Schizophrenia verbal hallucinations usually have negative and abusive

           Schizophrenia is one of the severely disabling mental disorders. It has been ranked one among the 25 leading causes of disability across the world (1). Nearly 1.9% of Indian population were affected with severe mental disorders in their lifetime and 0.

8% were identified to be currently affected with schizophrenia and related psychoses as per NMHS 2016. It accounts for 1%the total DALYs (disability-adjusted life years) and 3% of YLDs (years lived with disability) across the globe (2).  As per DSM – V, the five key symptoms of schizophrenia include delusions, hallucinations, disorganized speech, disorganized behaviour and negative symptoms.          Around 60-80% of patients with schizophrenia suffer from auditory verbal hallucinations (AVH) (3). These auditory verbal hallucinations usually have negative and abusive content (4)(5). Many patients suffer from chronic AVH which impairs their quality of life and also increase the risk for violence and suicide (6) . Neuroimaging studies have demonstrated the link between AVH and altered connectivity in tempero-parietal areas, broca’s area, amygdala and hippocampus-insula complex(7).

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In 25% of sufferers, AVH doesn’t respond to anti-psychotic treatment(8). Alternative treatment options include cognitive behavioural therapy (CBT), non-invasive brain stimulation including repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Cognitive behavioural therapies are successful in addressing distress associated with AVH but they are not effective in reducing loudness and frequency of AVH  and recent meta-analysis has shown low effect size (9) (10).           rTMS is a form brain stimulation which uses rapidly fluctuating electrical fields to induce fluctuating magnetic fields. It is a non-invasive method and is relatively safe. When applied to the brain, the fluctuating magnetic field depolarizes the underlying neurons and long-term application has longer lasting effects on neurons.  In rTMS, if the frequency of pulses delivered is less than 1 hertz it is termed as low frequency rTMS (LF-rTMS) and if frequency of pulses delivered is more than 1 hertz it is termed as high frequency rTMS (HF-rTMS). High frequency protocols of rTMS are excitatory in nature and low frequency protocols are inhibitory in nature (11).

There have been various newer paradigms of rTMS overactive that have been developed over the past decade which alter the cortical excitability(12). Theta burst stimulation (TBS) is a newer paradigm which is delivered either as continuous train (cTBS) where it is inhibitory in nature or as intermittent train (iTBS) where it is stimulatory in nature (13). TBS stimulation alters the excitability of cortex by mediating lon- term depression (LTD) or long-term potentiation (LTP) effects (14) (15).

It also brings metaplasticity changes in the neurons (16).            Various neuro-imaging studies have demonstrated that during AVH, the areas of brain involved in speech production and perception are overactive (7,17,18). rTMS has been demonstrated as an effective therapy in treating AVH and has been used as add-on therapy. Most commonly LF-rTMS has been administered at left tempero-parietal junction (TPJ) or Wernicke’s  area (19).Recent studies have shown the modest efficacy of LF-rTMS for AVH(20).Thus the diminishing efficacy of LF-rTMS for AVH has led to prompt search of other site and stimulation parameters.  Stimulation of right TPJ has been found to be beneficial in subjects suffering from AVH with high emotional salience (21). As mentioned above, cTBS is a newer rTMS protocol that delivers 3 pulse bursts at 50 hertz on every 200 ms in an un-interrupted train.

This induces plastic changes in cortical synapses in a long term depression like fashion(22) (13). cTBS has comparatively fewer side effects than conventional rTMS. It is easier to administer as it takes shorter duration as compared to conventional rTMS and produces longer lasting effects. There have been limited number of studies that have tested cTBS as a treatment for treatment resistant AVH. Few open labelled studies and case reports have demonstrated efficacy of cTBS in AVH. A recent single blind RCT has shown no significant difference between LF-rTMS and cTBS in treating resistant AVH (23). Another recent sham controlled trial did not find any significant benefit from cTBS in resistant AVH (24).

Both of these studies had shorter duration of treatment and targeted only left TPJ. A recent sham controlled pilot study with longer treatment duration and bilateral TPJ inhibition  has shown significant benefit of cTBS (25). As there is lack of research in this area, studies designed with longer duration of treatment with cTBS with bilateral TPJ inhibition are warranted.           With above issues in the background, this study aimed at analysing the efficacy of a course of cTBS administered to bilateral TPJ in treatment resistant AVH. Secondarily, this study also aimed to evaluate the effect of this treatment on other symptoms of schizophrenia.