Exploring adjunctive continuous theta burst stimulation for treatment-resistant auditory hallucinations in schizophrenia: Insights from a case series

Abstract

Background:

Auditory hallucinations affect 60%–80% of schizophrenia patients, often causing distress and functional impairment. Despite antipsychotic treatment, 30% remain resistant. Dysfunctional prefrontal-temporal connectivity has been found to be associated with these symptoms. Repetitive Transcranial Magnetic Stimulation (rTMS) is a neuromodulation technique that targets the dysfunctional area and is being used for treatment of persistent auditory hallucinations in Schizophrenia with mixed results. Continuous Theta Burst Stimulation (cTBS) is a novel neuromodulation technique that works on the principals of rTMS with similar or more robust clinical efficacy.

Cases:

We describe the cases of three patients where cTBS was applied.

Conclusion:

Significant improvement in auditory hallucinations was noticed in all three patients. While this evidence must be interpreted with caution, future studies on this topic with robust protocol to be conducted.

INTRODUCTION

Auditory hallucinations involve perceiving voices without external stimuli,[1] observed in around 60%–80% of schizophrenia patients,[2] which can cause significant distress, especially if the voices are abusive or commanding. Chronic hallucinations may impair emotional perception, increasing the risk of suicidal behavior and violence.[3] While antipsychotic medications are effective, up to 30% of patients do not benefit.[4] Brain connectivity dysfunction, especially between the prefrontal and temporal cortices, underlies these hallucinations.[5] Repetitive transcranial magnetic stimulation (rTMS) aims to regulate brain activity; however, its effectiveness remains debated, with studies showing mixed results.[6,7] To improve outcomes, novel techniques like theta burst stimulation (TBS) have been developed, offering enhanced cortical modulation with shorter sessions and lower intensities.[8,9] Here we present a series of three cases with a diagnosis of Schizophrenia (ICD-11), presenting with persistent auditory hallucination, who underwent cTBS treatment at All India Institute of Medical Sciences, Kalyani following the same protocol for all. The protocol is Continuous theta-burst stimulation (cTBS) at Left temporo-parietal region (Measured by 10–20 system), at 90% of resting motor threshold (RMT), with a frequency of 50 Hz and Burst frequency of 5 Hz, 3 Pulses/burst and 200 Bursts/cycle and a total number of three cycles per session; overall 1800 Pulses/session for 15 sessions (five Sessions/Week for 3 weeks).

Case 1

Mr DC, a 29-year-old unmarried Hindu male from lower-middle socioeconomic status hailing from Nadia district of West Bengal presented to the Out-Patient Department (OPD) with persecutory and referential delusion, 3^rd person auditory hallucination and thought broadcasting along with significant impairment in socio-occupational functioning for the last 6 months. He was treated on OPD basis with poor response to Olanzapine, Amisulpride and Aripiprazole. Finally, there was some response with Clozapine (350 mg/day), but the persistent auditory hallucination along with broadcasting and delusions were creating hindrances in his day-to-day activities. He was started on adjunctive cTBS for persistent auditory hallucinations. There was some response to the hallucinations after five sessions and significant improvement after 10 sessions, as evident by improvement in PANSS (Positive and Negative Syndrome Scale) total score by 26% and reduction of six points in PANSS positive scale [Table 1].

Table 1.

Assessment of symptoms over time using objective rating scales

Case No		PANSS								Modified PSYRATS						AVHRS
		BI		After 10 Session		After 15 Session		Improve-ment		BI		After 10 Session		After 15 Session		BI		After 10 Session		After 15 Session
1		95		83		70		26%		36		29		23		49		41		35
2		107		98		88		17%		35		31		26		51		45		38
3		94		88		68		27.6%		39		34		25		55		49		39

PANSS=Positive and Negative Symptoms Scale, BI=Before intervention (1 day prior to the first session of cTBS), PSYRATS=Psychotic Symptom Rating Scales, AVHRS=Auditory Vocal Hallucination Rating Scale

Case 2

Mr AM, a 42-year-old unmarried Hindu male from lower-middle socioeconomic status hailing from Nadia district of West Bengal with a diagnosis of Schizophrenia (a diagnosed case of schizophrenia for the past 10 years) presented to the OPD 3^rd person auditory hallucinations that were not improving with a combination of Clozapine, Risperidone and Aripiprazole. Although, he was working as a skilled laborer, the hallucinations were significantly distressful to him. Apart from that, he developed significant sexual side-effects from the antipsychotics. Risperidone and Aripiprazole was tapered and stopped, and Clozapine was up titrated to maximum tolerable level of 600 mg/day. Considering his symptom of persistent auditory hallucinations, cTBS was started [Table 1]. Although, there was not much improvement in PANSS score (19 points in Total score, 6 points in PANSS Positive scale), auditory hallucinations reduced significantly (13 points reduction, as measured with Auditory Vocal Hallucination Rating Scale (AVHRS) score) after completion of the treatment [Supplementary Table 1].

Supplementary Table 1.

Assessment of auditory hallucinations over time using Auditory Vocal Hallucination Rating Scale

Assessment of auditory hallucinations over time using Auditory Vocal Hallucination Rating Scale
		Case 1								Case 2						Case 3
		Before Intervention				After 10 Session		After 15 Session		Before Intervention		After 10 Session		After 15 Session		Before Intervention		After 10 Session		After 15 Session
Number of voices, Separately or simultaneously		3				3		3		3		3		3		3		3		3
Hypnagogic and/or hypnopompic voices		4				4		4		4		4		4		4		4		4
Frequency		3				2		2		3		3		2		4		3		2
Duration		4				4		2		3		3		2		3		3		2
Location		3				3		3		2		2		2		4		3		3
Loudness		2				2		2		3		2		2		3		3		2
Origin of the voices		3				3		3		4		4		4		4		3		3
Negative content		3				3		3		4		4		4		4		4		3
Severity of negative content		2				1		1		2		2		2		4		4		2
Frequency of distress or suffering		4				3		2		4		3		2		4		4		2
Intensity of distress or suffering		4				3		1		4		3		2		3		2		2
Interference with daily functioning		4				2		1		3		3		2		3		2		2
Control		4				3		3		3		2		2		3		3		2
Anxiety		3				2		2		4		3		2		3		3		2
Interference with thinking		2				2		1		4		3		2		4		3		3
1st, 2nd or 3rd person voices		1st		-		-		-		-		-		-		-		-		-
		2nd		-		-		-		-		-		-		1		1		1
		3rd		1		1		1		1		1		1		1		1		1
Total		49				41		34		51		45		38		55		49		39

Case 3

Mr SB, a 25-year-old unmarried male from a Hindu nuclear family of lower socioeconomic status in rural Nadia, West Bengal presented with a diagnosis of schizophrenia for 8–10 years with symptoms of 2^nd and 3^rd person auditory hallucinations, delusion of persecution, and somatic passivity, a socialism, avolition, alogia and affective flattening. The patient was admitted for detailed evaluation and treatment optimization. In the past, there was poor response to oral antipsychotics. During his In Patient stay, there was poor response to Risperidone. Clozapine was started but there was not much response to the maximum tolerable dose of 475 mg/day for 20 days, and then ECT augmentation was planned. There was not much response to 7 sessions of ECT augmentation either. In view of poor response to ECT augmentation, it was stopped. One week after stopping ECT, cTBS augmentation was started, where after 10 sessions auditory hallucination reduced, as evident by change in PANSS total score (27.6%), PANSS positive scale (reduction of six points from the baseline of 24) and AVHRS score (reduction in 16 points) [Table 1].

DISCUSSION

We present three cases with a diagnosis of Treatment resistant Schizophrenia, with poor response to Clozapine where continuous theta burst stimulation was effective in alleviating the symptoms of persistent auditory hallucinations. None of the patients reported any adverse effects during or after the cTBS sessions.

cTBS is an adaptation of rTMS protocol which exerts its inhibitory effects on cerebral cortex in a similar mechanism to Low-frequency repetitive transcranial magnetic stimulation (LF-rTMS). A positron emission tomography (FDG-PET) study demonstrated post-treatment metabolic reductions in the left frontotemporal network, regions ipsilateral to the stimulation site over the left temporoparietal junction (TPJ).[10] This reduction aligns with the inhibitory effects of LF-rTMS and the long-term depression phenomenon. Additionally, compensatory increased metabolism was observed in the contralateral right temporoparietal cortex, suggesting transcallosal interactions.

Functional changes post-rTMS, particularly in speech and language processing regions, have been highlighted in multiple studies. A study using magnetic resonance arterial spin labelling (MR-ASL) found decreased cerebral blood flow (CBF) in the primary auditory cortex (PAC) correlated with a reduction in AVH severity.[11] Similarly, reduced CBF in Broca’s area suggests that LF-rTMS exerts therapeutic effects by inhibiting hyperactive speech-related regions. Studies using functional MRI (fMRI) demonstrated normalized activation in speech generation (inferior frontal gyrus, superior frontal gyrus) and processing regions (left TPJ), reinforcing the hypothesis that LF-rTMS modulates aberrant neural circuits linked to AVH pathology.

Resting-state functional connectivity (FC) analyses have further elucidated the impact of LF-rTMS. While no significant changes were observed in TPJ-amygdala or TPJ-cingulate cortex connectivity, increased connectivity between the TPJ and right insula suggests a mechanism of transcallosal disinhibition.[12] Furthermore, improved FC within language-processing regions such as the middle temporal gyrus and ITG correlated with clinical improvements. Normalization of FC between TPJ and subcortical structures, including the putamen and supplementary motor area, indicates a role for dopaminergic modulation in symptom alleviation.

Electrophysiological studies employing EEG support these findings. LF-rTMS was associated with decreased beta-band activity in the left TPJ and increased activity in the contralateral hemisphere, paralleling PET findings.[10] Increased alpha-band activity suggests the restoration of inhibitory control, while gamma-band modulation may reflect large-scale neural network reorganization. Additionally, topological organization studies indicate that LF-rTMS normalizes global and local efficiency metrics, resembling healthy controls.

Recently, a study showed that a cTBS protocol used to induce long-term depression in brain slices can be adapted to a TMS protocol to rapidly produce long-lasting, effects on motor cortex physiology and behavior.[8] In a direct comparative trial with cTBS, both interventions demonstrated a reduction in PANSS scores. However, the cTBS cohort exhibited a more pronounced improvement across positive, negative, and general symptom domains, underscoring its superior therapeutic efficacy. Additionally, post-treatment analysis revealed elevated serum levels of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in both groups, with a greater increase observed following cTBS administration.[13]

Although, there are evidences of good response of TMS in auditory hallucinations, a recent meta-analysis with a total of 151 participants has found no significant advantage of active cTBS over sham in reducing auditory hallucination symptoms.[14]

Clozapine resistance remains one of the most challenging conditions in schizophrenia management. In the absence of definitive evidence-based guidelines, clinicians must navigate treatment based on expert consensus and look for individualized approach beyond existing research to optimize patient outcomes.[15] Our case series explores the possibility of application of theta burst stimulation in such cases in a population where the prevalence of Schizophrenia is significantly higher than the national average and such novel treatment modality has not been explored in the past.

CONCLUSION

The symptom of persistent auditory hallucination in all three patients in our case series were improved by the adjunctive cTBS therapy. The findings from the study should be interpreted with caution as the sample size is less, there was no control group, and the cases were heterogenous in nature. Trials using changes in functional neuroimaging and electrophysiological parameters during the stimulation might provide us with more robust evidence in the future.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.