Schizophrenia

Overview of cognitive impairment in Schizophrenia

Schizophrenia is a complex, chronic mental health disorder that severely affects quality of life. The worldwide prevalence of schizophrenia is estimated to be 20 million.1 

Schizophrenia is characterised by:

  • Positive symptoms (hallucinations, psychoses, and other perceptual distortions),
  • Negative symptoms (diminished emotional expression, inability to feel pleasure, or catatonia).
  • Cognitive symptoms (poor executive functioning, issues with working memory, and inability to focus or pay attention). 

There is no cure for schizophrenia. The symptoms are disabling and distressing for patients and have a substantial impact on their day-to-day life. While available therapies help with positive symptoms, they carry great risk of a host of side effects, and they do not have appreciable improvements on cognitive and functional impairment seen in schizophrenia. 

Cognitive impairment associated with schizophrenia (CIAS) is common, with about 75% of patients displaying cognitive symptoms. This represents a significant unmet medical need for both patients and clinicians, with no approved drugs to specifically treat cognitive dysfunction in schizophrenia.

One-third of the largest pharmaceutical companies have an interest in both schizophrenia and Alzheimer’s disease. Actinogen considers cognitive dysfunction in schizophrenia to be a substantial unmet clinical development opportunity.

1 James SL, Abate D, Abate KH, Abay SM, Abbafati C, Abbasi N, et al. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. 2018;392(10159):1789-858

Schizophrenia is a serious disease

Schizophrenia affects up to 1.7 million people in the US alone

Approximately 75 per cent of schizophrenia patients display cognitive symptoms

Estimates show the cost of schizophrenia to the US alone was $155 billion

One-third of the largest pharmaceutical companies have an interest in both schizophrenia and Alzheimer’s disease

No approved drugs to specifically treat cognitive impairment in associated schizophrenia (CIAS)

There are no drugs that have been specifically approved to treat CIAS.

Treatment of schizophrenia typically consists of pharmacological and psychological interventions coupled with psychosocial management typically for the rest of one’s life following diagnosis. While antipsychotic medication primarily targets positive and negative symptoms, there remains a substantial need for alternative therapies that allow for improved cognitive function in schizophrenia. 

Cognitive and functional impairment can impact the quality of life of those diagnosed with schizophrenia as well as the cost burden associated with some of the largest cost contributors to maintain treatment. Cognitive and functional difficulties play a major part in preventing the re-integration of treated schizophrenics back into normal society. 

Stress hormones and cognitive impairment in schizophrenia

Stress is an exacerbating factor in symptom severity and diminished function in psychiatric disorders. This is thought to occur due to chronic over-activation of the stress-regulation centre of the body, the hypothalamic-pituitary-adrenal axis (HPA-axis) and results in elevated cortisol (the stress hormone). 

Importantly for the treatment of schizophrenia, a dysfunctional stress response and chronically elevated cortisol, cause abnormally high production of dopamine. Chronically elevated cortisol has also been reported to be neurotoxic, leading to impaired neural signals from some areas of the brain including the hippocampus, the main part of the brain associated with consolidation of short-term memory.

Ordinarily, over-active dopamine signalling is counteracted by neural signals from the hippocampus. However, as there is cortisol-related neural toxicity in the hippocampus, these signals become uncontrolled, and patients may experience intensified psychotic and cognitive symptoms.

Research into the pro-cognitive effects of anti-stress treatments in psychosis has been promising but has not been specifically investigated in schizophrenia. Treatment options for cognitive impairment in schizophrenia represent a significant unmet clinical and medical need.

Xanamem could be a potential treatment for cognitive impairment in schizophrenia

Xanamem is considered a potential therapy for elevated cortisol and cognitive dysfunction in schizophrenia. 

Xanamem is a novel therapeutic product specifically designed to inhibit the production of excess cortisol in the brain. Xanamem works by inhibiting the 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme in the brain, which blocks the production of cortisol, in the brain. 

Given the role of elevated cortisol in symptom severity, cognitive impairment, and depressive symptoms, Xanamem has the potential to correct the stress response and mitigate cortisol-related cognitive impairment.

Xanamem presents an opportunity for a mechanistically unique and new therapeutic approach to improve neurocognitive functions. This could result in improvements to the quality of life, allow schizophrenia patients to take better care of themselves, aid employment, and reduce reliance on the disability sector.

Actinogen’s previous clinical results have shown that Xanamem can significantly reduce cortisol levels in healthy elderly subjects and improve cognition. Animal data also supports an improvement in cognitive function. Xanamem has been demonstrated to be efficacious and brain-penetrant, with a strong safety profile.


External Links

SANE Australia – National mental health charity
https://www.sane.org/information-stories/facts-and-guides/schizophrenia

Neuroscience Institute of Schizophrenia and Allied Disorders (NISAD)
https://www.neura.edu.au/sri/

Schizophrenia and Related Disorders Alliance of America (SARDAA)
https://sardaa.org/about-sardaa/