Left intermittent theta burst stimulation combined with right low-frequency rTMS as an additional treatment for major depression: A retrospective study.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for major depression (MD). We retrospectively analyzed the efficacy of intermittent theta burst stimulation (iTBS) on the left dorsolateral prefrontal cortex (DLPFC) combined with low-frequency rTMS (LF-rTMS) on the right DLPFC as an additional therapy to standard medication treatment. Materials and
Methods: The study included 54 patients with MD who completed 10 courses (5 days per week) of rTMS as an add-on therapy. Thirty patients were treated in the combination group (120% resting motor threshold; left DLPFC, iTBS, 600 stimuli + right DLPFC, 1-Hz rTMS, 600 stimuli), while 24 patients were in the high-frequency rTMS (HF-rTMS) group (120% resting motor threshold; left DLPFC, 10-Hz rTMS, 3000 stimuli). The outcome was assessed based on the changes in scores of 24-item Hamilton Depression Scale (HAMD-24) and 14-item Hamilton Anxiety Scale (HAMA-14).
Results: Both depression and anxiety were significantly improved after 2 weeks of treatment by rTMS combined with medication. The combination of iTBS and LF-rTMS was significantly superior to HF-rTMS in improving the scores of HAMD-24 (P = 0.041) and HAMA-14 (P = 0.0095), and the response rate (P = 0.027).
Conclusion: The pilot study showed that the combination of iTBS and LF-rTMS may hold promise as a potentially effective alternative therapy for MD due to its efficacy and time-saving benefit. The preliminary results shed light on the study of the efficacy and acceptability of the combination of iTBS and LF-rTMS for MD. Copyright:

INTRODUCTION

Major depression (MD) is one of the most common chronic and distressing diseases and the major cause of disability. There are more than 350 million people worldwide who struggle with MD every day.[1] Through standardized antidepressant medication and structured psychotherapy, up to 27% of patients with MD do not recover and gradually develop into a chronic disease.[2] Therefore, there is an urgent need for additional treatments. Physical therapy is an effective treatment and usually shows antidepressant effects in the first week of treatment.[34] The combination of physical therapy and medicine may allow patients to take a shorter course of treatment and reduce the recurrence of MD during antidepressant treatment.

Transcranial magnetic stimulation is a type of physical therapy for MD, based on electromagnetic induction and electromagnetic conversion. A coil placed on the scalp generates magnetic fields that pass through the electrically insulating skull efficiently and induce medium or high spatial focal intracranial currents in the brain tissue.[5] Repetitive transcranial magnetic stimulation (rTMS) is administered sequentially to produce a series of physiological and biochemical reactions in the cerebral cortex, such as activation and inhibition of neurons, as well as changes in neurotransmitters and blood flow, which causes change in corresponding functions and behaviors and generate short- and long-acting therapeutic effect. One of the biological mechanisms of MD is the weakened function of the left dorsolateral prefrontal cortex (DLPFC) and the activation of the right DLPFC.[6] rTMS treatment for MD improves the excitability of the left DLPFC and/or lowers the excitability of the right DLPFC, which enhances the positive emotional experience of patients and reduces their negative emotional experience. From the perspective of neurotransmitter, it may increase the concentration of g-aminobutyric acid and glutamate in the related brain area and have pro-dopaminergic effects on striatum after rTMS treatment.[7]

The effect of rTMS on the excitability of the central nervous system is frequency dependent. The high frequency and low frequency of rTMS produce two opposite effects, that is, low frequency (≤1 Hz, LF-rTMS) reduces cortical excitability, while high frequency (≥5 Hz, HF-rTMS) increases cortical excitability.[5] It produces long-term potentiation-like effect and long-term depression-like effect to regulate cortical plasticity.[8] Substantial evidence showed that HF-rTMS of the left DLPFC had an antidepressant effect and was approved by the US Food and Drug Administration (FDA) for the treatment of refractory depression. Several studies found that LF-rTMS of the right DLPFC also had an antidepressant effect. A meta-analysis concluded that HF-rTMS and LF-rTMS had comparable antidepressant effects, yet LF-rTMS had fewer side effects like seizures than HF-rTMS.[9] Taken together, the previous findings indicate LF-rTMS has great application prospects in the clinical context.

In 2005, a new type of rTMS simulation model named theta burst stimulation (TBS) was proposed, which was based on the endogenous hippocampal discharge pattern.[10] Intermittent TBS (iTBS) can increase the excitability of the cerebral cortex in a shorter time than conventional rTMS. A study found that iTBS had more antidepressant effects than the sham stimulation.[6] Both retrospective studies and randomized prospective studies found that the antidepressant effect of iTBS on the left DLPFC was indistinguishable from the effect of 10-Hz rTMS.[1112] Moreover, iTBS treatment could improve executive function,[13] and it could be considered as a first-line protocol[7] for treatment-resistant depression. The iTBS treatment is of good clinical use as more patients can be treated in the same period of time with similar clinical outcomes.[1214]

In this study, we aimed to investigate the efficacy of the combination treatment of iTBS and LF-rTMS (1 Hz) as an add-on therapy to MD. We compared the efficacy of the new combination treatment with HF-rTMS (10 Hz). To our best knowledge, this is the first study to test the efficacy of the combination of iTBS and LF-rTMS.

MATERIALS AND METHODS

Study design

This was a retrospective study conducted in Ningbo First Hospital between March 2019 and August 2020. The protocol was approved by the Ethics Committee of Ningbo First Hospital, Ningbo, China (approval number: 2020-R283), and it was registered in the registry website http://www.chictr.org (registration number: ChiCTR2100041669).

Participants

We included 54 patients (age, 18–75 years) who were diagnosed to have MD according to Diagnostic and Statistical Manual of Mental Disorders, fifth edition by structured conversations with professional psychiatrists. The exclusion criteria were contraindications to the use of rTMS, such as implanted cardiac pacemakers and other metal or electronic devices, epilepsy, brain tumors, and other organic encephalopathies. No patients started any new medications during the rTMS treatment course. Baseline characteristics of patients are shown in Table 1.

Table 1

Baseline characteristics of patients in the two groups

	Total	iTBS+1-Hz rTMS	10-Hz rTMS	P
Number	54	30	24	-
Age (years)	38.8 (17.5)	39.7 (18.1)	37.7 (17.0)	0.67
Gender (male/female)	12/42	6/24	6/18	0.66
SSRIs/SNRIs	38/16	23/7	15/9	0.26
BZDs/NBZDs	38/16	22/8	16/8	0.59
Baseline HAMD-24	31.2 (8.3)	32.4 (8.0)	29.8 (8.5)	0.26
Baseline HAMA-14	23.0 (7.2)	24.5 (6.9)	21.2 (7.2)	0.099

10-Hz rTMS=right frontal 10-Hz TMS, BZDs=benzodiazepines, HAMA-14=14-item Hamilton Rating Anxiety Scale, HAMD-24=24-item Hamilton Rating Depression Scale, iTBS+1-Hz rTMS=left frontal intermittent theta burst stimulation followed by right frontal 1-Hz rTMS, NBZDs=non-benzodiazepines, rTMS=repetitive transcranial magnetic stimulation, SD=standard deviation, SNRIs, serotonin–norepinephrine reuptake inhibitors, SSRIs=serotonin-specific reuptake inhibitors. Continuous variables are presented as mean (SD), whereas categorical variables are presented as counts

Repetitive transcranial magnetic stimulation

The iTBS and rTMS were applied with a figure-of-eight coil using a magnetic stimulator (Yiruide CCY-I, Wuhan, China). The stimulation was targeted at the DLPFC through the approach of positioning F3 and F4, according to the international 10–20 system for electroencephalography electrode placement. The rTMS and iTBS were performed at 120% resting motor threshold (RMT). Of the 54 patients, 30 were treated with the combination of iTBS and 1-Hz rTMS, while 24 were treated with 10-Hz rTMS for 10 courses of rTMS (5 days a week). The combination treatment group received a total of 13 min of treatment, consisting of 600 stimuli of iTBS (50 Hz triplet bursts repeated at 5 Hz, 3 min) applied to the left DLPFC and immediately followed by 600 stimuli of 1-Hz rTMS to the right DLPFC (one stimulus per second, 10 min). The 10-Hz rTMS group received 3000 stimuli of 10-Hz rTMS to the left DLPFC (75 trains with 40 stimuli and an intertrain interval of 26 s) and it lasted for 37 min and 30 s.

The same intensity of 120% RMT stimulation was used in the two groups to increase the comparability of the protocols, as previous research showed that the intensity of stimuli was related to antidepressant efficacy.[1516]

Assessments

The mood of depression and anxiety were evaluated by the 24-item Hamilton Depression Scale (HAMD-24) and the 14-item Hamilton Anxiety Scale (HAMA-14), respectively. For depression, a professionally trained scale assessor obtained patients’ pre-HAMD and pre-HAMA scores just before the first course of treatment. The assessor also obtained patients’ post-HAMD and post-HAMA scores just after the final course.

A HAMD-24 reduction of 50% or more was defined as a full response to antidepressant therapy. The mood improvement was compared within and between groups, and the response was compared between groups.

Statistics analysis

R statistical software was used for statistical analysis. Independent sample t-test was used to compare the continuous variables of baseline characteristics between the two groups, while Chi-square test was used to compare the categorical variables. Independent sample t-test was also used to test the score alteration and the Chi-square test was used to compare the response rate between the two groups. Paired t-test was used to compare mood improvement in each group before and after treatment. Statistical significance was accepted at P < 0.05 (two tailed).

RESULTS

Of the 54 patients, 38 took serotonin-specific reuptake inhibitors (SSRIs) and the remaining 16 took serotonin–norepinephrine reuptake inhibitors (SNRIs). All patients took sleep-improving drugs, of which 38 took benzodiazepines and 16 took non-benzodiazepines. The two groups of patients were comparable in terms of age, gender, and medications [Table 1].

Both HAMD-24 scores were greater than 20 (mean 32.4, standard deviation [SD] 8.0 in the combination group; mean 29.8, SD 8.5 in the 10-Hz rTMS group), suggesting mild to moderate severity of depression. Similarly, both HAMA-14 scores were greater than 14 (mean 24.5, SD 6.9 in the combination group; mean 21.2, SD 7.2 in the 10-Hz rTMS group), indicating that patients with depression had anxiety also. Besides, patients in the two groups did not differ in the baseline HAMD-24 and HAMA-14 scores (P > 0.05) [Table 1].

As to the posttreatment scores, both groups showed a significant decrease in HAMD-24 and HAMA-14 after 2 weeks of treatment. In the combination treatment group, the mean HAMD-24 score declined from 32.4 (SD 8.0) to 17.5 (SD 9.2) (P < 0.001) and the mean HAMA-14 score declined from 24.5 (SD 6.9) to 12.3 (SD 6.3) (P < 0.001) [Table 2]. In the 10-Hz rTMS group also, the mean HAMD score declined from 29.8 (SD 8.5) to 20.5 (SD 12.8) (P < 0.001) and the mean HAMA-14 score declined from 21.2 (SD 7.2) to 15.6 (SD 8.4) (P = 0.011) [Table 2].

Table 2

Score changes of HAMD-24 and HAMA-14 in patients after combination treatment

Scale	Group	Baseline	After treatment	Change	P*	P #
HAMD-24	iTBS +1-Hz rTMS	32.4 (8.0)	17.5 (9.2)	−14.9 (9.9)	<0.001	0.041
	10-Hz rTMS	29.8 (8.5)	20.5 (12.8)	−9.3 (9.8)	<0.001
HAMA-14	iTBS +1-Hz rTMS	24.5 (6.9)	12.3 (6.3)	−12.1 (7.0)	<0.001	0.0095
	10-Hz rTMS	21.2 (7.2)	15.6 (8.4)	−5.63 (9.9)	0.011

10-Hz rTMS=right frontal 10-Hz TMS, HAMA-14=14-item Hamilton Rating Anxiety Scale, HAMD-24=24-item Hamilton Rating Depression Scale, iTBS+1-Hz rTMS=left frontal intermittent theta burst stimulation followed by right frontal 1-Hz rTMS, rTMS=repetitive transcranial magnetic stimulation. *Baseline and final comparison of each group; #comparison of score alteration between two groups

The change in HAMD-24 after treatment was larger in the combination treatment group (mean − 14.9, SD 9.9) than in the 10-Hz rTMS group (mean − 9.3, SD 9.8) (P = 0.041) [Table 2 and Figure 1]. Regarding the change in HAMA-14, a similar trend was observed (mean − 12.1, SD 7.0 vs. mean − 5.6, SD 9.9) (P = 0.0095) [Table 2 and Figure 2].

Figure 1

(a) HAMD-24 baseline scores in the two groups (P = 0.26). (b) The HAMD-24 scores after 2 weeks of treatment in the two groups (P = 0.33). (c) HAMD-24 score alterations in the two groups (P = 0.041). HAMD-24 = 24-item Hamilton Depression Scale

Figure 2

(a) HAMA-14 baseline scores in the two groups (P = 0.099). (b) The HAMA-14 scores after 2 weeks of treatment in the two groups (P = 0.12). (c) HAMA-14 score alterations in the two groups (P = 0.0095). HAMA-14 = 14-item Hamilton Anxiety Scale

The mean and percentage of change in the HAMD-24 score of the combination treatment group showed a higher improvement than that of the 10-Hz rTMS group [Table 3]. Fifteen (50%) patients in the combination treatment group responded to the combination treatment with a decrease of 50% in HAMD-24, which is a higher responder rate than the corresponding rate of the 10-Hz rTMS group, that is, five patients (20.8%) (P = 0.027) [Table 3].

Table 3

Percentage change of HAMD-24 and responder rate after treatment

Group	Mean	Percentage			Responder rate (%)	P
		25	50	75
iTBS+1-Hz rTMS	−45.2	−69.04	−49.0	−22.5	50.0%	0.027
10-Hz rTMS	−32.5	−49.9	−33.7	−9.1	26.3%

10-Hz rTMS=right frontal 10-Hz TMS, HAMD-24=24-item Hamilton Rating Depression Scale, iTBS+1-Hz rTMS=left frontal intermittent theta burst stimulation followed by right frontal 1-Hz rTMS, rTMS=repetitive transcranial magnetic stimulation. Response is defined as a reduction of HAMD-24 by at least 50%

DISCUSSION

The present pilot study is the first trial to investigate the efficacy of the combination of iTBS and LF-rTMS treatment. The improvement in both depression and anxiety was significant after 2-week rTMS combined with medication treatment. The combination of iTBS and LF-rTMS exhibited merits in terms of treatment efficacy and saving time and may hold promise as a potentially effective alternative therapy for MD.

Several previous studies have reported the treatment effects of rTMS in MD. One study reported that more than 40% of patients with MD responded to at least 2-week rTMS treatment.[15] Two multisite randomized controlled trials reported a response rate of 49% for 4–6 weeks of iTBS treatment[12] and 23.9% for 6 weeks of HF-rTMS treatment.[17] These previous findings are consistent with our results of 50% responder rate in the combination of iTBS and LF-rTMS and 26.3% response rate in HF-rTMS. Nevertheless, the heterogeneity of rTMS parameters and patients may influence the comparability of results in different studies. The higher dose of stimulation, longer treatment time, and less refractory at the commencement of treatment in MD are associated with better prognosticating outcomes to rTMS treatment.[1518]

Our findings showed that the combination of iTBS and LF-rTMS is superior than HF-rTMS in terms of treatment efficacy. Two meta-analyses showed that bilateral LF-rTMS and HF-rTMS worked better in efficacy and acceptability for the treatment of MD.[1920] Similar to the bilateral rTMS, the present bilateral combination is based on the assumption of functional brain asymmetry.[21] It achieves stability combining iTBS (excitability cortical increasing) stimulation over the hypoactive left DLPF with LF-rTMS (excitability cortical decreasing) over the hyperactive right DLPFC. Additionally, the combination therapy of iTBS and LF-rTMS also saves more than half of the time and it can increase patients’ adherence.

With respect to the treatment effects for anxiety, previous findings have supported the positive effect of HF-rTMS, LF-rTMS, and bilateral rTMS (HF-rTMS + LF-rTMS) on anxiety symptoms in MD patients.[222324] A range of 39.5%–70% response rate was reported for MD with a diagnosed comorbidity including several anxiety disorders.[25] Recently, a multisite, randomized, noninferiority study observed iTBS may be effective for anxiety symptoms and depressive symptoms in MD.[26] The current research further found that both combination therapy and HF-rTMS monotherapy as an add-on therapy for depression improved anxiety in terms of decreased scores of HAMA-14. There are two possible explanations. First, anxiety and depression have the same neurobiological causes.[27] Second, the amygdala and DLPFC are related to threat attention and attention control, respectively, among mood regulation brain areas, and amygdala dysfunction is closely related to anxiety symptoms.[2829] The assumption is that reduced suppression of the amygdala caused by the incomplete arousal of prefrontal cortex (PFC) is a causative factor of anxiety.[29] We suppose rTMS treatment counteracts the reduced suppression of the amygdala and achieves therapeutic effects through upregulation/downregulation mechanisms.[29]

Our study has several limitations. First, we chose HF-rTMS as the control stimulation because it is recommended for definite efficacy for MD (Level A evidence).[30] We chose LF-rTMS and iTBS as mentioned above due to their great clinical application potential. Yet, the comparability between two groups is poor. Although the kinds of neuroplastic effects induced by TBS and rTMS are similar, there are some important differences. Future studies require further validation with sham controls and larger samples sizes. Second, the recommended duration of treatment is 4–6 weeks. Considering the acceptability of patients who were less treatment resistant in the real-world clinical settings, we adopted relatively short 2 weeks of treatment, whereas it may affect the treatment effect to some extent. Besides, we did not have adequate follow-up after treatment because of high dropout. Third, as a retrospective study, the fact that the patients were not randomized to a group, as would be the case in a clinical trial. The treatment effect may be confounded by other factors.

Nevertheless, the current findings suggest a more rigorous research to study the efficacy and acceptability of iTBS and LF-rTMS in the treatment of depression. We speculate boldly that rTMS therapy may be an effective treatment method for anxious depression according to the reports published so far. Future research is required to assess the effectiveness of rTMS treatment in potential subgroups that have characteristic symptoms and biological metrics. It is of great significance for guiding clinical application in choosing personalized and optimized targeted treatments for patients.

CONCLUSION

The pilot study showed that the combination of iTBS and LF-rTMS may hold promise as a potentially effective alternative therapy for MD. The preliminary results merit a prospective randomized trial to study the efficacy and acceptability of the combination of iTBS and LF-rTMS for depression.

Financial support and sponsorship

This study was funded by Public Welfare Fund of Zhejiang Province, China (No. LGF22G030010).

Conflicts of interest

There are no conflicts of interest.