Iclepertin (BI 425809): A Comprehensive Review of a GlyT1 Inhibitor's Development and the Outcome of the CONNEX Program for Cognitive Impairment in Schizophrenia

The Unmet Need: Cognitive Impairment Associated with Schizophrenia (CIAS)

Defining the Clinical and Humanistic Burden of CIAS

Schizophrenia is a severe and chronic psychiatric disorder characterized by a constellation of symptoms typically categorized into three domains: positive, negative, and cognitive.[1] While the positive symptoms (e.g., hallucinations, delusions) and negative symptoms (e.g., apathy, social withdrawal) are the most widely recognized hallmarks of the illness, it is the cognitive impairment that often represents the most profound and persistent barrier to functional recovery.[4] This domain of dysfunction, now formally referred to as Cognitive Impairment Associated with Schizophrenia (CIAS), is considered a core feature of the disorder, not merely a secondary consequence of psychosis.[4]

Evidence indicates that CIAS affects the majority of individuals with schizophrenia, with estimates suggesting a prevalence of up to 80%.[6] These cognitive deficits are often present before the first psychotic episode, are detectable in first-degree relatives, and persist even during periods of symptom remission, underscoring their fundamental role in the pathophysiology of the illness.[8] The humanistic burden of CIAS is immense. It is the single strongest correlate of poor real-world outcomes, severely impacting an individual's ability to maintain employment, live independently, manage finances, and sustain meaningful social relationships.[4] The lived experience of CIAS is one of profound disruption, as articulated by individuals with the condition who describe struggles with attention span, working memory, and organization: "After my first psychosis, I started to experience a shorter attention span, but also, I had issues with working memory… I could keep fewer things in my min