Schizophrenia researchers seek elusive ‘quantum leap’
Lessons from the latest research
One major thrust of research is to understand exactly how the glutamate system works and what goes wrong in schizophrenia patients. Here are some questions and answers from recent research:
Question: If NMDA receptors are crucial to glutamate, would an NMDA receptor channel blocker help improve symptoms in schizophrenia patients? What about memantine (Namenda), an Alzheimer’s disease medication that treats the cognitive problems caused by dementia?
Answer: A 2017 systematic review of 10 studies (including two case reports) found “unclear results”: “memantine therapy in schizophrenic patients seems to improve mainly negative symptoms while positive symptoms and cognitive symptoms did not improve significantly.”
The researchers add that the “use of memantine should be considered in patients with prevalent negative symptoms and cognitive impairment, even if further trials are required. Memantine could be a new opportunity to treat young patients in order to prevent further cognitive decline that will lead to global impairment” (J Amino Acids. 2017;2017:7021071).
The review did not include a 2017 double-blind, placebo-controlled study of 46 adult male patients (average age around 45 years) comparing the antipsychotic risperidone with risperidone plus memantine. The researchers found no difference in positive symptom improvement between the two groups, but the combination treatment group showed significant improvement in cognitive function (at 6 weeks and study completion at 12 weeks) and negative symptoms (at 12 weeks) (Psychiatry Res. 2017 Jan;247:291-5).
Q: We know that the cognitive symptoms of schizophrenia are difficult to treat. What hope does the glutamate system hold in this area?
A: A 2017 systematic review of 44 studies says “memory, working memory and executive functions appear to be most influenced by the glutamatergic pathway.” But there’s some added complexity: “evidence from the literature suggests that presynaptic components synthesis and uptake of glutamate is involved in memory, while postsynaptic signaling appears to be involved in working memory.”
In the big picture, the review says, “the glutamatergic system appears to contribute to the cognitive deficits in schizophrenia, whereby different parts of the pathway are associated with different cognitive domains” (Neurosci Biobehav Rev. 2017 Apr 13;77:369-87).
Q: Could imaging via proton magnetic resonance spectroscopy prove a link between schizophrenia and certain kinds of glutamate activity in the brain, giving mental health professionals a tool to identify at-risk people who are most likely to develop psychosis?
A: A 2016 meta-analysis examined 59 studies and reported that “schizophrenia is associated with elevations in glutamatergic metabolites across several brain regions. This finding supports the hypothesis that schizophrenia is associated with excess glutamatergic neurotransmission in several limbic areas and further indicates that compounds that reduce glutamatergic transmission may have therapeutic potential” (JAMA Psychiatry. 2016 Jul 1;73[7]:665-74).
A review published in 2016 examined 11 proton magnetic resonance spectroscopy studies in search of signs that the state of the glutamate system could predict future psychosis.
Researchers found that six studies reported “significant alterations in glutamate metabolites across different cerebral areas (frontal lobe, thalamus, and the associative striatum)” in at-risk patients. “A longitudinal analysis in two of these trials confirmed an association between these abnormalities and worsening of symptoms and final transition to psychosis.”
But the other five studies analyzed in the review “found no significant differences across these same areas” (Schizophr Res. 2016 Mar;171[1-3]:166-75).
