Steps towards more effective and better tolerated treatment options for schizophrenia

New more effective and better tolerated treatments for schizophrenia are needed to improve patient outcomes — current treatments may have a limited effect on cognitive or negative symptoms associated with schizophrenia, and many cause side effects. Constantly evolving understanding of the underlying pathophysiology and neurotransmitter networks has led to the development of many new pharmacological products, but most have proved disappointing when tested in large-scale trials except for partial Dopamine D3 and D2 agonists, experts explained at CINP 2018. Ongoing research into the role of abnormal hippocampal function in schizophrenia was described that may reveal new therapeutic targets.

New more effective and better tolerated medications are needed to improve patient outcomes

New more effective and better tolerated medications are needed to improve patient outcomes

Current treatments for schizophrenia improve positive symptoms, but have limited efficacy on the cognitive and negative symptoms that impair quality of life and psychosocial function, said Wolfgang Fleischhacker, Professor of Psychiatry, Medical University, Innsbruck, Austria.

In addition, many antipsychotics cause side effects — akathisia, tardive dyskinesia, weight gain, increased prolactin levels leading to sexual dysfunction — which further impair quality of life and everyday function.

Partial Dopamine D3 and D2 agonists show promising results in clinical trials

Increasing understanding about the pathophysiological and biological mechanisms of schizophrenia and how these relate to neurotransmitter —  dopaminergic, glutamatergic and cholinergic (nicotinergic and muscarinergic) —networks has led to many attempts to target potential sites of action pharmacologically.

The aim is to find better tolerated treatments that not only improve the positive symptoms, but also the negative symptoms and cognitive deficits, explained Professor Fleischhacker.

However, despite early promise, the results of large scale studies have generally been disappointing, he said, perhaps due to poor methodology or not targeting the right patients.

The most promising results so far have been obtained in clinical trials with Dopamine D3 and D2 partial agonists.

The most promising results so far have been obtained in clinical trials with Dopamine D3 and D2 partial agonists

In one large clinical trial, a D3 partial agonist that also has effects on the D2 and Serotonin 5HT1A and 5HT2B receptors has shown efficacy in treating predominant negative symptoms, and the symptom improvement translated into improved psychosocial function,1 said Professor Fleischhacker.

Furthermore, other research has demonstrated that a D2, D3, 5HT1A partial agonist may be better tolerated than other antipsychotics which target different receptors,2 he added.

Therapeutic targets in the hippocampus

Hyperactivity in CA3 may be a therapeutic target for biotype 2 psychosis

Extensive research carried out by Carol Tamminga, Professor of Psychiatry and Neuroscience, UT Southwestern Medical Center, USA, and her colleagues has contributed to understanding of the pathophysiology of schizophrenia.

Professor Tamminga explained that evidence supporting current understanding of the role of abnormal hippocampal function in the development of the psychotic and cognitive manifestations of schizophrenia includes research that has shown:

  • increased hippocampal blood flow and regional cerebral blood flow consistent with increased neuronal activity
  • a decrease in the NMDA receptor GluN1 subunit in the dentate gyrus (DG)
  • a preponderance of thorny excrescences on the apical dendrites in the CA3 subfield suggesting overactive synapses

Professor Tamminga described how she and her colleagues have reverse translated human disease pathology into a mouse model — the DG-specific GluN1 knock-out mouse — to decrease afferent stimulation in the DG. This resulted in psychotic behavior, increased sensitivity of NMDA and AMPA receptors in CA3, and increased activity of pyramidal neurons in CA3 and in CA1.

The group is now examining the neuronal pathways in DG-specific GluN1 knock-out mice using DREADDS (Designer Receptors Exclusively Activated by Designer Drugs) and hope to discover new therapeutic targets.

Professor Tamminga concluded that hyperactivity in CA3 may be a therapeutic target for biotype 2 psychosis characterized by sensorineural hyperactivity.3 For more on this topic, please see https://progress.im/en/content/reconceptualizing-psychosis-based-biomarker-analysis-%E2%80%93-personalized-therapy-prevent-disease). 3

This Satellite Symposium was sponsored by AsCNP/Sumiomo Dainippon Pharma

References
  1. Nemeth G et al. Lancet 2017;389:1103-13.
  2. Ishigooka J et al. Psychiatr Clin Neurosci 2018;72:445-53.
  3. Clementz BA et al. Am J Psychiatry. 2016;173:373-84.
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