Schizophrenia
Conditions
Keywords
neurologic and psychiatric disorders, rare disease, schizophrenia
Brief summary
OBJECTIVES: I. Determine the effect of repetitive transcranial magnetic stimulation on treatment refractory auditory hallucinations of patients with schizophrenia.
Detailed description
PROTOCOL OUTLINE: This is a randomized, double blind study. Patients are randomized to one of two treatment arms. Group I: Patients receive 9 sessions of active transcranial magnetic stimulation (rTMS) which consists of 8 minutes of rTMS during session 1, 12 minutes duration during session 2, and 16 minutes duration during sessions 3-9. The total duration of stimulation is 132 minutes. Each session was given on a separate day and in general each session occurred on consecutive days with the exception of weekends. Group II: Patients receive 9 sessions of sham stimulation, which consists of 8 minutes of sham stimulation during session 1, 12 minutes duration sham stimulation during session 2, and 16 minutes duration sham stimulation during sessions 3-9. The total duration of sham stimulation is 132 minutes. Each session was given conducted on a separate day and in general each session occured on consecutive days with the exception of weekends. This study provided pilot data supplying the basis for our current study - NCT00308997 -- see our website for details
Interventions
DEVICErepetitive transcranial magnetic stimulation (rTMS)
a total of 132 minutes of stimulation at one hertz, motor threshold set at 80%, delivered to TP3 scalp site
DEVICEsham stimulation
132 minutes of stimulation given at 80% motor threshold with coil tilted single wing 45 degrees away from scalp deliverd to TP3 site
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 60 Years
Healthy volunteers
No
Inclusion criteria
PROTOCOL ENTRY CRITERIA: Inclusion criteria: * Diagnosis of schizophrenia or schizoaffective disorder based on DSM-IV version of SCID * Auditory hallucinations of spoken speech occurring at least 5 times per day where subject able to discern verbal content * Right-handed * At least 4 weeks on stable antipsychotic medication
Exclusion criteria
* history of seizure (unless due to drug withdrawal or medication that is no longer prescribed) * history of epilepsy in first degree relatives * estimated IQ less than 80 * unable to provide informed consent * significant unstable medical condition * current treatment with clozapine or bupropion * cochlear implants or other metal in the head (surgical, etc.) * history of cardiac arrhythmia * cardiac pacemaker * active drug or alcohol abuse within prior 6 weeks * pregnancy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions | After the 9th active/sham rTMS session (up to 2 weeks or end of intervention) | Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions | After the 9th active/sham rTMS session (up to 2 weeks or end of intervention) | Difference between baseline hallucination frequency and hallucintion frequency at last assessment. Assessed on the basis of a 0-9 scale, with higher scores being more severe. |
| Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions | After the 9th active/sham rTMS session (up to 2 weeks or end of intervention) | Scaled from 1-7 as follows: 1=dramatically improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worsened, 6=moderately worsened, 7=dramatically worsened |
| Responder Status | After the 9th active/sham rTMS session (up to 2 weeks or end of intervention) | Responder defined as a participant who attains an endpoint hallucination change score (HCS) of 5 or lower after 9 active/shame rTMS sessions. Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Active Repetitive Transcanial Magnetic Stimulation Participants received active repetitive transcranial magnetic stimulation (rTMS) | 27 |
| Placebo Participants received sham stimulation | 23 |
| Total | 50 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | memory difficulties | 1 | 1 |
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Active Repetitive Transcanial Magnetic Stimulation | Placebo | Total |
|---|---|---|---|
| Age Continuous | 35.1 Years STANDARD_DEVIATION 11.9 | 35.5 Years STANDARD_DEVIATION 9.5 | 35.3 Years STANDARD_DEVIATION 10.8 |
| Medication Resistance Medication Resistant | 21 Participants | 18 Participants | 39 Participants |
| Medication Resistance Not Medication Resistant | 6 Participants | 5 Participants | 11 Participants |
| Sex: Female, Male Female | 9 Participants | 8 Participants | 17 Participants |
| Sex: Female, Male Male | 18 Participants | 15 Participants | 33 Participants |
| Total Auditory Hallucination Rate Scale (AHRS) score | 25.1 Scores on a scale STANDARD_DEVIATION 5 | 26.1 Scores on a scale STANDARD_DEVIATION 5.7 | 25.6 Scores on a scale STANDARD_DEVIATION 5.3 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 16 / 27 | 3 / 23 |
| serious Total, serious adverse events | 0 / 27 | 0 / 23 |
Outcome results
Primary
Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions
Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline
Time frame: After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)
Population: Last Observation Carried Forward (LOCF)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Repetitive Transcanial Magnetic Stimulation | Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions | 5.85 Units on a scale | Standard Deviation 2.85 |
| Placebo | Hallucination Change Score (HCS) After 9 Active/Sham rTMS Sessions | 8.61 Units on a scale | Standard Deviation 3.8 |
p-value: 0.00595% CI: [-4.65, -0.86]t-test, 2 sided
Secondary
Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions
Difference between baseline hallucination frequency and hallucintion frequency at last assessment. Assessed on the basis of a 0-9 scale, with higher scores being more severe.
Time frame: After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)
Population: LOCF
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Repetitive Transcanial Magnetic Stimulation | Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions | 1.42 Score on a scale | Standard Deviation 1.49 |
| Placebo | Change From Baseline in Hallucination Frequency After 9 Active/Shame rTMS Sessions | .15 Score on a scale | Standard Deviation 1.14 |
Comparison: null hypothesis is that the groups are the samep-value: 0.00295% CI: [0.507, 2.03]t-test, 2 sided
Secondary
Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions
Scaled from 1-7 as follows: 1=dramatically improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worsened, 6=moderately worsened, 7=dramatically worsened
Time frame: After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active Repetitive Transcanial Magnetic Stimulation | Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions | 2.84 Units on a scale | Standard Deviation 0.845 |
| Placebo | Clinical Global Improvement (CGI) Scale After 9 Active/Shame rTMS Sessions | 3.79 Units on a scale | Standard Deviation 0.882 |
p-value: 0.00195% CI: [-1.45, -0.44]t-test, 2 sided
Secondary
Responder Status
Responder defined as a participant who attains an endpoint hallucination change score (HCS) of 5 or lower after 9 active/shame rTMS sessions. Change in hallucination severity relative to baseline with scores ranging 1 in unit intervals to 20 anchored as follows: 0=hallucinations stopped, 10=no change, 20=hallucinations twice as severe as baseline
Time frame: After the 9th active/sham rTMS session (up to 2 weeks or end of intervention)
Population: LOCF
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Active Repetitive Transcanial Magnetic Stimulation | Responder Status | 14 Participants |
| Placebo | Responder Status | 4 Participants |
p-value: 0.01Chi-squared