Nicotine Addiction, Schizophrenia, Smoking Cessation
Conditions
Keywords
Transcranial magnetic stimulation, schizophrenia, MRI, smoking
Brief summary
In a double-blinded, randomized, parallel controlled design, patients with schizophrenia spectrum disorder will be exposed to active or sham repetitive transcranial magentic stimulation (TMS) which was guided by functional magnetic resonance image (MRI). Smoking reduction/cessation and brain functional connectivity changes will be assessed at baseline, different stages of rTMS and/or follow-ups.
Detailed description
Neuroimaging studies suggest that high rate of smoking in patients with schizophrenia may be due to an overlap of nicotine addiction related circuitries and schizophrenia related circuitries, such that schizophrenia impact some of the same circuitries that increase risks for severe nicotine addiction in general. Those identified overlapping circuitries have been linked to several key features of nicotine addiction and can be represented by resting state functional connectivities. Transcranial magnetic stimulation (TMS) provides a non-invasive means for altering brain electrical neural activity. TMS has been approved by FDA for treatment of depression. Other applications have not been approved but it has been used in a wide range of clinical research especially in neurology and psychiatry. There are preliminarily significant improvements in treatments of smoking cessation in schizophrenia using TMS with small samples, but those treatments are not robust in larger samples. The high inter-subject variability limits the efficacy of TMS treatment in schizophrenia patients. We aim to develop a TMS method targeting special brain circuits that are both smoking cessation and schizophrenia related. If the corresponding brain circuits were successfully modulated, the treatment efficacy will be significantly improved and schizophrenia patients will benefit from the TMS treatment of smoking cessation.
Interventions
DEVICEActive TMS stimulation
Multiple trains of active transcranial magnetic stimulation in a day, for multiple days.
DEVICESham TMS stimulation
Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days.
Sponsors
National Institute on Drug Abuse (NIDA)
University of Maryland, Baltimore
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
DOUBLE (Subject, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
No
Inclusion criteria
* Male and female between ages 18-60 * Ability to give written informed consent (age 18 or above) * Smoking in the last one year or more and average cigarette per day ≥ 5 in the past 4 weeks. * For patient participants, Evaluation to Sign Consent (ESC) above10.
Exclusion criteria
* Any history of seizures * Had smoking cessation treatment, clinical trial, or nicotine replacements within the past four weeks. * Significant alcohol or other drug use (substance dependence within 6 months or substance abuse within 1 month) other than nicotine or marijuana dependence. * Any major medical illnesses that may affect normal brain functioning. Examples of these conditions include, but not limited to, stroke, CNS infection or tumor, other significant brain neurological conditions. * Taking \> 400 mg clozapine/day * Failed TMS screening questionnaire * Cardiac pacemakers, implanted medication pumps, intracardiac lines, or acute, unstable cardiac disease, with intracranial implants (e.g. aneurysm clips, shunts, stimulators, cochlear implants, or electrodes) or any other metal object within or near the head, excluding the mouth, that cannot be safely removed. * History of head injury with loss of consciousness over 10 minutes; history of brain surgery * Can not refrain from using alcohol and/or marijuana 24 hours or more & cigarette smoking one hour or more prior to experiments. * Woman who is pregnant (child-bearing potential but not on contraceptive and missing menstrual period; or by self report; or by positive pregnancy test).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cigarette Per Day | 7 months | Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Functional Magnetic Resonance Imaging (fMRI) | 4 months | Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point). |
| Cotinine | 1 month | Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point). |
| End-expired Carbon Monoxide (CO) | 1 month | End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point). |
| Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG) | 4 months | EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point). |
Countries
United States
Participant flow
Pre-assignment details
Fourteen enrolled participants were excluded from the study before assignment to groups. Six of them were excluded because they failed inclusion/exclusion criteria; six of them were excluded due to schedule conflict; one was excluded because the participant cannot fit into MRI scanner; one was excluded because the participant changed mind and decided to quit.
Participants by arm
| Arm | Count |
|---|---|
| Active TMS Stimulation Real active rTMS stimulation.
Active TMS stimulation: Multiple trains of active transcranial magnetic stimulation in a day, for multiple days. | 18 |
| Sham TMS Stimulation Sham repetitive TMS stimulation.
Sham TMS stimulation: Multiple trains of sham transcranial magnetic stimulation in a day, for multiple days. | 12 |
| Total | 30 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 0 | 1 |
| Overall Study | Participant's schedule change and cannot participate in the study | 0 | 1 |
| Overall Study | The two participants dropped out due to COVID-19 lockdown. | 2 | 0 |
Baseline characteristics
| Characteristic | Active TMS Stimulation | Sham TMS Stimulation | 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 | 18 Participants | 12 Participants | 30 Participants |
| Age, Continuous | 44.3 years STANDARD_DEVIATION 11.8 | 41.9 years STANDARD_DEVIATION 12.8 | 43.3 years STANDARD_DEVIATION 12.1 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 18 Participants | 11 Participants | 29 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| 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 | 13 Participants | 9 Participants | 22 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 | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 4 Participants | 3 Participants | 7 Participants |
| Region of Enrollment United States | 18 participants | 12 participants | 30 participants |
| Sex: Female, Male Female | 7 Participants | 3 Participants | 10 Participants |
| Sex: Female, Male Male | 11 Participants | 9 Participants | 20 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 1 / 12 |
| other Total, other adverse events | 14 / 18 | 6 / 12 |
| serious Total, serious adverse events | 0 / 18 | 0 / 12 |
Outcome results
Primary
Cigarette Per Day
Cigarette per day (CPD) is measured to index smoking reduction and cessation. The change of CPD between baseline and end-of-treatment (1-month time point), 3-month follow up (4-month time point) and 6-month follow up (7-month time point) are reported. Negative values of the change of CPD indicate reductions in cigarette consumption.
Time frame: 7 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active TMS Stimulation | Cigarette Per Day | Baseline versus End-of-Treatment (1 month) | -3.2 cigarettes per day | Standard Deviation 4.9 |
| Active TMS Stimulation | Cigarette Per Day | Baseline versus 3-month follow up (4 months time point) | -2.71 cigarettes per day | Standard Deviation 3.1 |
| Active TMS Stimulation | Cigarette Per Day | Baseline versus 6-month follow up (7 months time point) | -2.50 cigarettes per day | Standard Deviation 2.04 |
| Sham TMS Stimulation | Cigarette Per Day | Baseline versus End-of-Treatment (1 month) | -3.0 cigarettes per day | Standard Deviation 5.1 |
| Sham TMS Stimulation | Cigarette Per Day | Baseline versus 3-month follow up (4 months time point) | -2.50 cigarettes per day | Standard Deviation 3.32 |
| Sham TMS Stimulation | Cigarette Per Day | Baseline versus 6-month follow up (7 months time point) | -3.50 cigarettes per day | Standard Deviation 4.95 |
Secondary
Cotinine
Cotinine level is an objective index of smoking status. Higher level of cotinine indicates more nicotine consumption. The change of cotinine level between baseline and end-of-treatment (1-month time point) is reported. Cotinine data were not collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).
Time frame: 1 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TMS Stimulation | Cotinine | -112 ng/ml | Standard Deviation 1114 |
| Sham TMS Stimulation | Cotinine | 31 ng/ml | Standard Deviation 561 |
Secondary
End-expired Carbon Monoxide (CO)
End-expired CO measure is an instant measure of smoking status. Higher CO level indicates more nicotine consumption. The change of CO level between baseline and end-of-treatment (1-month time point) is reported. No CO data were collected at 3-month follow up (4-month time point) or 6-month follow up (7-month time point).
Time frame: 1 month
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Active TMS Stimulation | End-expired Carbon Monoxide (CO) | -0.67 ppm | Standard Deviation 9.04 |
| Sham TMS Stimulation | End-expired Carbon Monoxide (CO) | -2.40 ppm | Standard Deviation 4.5 |
Secondary
Functional Magnetic Resonance Imaging (fMRI)
Resting-state functional connectivity (rsFC) obtained from fMRI is used to evaluate the TMS effect on smoking cessation. The strength of rsFC was first defined by correlation coefficient (r). Because the distribution of r values is highly skewed, z scores (normally distributed) were computed via fisher r-to-z transform. The z score central value (i.e., z score of 0) represents no relationship between the two brain regions. A positive (negative) z score indicates a positive (negative) association between the two brain regions. According to our pilot data determined from a separate study, stronger rsFC (i.e., larger positive z score) was related to less smoking severity. The changes of rsFC between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. A positive (negative) value of rsFC change suggests the rsFC was enhanced (weakened) by the intervention. No fMRI data were collected at 6-month follow up (7-month time point).
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active TMS Stimulation | Functional Magnetic Resonance Imaging (fMRI) | Baseline versus 3-month follow up (4 months time point) | 0.044 z score of functional connectivity | Standard Deviation 0.045 |
| Active TMS Stimulation | Functional Magnetic Resonance Imaging (fMRI) | Baseline versus End-of-Treatment (1 month time point) | 0.025 z score of functional connectivity | Standard Deviation 0.047 |
| Sham TMS Stimulation | Functional Magnetic Resonance Imaging (fMRI) | Baseline versus End-of-Treatment (1 month time point) | -0.014 z score of functional connectivity | Standard Deviation 0.047 |
| Sham TMS Stimulation | Functional Magnetic Resonance Imaging (fMRI) | Baseline versus 3-month follow up (4 months time point) | -0.034 z score of functional connectivity | Standard Deviation 0.011 |
Secondary
Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG)
EEG is used to evaluate the brain activities that are corresponding to the TMS. Auditory static state response (ASSR) at gamma frequency (i.e., 40 Hz) is obtained from the EEG recording. The gamma power of ASSR was normalized as the ratio between the power at 40 Hz (i.e., gamma power) and the power of its neighboring frequencies (i.e., 39 and 41 Hz). Increased normalized gamma ASSR is usually related to the improvement of psychosis symptoms. The change of ASSR between baseline and end-of-treatment (1-month time point) and 3-month follow up (4-month time point) are reported. No EEG data were collected at 6-month follow up (7-month time point).
Time frame: 4 months
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Active TMS Stimulation | Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG) | Baseline versus End-pf-Treatment (1 month time point) | 24.0 ratio | Standard Deviation 37 |
| Active TMS Stimulation | Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG) | Baseline versus 3-month follow up (4 months time point) | -5.5 ratio | Standard Deviation 15.5 |
| Sham TMS Stimulation | Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG) | Baseline versus End-pf-Treatment (1 month time point) | -38.0 ratio | Standard Deviation 64 |
| Sham TMS Stimulation | Normalized Gamma Power of Auditory Static State Response (ASSR) From Electroencephalography (EEG) | Baseline versus 3-month follow up (4 months time point) | 35.1 ratio | Standard Deviation 32.8 |