European Journal of Cardiovascular Medicine

Obsessive-compulsive disorder (OCD) is a debilitating condition that is estimated to impact 1% to 3% of people during their lifetime.¹ It is characterized by recurrent, unwanted thoughts (obsessions) and/or repetitive behaviours (compulsions) that are difficult to control. These symptoms can consume significant time and cause considerable distress, often interfering with daily activities and routines.

Disease burden and the associated significant distress demand effective treatment strategies to alleviate the symptoms. While the treatment options often involve a combination of Cognitive Behavioural Therapy (CBT), particularly techniques like Exposure and Response Prevention (ERP), alongside Selective Serotonin Reuptake Inhibitors (SSRIs), around 40% of patients fail to respond effectively.⁷⁰ Likewise, to effectively manage symptoms, SSRIs are often administered at higher doses and this increased dosage raises the likelihood of side effects, such as digestive issues and sexual dysfunction. This underscores the necessity for exploring and developing new treatment strategies. Transcranial magnetic stimulation (TMS) has recently emerged as a viable treatment option for individuals with OCD who do not respond to traditional therapies or experience only slight symptom relief. Over the past decade, TMS has transitioned from an experimental approach to a more widely accessible therapy accounting for the neurological basis of symptoms of OCD, which is supported by research studies that affirm its effectiveness.

Research involving repetitive transcranial magnetic stimulation (rTMS) aimed at different brain regions, such as the dorsolateral prefrontal cortex (dlPFC), dorsomedial prefrontal cortex (dmPFC), and orbitofrontal cortex (OFC), showed promising results in alleviating symptoms of OCD, but targeting deeper structures with small penetration power became a limitation. Introduction of deep transcranial magnetic stimulation (dTMS), which uses an H-shaped coil, proved effective as it penetrates depths of 3 to 5 cm to target midline areas like the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC), both of which are thought to exhibit increased activity in OCD. Further, the FDA approved protocol of use of deep TMS for treatment of OCD became a potent option but was found to be time consuming, each session lasting 20-30 min. The above challenges were addressed with the advent of a newer neuromodulation technique, theta-burst stimulation (TBS), which provided a way to administer larger doses of pulses in shorter sessions and also has demonstrable effects on brain activity that are comparable to, or even surpass, those of traditional rTMS. It can be applied in two ways: intermittently or continuously, and research indicates that intermittent theta burst stimulation (aiTBS) offers comparable efficacy to traditional methods but with significantly shorter session durations of just 3 to 10 minutes. Effectiveness of intermittent theta-burst stimulation (iTBS) in treatment of depression is well established and received FDA approval, but its efficacy is yet to be explored in treating symptoms of OCD.

A pilot study examined the effects of iTBS over the left dorsolateral prefrontal cortex (L-DLPFC) in ten individuals with treatment-resistant OCD, who were assessed over six months. It showed promising results where all showed symptom improvement after one month, with four maintaining benefits for up to three months.⁶⁷ Another randomized trial examined intensive orbitofrontal continuous Theta Burst Stimulation (iOFcTBS) in thirty-three (33) participants diagnosed with OCD who received either active cTBS or sham treatment twice daily for five days; the active cTBS group showed greater improvements in anxiety and symptom severity than the sham group, suggesting iOFcTBS as a potential OCD treatment.⁶⁸ With the knowledge of the above data from various studies, we found TBS to be quite effective in treating symptoms of OCD but its six-week treatment period can limit accessibility. This led to our need to explore accelerated TBS protocols which can potentially lead to quicker and more effective outcomes. Further, literature supporting aiTBS as a treatment option in OCD is scanty while it is a potential option. Hence, we tried to establish the efficacy of accelerated intermittent theta burst stimulation in alleviating symptoms of patients diagnosed with OCD who are receiving SSRIs concurrently.

REVIEW OF LITERATURE

Obsessive-compulsive disorder (OCD) is a debilitating condition that is estimated to impact 1% to 3% of people during their lifetime.¹ It features obsessions and compulsions that take up considerable time and result in significant distress and functional impairment.

Obsessions are defined as intrusive and recurrent thoughts, urges, or mental images that are difficult to manage and often cause significant distress. Compulsions, on the other hand, are repetitive behaviours or mental acts that individuals with OCD feel driven to perform to reduce the anxiety associated with their obsessions or to prevent a feared event from happening.² It presents as a clinically diverse condition.³ Typical obsessions and their corresponding compulsive behaviours include fears of contamination that result in excessive cleaning, concerns about safety that lead to repeated checking of protective measures, intrusive aggressive or sexual thoughts that are accompanied by mental rituals, and a preoccupation with symmetry that involves organizing or counting items.^3,4

Many adults with OCD experience distress due to the ego-dystonic nature of their obsessions and recognize that their compulsive behaviours are excessively irrational. In contrast, children often struggle to articulate their obsessions.^3,4

The understanding of OCD has changed considerably throughout history. Initially viewed in religious contexts as a moral failing or demonic possession, OCD was first medically documented by Esquirol. Freud later labeled the condition as obsessive neurosis, suggesting it stemmed from a regression during the anal stage of psychosexual development.

In the third edition of the Diagnostic and Statistical Manual (DSM-III), OCD was categorized with phobias under a single diagnosis. The DSM-IV subsequently reclassified it as an anxiety disorder. With the DSM-5, OCD has been included in the "Obsessive-Compulsive and Related Disorders" category, alongside other conditions like hoarding and body dysmorphic disorder. This reclassification reflects their shared features, including phenomenology, comorbidity, and common neurobiological mechanisms. In the fifth edition text revision of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5 TR), released by the American Psychiatric Association (APA) in 2022, OCD is categorized under obsessive-compulsive and related disorders. Diagnosing OCD involves a clinical evaluation to ascertain if the criteria outlined in the DSM-5 TR are fulfilled. These criteria require the presence of either obsessions or compulsions, with behaviours being time-consuming (lasting an hour or more each day) and significantly interfering with daily functioning.²

The subcategories included are as follows:

• OCD
• Body Dysmorphic Disorder (BDD)
• Hoarding Disorder
• Trichotillomania
• Excoriation (skin-picking) Disorder
• Substance- or medication-induced obsessive-compulsive and related disorder
• Obsessive-compulsive and related disorder due to another medical condition
• Other specified obsessive-compulsive and related disorder
• Unspecified obsessive-compulsive and related disorder

Epidemiology

With nearly a quarter of males showing symptoms before age 10, OCD often begins early in life, while females are more likely to experience onset during adolescence. The condition typically follows a chronic course and is most prevalent in individuals aged between 18 and 29.⁶ Women are approximately 1.6 times more likely than men to develop OCD, with lifetime prevalence rates of 1.5% in women and 1.0% in men. Women have heightened risk during the peripartum and postpartum periods, indicating that pregnancy and the postpartum period are associated with an elevated risk of developing or experiencing exacerbations of OCD symptoms, and incidence rates surpass those seen in nonpregnant women.⁷ The National Comorbidity Survey Replication (NCS-R) study identified contamination fears, symmetry obsessions, and intrusive thoughts involving aggression, harm, or taboo subjects as prevalent obsessions. Among these, contamination concerns were reported by around 25.7% of participants, while 57% experienced obsessions related to symmetry and order. Disturbing intrusive thoughts were present in approximately 30.2% of individuals. In terms of compulsive behaviors, checking rituals were the most frequently reported, affecting 79.3% of those diagnosed with OCD. Additionally, compulsive hoarding behaviors were noted in 62.3% of participants, and arranging items in a specific order to achieve a sense of perfection was common among 57% of individuals. These findings emphasize the varied and complex nature of OCD symptoms, highlighting the importance of personalized treatment strategies tailored to individual symptom profiles.⁵⁹

OCD commonly coexists with other mental health conditions, with approximately 70-90% of individuals meeting the criteria for at least one additional psychiatric disorder.⁸ Among adults with OCD, mood disorders such as major depressive disorder are particularly prevalent, while anxiety disorders, including generalized anxiety disorder and social anxiety disorder, are common across all age groups. In younger populations, neurodevelopmental conditions like ADHD and tic disorders are more frequently observed. Additionally, males with OCD tend to show higher rates of certain comorbidities, including tic disorders and ADHD.⁵⁸

Etiology

The causes of OCD are multifaceted, involving a range of factors such as cognitive, genetic, molecular, environmental, and neural influences. Twin studies indicate a notable genetic component, with an estimated heritability rate of around 48%.⁹

The SLC1A1 gene, which encodes the neuronal glutamate transporter EAAT3, has emerged as a potentially important candidate in the context of OCD.¹⁰

A study by the IOCDF Genetics Collaborative, encompassing individuals with OCD, Tourette's syndrome, and controls, examined copy number variations (CNVs) across these conditions. While no overall CNV burden was observed in either OCD or Tourette's syndrome, the research revealed a 3.3 times higher prevalence of large deletions on chromosome 16p13.1 in the OCD group, a chromosomal region previously linked to various neurodevelopmental disorders.¹¹

Neurobiology

Research suggests that OCD is fundamentally a network-based disorder, involving dysfunction in interconnected brain regions rather than isolated abnormalities. Many hypotheses have been proposed to understand the neuronal network based dysfunction.

The cortico-striato-thalamo-cortical (CSTC) loop is one of the crucial models for interpreting the pathophysiology of OCD. This loop consists of a network of interconnected circuits that enable the prefrontal cortex to interact with subcortical areas, such as the striatum and thalamus. It features two distinct pathways: the direct pathway, which promotes the initiation of behaviors, and the indirect pathway, which serves to inhibit or regulate these behaviors.¹² In OCD, there is a noted hyperactivity in the direct pathway compared to the indirect pathway. This imbalance may lead to the development of intrusive, repetitive thoughts and compulsive behaviors.^12,13 Studies also indicate disruption in the balance between the habit learning system and the goal-directed system leading to OCD symptoms. The habit learning system relies on past experiences regardless of previous rewards, which can contribute to inflexible behavior even when circumstances change. In contrast, the goal-directed system adapts habits based on evaluations of actions and their outcomes. A neurocomputational study revealed that individuals with OCD tend to make decisions primarily using model-free learning (associated with habits) instead of model-based learning (linked to executive control). This difficulty in adjusting future behavior based on immediate feedback suggests that habit formation is atypical in those with OCD. According to current theories, compulsive behaviors stem not from irrational thoughts but from an inability to manage goal-directed actions effectively, resulting in an increased reliance on habitual thinking.^12,13

The orbitofrontal and cingulate cortices, along with the caudate nucleus, play crucial roles in both habit learning and goal-directed control. The frontostriatal circuit, known as the CSTC loop, is crucial for habitual behaviors, and there is widespread agreement that dysfunction in these areas significantly contributes to OCD. Such dysfunction in the CSTC may disrupt the balance between goal-directed processes and habitual control, leading to an overdependence on the latter. Neuroimaging findings have linked these areas to OCD, revealing structural changes and alterations in brain activation and connectivity. The prevailing hypothesis suggests that hyperactivation or increased connectivity within the CSTC in OCD patients creates an uncontrolled feedback loop, triggering compulsive urges and reinforcing the habit of performing these compulsions, which perpetuates the cycle.^12,13

The CSTC heavily relies on glutamate, the primary neurotransmitter. Emerging theories, specifically the CSTC model of OCD, suggest glutamate's involvement in the development of obsessive-compulsive disorder.¹⁴ It is hypothesized that there is a deficit in glutamate levels in the anterior cingulate cortex, coupled with excessive glutamate activity in both the striatum and orbitofrontal cortex.¹⁵ Another explanation, connecting human OCD neuroimaging results with established basal ganglia models, suggests that overactivity within orbitofrontal-subcortical circuits resulting from an imbalance in activity between opposing basal ganglia pathways, particularly heightened direct pathway activity, is fundamental to the emergence of OCD symptoms.¹⁴ Research suggests that the pre-SMA is also implicated in OCD, particularly in the motor response inhibition deficits seen in individuals with OCD. Within the framework of Research Domain Criteria (RDoC), the pre-SMA plays a crucial role as a hub in the brain network governing action planning, selection, initiation, and termination. Consequently, the pre-SMA's function has implications for both impulsive and compulsive behaviors.¹⁶

Numerous studies demonstrate a robust association between OCD and elevated resting-state functional connectivity between the striatum and prefrontal areas, specifically the orbitofrontal cortex (OFC) and frontal pole.¹⁷ Moreover, the strength of this striato-prefrontal hyper-connectivity correlates directly with the intensity of OCD symptoms.¹⁸ One meta-analysis involving neuroimaging indicates heightened activity in the cingulo-opercular network when individuals with OCD perform tasks involving error processing. Furthermore, functional imaging research suggests that individuals with OCD exhibit elevated connectivity within orbito-striatal circuits at rest, a pattern that tends to resolve with successful treatment.^19-20

Additionally, OCD can be associated with other neurological disorders that affect the CSTC circuitry, such as Parkinson's disease, Sydenham chorea, traumatic brain injury, Tourette syndrome, Huntington's disease, and epilepsy.^21,22

In 1998, Swedo and colleagues suggested a possible link between some instances of childhood-onset OCD and an autoimmune reaction triggered by group A beta-hemolytic Streptococcus (GAS) infections, drawing a comparison to Sydenham's chorea. They termed this condition Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections, or PANDAS. Subsequent modifications to this hypothesis expanded the potential triggers to include pathogens other than GAS.²³

Treatment

OCD presents with distinct symptom dimensions that are linked to specific neurobiological mechanisms and can influence treatment outcomes. For instance, individuals with aggressive, sexual, or religious obsessions often experience heightened feelings of shame, which may delay seeking treatment. Research suggests these obsessions are associated with increased amygdala activity, a brain region involved in emotional regulation. Contamination fears and compulsive cleaning behaviors have been linked to hyperactivity in the CSTC circuits, particularly involving the orbitofrontal cortex and basal ganglia. Those with strong symmetry and ordering compulsions may exhibit dysfunctions in the parietal cortex, which is responsible for spatial organization.⁶⁰ Treatment responses can also vary across these dimensions. While cognitive-behavioral therapy (CBT), particularly Exposure and Response Prevention (ERP), is effective for most symptom types, individuals with aggressive or religious obsessions may initially hesitate to engage in therapy but can achieve outcomes comparable to other patients once treatment begins. Additionally, while SSRIs are commonly used in OCD treatment, individuals with intrusive obsessions may respond better to medication than CBT alone;⁶⁰ in another study, individuals with hoarding symptoms had a poorer response to SRIs.⁶² Understanding these symptom-specific patterns and their neurobiological underpinnings is vital for developing personalized treatment strategies that improve outcomes in OCD patients.

ERP therapy stands as the primary and most effective psychological treatment for OCD, showing substantial positive outcomes. The basis of ERP lies in understanding that troublesome, intrusive thoughts gain undue importance, leading to distress and maladaptive behaviours aimed at alleviating that distress. While intrusive thoughts are a common experience in OCD, these thoughts become obsessions when they are misinterpreted (for instance, believing that having a thought is the same as intending to act on it). This misinterpretation transforms a normal thought into something perceived as highly significant and threatening, resulting in obsessional distress. This distress, in turn, fuels compulsions or avoidance behaviours designed to lessen the anxiety and prevent the feared consequence. These compulsions and avoidance strategies reinforce the cycle by preventing the individual from learning that their fears are unlikely to materialize and that, even if they did, they could manage the situation effectively. ERP directly addresses this cycle by systematically and gradually exposing the individual to situations or thoughts that trigger distress, while simultaneously preventing them from engaging in their usual rituals or avoidance behaviours.^24,25

Pharmacotherapy

Well-designed randomized controlled trials have consistently demonstrated the effectiveness of both clomipramine and SSRIs such as fluoxetine, fluvoxamine, and sertraline, in treating OCD, showing significantly better outcomes compared to placebo. These findings have cemented their position as first-line pharmacological treatments for the disorder.^26-29 It has been suggested by multiple research teams that SRIs might alleviate OCD symptoms by reducing overactivity in orbitofrontal-subcortical circuits implicated in compulsive behaviors, potentially re-establishing equilibrium between direct and indirect frontal-cortical pathways.³⁰

For reasons such as their established effectiveness, safety profile, and how well they are generally tolerated, SSRIs are typically the preferred initial medication choice.³¹ Studies also indicated that larger doses of SSRIs correlated with better treatment outcomes, as measured by both the Y-BOCS score and the percentage of patients who responded positively to treatment.³² When choosing an SSRI for OCD, clinicians should consider factors such as previous responses to treatment, potential side effects, possible drug interactions, any existing medical issues, and the drug's price and accessibility. Although treatment guidelines advise an SSRI trial of 8 to 12 weeks to assess effectiveness, newer meta-analyses indicate that noticeable symptom improvement may occur within the first 2 weeks of SSRI therapy.^33,34

Neuromodulation

In an effort to address the biological underpinnings of the condition, medical professionals have explored brain-focused interventions. Initial approaches, such as prefrontal lobotomies and leukotomies, appeared to offer some symptom relief, but these procedures were associated with substantial adverse effects.³⁵ The advent of stereotactic surgery allowed for targeted procedures like cingulotomies and anterior capsulotomies, which demonstrated improved outcomes and reduced side effects. However, the development of increasingly effective medications with fewer adverse effects led to a decline in the popularity of surgical interventions.³⁶ Early studies using electroconvulsive therapy (ECT) for OCD yielded mixed results, with some demonstrating positive effects and others showing no change. Nevertheless, this research highlighted the potential of influencing brain neural networks through external stimulation.³⁷ Insights gained from both early surgical lesioning techniques and the application of electric fields to the brain, combined with a growing understanding of neurological abnormalities in OCD, paved the way for the development of more targeted neuromodulation approaches, such as TMS.³⁸ TMS is a non-invasive method of brain stimulation used to treat several neurological and psychiatric disorders. It is FDA-approved for conditions such as depression that hasn't responded to other treatments, anxiety related to depression, OCD that is resistant to treatment, smoking cessation, and migraine with aura.³⁹ The technique involves placing a coil on the head through which a short, powerful magnetic pulse is generated by sending electricity through the coil's wires. This magnetic field penetrates the scalp and skull, creating an electric field in the targeted area of the brain, which then depolarizes neurons. By repeating this process at different frequencies, TMS can modulate electrical activity in specific brain regions. Research exploring OCD has included numerous treatment trials. However, the studies published thus far have used markedly different approaches, likely due to the diverse theories regarding the condition's root causes. For TMS to be a successful therapy for OCD, targeting brain network activity, a solid understanding of the dysfunctional brain activity patterns driving OCD symptoms is essential.⁴⁰

While resting-state networks offer possible areas for TMS treatment in OCD, changes in brain network activity while performing certain tasks also reveal symptom-specific, state-dependent irregularities. Individuals with OCD exhibit greater task-related connectivity within a brain network that includes the anterior insula-frontal operculum and dorsal anterior cingulate cortex during cognitive tasks.⁴¹ Heightened activity in the anterior cingulate and mid-orbitofrontal cortices has been observed when individuals are exposed to stimuli that trigger obsessive thoughts. Given the varying patterns of brain activity seen in OCD patients performing different tasks, the context of TMS administration becomes crucial.⁴² Brain network activity is not fixed; it is constantly evolving based on internal and external factors. This dynamic nature of brain activity could account for some of the inconsistent results found in TMS clinical trials for OCD.⁴² When designing a symptom-directed TMS intervention, two crucial elements are: first, choosing whether to administer TMS while the patient is at rest or actively performing a mental task; and second, tailoring the intervention to target the most effective cortical area for that individual.^41-42 In 1997, a pilot study involving twelve participants diagnosed with OCD was conducted and repetitive TMS was administered to three different brain regions on separate days. The stimulation parameters included 80% of the motor threshold, a frequency of 20 Hz applied for 2 seconds per minute over a 20-minute period. The target regions were the right lateral prefrontal cortex, the left lateral prefrontal cortex, and the mid-occipital region, with the latter serving as a control. Following right LPC repetitive transcranial magnetic stimulation, compulsive urges showed a substantial decrease that lasted for 8 hours, while stimulation targeting the mid-occipital region resulted in only statistically insignificant increases in compulsive urges.⁴³

A double-blind, placebo-controlled study in 2001 investigated the effectiveness of rTMS targeting the right prefrontal cortex in individuals diagnosed with OCD. It found that low-frequency rTMS applied to the right prefrontal cortex did not significantly reduce OCD symptoms compared to a sham control.⁴⁴ In a study in 2005, ten daily sessions of low-frequency repetitive rTMS targeting the supplementary motor area (SMA) were administered to OCD and Tourette's Syndrome (TS) patients to investigate its potential to regulate overactive motor cortical areas and alleviate symptoms. The stimulation involved 1 Hz frequency, 100% of motor threshold, and 1200 stimuli per day. Initial indications of clinical benefits were observed within the first week of rTMS. Findings showed slow rTMS applied to the SMA can lead to substantial clinical improvement and a correction of right hemisphere hyperexcitability, ultimately re-establishing hemispheric symmetry in motor threshold.⁴⁵ A randomized, double-blind, sham-controlled trial done in 2006 investigated the effectiveness of rTMS in patients with OCD who had not responded to SRIs. The active rTMS protocol consisted of ten sessions of 1 Hz stimulation at 110% of the motor threshold (MT), applied to the left dorsolateral prefrontal cortex (DLPFC). They found no statistically significant difference in treatment outcomes between the two groups across any of the assessment measures.⁴⁶ In 2009, a study involving 23 right-handed inpatients with drug-resistant OCD treated them with low-frequency rTMS (1 Hz, 80% motor threshold) targeting the left orbitofrontal cortex (OFC) for 15 days. The active group received rTMS parallel to the scalp, while the sham group received it perpendicular to the scalp. OCD symptoms, mood, and anxiety were assessed at baseline, after treatment, and every 2 weeks for 3 months. Results showed a significant reduction in YBOCS scores for the active group compared to the sham group for up to 10 weeks post-treatment, though the effect diminished after 12 weeks. In conclusion, low-frequency rTMS to the left OFC led to a significant but time-limited improvement in OCD symptoms.⁴⁷ Another randomized, double-blind trial in 2010 with 21 participants evaluated the effectiveness of rTMS targeting the SMA in patients with treatment-resistant OCD. Those receiving active rTMS showed a response rate of 67%, compared to only 22% for the sham group after four weeks of treatment. The active treatment group experienced a 25% reduction in OCD symptoms on the YBOCS, while the sham group had a 12% reduction. Participants who underwent an extended eight-week treatment reported significant symptom improvement. The study also found that active rTMS led to increased motor threshold measurements and normalized abnormal hemispheric laterality in responders.⁴⁸

A study highlighting the hyperexcitability of motor and premotor cortices in individuals with OCD conducted the first randomized, double-blind clinical trial in 2012 to examine the effectiveness of rTMS in treating OCD, observing participants over a 3-month period. Twenty-two OCD patients were randomly assigned to receive either active or sham rTMS bilaterally to the supplementary motor area for two weeks. Results at the 14-week mark indicated a response rate of 41% (7 out of 12) in the active rTMS group, compared to a 10% (1 out of 10) response rate in the sham group. Furthermore, patients who received active rTMS experienced an average reduction of 35% on the Y-BOCS at 14 weeks, while those in the sham group showed a significantly smaller reduction of 6.2%.⁴⁹ A randomized, double-blind, crossover design in 2014 evaluated the potential of targeting the OFC with TMS as a treatment for OCD and found that both active and sham stimulation significantly reduced Y-BOCS scores, with active stimulation showing a greater reduction, though not statistically significant (P=0.07). PET scan data further revealed decreased OFC metabolism following active stimulation, reinforcing the OFC's role in OCD. The study also emphasized the potential advantage of a double-cone coil for improved and stronger clinical effects.⁵⁰ A randomized, double-blind, placebo-controlled clinical trial explored the effects of six weeks of low-frequency rTMS applied bilaterally and simultaneously over the sensory motor area in 22 patients with OCD who were randomly assigned to either the treatment group or the placebo group. The Y-BOCS was administered on day 1, and at weeks 2, 4, and 6 of treatment, as well as two and six weeks post-treatment. Results indicated patients in the active group experienced a significant reduction in Y-BOCS scores compared to their baseline measurements and this beneficial effect persisted for six weeks after the rTMS treatment ended, suggesting that rTMS may have a lasting impact on alleviating OCD symptoms in the treated individuals.⁵¹

 A study was conducted with 50 patients diagnosed with OCD who were unresponsive to SSRI treatments. The participants were randomly assigned to one of two groups: 25 patients received a three-week course of 1 Hz bilateral rTMS targeting the SMA, while the other 25 patients were treated with antipsychotic medications. Among patients in the rTMS group, 68% showed a response compared to 24% in the treatment-as-usual group. Furthermore, 17.6% of participants in the rTMS group achieved remission.⁵² In another study, a total of 40 patients with medication-resistant OCD were randomized to receive either active or sham rTMS targeting the presupplementary motor area, with neuronavigation guidance, over a four-week period. The findings indicate that low-frequency rTMS directed at the presupplementary motor area does not appear to be effective in treating severe, drug-resistant OCD, at least among the patients included in this study.⁵³ In a study, resting-state fMRI was employed to identify neural predictors and correlates of response to 20–30 sessions of bilateral 10 Hz dmPFC-rTMS in 20 treatment-resistant OCD patients, with 40 healthy controls serving as baseline comparators. Functional connectivity maps of the brain were generated pre- and post-treatment using a region of interest in the dmPFC. They found a reduction of fronto-striatal hyperconnectivity, which was linked to a positive response to dmPFC-rTMS in OCD patients. This aligned with previous fMRI studies on deep brain stimulation in OCD, hence predicting fMRI may prove valuable in assessing individual responses to dmPFC-rTMS in OCD.⁵⁴ A systematic review and meta-analysis examined 23 randomized controlled trials involving 960 participants to assess the effectiveness of TBS in treating depression. The study found that intermittent TBS (iTBS) over the left DLPFC and combined continuous TBS (cTBS) over the right DLPFC with iTBS over the left DLPFC showed improved response and remission rates compared to sham treatments. Both protocols demonstrated comparable safety and tolerability, with minimal adverse effects or treatment discontinuations. These findings highlight TBS as a promising and well-tolerated option for depression treatment.⁶⁴

A randomized controlled trial examined accelerated TBS as a treatment for TRD. Participants received either accelerated bilateral TBS at 80% or 120% RMT over 10 days, or standard 10 Hz rTMS over four weeks. The study found no significant differences in response or remission rates between the groups, with overall rates of 43.7% and 28.2%, respectively. These results suggest that accelerated TBS is a safe and effective alternative to traditional rTMS for TRD.⁶⁵ A meta-analysis of randomized controlled trials compared the efficacy and safety of TBS and rTMS in treating major depressive disorder (MDD). The analysis included nine studies with 1,124 patients, finding no significant differences between TBS and rTMS in response rates or adverse event rates. These results suggest that TBS is as effective and safe as standard rTMS for MDD treatment. Given TBS's shorter session durations, it may offer a more time-efficient alternative for patients.⁶⁶ A pilot study investigated the use of iTBS over the L-DLPFC in ten patients with OCD who had not responded adequately to conventional treatments. Participants received daily iTBS sessions, five days a week for one month, and were evaluated at multiple intervals up to six months post-treatment. The study found that all patients experienced symptom improvement up to one month after treatment, with four maintaining benefits up to three months. Notably, those with sustained improvement exhibited significant changes in frontal brain connectivity, which were electrophysiologically evaluated (EEG) by phase synchronization and coherence. These findings suggest that iTBS over the L-DLPFC may be a viable approach to alleviate OCD symptoms, particularly in patients demonstrating enhanced frontal connectivity modulation.⁶⁷

A randomized, placebo-controlled trial investigated the effectiveness of intensive orbitofrontal continuous Theta Burst Stimulation (iOFcTBS) for individuals with OCD. Thirty-three participants were divided into two groups: one received active cTBS (n=18) and the other a sham treatment (n=15). The intervention involved two sessions per day over five consecutive days. Researchers assessed participants using the Y-BOCS, HAM-D, HAM-A, and CGI-S scales at baseline, post-treatment, and two weeks later. Results showed that those in the active cTBS group experienced notable improvements in anxiety and overall symptom severity compared to the sham group, indicating that iOFcTBS may be a promising and well-tolerated treatment option for OCD.⁶⁸ A preliminary study explored the use of cTBS over the right pre-supplementary motor area (pre-SMA) as a potential treatment for individuals with moderate OCD. The study involved two phases: an initial trial with 50 inpatients and a follow-up validation involving 32 outpatients. Participants underwent either active cTBS or sham stimulation over five consecutive days, totaling ten sessions. Findings revealed a 56.52% response rate in the active cTBS group, which was significantly higher than the sham group. Notably, patients with moderate OCD showed greater improvement on the Y-BOCS compared to those with severe symptoms. The validation phase produced similar outcomes, with a 50% response rate and notable Y-BOCS reductions observed in moderate cases. These results highlight the potential of cTBS over the pre-SMA as an effective intervention for moderate OCD cases, emphasizing the role of symptom severity in treatment response.⁶⁹

AIM OF THE STUDY

To study the efficacy of accelerated intermittent theta burst stimulation (aiTBS) in patients diagnosed with obsessive compulsive disorder (OCD) receiving SSRIs.

Primary Objectives:

• To study the efficacy of accelerated intermittent theta burst stimulation (aiTBS) in patients diagnosed with obsessive compulsive disorder (OCD) receiving SSRIs.
• To compare the treatment outcomes in patients receiving aiTBS with those who are receiving sham iTBS.

Secondary Objectives:

To comment on the safety of the iTBS treatment in the subjects.

The patient's personal details like name, age, sex and address were used for identification. The importance of using the above details was clearly explained to patients and attenders before reporting. Confidentiality was thoroughly maintained throughout the conduct of this study.

Study Design:

Randomised double blind, sham controlled prospective study.

Study Area:

Outpatient and Inpatient Department of Asha Hospital.

Place of Study:

Asha Hospital, Hyderabad, Telangana.

Study Population:

The study participants included forty (40) patients diagnosed with OCD, all on standard pharmacotherapy for OCD, between April 2023 and April 2024.

Sample Size and Sampling Technique:

Forty (40) consenting patients, all diagnosed with OCD according to ICD-10 from Asha Hospital, were recruited for this study. Those patients who satisfied the inclusion criteria were divided into 2 groups by random, stratified sampling; the iTBS protocol was administered in ONE of the two groups. Group A received neuromodulation treatment by active aiTBS whereas Group B received sham aiTBS. The provider of iTBS treatment was not blinded but the assessing doctor and the patient were blinded. The rating scales were repeated at the end of the iTBS treatment on Day 6 and on the follow-up days at 1 month and 3 months.

Eligibility Criteria:

Inclusion Criteria:

1. Patients and their legally accepted relatives who provide consent to participate in the study
2. Diagnosis of OCD as per ICD-10
3. Patients who are on monotherapy with SSRIs for treatment of OCD
4. Y-BOCS >16-40
5. HAM-D >0-22
6. Age between 18-60 years, either gender

Exclusion Criteria:

1. Non-consenting patients or their relatives
2. Patients who are on >1 SSRI for the treatment of OCD
3. Patients with psychiatric conditions other than OCD
4. HAM-D >22 or with suicidal ideation
5. Patients who received ECT or any other neuromodulatory treatment in the last 6 months
6. Patients declared 'unfit' after screening for electromagnetic field compatibility
7. Patients with severe medical comorbidities

Ethics:

The study was carried out following approval from the Institutional Ethics Committee (IEC). Patients were given an information sheet detailing the illness and the study's purpose. Written, informed consent was obtained from all participants before the study began, and only those who agreed to participate were included.

Data Collection Techniques and Tools:

1. Socio-demographic and clinical data sheet: An initial profiling of the patients was done in a semi-structured format, based on socio-demographic details, disorder characteristics such as symptom profiling using the OCD symptom checklist, severity of presenting illness using Y-BOCS, HAM-A, HAM-D, total duration of illness, number of adequate medication trials done and their outcomes, outcomes of psychotherapy techniques, current treatment details and suitability to rTMS.

2. Diagnostic criteria defining the illness: The diagnosis was made using the ICD-10⁶¹ criteria.

3. Yale-Brown Obsessive Compulsive Scale (Y-BOCS):⁵⁵ The Y-BOCS is a test to assess the severity of OCD symptoms. Questions 1-5 are for obsessive thoughts, 6-10 for compulsive acts. If both obsessions and compulsions are present, the total score is interpreted as:

• 8-15: Mild OCD
• 16-23: Moderate OCD
• 24-31: Severe OCD
• 32-40: Extreme OCD

4. Hamilton Anxiety Rating Scale (HAM-A):⁵⁶ The HAM-A was one of the first rating scales developed to measure the severity of anxiety symptoms. The scale consists of 14 items, each defined by a series of symptoms, and measures both psychic anxiety (mental agitation and psychological distress) and somatic anxiety (physical complaints related to anxiety). Each item is scored on a scale of 0 (not present) to 4 (severe), with a total score range of 0-56, where:

• <17 indicates mild severity,
• 18-24 mild to moderate severity, and
• 25-30 moderate to severe.

5. Hamilton Depression Rating Scale (HAM-D):⁵⁷ The HAM-D scale is the most widely used, clinician-administered depression rating scale. The original version contains 17 items pertaining to symptoms of depression experienced over the past week. A later 21-item version included 4 items intended to subtype the depression. For the HAM-D 17-item version, a score of:

• 0-7: normal range (or clinical remission)
• 20 or higher: at least moderate severity

6. rTMS screening checklist: This includes a set of questions to determine the presence of ferromagnetic material in the vicinity of the head, history of seizure disorder, current seizure disorder, traumatic brain injury, etc., to assess the fitness of the patient to receive deep rTMS treatment.

7. rTMS side effect checklist: On a visual analog scale, this checklist enquires about side effects like headache, pain in the neck, discomfort in the neck, etc. after completion of each day of rTMS treatment.

Operational definitions of a typical treatment session:

Device used: Brainsway's deep TMS 104 system with H7 coil.

Target areas stimulated in the brain: Dorsomedial prefrontal cortex (dmPFC) and anterior cingulate cortex (ACC).

Stimulation intensity: 100% of Resting Motor Threshold (RMT).

Estimation of RMT: The subject will be comfortably seated in the treatment chair with the legs stretched and feet relaxed on a small table/chair. The subject will be asked to relax their feet and a single magnetic pulse will be delivered over the medial motor cortex. Starting from 50% of the maximal stimulator output, the RMT will be estimated using dose titration and visual inspection of the foot twitch on the right side. The increments or decrements in the stimulator output will be carried out at 5%. At least 3 out of 6 trials will be considered essential to find the RMT. RMT will be measured only on day 1.

Accelerated iTBS treatment: A 5 Hz-50 Hz iTBS stimulation will be given over the medial PFC and anterior cingulate cortex at 100% of resting motor threshold. 10 bursts, each composed of a set of 3 biphasic pulses with a frequency of 50 Hz, will be sent for 2 s duration at a train frequency of 5 Hz. The inter-train interval was 8 s. 40 trains were given, totalling 1200 pulses per session or 6000 pulses per day. The total duration of each session will be about 6 minutes. According to the accelerated iTBS protocol, 5 iTBS treatment sessions will be given per day, separated by a minimum of 1 hour. They will be repeated for 6 days, constituting a total of 30 treatment sessions.

The treatment will be administered by the deep rTMS operator, who will be blinded about the patient's initial YBOCS score and screening details but not blinded about giving active or sham treatment.

Final assessment of all patients will be repeated at the end of the 30 iTBS sessions (Day 6), and at Day 30 and Day 90 of follow-up. During the follow up, the patients will be advised to adhere to the medicines prescribed and follow the lifestyle advice, just to ensure uniformity in all patients.

Statistical Analysis

The data was entered in a spreadsheet and statistical analysis was performed using the Statistical Package for Social Sciences (SPSS) software. For categorical data, comparison of clinical variables across 2 groups was done using the chi-square test and Fisher exact test, with p value <0.05 considered statistically significant.

For continuous variables like Y-BOCS score at different days in cases and controls, Y-BOCS score difference at different days compared to day 1, and gender-wise response in Y-BOCS score, the independent t-test was applied and p-value <0.05 was considered significant. For measuring score reduction according to OCD theme, one-way ANOVA was applied. For measuring change in Y-BOCS score on different days and test of between-subject (cases/control) effect in Y-BOCS score, repeated measures ANOVA was used.

Table 1: Comparison of clinical variables across 2 groups

*t test used.  **Chi-square test used.  ***Fisher exact test used.  p value < 0.005 considered statistically significant (as stated in source).

A comparison of clinical variables between the cases (N=20) and control (N=19) groups was conducted.

1. The mean age of the cases was 30.7 ± 6.28 years, whereas the control group had a slightly higher mean age of 33.26 ± 10.1 years, with a p-value of 0.352, indicating no statistically significant difference.
2. Similarly, the total duration of illness did not show a significant difference between the two groups, with cases averaging 6.15 ± 3.96 years and controls averaging 6.89 ± 3.9 years (p = 0.558).
3. The mean age of onset was lower in the cases (19.95 ± 6.6 years) compared to controls (23.89 ± 6.7 years), though this difference was not statistically significant (p = 0.074).
4. Regarding gender distribution,
   • 60% of cases were male, while 47.4% of controls were male.
   • Conversely, 40% of cases and 52.6% of controls were female.

This distribution did not reveal a statistically significant difference (p = 0.527).

5. In terms of obsessive-compulsive (OC) themes,

• contamination was the most common theme, observed in 35% of cases and 36.8% of controls.
• Checking behaviors were present in 20% of cases and 10.5% of controls,
• while aggressive obsessions were reported in 10% of cases but absent in controls.
• Other themes included repeating rituals (10% in cases vs. 5.4% in controls), sexual obsessions (20% in cases vs. 10.5% in controls), and somatic obsessions (5% in cases vs. 36.8% in controls).
• These differences were not statistically significant (p = 0.139).

6. The presence of comorbid depression was similar in both groups, with 10% of cases and 10.5% of controls affected (p = 1.000).
7. Regarding medication use,

• escitalopram was the most commonly prescribed drug, used by 80% of cases and 84.2% of controls.
• Fluvoxamine was taken by 10% of cases but not used in the control group, while
• fluoxetine was prescribed to 5% of cases and 15.8% of controls.
• Clomipramine 150 mg was used by 5% of cases but not by any controls.

These differences in medication use were not statistically significant (p = 0.349).

Table 2: Day-wise Y-BOCS scores

p value < 0.05 considered statistically significant.

1. Y-BOCS was measured at 4 intervals during the study: Day 1, 6, 30, 90.
2. On Day 1 (baseline measurement) the Case group had a mean Y-BOCS score of 32.10 ± 1.77, while the Control group had a slightly lower mean score of 30.95 ± 3.79. There was no significant difference in Day 1 Y-BOCS scores between cases and controls (p = 0.228).
3. On Day 6 (early post-intervention assessment), the Case group mean score was 25.30 ± 2.61, while the Control group had a mean score of 26.74 ± 3.47. The mean difference was -1.43, with a p-value of 0.152, which suggests a reduction in symptom severity in the Case group, but this difference was not statistically significant.
4. On Day 30, the mean Y-BOCS score in the Case group declined to 19.70 ± 4.94, while the Control group had a mean score of 22.95 ± 4.68. The mean difference was -3.24, with a p-value of 0.042, indicating a statistically significant improvement in the Case group compared to the Control group.
5. By Day 90, the Y-BOCS score in the Case group dropped further to 17.55 ± 5.30, while the Control group had a mean score of 21.79 ± 5.01. The mean difference was -4.23, with a p-value of 0.015, demonstrating a statistically significant reduction in Y-BOCS scores in the Case group compared to the Control group.

In summary, the intervention in the form of accelerated TMS sessions was given for 6 days. There was a minimal difference between cases and controls immediately after the treatment, which was not statistically significant. The medical treatment continued to be the same throughout the study. On day 30, approximately 4 weeks after the treatment, the cases started showing better improvement as compared to the controls, which further improved at day 90.

Table 3: Difference in the Y-BOCS scores at different time intervals

The analysis of Y-BOCS score differences over time reveals a significant reduction in symptoms in both the case and control groups.

1. Between Day 1 and Day 6, the case group exhibited a mean score reduction of 6.8 ± 2.8, while the control group showed a smaller reduction of 4.2 ± 2.3. The mean difference of 2.58 was statistically significant (p = 0.004), suggesting that the intervention provided to the case group was more effective in the short term.
2. As the follow-up period extended to Day 30, both groups continued to improve, with the case group showing a reduction of 12.4 ± 5.4 compared to 8.0 ± 4.2 in the control group. The mean difference of 4.4 remained statistically significant (p = 0.008).
3. By Day 90, the case group demonstrated a substantial mean score reduction of 14.5 ± 5.6, compared to 9.1 ± 4.6 in the control group. The mean difference of 5.39 was highly significant (p = 0.002).

In summary, it is evident from Table 3 that the mean difference of Y-BOCS at different time intervals from the day 1 score has been consistently improving after the treatment. The 3-point difference between the cases and controls seen on Day 6 increased to about a 5-point difference on Day 90, which is highly significant.

Table 4: Change in Y-BOCS score on different days

*Repeated measures ANOVA used.

1. The study assessed changes in Y-BOCS (Yale-Brown Obsessive-Compulsive Scale) scores over four time points (Day 1, Day 6, Day 30 and Day 90) among 39 participants.
2. The mean Y-BOCS score at Day 1 was 31.5 ± 2.9, indicating the initial severity of obsessive-compulsive symptoms.
3. By Day 6, the score had decreased to 26.0 ± 3.1, suggesting early symptom improvement.
4. A further decline was observed at Day 30, with a mean score of 21.2 ± 5.0, reflecting continued progress.
5. By Day 90, the score reached 19.6 ± 5.5, demonstrating a sustained reduction in symptoms.

The analysis, conducted using repeated measures ANOVA, showed a statistically significant change over time (p < 0.001), confirming that the reduction in Y-BOCS scores was not due to chance.

These findings indicate that the treatment or intervention applied in the study led to significant and sustained improvement in obsessive-compulsive symptoms over the 90-day period.

Table 5: Test of within-subject effect

A repeated measures ANOVA was conducted to examine the effect of Y-BOCS score across different time points.

1. Results indicated a significant main effect of score, F(3, 111) = 138.54, p < .001, suggesting a strong effect.
2. Additionally, the interaction between time and category (cases vs. control) was also significant, F(3, 111) = 6.85, p < .001, indicating that the effect of score differed across cases and controls.

Table 6: Gender-wise responses in cases and controls

Coming to the gender-wise analysis of the difference in Y-BOCS scores on day 6, 30 and 90, the following observations could be made.

1. Men: The difference in Y-BOCS scores on Day 6 and 90 compared to Day 1 is more in Cases compared to controls, which is statistically significant with p value for Day 6 (0.0151) and Day 90 (0.0277). While the difference between Day 30 and Day 1 score is (0.0852), this difference is considered not quite statistically significant.
2. Women: The difference in Y-BOCS scores on Day 30 and 90 compared to Day 1 is more in Cases compared to controls, which is statistically significant with p value Day 30 (0.0323) and Day 90 (0.0395). While the difference between Day 6 and Day 1 score is (0.0821), this difference is considered not quite statistically significant.
3. Comparing the reductions in Y-BOCS scores across time intervals between men and women gave p values of Day 6 (0.2452), Day 30 (0.914) and Day 90 (0.7984), which are considered not statistically significant.

Table 7: Response to treatment based on type of obsession

Table 7 shows analysis of Y-BOCS score reduction across different OCD themes at various time points (Day 6, Day 30, and Day 90).

1. By Day 6, early symptom improvement was observed across all themes, with the

• aggressive theme showing the highest mean score reduction (9.0 ± 4.2), followed by
• repeating rituals (8.0 ± 5.6) and checking (7.5 ± 3.0), whereas
• contamination (5.7 ± 2.1) and somatic (4.0) themes exhibited the least reduction in scores.

2. By Day 30, further improvements were noted, with the

• aggressive theme again showing the highest reduction (17.00 ± 9.8), followed by repeating rituals (13.00 ± 1.4) and checking (12.2 ± 4.92), while other themes, including
• sexual (11.0 ± 7.3) and contamination (11.8 ± 5.3), also demonstrated notable reductions.

3. By Day 90, sustained symptom reduction was observed across all themes, with

• aggressive symptoms again showing the greatest reduction (19.0 ± 5.6), followed by checking (16.0 ± 3.6) and repeating rituals (15.5 ± 0.7), while
• contamination (12.8 ± 6.0) and sexual (14.0 ± 7.3) themes also continued to show improvement, while
• there was no further reduction of score in the somatic theme.

4. While all themes demonstrated symptom reduction over time, some themes showed greater improvements than others. However, the p-values at each time point (0.638 at Day 6, 0.908 at Day 30, and 0.828 at Day 90) indicate that the differences in score reductions among OCD themes were not statistically significant, suggesting that all themes responded similarly to the intervention.

In Figure 1, comparison of OC themes was done between cases and controls:

• Contamination compulsions were equally distributed between cases and controls, with 7 each in both study groups.
• Sexual obsessions were more in cases (n=4) compared to controls (n=2).
• Aggression obsessions were seen only in 2 cases.
• Checking compulsions were more in cases (n=4), while in controls they were 2.
• Repeating rituals were present in both cases (n=2) and controls (n=1).
• Somatic obsessions were more in controls (n=7) compared to cases (n=1).

Figure 1: Comparison of OC themes between Cases and Controls

In Figure 2, comparison of OC themes was done between Males and Females:

• Contamination compulsions were more in females (n=11), followed by checking compulsions (n=3) and somatic compulsions (n=3).
• Sexual compulsions were observed only in 1 female, while aggressive obsessions and repeating rituals were absent in females.
• Somatic obsessions (n=5) and sexual obsessions (n=5) were observed to be more in men.
• Contamination compulsions (n=3), checking compulsions (n=3) and repeating rituals (n=3) were present in equal occurrence in males.
• Aggressive obsessions were present only in male subjects, with an occurrence of n=2.

Figure 2: Comparison of OC themes between Males and Females

Table 8: Response based on reduction in Y-BOCS

Table 8 shows the treatment responders in both the groups on Day 6, 30 and 90, where:

• Response means >35% reduction in Y-BOCS scores from baseline [REF]
• Partial response means 25% to 34% reduction in Y-BOCS scores from baseline
• No response means <25% reduction in Y-BOCS scores from baseline
• Remission means <12 score on Y-BOCS scale

In Figure 3, while comparing outcome in the two study groups on Day 6, it was found that:

• Cases: 1 subject had response, 6 had partial response and 13 had no response.
• Controls: 3 subjects had partial response and 17 subjects had no response.
• No subject had remission.

Figure 3: Treatment outcome in Cases and Controls based on Y-BOCS scores on Day 6

In Figure 4, while comparing outcome in the two study groups on Day 30, it was found that:

• Cases: 14 subjects had response, 4 had partial response and 1 had no response.
• Controls: 5 subjects had response, 8 subjects had partial response, 6 subjects had no response.
• Remission: 4 cases and 1 control had remission.

Figure 4: Treatment outcome in Cases and Controls based on Y-BOCS scores on Day 30

In Figure 5, while comparing outcome in the two study groups on Day 90, it was found that:

• Cases: 14 subjects had response, 8 had partial response and 6 had no response.
• Controls: 5 had response, 8 subjects had partial response, 6 subjects had no response.
• Remission: 4 cases and 1 control had remission.

Figure 5: Treatment outcome in Cases and Controls based on Y-BOCS scores on Day 90

In Figure 6, while comparing treatment outcome in male cases on Day 6, 30, 90 (n=12):

• Day 6: 1 had response, 3 had partial response, 8 had no response and none had remission.
• Day 30: 7 had response, 2 had partial response, 3 had no response, 2 had remission.
• Day 90: 10 had response, 1 had partial response, 1 had no response, 2 had remission.

Figure 6: Treatment outcome in male cases based on Y-BOCS scores on Day 6, 30, 90

In Figure 7, while comparing treatment outcome in male controls on Day 6, 30, 90 (n=9):

• Day 6: 1 had partial response, 8 had no response and none had response or remission.
• Day 30: 1 had response, 4 had partial response, 4 had no response, 1 had remission.
• Day 90: 3 had response, 3 had partial response, 3 had no response, 1 had remission.

Figure 7: Treatment outcome in male controls based on Y-BOCS scores on Day 6, 30, 90

In Figure 8, while comparing treatment outcome in female cases on Day 6, 30, 90 (n=8):

• Day 6: 0 had response, 3 had partial response, 5 had no response and none had remission.
• Day 30: 4 had response, 3 had partial response, 1 had no response, 1 had remission.
• Day 90: 4 had response, 3 had partial response, 5 had no response, 2 had remission.

Figure 8: Treatment outcome in female cases based on Y-BOCS scores on Day 6, 30, 90

In Figure 9, while comparing treatment outcome in female controls on Day 6, 30, 90 (n=12):

• Day 6: 2 had partial response, 8 had no response and none had response or remission.
• Day 30: 1 had response, 5 had partial response, 4 had no response, none had remission.
• Day 90: 2 had response, 5 had partial response, 3 had no response, none had remission.

Figure 9: Treatment outcome in female controls based on Y-BOCS scores on Day 6, 30, 90

Of the 40 recruited subjects, 39 completed the study, with one dropout in the control group. Baseline characteristics were comparable between cases and controls, including age (30.7 ± 6.28 vs. 33.26 ± 10.1 years, p = 0.352), duration of illness (6.15 ± 3.96 vs. 6.89 ± 3.9 years, p = 0.558), age of onset (19.95 ± 6.6 vs. 23.89 ± 6.7 years, p = 0.074), gender distribution (p = 0.527), OC theme distribution (p = 0.139), comorbid depression (p = 1.000), and medication profile (p = 0.349). Baseline Y-BOCS scores were also comparable between groups (32.10 ± 1.77 in cases vs. 30.95 ± 3.79 in controls, p = 0.228). By Day 6, Y-BOCS scores reduced to 25.30 ± 2.61 in cases and 26.74 ± 3.47 in controls, but the between-group difference was not statistically significant (p = 0.152). Significant between-group differences emerged by Day 30, with scores of 19.70 ± 4.94 in cases versus 22.95 ± 4.68 in controls (p = 0.042), and persisted at Day 90, with scores of 17.55 ± 5.30 versus 21.79 ± 5.01 respectively (p = 0.015). Reduction from baseline was consistently greater in the active aiTBS group: Day 1–Day 6 reduction was 6.8 ± 2.8 in cases versus 4.2 ± 2.3 in controls (p = 0.004), Day 1–Day 30 reduction was 12.4 ± 5.4 versus 8.0 ± 4.2 (p = 0.008), and Day 1–Day 90 reduction was 14.5 ± 5.6 versus 9.1 ± 4.6 (p = 0.002). Repeated-measures ANOVA showed a significant overall reduction in Y-BOCS scores over time, from 31.5 ± 2.9 at baseline to 26.0 ± 3.1 at Day 6, 21.2 ± 5.0 at Day 30, and 19.6 ± 5.5 at Day 90 (p < 0.001), with a significant within-subject effect, F(3,111) = 138.54, p < 0.001, and a significant time-by-group interaction, F(3,111) = 6.85, p < 0.001. Treatment response, defined as >35% reduction in Y-BOCS score, was higher in cases than controls (70% vs. 26%), and remission, defined as Y-BOCS <12, was also higher in cases (20% vs. 5%).

Gender-wise analysis showed significant improvement among men at Day 6 (p = 0.0151) and Day 90 (p = 0.0277), and among women at Day 30 (p = 0.0323) and Day 90 (p = 0.0395), although male–female differences were not significant at any interval (Day 6 p = 0.2452, Day 30 p = 0.914, Day 90 p = 0.7984). Across OC themes, reductions were numerically greatest for aggressive, checking, and repeating-ritual symptoms, but differences across themes were not statistically significant at Day 6 (p = 0.638), Day 30 (p = 0.908), or Day 90 (p = 0.828). The intervention was well tolerated, with only one participant in the control group reporting dizziness, corresponding to a 2% side-effect rate.

Table 9: Key statistical findings

Table 10: Key statistical findings of the aiTBS trial

Note. Values are presented as mean ± SD or percentage where applicable. Y-BOCS, Yale-Brown Obsessive Compulsive Scale; aiTBS, accelerated intermittent theta burst stimulation; OC, obsessive-compulsive.

This study was a randomised double blind, sham controlled prospective study conducted at Asha Hospital, a private psychiatric and teaching facility in Hyderabad, involving both inpatient and outpatient departments.

The aim of the study was to establish the efficacy of accelerated intermittent theta burst stimulation (aiTBS) in patients diagnosed with obsessive compulsive disorder (OCD) receiving SSRIs and to compare the treatment outcomes in patients receiving aiTBS with those who were receiving sham iTBS.

1. Socio-Demographic variables

The study subjects were recruited from the outpatient and inpatient department of Asha Hospital by random, stratified sampling. The sample population was described based on socio-demographic details and disorder characteristics such as age, total duration of illness, age of onset, gender, obsessive compulsive (OC) themes, comorbid psychiatric conditions and choice of SSRI.

Total number of subjects recruited for the study was 40; 39 subjects completed the study with 1 drop out in controls, of whom 20 were cases and 19 were controls.

The mean age in Cases was 30 yrs and 33 yrs in controls, which was comparable between the 2 groups.

The age of onset of illness was early adulthood in both cases and controls, which aligns with the literature about the onset of illness. [REF]

Total duration of illness, on an average, in cases and controls is around 6 yrs, confirming the chronic course of the illness. [REF]

Men were slightly more in number (21) compared to women (18) in the study and the gender distribution was unequal in both the study groups. The higher prevalence of the disorder in women [REF] could not be established with the small sample size.

Coming to Obsessive-compulsive (OC) themes in the study subjects, contamination was found to be the most predominant theme in about 14 patients and was equally distributed in both the study groups. Other common themes were somatic obsessions, checking compulsions and sexual obsessions.

Depression was the only comorbid psychiatric disorder diagnosed in subjects and its prevalence was quite low, with only 4 out of 40 patients having the disorder. This could be because of the small sample size; the high prevalence of other comorbid disorders could not be established. [REF]

In pharmacotherapy, adhering to the inclusion criteria, only one Selective Serotonin Reuptake Inhibitor (SSRI) was used. Among the SSRIs used, escitalopram was the most commonly used in about 80% of the patients, indicating it as the preferred choice among SSRIs in treatment of OCD.⁷² Fluoxetine was the other SSRI which was commonly employed, and all of them were given at high doses as indicated in treatment of OCD. [REF]

2. Y-BOCS Scores

Y-BOCS scores were measured at 4 different time intervals, that is on Day 1, Day 6, Day 30 and Day 90.

Day 1 scores of the subjects were comparable in both cases and control groups and, based on the scores, they all belonged to the severe degree of severity of OCD. [REF]

A decrease in symptom severity was observed in cases and controls in terms of reduction in Y-BOCS scores by day 6, indicating the effectiveness of the intervention.

By day 30, there was a further decrease in scores on Y-BOCS but this time it was more in cases compared to controls, and this difference became greater by day 90.

This difference was further established by comparing the difference in Y-BOCS scores at the three time intervals between cases and controls, which was found to be extremely significant.

The initial improvement of symptoms immediately after the intervention, with sustained improvement over the three time intervals in cases more than controls, indicates efficacy of the treatment.

3. Gender-Based Responses

In both men and women, there was a reduction in symptom severity across different time intervals in all study groups.

We observed, based on reduction in Y-BOCS scores, that men responded better compared to controls immediately after the intervention. Further, the reduction of symptoms was consistent throughout the study.

Women showed reduction in scores more only after one month of intervention as compared to controls, which again was sustained for 90 days post intervention.

In spite of the above differences observed, both men and women responded equally to the intervention based on scores.

Among the OC themes, the contamination theme was predominant in women, while aggression obsessions and repeating rituals were absent in the women subjects.

Similarly, somatic obsessions and sexual obsessions were seen in men more than females, while aggression and repeating rituals themes were present only in men.

4. Obsessive-Compulsive (OC) Themes

Different themes responded differently to the intervention and the reduction in symptoms varied during the various time intervals; nevertheless, all themes had improvement in symptoms.

Aggressive obsessions showed the highest reduction in symptoms, followed by repeating rituals and checking compulsions, immediately after intervention and also throughout the follow up period.

At the same time, contamination compulsions and sexual obsessions had comparatively less improvement in symptoms with the intervention and throughout the follow up period.

The somatic theme was noticed to have the least improvement in symptoms with the intervention.

Based on the above results, when we compared OC themes between cases and controls, we found disparity in the distribution of the themes between the two groups, and in their response to intervention, and we found interesting results.

• In the contamination theme, cases and controls had equal distribution and we observed that 3 out of 7 cases had response and 1 case had remission, which was not found in controls, where only 1 had response.
• In the sexual theme, the distribution was unequal, with 4 in cases and 2 in controls, but the intervention had a significant effect, with 2 cases having response and one reaching remission.
• The aggression theme was found only in cases with no controls, and both the cases had response, with one of them reaching remission.
• Checking compulsions had response in the cases group and only partial response in the controls group.
• Repeating rituals had response and remission in cases compared to controls.
• Somatic compulsions had a significantly unequal distribution, with 90% of subjects in controls, leading to poor overall response to intervention.

5. Treatment Outcomes

We found a positive response across various time intervals in cases more than controls.

On day 6, response was observed in 1 case compared to none in controls, and partial response was also observed more in cases compared to controls, indicating early symptom recovery in cases.

This response became more profound by day 30, where more responders were observed in the cases group, with 4 subjects reaching remission in the treatment group.

By Day 90, we observed that more cases joined the responders group compared to the controls group, and the intervention had a sustained effect as the patients in remission on Day 30 remained in remission at the 3-month follow up too.

When the treatment outcomes were compared within men, we observed that men in cases responded much better than controls, with a 70% difference in subjects having treatment response.

In women, the response in cases was superior to controls, with a 50% difference in response rate in subjects having treatment response.

Furthermore, when the treatment response was compared between men and women, there was a 60% difference between the response in men and women among cases. Men responded significantly better than women.

Interestingly, men and women had similar remission rates among the cases, while men in controls had remission with none in women.

LIMITATIONS

• Our sample size was small, hence the generalizability of the results cannot be established.
• Employment of electrophysiological measures like error related negativity would have enhanced the understanding of the results.

STRENGTHS

• It is a pilot study using an accelerated iTBS intervention, unlike previous studies using either intermittent or continuous theta burst stimulation.
• It is a randomized double blind study, which decreases the interviewer bias and the chance factor in the presented results.
• Utilisation of tools establishes the reliability and validity of the results.

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