Neurometabolite changes in response to antidepressant medication: A systematic review of 1H-MRS findings

Abstract

Selective serotonin reuptake inhibitors (SSRIs), serotonin and noradrenaline reuptake inhibitors (SNRIs), and (es)ketamine are used to treat major depressive disorder (MDD). These different types of medication may involve common neural pathways related to glutamatergic and GABAergic neurotransmitter systems, both of which have been implicated in MDD pathology. We conducted a systematic review of pharmacological proton Magnetic Resonance Spectroscopy (¹H-MRS) studies in healthy volunteers and individuals with MDD to explore the potential impact of these medications on glutamatergic and GABAergic systems. We searched PubMed, Web of Science and Embase and included randomized controlled trials or cohort studies, which assessed the effects of SSRIs, SNRIs, or (es)ketamine on glutamate, glutamine, Glx or GABA using single-voxel ¹H-MRS or Magnetic Resonance Spectroscopic Imaging (MRSI). Additionally, studies were included when they used a field strength > 1.5 T, and when a comparison of metabolite levels between antidepressant treatment and placebo or baseline with post-medication metabolite levels was done. We excluded animal studies, duplicate publications, or articles with ¹H-MRS data already described in another included article. Twenty-nine studies were included in this review. Fifteen studies investigated the effect of administration or treatment with SSRIs or SNRIs, and fourteen studies investigated the effect of (es)ketamine on glutamatergic and GABAergic metabolite levels. Studies on SSRIs and SNRIs were highly variable, generally underpowered, and yielded no consistent findings across brain regions or specific populations. Although studies on (es)ketamine were also highly variable, some demonstrated an increase in glutamate levels in the anterior cingulate cortex in a time-dependent manner after administration. Our findings highlight the need for standardized study and acquisition protocols. Additionally, measuring metabolites dynamically over time or combining ¹H-MRS with whole brain functional imaging techniques could provide valuable insights into the effects of these medications on glutamate and GABAergic neurometabolism.

Keywords: (1)H-MRS; (es)ketamine; GABA; Glutamate; Major Depressive Disorder; SNRI; SSRI.

Fig. 1

Literature PRISMA flowchart.

Fig. 2

Changes in glutamate, glutamine, Glx and GABA following SSRI or SNRI administration or treatment in a) healthy volunteers and b) participants with MDD. Changes are depicted by symbols, with each symbol illustrating one finding. ↑illustrates a significant increase in metabolite concentration;^illustrates a trend increase (0.05 < p < 0.10); ↓ illustrates a significant decrease in metabolite concentration; v illustrates a trend decrease (0.05 < p < 0.10); = illustrates no changes in metabolite concentrations. dACC: dorsal anterior cingulate cortex; pgACC: pregenual anterior cingulate cortex; OCC: occipital cortex.

Fig. 3

Changes in glutamate, glutamine, Glx and GABA following (es)ketamine administration in A) healthy volunteers and B) participants with MDD. Changes are depicted by symbols, with each symbol illustrating one finding. ↑ illustrates a significant increase in metabolite concentration;^illustrates a trend increase (0.05 < p < 0.10); ↓ illustrates a significant decrease in metabolite concentration; v illustrates a trend decrease (0.05 < p < 0.10); = illustrates no changes in metabolite concentrations. dACC: dorsal anterior cingulate cortex; pgACC: pregenual anterior cingulate cortex; PCC: posterior cingulate cortex; OCC: occipital cortex.