Abstract
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). 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. 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. 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.
Highlights
Insufficient response to antipsychotic medication is a major challenge in the treatment of psychotic disorders
To the best of our knowledge, this is the first longitudinal study of initially antipsychotic-naïve patients with first-episode psychosis investigating whether baseline glutamate and glutamate and γ-aminobutyric acid (GABA) levels are associated with treatment response compared with reference levels in healthy controls (HCs)
The main results are that higher baseline levels of glutamate in the left thalamus and lower GABA levels in anterior cingulate cortex (ACC) are associated with poor treatment response at 6 and 26 weeks
Summary
Insufficient response to antipsychotic medication is a major challenge in the treatment of psychotic disorders. Recent findings suggest that glutamate and γ-aminobutyric acid (GABA) levels are increased in antipsychotic-naïve or minimally treated non-responding patients when compared with levels in responders (de la Fuente-Sandoval et al, 2017; Egerton et al, 2018), whereas responding patients have higher striatal dopamine activity than nonresponding patients (Wulff et al, 2015, 2019). These findings suggest the existence of a subgroup of non-responding patients with higher glutamate levels compared with responders It is unknown if levels of glutamate and GABA in antipsychotic-naïve patients can serve as biomarkers for poor response to antipsychotic treatment compared with levels in healthy controls (HCs). Normative reference levels for glutamate and GABA may aid estimation of clinical prognosis in first-episode psychosis patients
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