Liam Davenport

September 07, 2017

PARIS ― Applying precisely guided repetitive transient magnetic stimulation (rTMS) to areas of the brain associated with language may help silence auditory verbal hallucinations (AHV) in patients with schizophrenia, new research suggests.

Results of the first randomized controlled trial to test the technique show that targeting an area of the temporal lobe with high-frequency rTMS effectively reduced AHV compared with sham treatment.

Study investigator Sonia Dollfus, MD, PhD, Service de Psychiatrie, Caen University Hospital, France, said the results mean "we now can say with some certainty that we have found a specific anatomical area of the brain associated with auditory verbal hallucinations in schizophrenia.

"Secondly, we have shown that treatment with high-frequency TMS makes a difference to at least some sufferers, although there is a long way to go before we will know if TMS is the best route to treat these patients in the long term."

The findings were presented here at the 30th European College of Neuropsychopharmacology (ECNP) Congress.

Controversial Treatment

The use of low-frequency rTMS at temporoparietal targets for the treatment of AVH for patients with schizophrenia remains controversial. Despite extensive testing and promising results with both high-frequency and neuronavigated rTMS, no controlled studies have been conducted.

To further examine the efficacy of high-frequency rTMS, the researchers recruited 59 clinically stable patients with schizophrenia or schizoaffective disorder whose scores on the Auditory Hallucinations Rating Scale (AHRS) were greater than 10.

The patients were randomly assigned in a double-blind fashion to receive either 20-Hz high-frequency magnetic pulses for two 13-min sessions a day for 2 days (active group, n = 26) or a sham procedure (control group, n = 33).

The rTMS, totaling 10,400 delivered stimuli, was precisely guided under MRI, using neuronavigation software, to an area in the temporal lobe associated with language: the crossing of the projection of the ascending branch of the left lateral sulcus and the left superior temporal sulcus.

There were no significant differences in baseline characteristics between the two groups. The average age of patients in the active and sham groups was 35.3 years and 39.6 years, respectively; the mean age at onset of schizophrenia was 23.0 years for both groups.

The patients underwent follow-up assessments at days 1, 2, 7, 14, 21, and 28. At day 28, there was no significant difference in the proportion of patients who achieved a response to treatment, defined as an AHRS score of more than 30%, between the active and controls groups.

However, there was a significant difference in patients who responded to treatment at day 14: 34.6% of patients in the active treatment group achieved a >30% decrease in AHRS scores, vs 9.1% of those in the control group (P = .016).

The difference remained significant after taking into account the neuronavigation system used, the kind of TMS employed, and the university hospital center, yielding an odds ratio of a response at day 14 with active vs sham treatment of 5.29.

There was no significant difference in the proportion of patients who experienced a response at any other time point during follow-up.

No Major Adverse Events

Patients given active treatment experienced more adverse events than those in the control group, with significantly increased rates of squeezing, local pain, clenched jaw, and blepharospasm. However, there were no major adverse events reported in either group.

The team says that their findings "confirm the value of high-frequency rTMS applied to the left temporal cortex for the treatment of AHVs." However, they note that the effect is transient, and they call for additional clinical trials and measures to improve its efficacy and durability.

Dr Dollfus told Medscape Medical News that the effect of rTMS on AVH can last from 1 week to 6 months, depending on the patient. In the current study, if a transient effect lasted 14 days after treatment, the treatment would need to be repeated every 14 days.

Dr Dollfus also underscored the fact that the treatment was very well accepted by the patients.

"When the patient improves, he is very happy and asks for other sessions and other treatments," she said, adding: "We have some patients, for example, who come into the department frequently to have sessions once a month or once every 2 months; it depends on the patient and their response."

Dr Dollfus also believes that the treatment could be easily adopted by other hospitals. She noted that the TMS machine "is not very expensive...and you can use the machine for other indications, for example, to treat depression, so it could be very interesting for psychiatric departments. What is more expensive is neuronavigation...and you need to have MRI, so this is more costly," she said.

For the future, Dr Dollfus wants to investigate whether remission can be maintained through regular rTMS sessions. "I also think it's important to use TMS in other indications in schizophrenia, in particular in negative symptoms. Probably, if you use this treatment in negative symptoms, you have to stimulate other parts of the brain. We need much more research in this domain. We don't know enough about how it works, which indications are the best, and so on."

Andreas Meyer-Lindenberg, MD, PhD, director, Central Institute of Mental Health, Mannheim, Germany, commented in the statement that the study "builds on previous studies that have shown a critical role of excessive activity of subregions of the temporal lobe in the generation of voice hallucinations in schizophrenia.

"To move this into treatment, controlled trials such as the one by Dollfus and coworkers are important. While response rates were moderate, TMS is a welcome addition to the therapeutic repertoire, especially for patients who do not respond to medication," he said.

The research was funded by the French Health Ministry (PHRC) and the regional council (Basse Normandie). No relevant financial relationships have been disclosed.

30th European College of Neuropsychopharmacology (ECNP) Congress. Poster P.3.d.044, presented September 5, 2017.

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