Auditory Hallucination, Schizophrenia
Conditions
Keywords
transcranial magnetic stimulation (TMS), brain stimulation, medication-free
Brief summary
This is a randomized, placebo controlled, double-blind clinical trial. The investigators aim to examine the safety and efficacy of repeated transcranial magnetic stimulation (rTMS) for the treatment of auditory verbal hallucinations (AVH) in patients with schizophrenia who are not taking antipsychotic medication. The investigators employ a novel, accelerated protocol with only four sessions of low-frequency rTMS in one day. The effects of this accelerated protocol will be compared to the sham stimulation. Additionally, the investigators will examine the effects of rTMS on a neurophysiological level by evaluating mechanism of action in the temporo-parietal lobe by means of functional magnetic resonance imaging.
Detailed description
Auditory verbal hallucinations affect up to 70% of schizophrenia patients (Waters, 2012), yet, even extended antipsychotic medication does not ameliorate AVH in 20-30% of patients (Sukhwinder S Shergill et al., 2007) and is often accompanied by side effects (Leucht et al., 2009). Therefore, it is crucial to develop and assess promising potentially beneficial therapeutic options. Non-invasive brain stimulation techniques like repetitive transcranial magnetic stimulation (rTMS) have been proposed to disrupt mechanisms in question. A number of meta-analyses (Aleman, Sommer, & Kahn, 2007; Demeulemeester et al., 2012; Freitas, Fregni, & Pascual-Leone, 2009; C. W. Slotema, Blom, van Lutterveld, Hoek, & Sommer, 2014; C. W. Slotema, Dirk Blom, Hoek, & Sommer, 2010; Tranulis, Sepehry, Galinowski, & Stip, 2008) found significant effect sizes ranging from 0.42 to 1.04 for 1Hz rTMS over the left temporo-parietal junction for the treatment of AVH. However, the majority of studies so far investigated the effects of rTMS in treatment resistant schizophrenia patients as an ad-on or second-line treatment. No study to date has explored the effects of rTMS either as a first-line treatment or in the initial stage of the illness. This is surprising, considering the fact that rTMS is a safe treatment with minimal side-effects (Rossi, Hallett, Rossini, & Pascual-Leone, 2009) that could be used already in the earlier phase of treatment. This stands in considerable contrast to the range of side-effects associated with antipsychotics (Leucht et al., 2017) that can be disabling for patients and lead to lower quality of life. Therefore, the crucial next step is (1) to explore the effects of rTMS in medication-free patients from the whole schizophrenia spectrum and (2) to use an accelerated protocol of multiple rTMS-sessions within a short period of time. To make this assessment feasible, considering that patients have to be off medication, the safest and also most efficient way is an accelerated rTMS protocol. The great advantage of such an approach is that the effects of rTMS can be investigated independently of potentially influencing effects of antipsychotics and at the same time assess the efficacy of rTMS within a very short amount of time. In the proposed study, the investigators aim to determine the efficacy of rTMS as a potential treatment for AVH in schizophrenia and thus reduce suffering in patients and their relatives.
Interventions
DEVICEtranscranial magnetic stimulation
We will assess safety and efficacy of the following protocol: 1Hz of rTMS over the Sylvian parietal temporal area (area Spt) four times on 1 day (1 pulse/second and a total of 1'000 pulses: 16 minutes' protocol at 100 % of motor threshold modified based on Hoffman et al., 1999). Area Spt will be localized via baseline structural imaging and our Localite TMS navigation system.
Sponsors
Northwell Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Provision of signed and dated informed consent form 2. Stated willingness to comply with all study procedures and availability for the duration of the study 3. Male or female, aged 18 to 65 4. Diagnosed with Diagnostic and Statistical Manual (DSM) V diagnosis of schizophrenia (295.90), schizoaffective disorder (295.70), or brief psychotic disorder (298.80), prone to AVH in the acute phases of the disorder 5. Willing to adhere to the rTMS regimen 6. No antipsychotic medication in the last two weeks prior to the start of the study as well as no antipsychotic medication during participation in the study 7. Agreement to adhere to Lifestyle Considerations throughout study duration
Exclusion criteria
1. Current use of antipsychotic medication within the last 2 weeks 2. Electroconvulsive therapy or rTMS within three months (see the TMS screening questionnaire) 3. History of seizures 4. Presence of implanted electronic device or metal implant in the head and neck region (DBS, cochlear implant, etc.) 5. Pregnancy, as assessed with a pregnancy test prior to every MRI measurement, or lactation 6. Any active general medical condition or central nervous system disease which can affect cognition or response to treatment 7. Treatment with another investigational drug or other intervention within 2 weeks 8. Current diagnosis of delirium, dementia, or amnestic amnesiac disorder; Diagnosis of mental retardation; Current (within the past three months) diagnosis of active substance dependence, or active substance abuse within the past week as indicated by self-report. 9. Patients who are cognitively impaired and are thus not able to give informed consent
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations Assessed With the Hallucination Change Scale | Four timepoints of the Hallucination Change Scale (after every TMS session). Here, score after final session is reported. | Examine change in AVH severity, measured with the Hallucination Change Scale, due to low-frequency rTMS. The Hallucination Change Scale is a self-rating assesses severity of hallucinations. It is anchored at baseline using the patient's description of AVH for the previous 24-hours which is assigned a score of 10. The subsequent assessments are in relation to the baseline where a reduction of AVH relates to a value \< 10 (best being a value of 0) and a worsening of AVH relates to a value \> 10 (twice as severe as baseline being a value of 20). |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Real Transcranial Magnetic Stimulation In the treatment arm, patients will receive 1Hz of repetitive transcranial magnetic stimulation (rTMS) over the left Sylvian parietal temporal area (area Spt) four times on 1 day (1 pulse/second and a total of 1'000 pulses: 16 minutes' protocol at 100 % of motor threshold modified based on Hoffman et al.,1999). Area Spt will be localized via baseline structural imaging and our Localite TMS navigation system.
Transcranial magnetic stimulation: We will assess safety and efficacy of the following protocol: 1Hz of rTMS over the Sylvian parietal temporal area (area Spt) four times on 1 day (1 pulse/second and a total of 1'000 pulses: 16 minutes' protocol at 100 % of motor threshold modified based on Hoffman et al., 1999). Area Spt will be localized via baseline structural imaging and our Localite TMS navigation system. | 2 |
| Sham Transcranial Magnetic Stimulation In the comparator arm, patients will receive no stimulation. The TMS coil adjusted to the patients head will not be plugged into the TMS machine and can thus not have an effect on the brain. Yet, patients will hear the same noises from a coil that is plugged in, see the TMS machine running, and area Spt localized via baseline structural imaging and our Localite TMS navigation system.
Transcranial magnetic stimulation: We will assess safety and efficacy of the following protocol: 1Hz of rTMS over the Sylvian parietal temporal area (area Spt) four times on 1 day (1 pulse/second and a total of 1'000 pulses: 16 minutes' protocol at 100 % of motor threshold modified based on Hoffman et al., 1999). Area Spt will be localized via baseline structural imaging and our Localite TMS navigation system. | 2 |
| Total | 4 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Sham Transcranial Magnetic Stimulation | Total | Real Transcranial Magnetic Stimulation |
|---|---|---|---|
| Age, Continuous | 27.02 years STANDARD_DEVIATION 3.75 | 29.84 years STANDARD_DEVIATION 5.22 | 32.67 years STANDARD_DEVIATION 5.98 |
| BPRS Total Score | 38 units on a scale | 37 units on a scale | 36 units on a scale |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 2 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| GAS | 30 units on a scale STANDARD_DEVIATION 7.07 | 52.5 units on a scale | 75 units on a scale |
| Hallucination Change Score | 7.5 units on a scale | 7.5 units on a scale | 7.5 units on a scale |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 1 Participants | 2 Participants | 1 Participants |
| Region of Enrollment United States | 2 participants | 4 participants | 2 participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 2 | 0 / 2 |
| other Total, other adverse events | 0 / 2 | 0 / 2 |
| serious Total, serious adverse events | 0 / 2 | 0 / 2 |
Outcome results
Primary
Efficacy of Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations Assessed With the Hallucination Change Scale
Examine change in AVH severity, measured with the Hallucination Change Scale, due to low-frequency rTMS. The Hallucination Change Scale is a self-rating assesses severity of hallucinations. It is anchored at baseline using the patient's description of AVH for the previous 24-hours which is assigned a score of 10. The subsequent assessments are in relation to the baseline where a reduction of AVH relates to a value \< 10 (best being a value of 0) and a worsening of AVH relates to a value \> 10 (twice as severe as baseline being a value of 20).
Time frame: Four timepoints of the Hallucination Change Scale (after every TMS session). Here, score after final session is reported.
Population: Pat. lost for followup.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Real Transcranial Magnetic Stimulation | Efficacy of Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations Assessed With the Hallucination Change Scale | 15 score on a scale |
| Sham Transcranial Magnetic Stimulation | Efficacy of Transcranial Magnetic Stimulation for Auditory Verbal Hallucinations Assessed With the Hallucination Change Scale | 7.5 score on a scale |