Trigger warning: pass
On September 26, the US Food and Drug Administration (FDA) approved a drug called Cobenfy to treat schizophrenia. Cobenfy is a combination of xanomeline and trospium chloride that has a new mechanism of action that also prevents the side effects of older drugs. It has its own side effects, of course.
Schizophrenia is one of the most serious psychiatric disorders. It has life-changing consequences, including social isolation, stigma, and reduced prospects for finding a partner. People with schizophrenia have a 13-15 year lower life expectancy, with contributions from being overweight, poor dietary habits, smoking, and comorbid substance use. Five percent of people with schizophrenia die by suicide.
Schizophrenia affects one in a hundred people in their lifetime. More recent evidence has challenged the idea that it is common in both sexes, finding it is slightly more common in men. It usually develops in late adolescence and early adulthood. In men, it peaks in the early 20s; new cases among women are also seen in their mid to late 40s.
Appreciating the novelty of Cobenfy and the difference it can make requires an awareness of the various effects of schizophrenia, its diagnosis, and scientists’ understanding of what causes it.
Clinical symptoms of schizophrenia
Most people with schizophrenia show prodromal symptoms. They last for a little under 12 months on average and may include unexplainable feelings of major change, the development of novel spiritual and philosophical interests, anger, irritability, anxiety, depression, and social withdrawal.
The clinical phenotype of schizophrenia is divided into three categories: reality distortion, disorganization, and negative symptoms. The so-called positive symptoms are characterized by delusions, hallucinations, and difficult speech patterns; The technical name of this disorder is formal thinking.
Swiss psychiatrist Paul E. Bleuler used the “four As” to characterize schizophrenia in 1911: affect, association, ambivalence, and autism. Contemporary descriptions are richer and more sensitive to symptom differences. These include negative symptoms such as decreased number of words spoken, decreased goal-directed activity, apathy or lack of motivation, anergia, decreased happiness, and decreased emotional expression.
Symptoms of disorganization include formal thought disorders (also considered positive symptoms), disorganized behavior, and inappropriate affect. Another interesting symptom that is now uncommon, especially in economically developed countries, is catatonia: it is characterized by a series of abnormal motor behaviors that occur together with stupor or excitement. It is no longer considered a characteristic of schizophrenia as it is seen in other psychiatric disorders as well.
German psychiatrist Kurt Schneider has described the “first stage” symptoms that were previously considered pathognomonic of schizophrenia. These include auditory hallucinations that show the patient in the third person, subjective changes in mind ownership, and the experience that actions, bodily sensations or emotions are controlled by external forces.
Cognitive impairment is ubiquitous in schizophrenia. Patients show impaired performance in various cognitive tests that measure judgment, attention, memory, and general intellectual function.
What causes schizophrenia?
Schizophrenia is a multifactorial disorder. Looking through the lens of a single construct is pointless. The role of genetics in the pathophysiology of schizophrenia cannot be overemphasized. Genetic variants associated with risk play a direct role in the brain by changing the expression of genes that disrupt brain development and function.
A genome-wide association study in 2014 identified 108 genetic loci associated with schizophrenia. (Warning: correlation does not mean causation.) Disorders like Huntington’s disease, cystic fibrosis, hemochromatosis, and sickle cell anemia are caused by mutations in a single gene. Unlike them, schizophrenia is polygenic, meaning it is the result of hundreds and possibly thousands of genes with small effect sizes. Rare genetic variants of moderate to large effect sizes have also been identified.
According to the neurodevelopmental theory, the causes include events early in life, at birth or even in utero. Prenatal and perinatal complications are the most common environmental risk factors for schizophrenia. Genetic risk for schizophrenia is associated with early life complications and increases the risk by five times when early life complications are present.
The discovery of risk genes and the neurodevelopmental origins of schizophrenia has expanded our understanding of the pathophysiology of the disease.
Xanomeline and trospium
Dopamine and glutamate, two neurotransmitters, have been implicated in the genesis of schizophrenia. But studies investigating the neurochemical origins of these disorders have produced conflicting results.
Amphetamine abuse stimulates the release of dopamine and produces a clinical syndrome that resembles schizophrenia. Antipsychotics work by blocking the brain’s dopamine receptors. These two premises lead to the dopamine hypothesis. An early version of the dopamine hypothesis is now being discredited due to new evidence. Many studies have shown that people with schizophrenia have an increased capacity for dopamine synthesis, and so far only one attempt at replication has failed to replicate these findings.
Cobenfy, a new drug recently approved by the FDA, “is the first antipsychotic drug approved for the treatment of schizophrenia that targets cholinergic receptors instead of dopamine receptors, which has long been the standard of care,” the FDA said in a statement.
According to a review of xanomeline and trospium chloride published in 2022, early development of xanomeline as a drug candidate to treat Alzheimer’s disease and schizophrenia was halted due to the compound’s side effects. It gained favor again after researchers considered using it with trospium. Xanomeline is an agonist of the muscarinic receptor (that is, the parasympathetic nervous system) and “can lead to improvement in all types of symptoms of schizophrenia” while “trospium is expected to reduce the side effects of xanomeline” because “its role is an antimuscarinic agent” .
The FDA says the most common side effects of Cobenfy include nausea, indigestion, hypertension, tachycardia, and dizziness. The drug includes Bristol Myers Squibb, which costs $ 1,850 per month.
Help to overcome suicidal thoughts is available through Tele-MANAS 14416, Sneha suicide prevention helpline 044-24640050, and Speak2Us mental health helpline 9375493754.
Alok Kulkarni is a senior interventional neuropsychiatrist at Manas Institute of Mental Health and Neuroscience in Hubli in Karnataka.
Published – 23 October 2024 05:30 IST
