Antipsychotic breakthrough innovates 70 years of schizophrenia treatment

Key points:

• Schizophrenia has both positive and negative symptoms — ‘positive’ symptoms are things that the condition imparts, such as delusions or hallucinations and ‘negative’ symptoms are things which are absent in someone with the condition, such as self-expression

• Existing antipsychotic medications target D2 dopamine receptors in the brain to block positive symptoms

• The new treatment is currently pending approval from the North American Food and Drug Administration (FDA), but the range of side effects is proving to be less severe than existing antipsychotic adverse effects

New York Medical College in Valhalla, New York, is currently seeking approval from regulatory institutions in the United States of America (USA) to overhaul 70 years of treatment for schizophrenia and associated psychotic disorders.

Clinical Professor of Psychiatry and Behavioural Sciences Leslie Citrome — Doctor of Medicine/Master of Public Health — tells Psychiatrist.com that this new innovative form of treatment does not focus on dopamine D2 receptors in the stratum.

The existing theory behind the use of first and second-generation antipsychotics relies on the premise that a hyperactive dopamine system leads to the ‘positive’ symptoms of schizophrenia, such as delusions and hallucinations.

• First-generation antipsychotics exclusively block dopamine D2 receptors, with intent to stop ‘positive’ symptoms of psychotic disorders
• Second-generation antipsychotics block dopamine D2 receptors in addition to serotonin receptors, in order to address ‘positive’ symptoms and ‘negative’ symptoms associated with schizophrenia, such as a flat affect and asocial manner
• Dopamine receptor partial agonists may also be used as a form of treatment, which assist with regulating the extreme highs and lows of neurochemical activity

However, antipsychotics lead to a greater probability of weight gain than treatments used for other conditions such as depression and a higher likelihood of correlated disorders impacting the circulatory system, along with an increase in development of type two diabetes. Antipsychotic treatments may also be a contributing factor to the development of movement disorders, including parkinsonism and tardive dyskinesia.

Earlier ‘emergent’ trials by researchers at bio-tech company Karuna Therapeutics reveal significant dips in positive and negative symptoms throughout treatment trials, with the hope of launching the drug, KarXT, in 2024.

KarXT is a revolution in the field of medicine, as it takes a different approach to dealing with symptoms through activating the M1 and M4 receptors — responsible for learning, memory and cognition — as opposed to targeting and blocking the dopamine D2 receptors. The drug is a combination of xanomeline and trospium, which work together due to their differing relationship on the nervous system and ability to cross the blood – brain barrier.

Essentially, existing treatments affect the nervous system, in addition to causing sedation — something which KarXT addresses through regulating the body and the mind with the combination two-in-one treatment.

“One of the things that I think thought leaders and clinicians are excited about is having something that is a truly different mechanism of action from that of currently available antipsychotics,” Karuna Therapeutics’ Chief Medical Officer Stephen Brannan says of the breakthrough, “we hope it becomes another arrow in their available treatment quiver.”

Importantly, the team at Karuna Therapeutics hope that KarXT will be viable as a sustainable and reliable treatment method for people living with schizophrenia or a prolonged chronic psychosis disorder. Side effects such as weight gain, lethargy, cardiac arrhythmia, breast growth and sedation may lead patients to avoid or intentionally prolong finding help.