Treatment response after 6 and 26 weeks is related to baseline glutamate and GABA levels in antipsychotic-naïve patients with psychosis

Abstract

BackgroundPoor response to dopaminergic antipsychotics constitutes a major challenge in the treatment of psychotic disorders and markers for non-response during first-episode are warranted. Previous studies have found increased levels of glutamate and γ-aminobutyric acid (GABA) in non-responding first-episode patients compared to responders, but it is unknown if non-responders can be identified using reference levels from healthy controls (HCs).MethodsThirty-nine antipsychotic-naïve patients with first-episode psychosis and 36 matched HCs underwent repeated assessments with the Positive and Negative Syndrome Scale and 3T magnetic resonance spectroscopy. Glutamate scaled to total creatine (/Cr) was measured in the anterior cingulate cortex (ACC) and left thalamus, and levels of GABA/Cr were measured in ACC. After 6 weeks, we re-examined 32 patients on aripiprazole monotherapy and 35 HCs, and after 26 weeks we re-examined 30 patients on naturalistic antipsychotic treatment and 32 HCs. The Andreasen criteria defined non-response.ResultsBefore treatment, thalamic glutamate/Cr was higher in the whole group of patients but levels normalized after treatment. ACC levels of glutamate/Cr and GABA/Cr were lower at all assessments and unaffected by treatment. When compared with HCs, non-responders at week 6 (19 patients) and week 26 (16 patients) had higher baseline glutamate/Cr in the thalamus. Moreover, non-responders at 26 weeks had lower baseline GABA/Cr in ACC. Baseline levels in responders and HCs did not differ.ConclusionGlutamatergic and GABAergic abnormalities in antipsychotic-naïve patients appear driven by non-responders to antipsychotic treatment. If replicated, normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients.

Baseline measures of cerebral glutamate and GABA levels in individuals at ultrahigh risk for psychosis: Implications for clinical outcome after 12 months

“…Since we found no group-level differences in baseline metabolite levels between the remission and nonremission group and did not find any single metabolite to be predictive of clinical, functional, or cognitive outcomes, this suggests that-if present-metabolite perturbances are subtle and possibly only present in part of the UHR group. This does, however, contrast findings in a first episode cohort finding higher levels of glutamate to be related to shortterm lack of remission [50], which could be explained by some studies suggesting that glutamatergic disturbances originate in thalamus and are different as the illness progresses from UHR stages to established schizophrenia [51].…”

Region-specific and dose-specific effects of chronic haloperidol exposure on [3H]-Flumazenil and [3H]-Ro15-4513 GABAA receptor binding sites in the rat brain

“…Changes in GABA release during haloperidol exposure thus likely account for the effect of haloperidol on GABA A R availability observed herein and by others (McLeod et al, 2008). Studies of bulk tissue GABA levels in the frontal cortex of schizophrenia patients using proton magnetic resonance spectroscopy ( 1 H-MRS), however, report either no effect (Bojesen et al, 2019;Tayoshi et al, 2010) or a normalisation of elevated GABA levels (de la Fuente-Sandoval et al, 2017) following antipsychotic exposure, although this method only measures bulk tissue GABA and not synaptic levels. In contrast, rodent slice electrophysiology data suggest that D2R mediate synaptic GABA release onto pyramidal neurons in the PFC, whereby GABA release is decreased following dopamine administration (Xu and Yao, 2010).…”

Associations Between Cognitive Function and Levels of Glutamatergic Metabolites and Gamma-Aminobutyric Acid in Antipsychotic-Naïve Patients With Schizophrenia or Psychosis

“…In dorsal striatum higher glutamate levels have been found (12,13), and in left thalamus higher glutamine and glutamate levels have been reported (2,3,7), whereas a recent study did not find alterations in glutamate levels (9). Importantly, our group recently reported that thalamic glutamate levels in twins are heritable and associated with schizophrenia spectrum disorder (17) and that higher thalamic glutamate levels and lower GABA levels in dorsal ACC of antipsychoticnaïve patients were related to subsequent poor treatment outcome (7). Moreover, two other groups have reported an association between high levels of glutamate and GABA in pregenual ACC and lack of treatment response (6,9).…”

“…A growing body of studies suggest that glutamatergic and GABAergic (gamma-aminobutyric acidergic) neurotransmission is disturbed in first-episode patients with schizophrenia or psychosis. Glutamate and GABA levels in antipsychotic-naïve or minimally treated patients have primarily been investigated in anterior cingulate cortex (ACC) (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11), thalamus (2,3,7,9), and dorsal striatum (12,13) using proton magnetic resonance spectroscopy ( 1 H-MRS). These regions are part of corticostriato-thalamo-cortical networks that are believed to be dysregulated in psychotic disorders (14,15).…”

“…In the majority of the studies, higher levels of glutamine, glutamine1glutamate (Glx), glutamine/glutamate, and GABA have been found in pregenual ACC (1)(2)(3)(4)(5)(6), and lower levels of glutamate (7) or Glx (11) have been found in dorsal ACC, although no differences in pregenual ACC also have been reported in some studies (5,(8)(9)(10) and in a recent meta-analysis of antipsychotic-naïve/free patients (16). In dorsal striatum higher glutamate levels have been found (12,13), and in left thalamus higher glutamine and glutamate levels have been reported (2,3,7), whereas a recent study did not find alterations in glutamate levels (9). Importantly, our group recently reported that thalamic glutamate levels in twins are heritable and associated with schizophrenia spectrum disorder (17) and that higher thalamic glutamate levels and lower GABA levels in dorsal ACC of antipsychoticnaïve patients were related to subsequent poor treatment outcome (7).…”