Combining Clemastine and Aerobic Exercise to Treat Cognitive Dysfunction in Schizophrenia by Targeting Myelin Plasticity - Trial NCT06315972

Timeline & Enrollment

Primary Outcome

change in Global Assessment of Functioning,change in working memory performance

Summary

Schizophrenia (SZ) is a broad clinical entity characterized by different subjective
 symptoms,behavioural signs, and disease course. Research has pointed to numerous biological
 indicators tentatively associated with neurocognitive dysfunction, brain structural and
 neurochemical alterations. Cognitive deficits occur as early as the prodromal phase of the
 illness and significantly determine its outcome. Pathophysiologically, SZ is regarded as a
 disconnectome disorder in which frontal and temporal brain regions are functionally
 disconnected, which contributes substantially to the development of cognitive dysfunction.
 
 Impaired connectivity is related to synaptic (microconnectivity) and myelin
 (macroconnectivity) plasticity. With design-based stereology, a decreased number of
 oligodendrocytes (OLs) in the CA4 hippocampal subregion as the basis for disturbed
 myelination and impaired cognition, but also a decrease in the prefrontal cortex were
 observed. Animal studies demonstrated that clemastine enhances remyelination by increasing
 the differentiation of oligodendrocyte precursor cells (OPCs) and showed that aerobic
 exercise increases the rate of remyelination and proliferation of OPCs; this clinically
 meaningful effect of aerobic exercise is stronger in combination with clemastine.
 Furthermore, aerobic exercise improves everyday functioning, measured by the Global
 Assessment of Functioning (GAF) scale, and cognitive dysfunction in SZ and increases
 hippocampal volume, especially the volume in the hippocampal CA4 subregion. This regional
 volume change correlates negatively with global and cell-specific polygenic risk scores
 (PRSs), indicating that OPCs are involved in the genetic risk mechanisms and disturbed
 plasticity underlying SZ. In patients with multiple sclerosis, 90 days' administration of
 clemastine fumarate 10.72 mg/day, corresponding to clemastine 8 mg/day, significantly
 decreased the P100 latency delay of visual evoked potentials (VEPs) as a sign of myelin
 repair. In a bicentric, randomized, double-blind, controlled phase IIb clinical trial with a
 2-arm parallel group design in patients with SZ, the study will compare the effects of
 aerobic exercise training plus clemastine vs. aerobic exercise training plus placebo over a
 period of 3 months on 1) everyday functioning and 2) working memory as primary outcomes.

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