Clinical trial NCT00308997: Transcranial Magnetic Stimulation for "Voices"
Official title: Transcranial Magnetic Stimulation Guided by Neuroimaging for Patients With Persistent "Voices"
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Schizophrenia
Hallucinations
Keywords: Auditory Hallucinations
Schizophrenia
Schizoaffective Disorder
Repetitive Transcranial Magnetic Stimulation
Wernicke's Area
Superior Temporal Gyrus
Lead sponsor: Yale University
Sponsor class: OTHER
Collaborators: name: National Institute of Mental Health (NIMH)
First posted: 2006-03-30
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will determine the efficacy of MRI-guided transcranial magnetic stimulation (TMS)in reducing "voices" and other symptoms experienced by people with schizophrenia and schizoaffective disorder. In addition, the study will determine duration of improvement obtained during the course of trial participation via on-going monthly contact with study participants for up to 1 year after the trial.

Detailed description: Schizophrenia is a severely disabling brain disorder that affects about 1% of the United States population. Approximately 50 to 80% of people with schizophrenia experience "voices," also known as auditory hallucinations. These hallucinations consist of spoken speech, which sometimes replicates the speaking voice of a familiar person, and sometimes reflects a speaking voice that is not known but becomes highly recognizable. The phrases and sentences expressed by "voices" are often highly disruptive, and may comment, cajole, criticize, and, in some cases, command the patient. They are often but not invariably distressing, and can disrupt one's ability to interact with others, work, study, and sleep. In about 25% of cases, medication treatment is either completely ineffective or only partially effective in relieving "voices." Effective treatment alternatives are needed to improve this troubling and often disabling symptom.

Recent studies have suggested that auditory hallucinations arise from parts of the brain that are ordinarily involved in perceiving actual spoken speech. Low frequency repetitive transcranial magnetic stimulation (rTMS), a technique that uses an electromagnet to induce reductions in cortical brain activity, may therefore be effective in quieting auditory hallucinations. The potential usefulness of this approach has been demonstrated by previous studies conducted at our medical center. This new study uses magnetic resonance imaging (MRI) to locate two areas of the brain involved in speech perception. These areas are in Wernicke's area in the left superior temporal gyrus, and in the right hemisphere in an analogous site in the superior temporal gyrus. Repetitive TMS is specifically positioned to reduce cortical excitability or reactivity at these two brain regions.

Participants in this double blind study will be randomly assigned to receive either real rTMS, or placebo stimulation, which feels similar to real rTMS but does not produce direct brain effects. Depending on group assignment, participation may last 4 to 8 weeks. Over the first 2 weeks, all participants will undergo two sequences of rTMS, each consisting of five 16-minute sessions. One sequence is directed to left Wernicke's area and the other sequence is directed to the right-sided equivalent area. During the third week, participants will receive five additional sessions to the left or right site that appeared to produce greater clinical improvement. All participants will then be informed as to whether they received real or placebo stimulation. Participants who received real stimulation will be offered 5 additional stimulation sessions at the brain site that achieved the best response. Participants who received placebo stimulation will be offered real stimulation for up to twenty sessions over 4 weeks using the same schedule described above. Assessments of severity of hallucinations and other clinical symptoms will be conducted after every fifth rTMS session by a clinician who does not know whether the participant is receiving real or placebo stimulation.

Neuropsychological testing will also be done before, during, and after the trial. Our previous trial demonstrated some improvement in verbal processing with no significant impairments in terms of memory, language or cognitive function. However, insofar as this trial involves a greater total "dose" of rTMS, careful monitoring of these functions is conducted throughout the trial.

In addition, the study will determine the degree to which improvement obtained during the course of trial is sustained over the ensuing months. This is accomplished via on-going monthly contact with study participants for up to 1 year after the last rTMS stimulation session.

Eligibility criteria: Inclusion Criteria:

* Auditory hallucinations that occur at least five times per day, on average
* Diagnosis of schizophrenia or schizoaffective disorder

Exclusion Criteria:

* Pregnant
* History of seizure that is not drug-induced or secondary to alcohol withdrawal
* Drug or alcohol abuse within 6 weeks of study entry (prior history of drug or alcohol abuse is not an exclusion)
* Changes in antipsychotic drug dosages within 4 weeks of study entry (patients do not need to be on antipsychotic medication to be included)
* Current significant untreated or unstable medical illness (e.g., poorly controlled diabetes mellitus, severe hypertension, unstable cardiac arrhythmia)
* Inability to understand the nature of the study due to severe psychotic disorganization, mental retardation, etc.
* Significant neurological condition (e.g., traumatic brain injury, multiple sclerosis)
* Factors that would preclude an MRI scan (e.g., severe obesity, claustrophobia, certain surgical implants with metallic components, metal shavings in the eye acquired while working as machinist)
* Cardiac pacemaker

Primary outcomes:
measure: Hallucination Change Score - Right (HCS-right)
timeFrame: After 5 sessions of rTMS
measure: Hallucination Change Score - Left (HCS-left)
timeFrame: After 5 sessions of rTMS
measure: Hallucination Change Score (HCS)
timeFrame: After 15 sessions of rTMS
Secondary outcomes:
measure: Change in Hallucination Frequency
timeFrame: After 15 sessions of rTMS
measure: Change in Total Auditory Hall Rating Scale (AHRS) Score
timeFrame: After 15 sessions of rTMS
measure: Clinical Global Improvement (CGI)Improvement
timeFrame: After 15 sessions of rTMS
Other outcomes:
Locations:
city: New Haven
country: United States
facility: Yale Psychiatric Research
state: Connecticut
Study officials:
affiliation: Yale University School of Medicine, Department of Psychiatry
name: Ralph E. Hoffman, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Hoffman RE, Gueorguieva R, Hawkins KA, Varanko M, Boutros NN, Wu YT, Carroll K, Krystal JH. Temporoparietal transcranial magnetic stimulation for auditory hallucinations: safety, efficacy and moderators in a fifty patient sample. Biol Psychiatry. 2005 Jul 15;58(2):97-104. doi: 10.1016/j.biopsych.2005.03.041.
citation: Hoffman RE, Boutros NN, Hu S, Berman RM, Krystal JH, Charney DS. Transcranial magnetic stimulation and auditory hallucinations in schizophrenia. Lancet. 2000 Mar 25;355(9209):1073-5. doi: 10.1016/S0140-6736(00)02043-2.
citation: Hoffman RE, Cavus I. Slow transcranial magnetic stimulation, long-term depotentiation, and brain hyperexcitability disorders. Am J Psychiatry. 2002 Jul;159(7):1093-102. doi: 10.1176/appi.ajp.159.7.1093.
citation: Poulet E, Brunelin J, Bediou B, Bation R, Forgeard L, Dalery J, d'Amato T, Saoud M. Slow transcranial magnetic stimulation can rapidly reduce resistant auditory hallucinations in schizophrenia. Biol Psychiatry. 2005 Jan 15;57(2):188-91. doi: 10.1016/j.biopsych.2004.10.007.
citation: Chibbaro G, Daniele M, Alagona G, Di Pasquale C, Cannavo M, Rapisarda V, Bella R, Pennisi G. Repetitive transcranial magnetic stimulation in schizophrenic patients reporting auditory hallucinations. Neurosci Lett. 2005 Jul 22-29;383(1-2):54-7. doi: 10.1016/j.neulet.2005.03.052. Epub 2005 Apr 15.
citation: Fitzgerald PB, Benitez J, Daskalakis JZ, Brown TL, Marston NA, de Castella A, Kulkarni J. A double-blind sham-controlled trial of repetitive transcranial magnetic stimulation in the treatment of refractory auditory hallucinations. J Clin Psychopharmacol. 2005 Aug;25(4):358-62. doi: 10.1097/01.jcp.0000168487.22140.7f.
citation: Hoffman RE, Hampson M, Wu K, Anderson AW, Gore JC, Buchanan RJ, Constable RT, Hawkins KA, Sahay N, Krystal JH. Probing the pathophysiology of auditory/verbal hallucinations by combining functional magnetic resonance imaging and transcranial magnetic stimulation. Cereb Cortex. 2007 Nov;17(11):2733-43. doi: 10.1093/cercor/bhl183. Epub 2007 Feb 13.
citation: Hoffman RE, Wu K, Pittman B, Cahill JD, Hawkins KA, Fernandez T, Hannestad J. Transcranial magnetic stimulation of Wernicke's and Right homologous sites to curtail "voices": a randomized trial. Biol Psychiatry. 2013 May 15;73(10):1008-14. doi: 10.1016/j.biopsych.2013.01.016. Epub 2013 Feb 26.