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

Abstract

Background: Poor 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).

Methods: Thirty-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.

Results: Before 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.

Conclusion: Glutamatergic 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.

Keywords: Anterior cingulate cortex; GABA; antipsychotic-naïve; first-episode psychosis; glutamate; magnetic resonance spectroscopy; thalamus; treatment outcome.

Fig. 1.

The trajectory of mean glutamate/Cr levels in the left thalamus (a) and anterior cingulate cortex (ACC) (b) and GABA/Cr levels in ACC (c) of initially antipsychotic-naïve patients with first-episode psychosis (black line) and healthy controls (grey line) at baseline, and after 6 weeks monotherapy with aripiprazole, and 26 weeks of naturalistic antipsychotic treatment. The vertical bars represent standard errors. *p < 0.05 in post hoc testing. Note that the Y-axis does not origin in 0;0.

Fig. 2.

Baseline levels of glutamate/Cr in the thalamus and GABA/Cr in the anterior cingulate cortex (ACC) of responders (black plusses), non-responders (black circles), and healthy controls (grey diamonds). Mean values are represented by horizontal bars. Baseline glutamate/Cr levels in the left thalamus are shown according to treatment response after 6 weeks (A) and 26 weeks (B), and baseline GABA/Cr levels are shown according to treatment response after 26 weeks (C). *p < 0.025. Note that the Y-axis does not origin in 0;0.