Treatment of medication-resistant hallucinations with repetitive Transcranial Magnetic Stimulation.

Aim To develop an effective therapy for medication-resistant hallucinations in schizophrenia. Objective There is strong support that Repetitive Transcranial Magnetic Stimulation (rTMS) to the left temporal area can be an effective treatment for medication-resistant hallucinations (see systematic review). Presently, rTMS is not clinically used for this purpose. The effect of rTMS can probably be increased when it is applicated precisely over the cerebral area that is involved in hallucinations. When an activation map of hallucinations can be obtained with functional Magnetic Resonance Imaging (fMRI), this map can be used to guide the TMS probe to the skull area directly overlying the hallucination hotspot. When this method is used in clinical practice, it may reduce chronic invalidation of patients, reducing their healthcare and social costs. Design Hallucination-related activity will be located in 60 patients with fMRI. We aim to obtain adequate activation maps of 50% of the patients, since not all patients are expected to have discrete periods of hallucinations during the fMRI scan. In the patients from whom adequate fMRI scans will be obtained, the largest activated cerebral area on the activation map will be the focus for the rTMS treatment. Patients without an adequate activation map will undergo rTMS to the left temporo-parietal area. Patients of both groups will be randomly assigned to a treatment and a placebo condition, in a double blind fashion. Both groups will be treated for 20 minutes on 15 days. In the sham condition, a placebo-coil is used. Number of days of normal functioning, severity of hallucinations and of general psychiatric symptoms will be assessed at basline,during treatment and in a 6 months follow-up. Innovation Functional imaging studies have shown that hallucination-related activity is in approximately 50% of patients located predominately in the right hemisphere. These patients will not benefit from rTMS directed to the left temporal lobe, which is currently the standard for experimental rTMS treatment. Exact location of the hallucination activity with fMRI can pinpoint rTMS to the cortical area involved in hallucinations, thereby increasing the effectivity of the treatment. Parameters and analysis Primary outcome is the number of days the patients can maintain normal function, the secondary outcome is the severity of hallucinations and of general psychiatric symptoms. The effect of the fMRI-guided and the non guided treatment will first be compared to their placebo conditions. The relative effects of both treatments will then be compared in a General Linear Model analysis. Power calculation The mean score on the hallucination list at baseline is set at 15, sd 3, based on our earlier study. For the calculation of the sample size,  was set at 5%. The minimal effect of the experimental treatment to be of clinical significance was set at 25%. We estimated the placebo effect to be a 3% improvement. To obtain a power of 80%, the sample size should be at least 15 per group. Since the drop-out rate of the fMRI part is estimated to be 50%, 60 patients should be included. Economic evaluation The balance between costs and effects will be compared between the experimental and the sham treatments and between the fMRI-guided and the non-guided treatment conditions. Primary outcome measure, the number of days that patients function within the normal range, is measured by the outcomes on the PSYRATS and the SFS. Costs and consequences of the interventions will be assessed from a societal perspective during a period of 6 months. Time schedule September - November 2005: optimizing the scan paradigm, advertisement and presentations of the study for patients, psychiatrists and the patient?s association. December 2005 ? July 2006: inclusion of patients and fMRI scans of included patients, experimental treatment of patients, follow-up of treated patients. July 2007? September 2007: analysis and interpretation of the data, economical analysis, writing scientific manuscripts, reports for the patient?s associations and public press.