New hope for schizophrenia: iTBS over the left DLPFC improves negative and cognitive symptoms

Schizophrenia, which is characterized by positive symptoms (e.g., hallucinations and delusions), negative symptoms (diminished emotional expressions or avolition), and cognitive impairments (attention deficits and poor learning skills), is a serious mental health condition that affects how individuals think, behave, and perceive the world. By far, schizophrenia is one of the most chronic and disabling mental health conditions, with an estimated one percent of the population affected globally. Despite the advancements made in managing the condition, finding an effective treatment procedure for alleviating negative and cognitive symptoms remains limited.

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.”

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Reference
DOI: 10.1001/jamanetworkopen.2024.41159

*Cited references:
1. Kishi T, et al., Theta burst stimulation for depression: a systematic review and network and pairwise meta-analysis. Mol Psychiatry. 2024 in press.

2. Kishi T, et al., Repetitive transcranial magnetic stimulation for bipolar depression: a systematic review and pairwise and network meta-analysis. Mol Psychiatry. 2024 Jan;29(1):39–42.

About Fujita Health University
Fujita Health University is a private university situated in Toyoake, Aichi, Japan. It was founded in 1964 and houses one of the largest teaching university hospitals in Japan in terms of the number of beds. With over 900 faculty members, the university is committed to providing various academic opportunities to students internationally. Fujita Health University has been ranked eighth among all universities and second among all private universities in Japan in the 2020 Times Higher Education (THE) World University Rankings. THE University Impact Rankings 2019 visualized university initiatives for sustainable development goals (SDGs). For the “good health and well-being” SDG, Fujita Health University was ranked second among all universities and number one among private universities in Japan. The university became the first Japanese university to host the "THE Asia Universities Summit" in June 2021. The university’s founding philosophy is “Our creativity for the people (DOKUSOU-ICHIRI),” which reflects the belief that, as with the university’s alumni and alumnae, current students also unlock their future by leveraging their creativity.

Website: https://www.fujita-hu.ac.jp/en/index.html

About Dr. Taro Kishi from Fujita Health University
Dr. Taro Kishi is a Professor at the Department of Psychiatry, Fujita Health University School of Medicine. He spent two years as a Postdoctoral Fellow at the Zucker Hillside Hospital in New York. He has been conducting a number of clinical trials to find an effective treatment for schizophrenia and mood disorders. His research using a systematic review and meta-analysis contributes to evidence-based mental health and the development of clinical practice guidelines for psychiatric disorders. His research interests also include psychiatric genetics and pharmacogenetics. He has published more than 240 articles till date. 

Funding information
The authors acknowledge funding provided by JSPS KAKENHI (19K08082).