Current treatments, including antipsychotic drugs, are effective for the associated positive symptoms. However, these medications often fail to improve negative symptoms and cognitive symptoms. There is thus, a need for new therapeutic strategies other than medication-based treatment to effectively manage the symptoms associated with schizophrenia.

One promising approach is theta burst stimulation (TBS) — a non-invasive, therapeutic brain stimulation technique that has shown potential for modulating brain activity and improving behavior. Dr. Taro Kishi, a Professor from Fujita Health University, Japan led a team of scientists who conducted a systematic review and network meta-analysis aimed at identifying the most effective TBS protocols for treating schizophrenia, particularly focusing on negative and cognitive symptoms. The finding of this study was published in Volume 7 Issue 10 of the JAMA Network Open on October 10, 2024.

Prof. Kishi explains, “The left dorsolateral prefrontal cortex (DLPFC) is connected to parts of the brain, which are associated with the pathophysiology of schizophrenia, and its impairment may play a crucial role in the negative and cognitive symptoms. Therefore, this is a promising target for treating negative and cognitive symptoms in people suffering from schizophrenia.” Several TBS protocols, including continuous TBS and intermittent TBS (iTBS), have been proposed till date, but previous randomized controlled trials of these protocols reported inconsistent results regarding their effectiveness.

The researchers evaluated data from 30 randomized, sham-controlled clinical trials, involving 1,424 participants, from nine different TBS protocols. For the network meta-analysis, 11 outcomes related to the efficacy, acceptability, tolerability, and safety of the TBS were considered. Explaining further, Dr. Toshikazu Ikuta, one of the researchers, said, “The primary outcome for our study was improvement in scores related to negative symptoms.” Additional efficacy outcomes such as positive symptoms, depressive symptoms, anxiety symptoms, and cognitive function were also considered. Dr. Kenji Sakuma, another researcher of the group stated, “Our network meta-analysis also evaluated acceptability, tolerability, and safety profiles in each protocol.”

The network meta-analysis demonstrated that iTBS over the left DLPFC significantly improved negative symptom scores, overall symptom scores, anxiety symptom scores, depressive symptom scores, and overall cognitive function scores compared to a sham. Moreover, the protocol was well-accepted and well-tolerated by the people.

So, what makes this review significant? Prof. Kishi said, “In people with schizophrenia, iTBS over the left DLPFC could improve negative, depressive, anxiety symptoms, and cognitive impairment. Negative symptoms are primary or secondary to depression or overlap with depressive symptoms (e.g., anhedonia and psychomotor retardation). Moreover, negative symptoms are associated with neurocognitive symptoms. Our previous meta-analyses have revealed that iTBS over the left DLPFC could improve depressive symptoms in individuals with mood disorders*^1,2. These results indicate that iTBS over the left DLPFC is not specifically effective against negative and depressive symptoms of schizophrenia but is effective against these symptoms experienced by individuals with various psychiatric disorders across diseases. Therefore, the therapeutic effects of iTBS over the left DLPFC may be specific to symptoms but not diagnostic categories.”

However, the researchers acknowledge some limitations. Prof. Shinsuke Kito, a supervisor of the research group, says, “The sample size was relatively small for this study. Also, multiple participants were receiving psychotropic drugs during the study, which might have affected the result. In the future, we are planning to conduct large-scale, long-term studies to provide a more detailed insight.” Adding further, Prof. Nakao Iwata, another supervisor of the research group, says, “In our future studies, we will also consider other factors, including the detailed TBS methods and the characteristics of the people with schizophrenia.”