Hallucinations, Schizophrenia
Conditions
Keywords
Auditory Hallucinations, Schizophrenia, Schizoaffective Disorder, Repetitive Transcranial Magnetic Stimulation, Wernicke's Area, Superior Temporal Gyrus
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.
Interventions
DEVICE1-hertz Repetitive Transcranial Magnetic Stimulation
Sham stimulation given to Wernicke's area or a right homologous area for 16 minutes per day x 5 days for week I, the same for week II with switch from right to left or left to right, and 5 more stimulation sessions (16 minutes per session) to the side producing greater benefit for week III.
DEVICEActive 1-Hertz Repetitive transcranial magnetic stimulation
Active stimulation given to Wernicke's area or a right homologous area for 16 minutes per day x 5 days for week I, the same for week II with switch from right to left or left to right, and 5 more stimulation sessions (16 minutes per session) to the side producing greater benefit for week III.
Sponsors
National Institute of Mental Health (NIMH)
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hallucination Change Score - Right (HCS-right) | After 5 sessions of rTMS | HCS score for participants assessed after 5 sessions, 16 minutes per session, who received either rTMS or sham stimulation delivered to the right superior temporal gyrus. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement |
| Hallucination Change Score - Left (HCS-left) | After 5 sessions of rTMS | HCS score for participants assessed after 5 sessions, 16 minutes per session, who received either rTMS or sham stimulation delivered to the left superior temporal gyrus. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement |
| Hallucination Change Score (HCS) | After 15 sessions of rTMS | HCS score assessed after 15 sessions, 16 minutes per session, delivered to both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation. For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Hallucination Frequency | After 15 sessions of rTMS | AHRS frequency scale score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The hallucination frequency range is from 0-9. The scores reported are difference scores, and an improvement is a higher score. Hallucination frequency is one of the variables incorporated into the AHRS (Auditory Hallucinations Rating Scale). The score is measured as change relative to baseline (i.e., baseline minus endpoint). Larger (positive) scores correspond to greater improvement. |
| Change in Total Auditory Hall Rating Scale (AHRS) Score | After 15 sessions of rTMS | Total AHRS score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The score range is from 0-42. This is reported as a difference score and a higher score is an improvement. Total AHRS score is measured as change relative baseline (i.e., baseline minus endpoint). Larger (positive) scores correspond to greater improvement. |
| Clinical Global Improvement (CGI)Improvement | After 15 sessions of rTMS | CGI score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The range for this score is from 1 to 7. Lower scores correspond to greater improvement |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Arm Active 1-hertz Repetitive Transcranial Magnetic Stimulation to Wernicke's area and right homologous area
Active 1-Hertz Repetitive transcranial magnetic stimulation : Active stimulation given to Wernicke's area or a right homologous area for 16 minutes per day x 5 days for week I, the same for week II with switch from right to left or left to right, and 5 more stimulation sessions (16 minutes per session) to the side producing greater benefit for week III. | 55 |
| Placebo Arm sham rTMS to Wernicke's area and a right homologous area
1-hertz Repetitive Transcranial Magnetic Stimulation : Sham stimulation given to Wernicke's area or a right homologous area for 16 minutes per day x 5 days for week I, the same for week II with switch from right to left or left to right, and 5 more stimulation sessions (16 minutes per session) to the side producing greater benefit for week III. | 28 |
| Total | 83 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Subject feigned clinical data | 0 | 1 |
| Overall Study | Unable to tolerate intervention | 1 | 0 |
Baseline characteristics
| Characteristic | Active Arm | Placebo Arm | Total |
|---|---|---|---|
| Age, Continuous | 36.7 years STANDARD_DEVIATION 11 | 34.0 years STANDARD_DEVIATION 10 | 35.8 years STANDARD_DEVIATION 10.7 |
| Sex: Female, Male Female | 29 Participants | 15 Participants | 44 Participants |
| Sex: Female, Male Male | 26 Participants | 13 Participants | 39 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 30 / 55 | 5 / 28 |
| serious Total, serious adverse events | 0 / 55 | 0 / 28 |
Outcome results
Primary
Hallucination Change Score (HCS)
HCS score assessed after 15 sessions, 16 minutes per session, delivered to both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation. For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement
Time frame: After 15 sessions of rTMS
Population: Subjects who did not complete the intervention were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Hallucination Change Score (HCS) | 6.45 units on a scale | Standard Deviation 3.42 |
| Placebo Arm | Hallucination Change Score (HCS) | 7.51 units on a scale | Standard Deviation 2.26 |
Primary
Hallucination Change Score - Left (HCS-left)
HCS score for participants assessed after 5 sessions, 16 minutes per session, who received either rTMS or sham stimulation delivered to the left superior temporal gyrus. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement
Time frame: After 5 sessions of rTMS
Population: Subjects who did not complete the intervention were not included in the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Hallucination Change Score - Left (HCS-left) | 8.65 units on a scale | Standard Deviation 2.74 |
| Placebo Arm | Hallucination Change Score - Left (HCS-left) | 8.50 units on a scale | Standard Deviation 1.59 |
Primary
Hallucination Change Score - Right (HCS-right)
HCS score for participants assessed after 5 sessions, 16 minutes per session, who received either rTMS or sham stimulation delivered to the right superior temporal gyrus. HCS was anchored at 0 (corresponding to no AVHs), 10 (no change in hallucination severity) and 20 (AVHs twice as severe as baseline). Lower scores correspond to greater improvement
Time frame: After 5 sessions of rTMS
Population: Subjects who did not complete the intervention were not analyzed
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Hallucination Change Score - Right (HCS-right) | 7.78 units on a scale | Standard Deviation 2.68 |
| Placebo Arm | Hallucination Change Score - Right (HCS-right) | 9.30 units on a scale | Standard Deviation 1.47 |
Secondary
Change in Hallucination Frequency
AHRS frequency scale score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The hallucination frequency range is from 0-9. The scores reported are difference scores, and an improvement is a higher score. Hallucination frequency is one of the variables incorporated into the AHRS (Auditory Hallucinations Rating Scale). The score is measured as change relative to baseline (i.e., baseline minus endpoint). Larger (positive) scores correspond to greater improvement.
Time frame: After 15 sessions of rTMS
Population: Subjects who did not complete the intervention were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Change in Hallucination Frequency | 1.31 units on a scale | Standard Deviation 1.57 |
| Placebo Arm | Change in Hallucination Frequency | 0.30 units on a scale | Standard Deviation 1.61 |
Secondary
Change in Total Auditory Hall Rating Scale (AHRS) Score
Total AHRS score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The score range is from 0-42. This is reported as a difference score and a higher score is an improvement. Total AHRS score is measured as change relative baseline (i.e., baseline minus endpoint). Larger (positive) scores correspond to greater improvement.
Time frame: After 15 sessions of rTMS
Population: Subjects who did not complete the intervention were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Change in Total Auditory Hall Rating Scale (AHRS) Score | 4.48 units on a scale | Standard Deviation 6.9 |
| Placebo Arm | Change in Total Auditory Hall Rating Scale (AHRS) Score | 3.0 units on a scale | Standard Deviation 6.21 |
Secondary
Clinical Global Improvement (CGI)Improvement
CGI score assessed after 15 sessions, 16 minutes per session, of both right superior temporal and left superior temporal gyrus sites using either rTMS or sham stimulation (3 weeks). For patients dropping out of the trial prematurely, last-observation-carried-forward data were used for this outcome variable. The range for this score is from 1 to 7. Lower scores correspond to greater improvement
Time frame: After 15 sessions of rTMS
Population: Subjects who did not complete the intervention were excluded from the analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Arm | Clinical Global Improvement (CGI)Improvement | 2.72 units on a scale | Standard Deviation 1.15 |
| Placebo Arm | Clinical Global Improvement (CGI)Improvement | 3.21 units on a scale | Standard Deviation 1.35 |