Efficacy of Adjunctive Use of Repetitive Transcranial Magnetic Stimulation in Patients with Schizophrenia with Prominent Negative Symptoms: A Randomized Controlled Trial

INTRODUCTION

Schizophrenia is one of the most serious and debilitating mental illness. About 1% of the population suffers from schizophrenia in their lifetime worldwide.¹ The symptoms of schizophrenia are broadly divided into positive and negative symptoms. Blunted affect, alogia, asociality, anhedonia, and avolition (amotivation) are the negative symptoms of schizophrenia.

Since the ages of Emil Kraepelin, negative symptoms were recognized and included as “Emotional Dullness”, and Eugen Bleuler referred them to as “Emotional deterioration”. Kurt Schneider appreciated Bleuler’s views but did not include it in his first-rank symptoms. That is why negative symptoms remained under-recognized and under-treated since those days.

“Expressive deficits” can be explained as a decrease in verbal output and expressiveness with blunted affect, which appears as diminished expressibility of emotions over the face, poor eye-to-eye contact, and reduced spontaneity in movement and behavior. The hallmark of another “Avolition/Amotivation” subdomain is a subjective reduction in interests, desires and goals, and a behavioral reduction in purposeful acts, with a lack of self-initiated social interactions.²

The primary negative symptoms are persistent deficit state, which suggests a poor prognosis, and they do not improve over time, while secondary negative symptoms are consequences of positive psychotic symptoms, depression, demoralization, or adverse effects of medication such as bradykinesia, tremors, and rigidity.^3,4 Other conditions giving rise to secondary negative symptoms may include chronic substance/alcohol use, high-dose antipsychotic medication, social deprivation, lack of stimulation, and hospitalization.

In people with established schizophrenia, negative symptoms are seen to a varying degree in up to three-quarters, with up to 20% having persistent primary negative symptoms.⁵ The negative symptoms of schizophrenia are closely associated with poorer prognosis and bring in a significant amount of stress to the caregivers of the patient.^6,7

Limited response to pharmacological agents and psychosocial interventions necessitates exploration of newer treatment modalities for negative symptoms. Repetitive transcranial magnetic stimulation (rTMS) is the latest noninvasive neuromodulation technique being applied in the field of neurology and psychiatry. It works on the principle of stimulating hypo-functional neuronal circuitry by generation of a small amount of electricity, enough to depolarize neurons in the brain through a rapidly changing magnetic field generated by the rTMS coil. Though the exact mechanism of action is not entirely clear, an established fact known is that brain excitability decreases by applying a low-frequency rTMS (1 Hz and lower) and increases by applying a high-frequency (HF) rTMS (HF rTMS) (5–20 Hz).⁸ This mechanism is supposed to alter the functionality of the brain area being stimulated.

The pathophysiology of negative symptoms is considered to be because of the combined effect of hypometabolism in the prefrontal cortex, altered serotonin, and NMDA receptor functions. It indicates a strong association between the severity of negative symptoms and hypometabolism of the prefrontal cortex.⁹ Evidences from animal studies found that the density of N-methyl-D-aspartate (NMDA) receptors was significantly increased with HF rTMS.¹⁰ High-frequency rTMS also leads to serotonin receptors upregulation.¹¹ Elevation of dopamine levels in mesolimbic and mesostriatal pathways has also been evidenced in animal as well as human studies.¹² That is why it is expected that if rTMS improves perfusion and metabolism in the prefrontal cortex, negative symptoms shall also improve.¹³ Since it’s approval for treatment of depression by the FDA in 2008, rTMS has drawn the attention of researchers for exploring its efficacy in the negative symptoms. Many studies have suggested promising results for negative symptoms, but till date, relatively fewer studies have taken place and their results are not consistent. That is why more research is needed to explore and determine its efficacy for negative symptoms.

MATERIALS AND METHODS

Patients were taken up for this study from the inpatient Department of Psychiatry at the Institute of Mental Health and Hospital, Agra, who were between the ages of 18 and 60 years, met the International Classification of Diseases, Tenth Revision-Diagnostic Criteria for Research criteria for schizophrenia, were voluntary and competent to consent for treatment, and able to pass the TMS adult safety-screening (TASS) questionnaire that is a safety questionnaire to prevent physical side effects due to rTMS administered by a psychiatrist only during the study.

The study was a double-blind randomized control trial with a follow-up period of 4 weeks. About 50 male patients with prominent negative symptoms were taken who were fit to initiate rTMS.

Patients who did not pass the TASS questionnaire, have a significant history of seizures, active suicidal intent, pregnant or may be pregnant, any significant neurological disorder or insult, an intracranial implant, and had changes in dose or initiation of any psychotropic medication in the 4 weeks prior to screening. Currently (or in the last 4 weeks), taking Lorazepam more than 2 mg daily (or equivalent) or any dose of an anticonvulsant due to the potential to limit rTMS efficacy or other psychiatric comorbidity or substance use except nicotine, caffeine, and tobacco, was excluded from the study. The principles enunciated in the Declaration of Helsinki and the Indian Council of Medical Research were complied with and the study was approved by the Ethical Review Committee of the Institution. The patient’s sociodemographic and clinical details were recorded on structured performa.

ANALYSIS

The Statistical Package for the Social Sciences Version 16 (SPSS-16) was used for analysis.¹⁴ Frequencies with percentages were calculated for the categorical variables. Mean and standard deviation were computed for the continuous variables. Comparisons were done by using t-tests and Chi-square tests.

RESULTS

The demographic characteristics (age, duration of education, employment, religion, background, marital status, socioeconomic status, and family type) (Table 1) and clinical profile (age of onset, illness duration, family history, past history and response of rTMS, motor threshold, Simpson Angus baseline score, and CDSS baseline score) were also noted (Table 2). There were no significant group differences between true and sham group with respect to age, age of onset, total duration of illness, motor threshold, Simpson Angus baseline score, and CDSS baseline score (Supplementary Material, Table A1). There was a significant difference over both SANS and SDS scales when compared from baseline within the true group at a statistical significance level 0.01 (Table 3), but there was no significant difference between the true and sham group over SANS and SDS scales across the 4-week duration (Supplementary Material, Tables A2 and A3). There was more reduction over SANS and SDS scores in the true group as compared with the sham group (Figs 1 and 2). There was a greater reduction of negative symptoms in both SANS (9.04%) and SDS (9.75%) scales in the true group as compared with the sham group where SANS and SDS scores were reduced by 1.32% and 0.48%, respectively (Fig. 3).

DISCUSSION

This paper presents a study that was conducted at the Institute of Mental Health and Hospital, Agra, from June 2019 to October 2020, with the aim to evaluate the efficacy of HF rTMS as an adjunctive intervention along with antipsychotics, on negative symptoms of schizophrenia. The study was a hospital-based, prospective, randomized, double-blind, sham-(placebo) controlled, interventional, two-armed trial. The study is part of an emerging area of interest in the field of noninvasive techniques of brain stimulation, and was conducted with an intention to contribute to the body of literature on the topic.

Numerous studies utilizing rTMS have been conducted to treat negative symptoms of schizophrenia.^10,15 The Positive and Negative Syndrome Scale (PANSS) has been frequently utilized to evaluate negative symptoms. However, in this study, we used scales specifically designed for negative symptoms, namely SANS and SDS. The presence of deficit syndrome in a patient ensures the existence of significant negative symptoms. Assessment of negative symptoms requires careful observation, and although the SANS is a sensitive and specific scale for negative symptoms, it is time-consuming and requires experience. On the other hand, the SDS is a short and easy-to-apply scale that can be used by moderately experienced raters who are relatively new to the field of behavioral sciences. Both scales measure similar domains of negative symptoms.

A meta-analysis by Osoegawa et al.¹⁶ in 2018 analyzed 30 rTMS-based studies on negative symptoms and found that the sample sizes ranged from 11 to 157 with a mean of 36.21. The sample size in our study is greater than this mean value, indicating that it is in line with other studies. In our study, 50 patients were randomized equally into true and sham groups, and double-blinding was used to increase authenticity and reduce bias. Previous studies found major improvement in the negative symptoms when rTMS was applied over the DLPFC area^10,15 and also the pathophysiology of negative symptoms considered due to hypometabolism in the prefrontal region leads us to choose the DLPFC region to apply rTMS.

Sociodemographic variables, such as age, sex, education, marital status, religion, type of family, age of onset, occupation, rural/urban background, substance abuse, total duration of illness, co-morbidities, and history of mental illness in the family, may affect study results and prognosis. In this study, both groups were comparable with respect to these factors and did not show significant differences in these variables. Therefore, it is expected that these factors will not significantly influence the outcome measures of the study.

CONCLUSION

This study suggests that the 10 Hz rTMS protocol is an efficacious, adjunctive, noninvasive, interventional strategy for treatment of negative symptoms of schizophrenia if applied after screening out the risk factors for adverse events related to rTMS.

SUPPLEMENTARY MATERIAL

The cited supplementary file is available on the website of https://www.ijpp.in/.

ORCID

Alok Kumar Shukla https://orcid.org/0009-0007-3451-1772

Paramvir Singh https://orcid.org/0009-0002-8663-1366

Abhinav Pandey https://orcid.org/0009-0002-4720-824X

Chitrakshee Singh https://orcid.org/0009-0005-6323-8870

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