AMEND - Add-on MEmaNtine to Dopamine Modulation to Improve Negative Symptoms at First Psychosis

BACKGROUND Scientific basis/Rationale Antipsychotic medication is efficacious in treating positive psychotic symptoms such as delusions, hallucinations, and disorganized thinking, which are cardinal symptoms of schizophrenia spectrum disorders. However, antipsychotic treatment does not ameliorate the accompanying negative symptoms (e.g. anhedonia, avolition, and social withdrawal), and cognitive deficits, which are highly disabling and predictive of patients' long-term prognosis. Importantly, shortening the interval between onset of psychosis and initiation of an efficient intervention lead to better long-term outcome.

The pathophysiology of psychosis is complex and involves multiple neurotransmitters, e.g. serotoninergic-, GABAergic, and glutamatergic systems, but modulation (particularly antagonism) of striatal dopamine D2 receptors (D2R) remain the key common denominator of all licensed antipsychotics. Nevertheless, around one third of patients with psychosis display inadequate response to antidopaminergic treatment, and persistent negative symptoms is a critical predictor for future treatment resistance.

Glutamate hypothesis of psychosis Mounting evidence from post-mortem-, brain imaging-, genetic-, and pharmacologic challenge studies indicate glutamatergic dysregulation, specifically of the N-methyl-D-aspartate receptor (NMDAR), as part of the pathophysiology of psychosis and schizophrenia. Through excitotoxicity, glutamate dysregulation may underlie structural degeneration, e.g. in hippocampus, which is a key finding in schizophrenia spectrum patients. Nevertheless, cross-sectional 3T MRS glutamate levels between first-episode patients and HC have shown equivocal results, e.g. likely reflecting differences in glutamate levels across brain regions and in variable previous antipsychotic exposure of included patients. Using 3T MRS, investigator recently reported increased thalamic glutamate levels in antipsychotic-naïve patients with first-episode psychosis compared to HC. Importantly, high thalamic levels predicted poor treatment response. Other studies have also associated glutamate levels with outcome. Investigator have shown that aberrations in the thalamic glutamate levels are heritable, related to psychosis, and extend to individuals at ultra-high risk for psychosis (UHR). Investigator have found that thalamic and ACC levels of glutamate are associated with symptomology and cognition, specifically spatial working memory, set-shifting, and attention both in UHR and first episode psychosis. Cutting-edge 7T MRS can non-invasively determine brain metabolite levels of e.g. γ-aminobutyric acid (GABA), N-acetylaspartate, N-acetylaspartyl, and importantly, 7T allows to discriminate glutamate concentrations from glutathione and glutamine. Moreover, multiple voxels/brain regions can be investigated with 7T. In the context of glutamate and psychosis, the thalamus, anterior cingulate cortex (ACC), hippocampus, dorsolateral prefrontal cortex (DLPFC), and basal ganglia are of particular interest.

Regarding brain structure, application of structural 7T sequences allows for increased sensitivity to quantify neurodegeneration e.g. hippocampal subfield segmentation. Finally, high resolution quantification of tissue parameters such as iron deposition using quantitative susceptibility mapping allow characterization of subtle changes in the 'dopaminergic regions' of the basal ganglia, including striatum, pallidum, and substantia nigra.

Glutamate antagonist treatment Against this background, modulation of glutamatergic NMDAR has been investigated as a potential treatment target in patients with psychosis and schizophrenia. Memantine is a non-competitive NMDAR antagonist used for treatment of Alzheimer's disease. Two recent meta-analyses and one systematic review have concluded that adjunctive memantine to antipsychotics is safe and significantly improves negative symptoms in chronic medicated patients with schizophrenia. One of the meta-analyses also indicated a potential effect on global levels of cognition. Memantine has been theorized to ameliorate progression of negative symptoms by counteracting excitotoxicity correlated to high glutamate levels in early stages of psychosis, but this has not been investigated in initially antipsychotic-naïve patients. Finally, the intriguing fact that pharmacologically similar antagonists of NMDARs (e.g. memantine and ketamine) exert almost paradoxical effects in humans highlights the importance of understanding the pathophysiology of NMDAR modulation in psychosis.