalities, Lawrence Kegeles, Columbia University, and colleagues conducted a study investigating EEG, working memory, and GABA signaling in the DLPFC in patients with schizophrenia and healthy controls. On the Sternberg working memory test, patients with schizophrenia were found to have impaired working memory in comparison with healthy controls. γ band power and GABA levels (assessed by MRS) in the DLPFC were positively correlated with baseline recordings in all subjects. In all different stages during the working memory test—recording, retention, and probe—γ band power and GABA levels were correlated and patients with schizophrenia had lower γ band power than controls did at all three stages. Kegeles and coworkers thus presented crucial in vivo evidence for GABAergic signaling as related to γ band power and working memory in the DLPFC.—Caroline Wass.

Comments on Related News

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Comment by:  Kimberly E. Vanover
Submitted 20 June 2011
Posted 20 June 2011

Thank you for your summary of the presentations from the New Drug Session at ICOSR 2011 on the Schizophrenia Research Forum. The Forum is a helpful and important resource.

I just wanted to clarify your description of ITI-007’s properties at the D2 site. As a dopamine phosphorylation modulator, ITI-007 acts as a pre-synaptic partial agonist and a post-synaptic antagonist with mesolimbic/mesocortical selectivity (Wennogle et al., 2008). In addition to its antagonism of 5-HT2A receptors and unique interaction with D2 receptors, it has affinity for D1 receptors, consistent with partial agonism linked to downstream increases in NMDA NR2B receptor phosphorylation (Zhu et al., 2008), and it is a serotonin reuptake inhibitor (Wennogle et al., 2008). Unfortunately, the short, 10-minute talk during the ICOSR session wasn’t sufficient time to go into the details of the mechanism and supporting preclinical data.

I did notice that a brief description for the mode of action for ITI-007 is listed as “5-HT2A antagonist + dopamine phosphoprotein modulator” with a role in schizophrenia listed as “DA stabilizer + 5hT-T inhibitor” in the Forum’s Drugs in Clinical Trials section. This is a nice, brief way to describe a rather complex mechanism.


Wennogle LP, Snyder GL, Hendrick JP, Vanover KE, Tomesch JT, Li P, O’Callaghan JP, Miller DB, Fienberg AA, Davis RE, Mates S (2008) Unique antipsychotic profile of a novel 5-HT2A receptor antagonist and dopamine receptor protein phosphorylation modulator. Schizophrenia Research 98:Suppl1:15.

Zhu H, Snyder GL, Vanover KE, Rana M, Tsui T, Hendrick JP, Li P, Tomesch J, O’Brien JJ, Guo H, Davis RE, Fienberg AA, Wennogle LP, Mates S (2008) ITI-007: A novel 5-HT2A antagonist and dopamine protein phosphorylation modulator (DPPM) induces a distinct NR2B expression pattern in mouse brain. Program No. 155.14 2008 Neuroscience Meeting Planner. Washington, DC Society for Neuroscience, 2008. Online.

View all comments by Kimberly E. Vanover