Boost rTMS for Auditory Verbal Hallucinations

This is a randomized, placebo controlled, double-blind clinical trial. The investigators aim to examine the safety and efficacy of repeated transcranial magnetic stimulation (rTMS) for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia who are not taking antipsychotic medication. The investigators employ a novel, accelerated protocol with only four sessions of low-frequency rTMS in one day. The effects of this accelerated protocol will be compared to the sham stimulation. Additionally, the investigators will examine the effects of rTMS on a neurophysiological level by evaluating mechanism of action in the temporo-parietal lobe by means of functional magnetic resonance imaging.

Auditory verbal hallucinations affect up to 70% of schizophrenia patients (Waters, 2012), yet, even extended antipsychotic medication does not ameliorate AVH in 20-30% of patients (Sukhwinder S Shergill et al., 2007) and is often accompanied by side effects (Leucht et al., 2009). Therefore, it is crucial to develop and assess promising potentially beneficial therapeutic options.

Non-invasive brain stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) have been proposed to disrupt mechanisms in question. A number of meta-analyses (Aleman, Sommer, \& Kahn, 2007; Demeulemeester et al., 2012; Freitas, Fregni, \& Pascual-Leone, 2009; C. W. Slotema, Blom, van Lutterveld, Hoek, \& Sommer, 2014; C. W. Slotema, Dirk Blom, Hoek, \& Sommer, 2010; Tranulis, Sepehry, Galinowski, \& Stip, 2008) found significant effect sizes ranging from 0.42 to 1.04 for 1Hz rTMS over the left temporo-parietal junction for the treatment of AVH. However, the majority of studies so far investigated the effects of rTMS in treatment resistant schizophrenia patients as an ad-on or second-line treatment.

No study to date has explored the effects of rTMS either as a first-line treatment or in the initial stage of the illness. This is surprising, considering the fact that rTMS is a safe treatment with minimal side-effects (Rossi, Hallett, Rossini, \& Pascual-Leone, 2009) that could be used already in the earlier phase of treatment. This stands in considerable contrast to the range of side-effects associated with antipsychotics (Leucht et al., 2017) that can be disabling for patients and lead to lower quality of life.

Therefore, the crucial next step is (1) to explore the effects of rTMS in medication-free patients from the whole schizophrenia spectrum and (2) to use an accelerated protocol of multiple rTMS-sessions within a short period of time. To make this assessment feasible, considering that patients have to be off medication, the safest and also most efficient way is an accelerated rTMS protocol. The great advantage of such an approach is that the effects of rTMS can be investigated independently of potentially influencing effects of antipsychotics and at the same time assess the efficacy of rTMS within a very short amount of time.

In the proposed study, the investigators aim to determine the efficacy of rTMS as a potential treatment for AVH in schizophrenia and thus reduce suffering in patients and their relatives.

Eligibility Criteria:
Inclusion Criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged 18 to 65
4. Diagnosed with Diagnostic and Statistical Manual (DSM) V diagnosis of schizophrenia (295.90), schizoaffective disorder (295.70), or brief psychotic disorder (298.80), prone to AVH in the acute phases of the disorder
5. Willing to adhere to the rTMS regimen
6. No antipsychotic medication in the last two weeks prior to the start of the study as well as no antipsychotic medication during participation in the study
7. Agreement to adhere to Lifestyle Considerations throughout study duration

Exclusion Criteria:

1. Current use of antipsychotic medication within the last 2 weeks
2. Electroconvulsive therapy or rTMS within three months (see the TMS screening questionnaire)
3. History of seizures
4. Presence of implanted electronic device or metal implant in the head and neck region (DBS, cochlear implant, etc.)
5. Pregnancy, as assessed with a pregnancy test prior to every MRI measurement, or lactation
6. Any active general medical condition or central nervous system disease which can affect cognition or response to treatment
7. Treatment with another investigational drug or other intervention within 2 weeks
8. Current diagnosis of delirium, dementia, or amnestic amnesiac disorder; Diagnosis of mental retardation; Current (within the past three months) diagnosis of active substance dependence, or active substance abuse within the past week as indicated by self-report.
9. Patients who are cognitively impaired and are thus not able to give informed consent