What is KarXT?
KarXT is a novel drug developed for the treatment of schizophrenia by the pharmaceutical companies Karuna Therapeutics and Bristol Myers Squibb. The drug recently made headlines as it was granted approval by the FDA (Food and Drug Administration) - the authority that regulates therapeutics in the USA. It is a drug formulated of two compounds - xanomeline and trospium [1].
Molecular mechanism of action of KarXT
KarXT exerts its effect by activating the muscarinic receptors M1 and M4. Muscarinic receptors are a type of receptor in the nervous system, with diverse roles in regulating vital processes such as heart rate, learning or memory.
The mechanism of KarXT is based on the action of acetylcholine, which is a type of neurotransmitter, in regulating cognitive processes. A neurotransmitter is a molecule that helps transmit electrical stimuli between neurons, the cells of the nervous system.
KarXT is a formulation of two compounds. The first compound, xanomeline, crosses the blood-brain barrier (a type of protective filter that keeps potentially harmful substances out of the brain), and stimulates the M1 and M4 muscarinic receptors in the brain. This had been shown to target the negative symptoms of schizophrenia.
The second component, trospium, does not cross the blood-brain barrier, so it remains in the peripheral tissues. Trospium is a non-selective antimuscarinic agent, which means that it blocks the muscarinic receptors. In the case of KarXT, this is used to ensure that xanomeline only acts in the brain, therefore alleviating potential side effects from a broad muscarinic receptor activation [1, 2].
Efficacy of KarXT
KarXT appears to be successful at improving the symptoms of schizophrenia. The pivotal clinical trial for KarXT, EMERGENT-2, demonstrated superiority of the drug over placebo in a 5-week regimen. KarXT was effective at reducing symptoms of schizophrenia, as measured on the Positive and Negative Syndrome Scale, which is a standardised scale used to quantify the symptoms of schizophrenia.
KarXT was also effective at treating complex cases characterised by severe negative symptoms as demonstrated in a study on a subgroup of patients with prominent negative symptoms.
In addition to improving symptoms, the drug also improved cognitive function of the treated patients.
Adverse effects of KarXT
Generally, the side effects of KarXT during the trials were reported as mild and transient. Most side effects occurred during the first two weeks of treatment.
Commonly reported adverse effects include constipation, nausea, vomiting, indigestion and dry mouth. Importantly, despite some side effects to the digestive system, KarXT was associated with no significant or clinically relevant changes in body weight, metabolic parameters, or vital signs.
Potential alternative indications for KarXT
While the primary indication for KarXT has been schizophrenia, there may be scope for exploring its use in other neurological disorders. The broad role of acetylcholine in the regulation of cognitive processes suggests that KarXT could be used in Alzheimer's disease treatment, and potentially in substance use disorders. However, this requires further research and clinical trials [2].
What is Schizophrenia?
Schizophrenia is a chronic mental health disorder that significantly impacts the individual's thoughts, emotions and behaviour. The condition often results in problematic social and occupational functioning and self-care alike, making it one of the world's top ten causes of long-term disability [3, 4, 5].
Signs and symptoms of schizophrenia
The symptoms of schizophrenia are divided into two categories: positive and negative.
Positive symptoms are "additive" to the person experience. These include:
- hallucinations,
- delusions,
- disorganised speech.
Negative symptoms "subtract" from the person's experience. These can include:
- reduced speech (alogia),
- lack of motivation (avolition),
- lack of social interaction (asociality),
- inability to experience pleasure (ahedonia) [6, 5, 7, 8, 9, 10].
Treatment of schizophrenia
The treatment of schizophrenia typically involves a combination of pharmacological and psychosocial interventions.
Antipsychotic medications are the mainstay treatment for managing schizophrenia. Second-generation antipsychotics such as Olanzapine, Risperidone or Quetiapine are now preferred, due to being associated with a lower incidence of movement disorders as an adverse effect over first generation. Antipsychotics are more effective at treating positive symptoms than negative [6, 3, 5].
Medications are usually complemented by psychosocial treatments. These can include cognitive-behavioural therapy to treat psychosis, training in social skills, teaching self-management skills, or assertive community treatment [6, 3, 5, 10].
Outcomes for patients with schizophrenia
There is no cure for schizophrenia - it is a lifelong condition requiring continuous treatment and support.
Schizophrenia is associated with a 20% reduction in life expectancy. Suicides amount to 40% of deaths of schizophrenia patients.
Additionally, the response rate to antipsychotic medication is low - only about one third of patients respond to the drugs. Furthermore, side effects and long-term risks associated with these medications can also contribute to poor outcomes [10].