Schizophrenia and Related Disorders
Conditions
Keywords
Hallucinations, Auditory Verbal Hallucinations
Brief summary
The Repetitive Transcranial Magnetic Stimulation (rTMS) is a type of brain stimulation that uses a magnet to change activity in the brain. rTMS uses magnetic pulses to induce an electrical current in the brain to alter brain activity and function in specific areas. For example, stimulating the part of the brain controlling movement will cause parts of the foot or leg to twitch. TMS is proposed as a novel treatment for people with schizophrenia. The investigators want to see if low frequency rTMS can lessen some of the symptoms of schizophrenia, specifically auditory verbal hallucinations. Auditory verbal hallucinations describe the experience of hearing voices that are not really there.
Detailed description
The large majority of patients with schizophrenia (Sz) experience auditory verbal hallucinations (AVH) as a core feature of their disorder. Treatment-resistant auditory verbal hallucinations (AVH) affect a third of patients with schizophrenia and can cause increased aggression, distress, suicide, and social dysfunction. The current standard of care is antipsychotic medication which can cause metabolic syndrome, sedation, orthostatic hypotension, extrapyramidal symptoms, and tardive dyskinesia among other adverse effects. Transcranial magnetic stimulation (TMS) emits a rapidly changing magnetic field over the scalp which induces current flow in underling brain tissue, either enhancing or disrupting function depending on the frequency of stimulation. It is generally well tolerated and repetitive TMS (rTMS) is currently FDA approved for treatment of depression. rTMS carries potential as an alternative treatment for schizophrenia patients with AVH who either do not respond to or do not tolerate medication. Inhibitory (1-Hz) standard TMS approaches, which use scalp-based targeting of speech perception areas such as left temporoparietal junction (TPJ) have yielded mixed results in reducing AVH, possibly due to variability of underlying brain anatomy between individual subjects. The influence of anatomical variability could be eliminated by individually positioning the TMS coil according to each patient's structural brain MRI. The proposed pilot project will investigate the clinical efficacy of open-label individualized MRI-guided TMS applied to the left TPJ in ten patients with schizophrenia or schizoaffective disorder. If the results of the pilot study show promising reductions in AVH, it will set up the foundation for a larger sham-controlled clinical trial.
Interventions
DEVICERepetitive Transcranial Magnetic Stimulation (rTMS)
During the rTMS session, an electromagnetic coil is placed against the subjects scalp on the left side of the head. The electromagnet painlessly delivers a magnetic pulse that stimulates nerve cells in the region of the brain involved in speech perception.
Sponsors
National Institute of Mental Health (NIMH)
Columbia University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
This is an open-label study for participants with a diagnosis of either schizophrenia or schizoaffective disorder with persistent auditory verbal hallucinations (AVH) that are eligible to have repetitive transcranial magnetic stimulation (rTMS) targeting the left temporoparietal junction (TPJ).
Eligibility
Sex/Gender
ALL
Age
22 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
* The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) diagnosis of schizophrenia or schizoaffective disorder * Capacity and willingness to provide informed consent * Mean Auditory Hallucination Rating Scale (AHRS) item score of greater or equal to 2 * If female and not infertile, must agree to use one of the following forms of contraception for the duration of study participation: systemic hormonal treatment, an intrauterine device (IUD) which was implanted at least 2 months prior to screening, or double-barrier contraception. Women of child bearing potential must have a negative pregnancy test at screening * Right handed * Normal hearing * Taking an antipsychotic medication at a stable dose for at least 4 weeks. All oral and depot antipsychotics are allowable.
Exclusion criteria
* Substance use disorder (excluding nicotine) within last 90 days, or positive toxicology screen for any substance of abuse * Pregnancy * Participation in study of investigational medication/device within 4 weeks * History of seizure, epilepsy and neurologic conditions with structural cerebral damage, including stroke, multiple sclerosis, traumatic brain injury, Alzheimer's and other neurodegenerative diseases, meningoencephalitis or intracerebral abscess, parenchymal or leptomeningeal cancers, dementia, developmental disability, cerebrovascular disease, increased intracranial pressure, or central nervous system (CNS) tumors, brain surgery, head injury with loss of consciousness \>1 hour or clear cognitive sequelae, intracranial metal implants, known structural brain lesion * Subjects with devices that may be affected by TMS (pacemaker, cardioverter defibrillator, medication pump, intracardiac line, cochlear implant, implanted brain stimulator/neurostimulator) * Subjects with suicidal ideation with intent or plan (indicated by affirmative answers to items 4 or 5 of the Suicidal Ideation section of the baseline C-SSRS) in the 6 months prior to screening or subjects who represent a significant risk of suicide in the opinion of the investigator * Frequent and persistent migraines * Clinically significant skin disease * Presence of unstable medical disorders, including those that are previously undiagnosed, untreated, inadequately treated, or active to an extent which might make participation hazardous. For example, hypertension, previous stroke, brain lesions, or heart disease * History of prior clinically significant, adverse response to neurostimulation * Current treatment with ototoxic medications (amino-glycosides, cisplatin) * MRI incompatible implants * Claustrophobia
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Total Number of Treatment Emergent Adverse Events | 2 weeks. | The total number of treatment emergent adverse events. An emergent adverse event is defined as any rTMS risk induced incident in research such as headache and seizure. |
| Total Number of rTMS Sessions Completed | 2 weeks. | The total number of rTMS sessions completed. A session is defined as 20 minutes of rTMS. The outcome measure data comprises the cumulative count of all completed TMS sessions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Psychotic Symptom Rating Scale (PSYRATS) - Delusion Symptoms | Baseline and 4 weeks | The PSYRATS consists of 17 items on delusions and auditory hallucinations, with each item being rated from 0 (absent) to 4 (severe). The score range for the delusion subscale is 0-24 with a higher score indicating more delusion symptoms. |
| Change in Scale for the Assessment of Positive Symptoms (SAPS)- Hallucinations | Baseline and 4 weeks | The SAPS includes 34 items that focus on the positive symptoms on schizophrenia. Each item is rated on a severity scale that ranges from 0 (none) to 5 (severe). The hallucination subscale scores range from 0-35 with a higher score indicating more severe hallucinations. |
| Change in Scale for the Assessment of Positive Symptoms (SAPS)- Delusions | Baseline and 4 weeks | The SAPS includes 34 items that focus on the positive symptoms on schizophrenia. Each item is rated on a severity scale that ranges from 0 (none) to 5 (severe). The delusion subscale has a range from 0-65 with a higher score indicating more severe delusion symptoms. |
| Change in Positive and Negative Syndrome Scale (PANSS)- General Psychopathology | Baseline and 4 weeks | The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. The general psychopathology subscale is a measure of deficits in cognition with scores ranging from 16-112. Higher scores indicate more severe symptoms. |
| Change in Auditory Hallucination Rating Scale (AHRS) | Baseline and 4 weeks | The AHRS is an investigator-administered scale assessing multiple characteristics of auditory verbal hallucinations. The total score ranges from 2 to 41, with higher scores indicating more severe symptoms. |
| Change in Positive and Negative Syndrome Scale (PANSS)- Negative Symptoms | Baseline and 4 weeks | The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. Negative symptoms defined as a deficit in the ability to perform the normal functions of living-for example, logical thinking, self-care, social interaction, and planning, initiating, and carrying out constructive actions-as shown in apathy, blunted affect, emotional withdrawal, poor rapport, and lack of spontaneity. The negative symptoms sub scale scores range from 7-49 with a higher score indicating more severe symptoms. |
| Change in Cardiff Anomalous Perceptions Scale (CAPS) | Baseline and 4 weeks | The CAPS is a 32 item scale for measuring perceptual anomalies, that includes subscales for measuring distress, intrusiveness and frequency. A higher score indicates a higher number of perceptual anomalies, total scores range from 0 (low) to 32 (high). |
| Number of Participants Withdrawn Resulting From a Change in Clinical Global Impression Improvement (CGI-I) Scale Score | Baseline and 2 weeks | The CGI-I is a clinician-rated scale to quantify overall clinician impression of improvements in level of illness.The CGI-I is rated on a 7-point scale, to assess illness improvement. CGI-I scores range from 1 (very much improved) through to 7 (very much worse). The scale is used as a safety stop in this study. A worsening in CGI-I score of 2 or greater from baseline for two consecutive days results in withdrawal of the participant from the study. |
| Number of Participants Withdrawn Resulting From the Clinical Global Impression Severity (CGI-S) Scale Score | 2 weeks | The CGI-S is a clinician-rated scale to quantify overall clinician impression of illness severity. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). The scale is used as a safety stop in this study. A score of 6 or 7 at the two week timepoint results in withdrawal of the participant from the study. |
| Change in Positive and Negative Syndrome Scale (PANSS)- Positive Symptoms | Baseline and 4 weeks | The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. Positive symptoms defined as a symptom of schizophrenia that represents an excess or distortion of normal function, as distinct from a deficiency in or lack of normal function (compare negative symptom). Positive symptoms include delusions or hallucinations, disorganized behavior, and manifest conceptual disorganization. Positive symptom subscale ranges from 7-49 with a higher score indicating more severe symptoms. |
| Change in Psychotic Symptom Rating Scale (PSYRATS)- Auditory Hallucinations | Baseline and 4 weeks | The PSYRATS consists of 17 items on delusions and auditory hallucinations subscales, with each item being rated from 0 (absent) to 4 (severe). The score range for the auditory hallucinations subscale is 0-44 with a higher score indicating more severe auditory hallucinations. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS Participants will receive a type of TMS called repetitive TMS (rTMS) wherein the magnetic pulses delivered will be close together in a rapid sequence. They will receive a 20-min once-daily rTMS sessions over a period of 2 weeks (weekends off), and therefore accrue a total of 10 rTMS stimulation sessions. The rTMS parameters that will be used are a frequency of 1 Hz (1 pulse per second) at an intensity of 90% of the motor threshold (MT). Therefore, the investigators will deliver 1200 continuous pulses per session/day which adds up to 12,000 pulses in total for the whole treatment.
Repetitive Transcranial Magnetic Stimulation (rTMS): During the rTMS session, an electromagnetic coil is placed against the subjects scalp on the left side of the head. The electromagnet painlessly delivers a magnetic pulse that stimulates nerve cells in the region of the brain involved in speech perception. | 11 |
| Total | 11 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 4 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Individualized Magnetic Resonance Imaging (MRI) Guided rTMS |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants |
| Race/Ethnicity, Customized Black or African American | 5 Participants |
| Race/Ethnicity, Customized Haitian | 1 Participants |
| Race/Ethnicity, Customized Hispanic | 1 Participants |
| Race/Ethnicity, Customized Unknown | 1 Participants |
| Race/Ethnicity, Customized White | 2 Participants |
| Region of Enrollment United States | 11 participants |
| Sex: Female, Male Female | 4 Participants |
| Sex: Female, Male Male | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 11 |
| other Total, other adverse events | 4 / 11 |
| serious Total, serious adverse events | 0 / 11 |
Outcome results
Primary
Total Number of rTMS Sessions Completed
The total number of rTMS sessions completed. A session is defined as 20 minutes of rTMS. The outcome measure data comprises the cumulative count of all completed TMS sessions.
Time frame: 2 weeks.
Population: Out of the 11 participants, 5 successfully finished all 10 treatment sessions, resulting in a combined total of 50 sessions. Additionally, two participants withdrew from the study early: one managed to complete 1 TMS treatment session, while the other completed 3 treatment sessions.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Total Number of rTMS Sessions Completed | 54 sessions |
Primary
Total Number of Treatment Emergent Adverse Events
The total number of treatment emergent adverse events. An emergent adverse event is defined as any rTMS risk induced incident in research such as headache and seizure.
Time frame: 2 weeks.
Population: We enrolled 11 participants in total, out of which 5 successfully completed all study procedures. Among the 6 participants who withdrew from the study midway, only 2 managed to complete a few TMS treatment sessions (the other 4 participants dropped out before the TMS treatment procedures began). As a result, we conducted an analysis in the 7 participants that completed at least one session, to assess any adverse events that occurred during the 2-week treatment session.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Total Number of Treatment Emergent Adverse Events | 22 events |
Secondary
Change in Auditory Hallucination Rating Scale (AHRS)
The AHRS is an investigator-administered scale assessing multiple characteristics of auditory verbal hallucinations. The total score ranges from 2 to 41, with higher scores indicating more severe symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Auditory Hallucination Rating Scale (AHRS) | 13.8 score on a scale | Standard Deviation 8.8 |
Secondary
Change in Cardiff Anomalous Perceptions Scale (CAPS)
The CAPS is a 32 item scale for measuring perceptual anomalies, that includes subscales for measuring distress, intrusiveness and frequency. A higher score indicates a higher number of perceptual anomalies, total scores range from 0 (low) to 32 (high).
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Cardiff Anomalous Perceptions Scale (CAPS) | 3.6 score on a scale | Standard Deviation 3.2 |
Secondary
Change in Positive and Negative Syndrome Scale (PANSS)- General Psychopathology
The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. The general psychopathology subscale is a measure of deficits in cognition with scores ranging from 16-112. Higher scores indicate more severe symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Positive and Negative Syndrome Scale (PANSS)- General Psychopathology | 1.8 score on a scale | Standard Deviation 0.8 |
Secondary
Change in Positive and Negative Syndrome Scale (PANSS)- Negative Symptoms
The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. Negative symptoms defined as a deficit in the ability to perform the normal functions of living-for example, logical thinking, self-care, social interaction, and planning, initiating, and carrying out constructive actions-as shown in apathy, blunted affect, emotional withdrawal, poor rapport, and lack of spontaneity. The negative symptoms sub scale scores range from 7-49 with a higher score indicating more severe symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Positive and Negative Syndrome Scale (PANSS)- Negative Symptoms | 2.4 score on a scale | Standard Deviation 1.1 |
Secondary
Change in Positive and Negative Syndrome Scale (PANSS)- Positive Symptoms
The PANSS rates the presence and severity of positive and negative symptoms, as well as general psychopathology associated with schizophrenia. Positive symptoms defined as a symptom of schizophrenia that represents an excess or distortion of normal function, as distinct from a deficiency in or lack of normal function (compare negative symptom). Positive symptoms include delusions or hallucinations, disorganized behavior, and manifest conceptual disorganization. Positive symptom subscale ranges from 7-49 with a higher score indicating more severe symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Positive and Negative Syndrome Scale (PANSS)- Positive Symptoms | 3.2 score on a scale | Standard Deviation 4.1 |
Secondary
Change in Psychotic Symptom Rating Scale (PSYRATS)- Auditory Hallucinations
The PSYRATS consists of 17 items on delusions and auditory hallucinations subscales, with each item being rated from 0 (absent) to 4 (severe). The score range for the auditory hallucinations subscale is 0-44 with a higher score indicating more severe auditory hallucinations.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Psychotic Symptom Rating Scale (PSYRATS)- Auditory Hallucinations | 12.8 score on a scale | Standard Deviation 14.3 |
Secondary
Change in Psychotic Symptom Rating Scale (PSYRATS) - Delusion Symptoms
The PSYRATS consists of 17 items on delusions and auditory hallucinations, with each item being rated from 0 (absent) to 4 (severe). The score range for the delusion subscale is 0-24 with a higher score indicating more delusion symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Psychotic Symptom Rating Scale (PSYRATS) - Delusion Symptoms | 2 score on a scale | Standard Deviation 8.7 |
Secondary
Change in Scale for the Assessment of Positive Symptoms (SAPS)- Delusions
The SAPS includes 34 items that focus on the positive symptoms on schizophrenia. Each item is rated on a severity scale that ranges from 0 (none) to 5 (severe). The delusion subscale has a range from 0-65 with a higher score indicating more severe delusion symptoms.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Scale for the Assessment of Positive Symptoms (SAPS)- Delusions | 0.2 score on a scale | Standard Deviation 1.5 |
Secondary
Change in Scale for the Assessment of Positive Symptoms (SAPS)- Hallucinations
The SAPS includes 34 items that focus on the positive symptoms on schizophrenia. Each item is rated on a severity scale that ranges from 0 (none) to 5 (severe). The hallucination subscale scores range from 0-35 with a higher score indicating more severe hallucinations.
Time frame: Baseline and 4 weeks
Population: Scale scores were collected at both baseline and 4 weeks in the 5 participants that completed the study.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Change in Scale for the Assessment of Positive Symptoms (SAPS)- Hallucinations | 1.6 score on a scale | Standard Deviation 1.3 |
Secondary
Number of Participants Withdrawn Resulting From a Change in Clinical Global Impression Improvement (CGI-I) Scale Score
The CGI-I is a clinician-rated scale to quantify overall clinician impression of improvements in level of illness.The CGI-I is rated on a 7-point scale, to assess illness improvement. CGI-I scores range from 1 (very much improved) through to 7 (very much worse). The scale is used as a safety stop in this study. A worsening in CGI-I score of 2 or greater from baseline for two consecutive days results in withdrawal of the participant from the study.
Time frame: Baseline and 2 weeks
Population: The investigators enrolled a total of 11 participants. Seven of 11 completed the CGI-I scale at the 2 week timepoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Number of Participants Withdrawn Resulting From a Change in Clinical Global Impression Improvement (CGI-I) Scale Score | 0 Participants |
Secondary
Number of Participants Withdrawn Resulting From the Clinical Global Impression Severity (CGI-S) Scale Score
The CGI-S is a clinician-rated scale to quantify overall clinician impression of illness severity. The CGI-S is rated on a 7-point scale, with the severity of illness scale using a range of responses from 1 (normal) through to 7 (amongst the most severely ill patients). The scale is used as a safety stop in this study. A score of 6 or 7 at the two week timepoint results in withdrawal of the participant from the study.
Time frame: 2 weeks
Population: The investigators enrolled a total of 11 participants. Seven of 11 completed the CGI-I scale at the 2 week timepoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Individualized Magnetic Resonance Imaging (MRI) Guided rTMS | Number of Participants Withdrawn Resulting From the Clinical Global Impression Severity (CGI-S) Scale Score | 0 Participants |