SINGAPORE – A fast, non-invasive form of brain stimulation to reduce persistent negative symptoms such as social withdrawal and lack of motivation in patients with schizophrenia is being tested at the Institute of Mental Health (IMH).
A few trials overseas on the use of intermittent theta burst stimulation, or iTBS, for this purpose have had patients showing significant improvement.
The IMH study will test an accelerated form of iTBS using a changing magnetic field to modify brain activity in a specific brain location over multiple sessions, for a total of five working days.
iTBS is a form of transcranial magnetic stimulation, or TMS, which is being used to treat depression in Singapore.
So far, 22 patients out of a target pool of 40 have been enrolled in the trial in Singapore’s only psychiatric hospital, where schizophrenia is the most common disorder seen. The study could be completed by July 2025.
In 2023, about 27 per cent of IMH’s patients had schizophrenia. That year, it saw 55,782 patients, of whom nearly 15,000 patients with schizophrenia had an inpatient admission or made outpatient visits.
Overall, it had 27,200 patients with a diagnosis of schizophrenia as at end-2023.
The principal investigator of the IMH study, Dr Tan Xiaowei, said its aim is to work out the best iTBS treatment procedure for schizophrenia patients here who suffer from persistent negative symptoms.
Individuals with negative symptoms may avoid social interaction, show very little facial expression and hardly speak. This makes it hard for them to take care of themselves, stay organised or hold down a job, said Associate Professor Jimmy Lee, a senior consultant in IMH’s department of psychosis.
These negative symptoms are often misunderstood, and individuals are mistaken as lazy and not doing their chores or finding work, he added.
A recent study by Dr Li Yanhui, a second-year psychiatry resident at IMH, and Prof Lee showed that negative symptoms affect a patient’s ability to live a fulfilling life. The lack of social interaction is particularly damaging, she said.
“The more social the patients are, the better their quality of life,” she added.
Prof Lee said that in clinical practice, doctors tend to pay less attention to negative symptoms, and focus instead on the patient’s positive symptoms, meaning behaviour and thoughts such as delusions and hallucinations.
In large part, it is due to the lack of effective treatment strategies for both negative and cognitive symptoms such as impaired executive function and a working memory deficit, he said.
However, some patients benefit from rehabilitation programmes such as cognitive remediation therapy, a behavioural intervention programme conducted by IMH occupational therapists, he added.
Doctors sometimes also prescribe antidepressants in case the negative symptoms are a result of mood disorders such as depression, but these do not always help, Prof Lee said.
Negative symptoms can lead to an individual neglecting self-care and hygiene habits, and this is an area mental health workers assess and, through rehabilitation, teach and motivate the individual to improve, he added.
Schizophrenia is poorly understood and the pharmaceutical arsenal for it is limited, but research holds promise for new and more effective treatments.
In September 2024, a new antipsychotic drug to ease positive symptoms – such as delusions and hallucinations – and negative symptoms, without causing side effects such as weight gain and drowsiness, was approved for use in adults with schizophrenia in the US.
Known as Cobenfy, the medication is said to be the first potential breakthrough for the disorder in decades.
Thus far, drugs for schizophrenia have worked by blocking dopamine – a neurotransmitter usually associated with motivation and reward – as dopamine imbalances in the brain are associated with schizophrenia symptoms.
Cobenfy, however, targets a different family of receptors in the brain, known as muscarinic receptors. Clinical trials have shown that the activation of these receptors can alleviate positive, negative and cognitive symptoms in people with schizophrenia.
Prof Lee said Cobenfy is promising, but there is no evidence that it specifically treats negative symptoms. Still, with the emergence of this new class of drugs, other new and effective drugs could appear on the market in the future.
There are other new schizophrenia drugs being trialled, including one that targets cognitive impairment, he said.
In recent years, too, researchers have been studying the association between immune system changes and the development of mental health conditions.
A recent study by researchers from IMH and A*Star has reaffirmed the connection between the immune system and a person’s resistance to antipsychotic medications in schizophrenia.
Their paper was published in the journal Brain, Behaviour And Immunity, and adds to a growing body of research suggesting that a dysregulated immune system may contribute to the development of schizophrenia.
The study found significant differences in certain immune cell populations between healthy individuals and people with schizophrenia. It also found differences in the immune cell populations of people with the disorder who responded to treatment and those who were treatment-resistant.
Furthermore, the degree of the changes in immune cell populations that were detected correlated with how resistant a patient with schizophrenia might be to treatment.
Prof Lee said that this means doctors may be able to soon utilise certain immune markers to predict if a patient will be treatment-resistant to the usual crop of drugs that are first given to newly diagnosed patients.
This could pave the way for earlier and more targeted interventions – for instance, in initiating clozapine treatment, which is usually reserved for severely ill patients who do not respond to the usual drugs. Studies have found that globally, clinicians and patients tend to delay the initiation of clozapine because of the intense monitoring that is required to make sure patients do not develop potentially life-threatening side effects. However, a delay of several years can affect the patient’s health outcomes.
“As scientists learn more about the biology of schizophrenia, we will get closer to getting the right treatment to the right schizophrenia patient at the right time,” said Prof Lee.
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