Therapeutic Efficacy of Transcranial Magnetic Stimulation in Schizophrenia

Therapeutic Efficacy of Cerebellar Repetitive Transcranial Magnetic Stimulation in Patients With Schizophrenia

Status

Completed

Phases

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01551979

Enrollment

Registered

2012-03-13

Start date

2012-02-29

Completion date

2015-11-30

Last updated

2018-04-12

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Schizophrenia

Keywords

Schizophrenia, repetitive Transcranial Magnetic Stimulation

Brief summary

The aim of this study is to look at the effectiveness of repetitive transcranial magnetic stimulation (rTMS) as a therapeutic intervention for patients with schizophrenia. The primary outcome is improvement in negative symptoms related to schizophrenia. The investigators are focusing on negative symptoms given their greater resistance to pharmacological and other established therapies. If the investigators trial were to show beneficial effects, its clinical significance would be great.

Detailed description

This study builds on the results of a previous phase 1, single-site study in which we demonstrated the safety of image-guided theta burst stimulation (TBS) form of rTMS over the cerebellar vermis (Demirtas-Tatlidede et al., 2010) in eigh patients with schizophrenia. The primary goal of the present study is to assess efficacy of iTBS to the cerebellar vermis on positive and negative symptoms of schizophrenia. A second, added goal is to investigate the mechanisms of the expected clinical improvement. Schizophrenia is a leading cause of mental disability and current treatments still remain only partially successful for many patients. Our underlying hypothesis is that modulation of the cerebellar vermis may enhance activity of the neural systems that sub-serve cognition and emotion, reestablish the disturbed cerebellar regulation in schizophrenic patients, and produce clinical improvement.

Interventions

DEVICERepetitive Transcranial Magnetic Stimulation

intermittent Theta Burst (iTBS) pattern (20 trains of 10 bursts given with 8s intervals) will be applied at 80% of active motor threshold. Each participant will receive 600 pulses per session. Sham participants will undergo the same procedures as those in the active rTMS group.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

* Age between 18-65 years * Diagnosis of schizophrenia according to DSM-IV criteria (Diagnostic and Statistical Manual) by a board-certified psychiatrist

Exclusion criteria

* Preexisting or progressive neurological disorders * Prior neurological procedures * Previous head injury * Change in antipsychotic medication during the last 4 weeks * Been an inpatient in a psychiatry clinic within the last month * Any other axis 1 diagnosis * Patients may not be actively enrolled in a separate intervention study * Patients unable to undergo a brain MRI * Any unstable medical condition * History of seizures, diagnosis of epilepsy, history of abnormal (epileptiform\_ EEG, or family history of treatment resistant epilepsy * Possible pregnancy. All female participants of child bearing age are required to have a pregnancy test. * Any metal in the brain, skull, or elsewhere unless approved by the responsible MD * Any medical devices (ie. cardiac pacemaker, deep brain stimulator, medication infusion pump, cochlear implant, vagal nerve stimulator) unless otherwise approved by the responsible MD * Substance abuse (alcohol, amphetamines, cocaine, MDMA \[methylenedioxymethamphetamine\], ecstasy, PCP \[phencyclidine\], Angle dust) or dependence within the past six months * No medication is an absolute exclusion from TMS. Medications will be reviewed by the responsible MD and a decision about inclusion will be made based on the following: the patient's past medical history, drug dose, history of recent medication changes or duration of treatment, and combination with other CNS (central nervous system) active drugs (the published TMS guidelines review of medications to be considered with TMS)

Design outcomes

Primary

Measure	Time frame	Description
Change From Baseline on the Positive and Negative Syndrome Scale (PANSS) Positive Subscale	Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	Therapeutic efficacy was evaluated with the Positive and Negative Syndrome Scale (PANSS) Positive Subscale, a 7 item subscale measuring the presence/absence and severity of positive symptoms of schizophrenia. The minimum score is 7 and the maximum score is 49, with higher values representing greater symptom severity. Change from baseline on the PANSS Positive Subscale can range from -42 to +42; negative values represent an improvement in symptom severity, and positive values represent worsening symptom severity. Therapeutic efficacy was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.
Change From Baseline on the Positive and Negative Syndrome Scale (PANSS) Negative Subscale	Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	Therapeutic efficacy was evaluated with the Positive and Negative Syndrome Scale (PANSS) Negative Subscale, a 7 item subscale measuring the presence/absence and severity of negative symptoms of schizophrenia. The minimum score is 7 and the maximum score is 49, with higher values representing greater symptom severity. Change from baseline on the PANSS Negative Subscale can range from -42 to +42; negative values represent an improvement in symptom severity, and positive values represent worsening symptom severity. Therapeutic efficacy was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.
Change From Baseline on the Positive and Negative Syndrome Scale (PANSS) General Subscale	Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	Therapeutic efficacy was evaluated with the Positive and Negative Syndrome Scale (PANSS) General Subscale, a 16 item subscale measuring the presence/absence and severity of general psychopathology of schizophrenia. The minimum score is 16 and the maximum score is 112, with higher values representing greater psychopathology severity. Change from baseline on the PANSS General Subscale can range from -96 to +96; negative values represent an improvement in symptom severity, and positive values represent worsening symptom severity. Therapeutic efficacy was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.
Change From Baseline on the Clinical Global Impression (CGI) Severity of Illness	Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	Treatment response was evaluated with the Clinical Global Impressions (CGI) Scale, which is comprised of two companion one-item measures that use 7-point scales to evaluate severity of psychopathology and improvement from the initiation of treatment; each component is rated separately and the CGI does not yield a global score. The CGI Severity of Illness is a 7-point subscale in which a clinician rates the severity of the patient's illness at the time of assessment. Ratings range from 1 to 7 and higher values represent more severe psychopathology: 1 indicates a normal and not at all ill patient and 7 indicates among the most extremely ill patients. Change from baseline on the CGI Severity of Illness subscale can range from -6 to +6, with negative values representing an improvement in psychopathology and positive values representing worsening psychopathology. Severity of Illness was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.
Clinical Global Impression (CGI) Global Improvement	Last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	Treatment response was evaluated with the Clinical Global Impressions (CGI) Scale, which is comprised of two companion one-item measures that use 7-point scales to evaluate severity of psychopathology and improvement from the initiation of treatment; each component is rated separately and the CGI does not yield a global score. The CGI Global Improvement is a 7-point subscale in which a clinician assesses how much a patient's illness has changed compared to baseline. Ratings range from 1 to 7, with 1 indicating very much improved and 7 indicating very much worse. Change from baseline on the CGI Global Improvement subscale can range from -6 to +6, with negative values representing an improvement in psychopathology and positive values representing worsening psychopathology. Global Improvement was assessed after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.

Secondary

Measure	Time frame	Description
Change From Baseline on the Calgary Depression Scale for Schizophrenia	Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment	The Calgary Depression Scale for Schizophrenia is a 9-item scale that assesses depressive symptoms in patients with schizophrenia. Each item is rated separately and ratings range from 0 to 3. Higher values represent more severe depressive symptoms: 0 indicates an absent symptom and 3 indicates a severe symptom. The overall Calgary Depression Scale score is computed by summing each item. The total Calgary Depression Scale score ranges from 0 to 27, with higher values representing more severe depression in patients with schizophrenia. Change from baseline on the Calgary Depression Scale can range from -27 to +27, with negative values representing an improvement in depressive symptoms and positive values representing worsening depressive symptom severity. Depression was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.

Countries

United States

Participant flow

Pre-assignment details

22 patients gave informed consent for the study during the initial screening visit. After patients were found ineligible to participate following review of medical records, withdrew consent, or were lost to follow-up, only 17 remained for the randomization phase and started the study.

Participants by arm

Arm	Count
Active rTMS High frequency rTMS stimulation of the vermis(lobule VII) of the cerebellum. Repetitive Transcranial Magnetic Stimulation: intermittent Theta Burst (iTBS) pattern (20 trains of 10 bursts given with 8s intervals) will be applied at 80% of active motor threshold. Each participant will receive 600 pulses per session. Sham participants will undergo the same procedures as those in the active rTMS group.	10
Sham rTMS Sham rTMS to the vermis (lobule VII) of the cerebellum. Repetitive Transcranial Magnetic Stimulation: intermittent Theta Burst (iTBS) pattern (20 trains of 10 bursts given with 8s intervals) will be applied at 80% of active motor threshold. Each participant will receive 600 pulses per session. Sham participants will undergo the same procedures as those in the active rTMS group.	7
Total	17

Baseline characteristics

Characteristic	Active rTMS	Sham rTMS	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	10 Participants	7 Participants	17 Participants
Region of Enrollment United States	10 participants	7 participants	17 participants
Sex: Female, Male Female	2 Participants	2 Participants	4 Participants
Sex: Female, Male Male	8 Participants	5 Participants	13 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 0	0 / 0
other Total, other adverse events	5 / 10	1 / 7
serious Total, serious adverse events	1 / 10	0 / 7

Outcome results

Primary

Change From Baseline on the Clinical Global Impression (CGI) Severity of Illness

Treatment response was evaluated with the Clinical Global Impressions (CGI) Scale, which is comprised of two companion one-item measures that use 7-point scales to evaluate severity of psychopathology and improvement from the initiation of treatment; each component is rated separately and the CGI does not yield a global score. The CGI Severity of Illness is a 7-point subscale in which a clinician rates the severity of the patient's illness at the time of assessment. Ratings range from 1 to 7 and higher values represent more severe psychopathology: 1 indicates a normal and not at all ill patient and 7 indicates among the most extremely ill patients. Change from baseline on the CGI Severity of Illness subscale can range from -6 to +6, with negative values representing an improvement in psychopathology and positive values representing worsening psychopathology. Severity of Illness was assessed at baseline, after 5 days of treatment, 1 week post treatment, and 3 weeks post treatment.

Time frame: Before treatment (baseline), last day of treatment (after 5 days of treatment), 1 and 3 weeks post treatment