No alterations of brain GABA after 6 months of treatment with atypical antipsychotic drugs in early-stage first-episode schizophrenia

Abstract

We investigated the effects of atypical antipsychotic drugs on GABA concentrations in early-stage, first-episode schizophrenia patients. Sixteen (8 males, 8 females; age, 30 ± 11 years old) patients were followed up for six months. We also included 18 sex- and age-matched healthy control subjects. All patients were treated with atypical antipsychotic drugs (5 patients with risperidone, 5 patients with olanzapine, 4 patients with aripiprazole, and 2 patients with quetiapine). In all three regions measured (frontal lobe, left basal ganglia, and parieto-occipital lobe), no differences in GABA concentrations were observed in a comparison of pre-treatment levels and those six months after treatment. These results suggest that relatively short-term treatment with atypical antipsychotic drugs may not affect GABAergic neurotransmission; however, it is also possible that such treatment prevents further reductions in brain GABA levels in people with early-stage, first-episode schizophrenia.

Introduction

GABAergic dysfunction is generally considered to play an important role in the pathophysiology of schizophrenia. Decreased gamma-aminobutyric acid (GABA) levels in the cerebrospinal fluid and plasma of schizophrenic subjects have been reported (Van Kammen et al., 1982, Van Kammen et al., 1998). Among the reported brain alterations in postmortem studies of schizophrenia is a deficit in mRNA expression of the 67 kD form of glutamic acid decarboxylase (GAD67), which is principally responsible for GABA synthesis; this finding appears to be very consistent and widely replicated in the literature (Akbarian and Huang, 2006, Torrey et al., 2005). GAD67 mRNA expression in schizophrenia has been most widely studied in the context of the dorsolateral prefrontal cortex (DLPFC). The activity of GABA neurons is essential for normal working memory in non-human primates (Rao et al., 2000, Sawaguchi et al., 1989), and therefore reduced GAD67 mRNA expression and subsequently altered GABA neurotransmission in the DLPFC could contribute to impairments in working memory seen in patients with schizophrenia (Lewis and Lieberman, 2000, Lewis et al., 2005). Presynaptic markers of both GABA synthesis and reuptake are decreased in the cerebral cortex of schizophrenic subjects (Simpson et al., 1989, Sherman et al., 1991, Impagnatiello et al., 1998), while the density of postsynaptic GABA_A receptors is upregulated in the prefrontal cortex (Hanada et al., 1987, Benes et al., 1996). Gonzalez-Burgos et al. (2010) reviewed recent studies further indicating that inhibition from paravalbumin-positive GABA neurons is necessary to produce gamma oscillations in cortical circuits; their review also provided an update on postmortem studies documenting that the synthesis of GABA in the cortex is widely observed in schizophrenia, and the review also considered studies examining GABA, cortical-circuit oscillation, and cognitive function in schizophrenia. Yoon et al. (2010) demonstrated that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in the visual cortex plays a critical role in orientation-specific surround suppression, a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission.

Recent magnetic resonance spectroscopy (MRS) studies conducted at 1.5 T by Choe et al. (1996) demonstrated bilateral elevation in the (GABA + glutamate)/creatine complex ratio in the prefrontal cortex in schizophrenia patients before they had been administered antipsychotic treatment as compared to that of controls, whereas this ratio in the patient group decreased post-treatment. Tayoshi et al. (2010) reported finding no differences in GABA concentrations in either the anterior cingulate cortex or the left basal ganglia of chronic schizophrenia patients compared to those of healthy controls. On the other hand, we previously demonstrated using 3 T-MRS a decrease in GABA concentrations in the left basal ganglia in patients with early-stage, first-episode schizophrenia (Goto et al., 2009). Taken together, these findings suggest that brain GABA levels might fluctuate according to the stage of schizophrenia and/or with the administration of antipsychotic drugs. We hypothesized that atypical antipsychotic drugs might restore GABA levels in the left basal ganglia of early-stage first-episode schizophrenia patients to those of healthy controls. To confirm this hypothesis, we investigated the effects of atypical antipsychotic drugs on GABA concentrations in the same patients as those examined in our previous study (Goto et al., 2009). To the best of our knowledge, this is the first longitudinal follow-up study of brain GABA levels in patients undergoing treatment with atypical antipsychotic drugs.