Trigger warning: suicide
On September 26, the U.S. 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 novel mechanism of action that steers clear of older drugs’ side-effects, too. It has side-effects of its own, of course.
Schizophrenia is one of the most serious of all psychiatric disorders. It has life-changing consequences, including social isolation, stigma, and diminished prospects of finding a partner. Persons with schizophrenia have a life expectancy lower by 13-15 years, with contributions from weight gain, 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. Newer evidence has challenged the idea that it is equally prevalent in both sexes, finding it is slightly more common in men. It typically develops during late adolescence and early adulthood. In men, it peaks in the early 20s; new cases among women are also seen in the mid- to late 40s.
Appreciating Cobenfy’s novelty and the difference it can make requires awareness of the various effects of schizophrenia, its diagnosis, and scientists’ understanding of what causes it.
Clinical symptoms of schizophrenia
Most people who develop schizophrenia display prodromal symptoms. They last for a little under 12 months on average and may include unexplainable feelings of inner change, development of novel spiritual and philosophical interests, anger, irritability, anxiety, depression, and social withdrawal.
The clinical phenotype of schizophrenia falls into three categories: reality distortion, disorganisation, and negative symptoms. The so-called positive symptoms are characterised by delusions, hallucinations, and a pattern of speech that is difficult to follow; the technical name for this is formal thought disorder.
The Swiss psychiatrist Paul E. Bleuler used the “four As” to characterise schizophrenia in 1911: affect, associations, ambivalence, and autism. Contemporary descriptions are richer and more sensitive to differences in symptoms. They include negative symptoms like reduction in the quantity of words spoken, reduced goal-directed activities, apathy or lack of motivation, anergia, reduced experience of pleasure, and reduced expression of emotions.
Disorganisation symptoms include formal thought disorder (also considered a positive symptom), disorganised behaviour, and inappropriate affect. Another intriguing symptom that has today become more uncommon, especially in the economically developed world, is catatonia: characterised by a host of abnormal motor behaviours occurring alongside stupor or excitement. It is no longer considered characteristic of schizophrenia as it is seen in other psychiatric disorders as well.
The German psychiatrist Kurt Schneider had described “first rank” symptoms previously considered to be pathognomonic of schizophrenia. These included auditory hallucinations referring to the patient in the third person, subjective changes in the ownership of thinking, and the experience that one’s actions, bodily sensations or emotions are controlled by external forces.
Cognitive impairment is ubiquitous in schizophrenia. Patients have shown impaired performance on various cognitive tests that measure judgement, attention, memory, and general intellectual functions.
What causes schizophrenia?
Schizophrenia is a multifactorial disorder. Viewing it through the lens of a single construct is futile. The role of genetics in the pathophysiology of schizophrenia cannot be overemphasised. Genetic variants associated with risk play a direct role in the brain by changing gene expression that disrupt brain development and function.
A genome-wide association study in 2014 identified 108 genetic loci associated with schizophrenia. (Reminder: correlation does not imply causation.) Disorders like Huntington’s disease, cystic fibrosis, hemochromatosis, and sickle cell anaemia 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 of small effect sizes. Rare genetic variants of moderate to large effect sizes have also been identified.
According to neurodevelopmental theory, the causes include events in early life, at birth or even in utero. Prenatal and perinatal complications represent the most common environmental risk factor for schizophrenia. The genetic risk for schizophrenia interacts with early life complications and increases the risk probability up to fivefold when there are early-life complications.
The discovery of genes that confer risk and the neurodevelopmental origins of schizophrenia have expanded our understanding of disease pathophysiology.
Xanomeline and trospium
Dopamine and glutamate, two neurotransmitters, have been implicated in the genesis of schizophrenia. But studies investigating the neurochemical origins of the disorder have thrown up conflicting results.
Amphetamine abuse stimulates dopamine release and produces a clinical syndrome resembling schizophrenia. Antipsychotics act by blocking brain dopamine receptors. These two premises gave rise to the dopamine hypothesis. The initial version of the dopamine hypothesis now stands discredited in light of new evidence. Multiple studies have demonstrated people with established schizophrenia have an increased dopamine synthesis capacity, and so far only one replication effort has failed to reproduce their findings.
Cobenfy, the new drug that has just received the FDA’s approval, “is the first antipsychotic drug approved to treat schizophrenia that targets cholinergic receptors as opposed to 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, the early development of xanomeline as a drug candidate to treat Alzheimer’s disease and schizophrenia was stopped due to the compound’s adverse effects. It gained favour again after researchers considered using it with trospium. Xanomeline is an agonist of muscarinic receptors (i.e. of the parasympathetic nervous system) and “might lead to improvement in all symptom types of schizophrenia” while “trospium is expected to reduce the adverse effects of xanomeline” given “its role as an antimuscarinic agent”.
The FDA said Cobenfy’s most common side-effects include nausea, indigestion, hypertension, tachycardia, and dizziness. The drug belongs to Bristol Myers Squibb, which has priced it at $1,850 a month.
Assistance for overcoming suicidal thoughts is available via Tele-MANAS 14416, Sneha’s suicide prevention helpline 044-24640050, and Speak2Us mental health helpline 9375493754.
Alok Kulkarni is a senior interventional neuropsychiatrist at the Manas Institute of Mental Health and Neurosciences at Hubli in Karnataka.
Published – October 23, 2024 05:30 am IST
