Clinical trial NCT04449055: Pilot TMS for Methamphetamine Use Disorder
Official title: A Pilot Study of Transcranial Magnetic Stimulation for Treatment of Methamphetamine Use Disorders
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Stimulant Dependence
Methamphetamine-dependence
Addiction, Drug
Keywords: methamphetamine
addiction treatment
transcranial magnetic stimulation
Lead sponsor: University of Iowa
Sponsor class: OTHER
Collaborators: name: University of New Mexico
name: University of Utah
First posted: 2020-06-26
Enrollment: 19
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized order of TMS site stimulated first
Primary purpose: TREATMENT

Brief summary: This is a pilot study to test the feasibility of a recruitment strategy and study protocol to examine the effects of a dual target transcranial magnetic stimulation treatment in methamphetamine use disorder. The study will test intermittent theta burst stimulation (TBS) targeting the dorsolateral prefrontal cortex (DLPFC) combined with continuous TBS targeting the medial prefrontal cortex (MPFC) in people with methamphetamine use disorder (MAUD) who are engaged in psychosocial treatment. Intermittent TBS targeting the DLPFC is approved by the Food and Drug Administration for major depressive disorder, and continuous TBS targeting the MPFC has been studied in cocaine use disorder. We will administer this dual target TBS daily for 2 weeks, followed by three times weekly for 2 weeks, and monitor depressive symptoms, anxiety, sleep, craving, quality of life, and methamphetamine use for three months. Changes in functional connectivity of brain circuits will be evaluated with functional magnetic resonance imaging (fMRI) before and after treatment. We expect to observe changes in connectivity between the DLPFC, MPFC, and other regions implicated in addiction and impulsivity. Furthermore, we will evaluate if baseline differences in functional connectivity can be used to predict response. Psychological tests focusing on state impulsivity and risk taking will be administered, and we expect to observe reductions in these characteristics after treatment. We will test this protocol in 20 patients recruited from clinical care settings at University of Iowa Hospitals and Clinics, University of New Mexico Health System, and University of Utah Health to illustrate the feasibility of recruitment and completing the protocol, to support an external funding proposal.

Detailed description: Overview: This is a single-arm clinical trial, with historical controls as a comparison group for select outcomes. Subjects with MAUD will receive 16 sessions of dual-target theta burst stimulation to the DLPFC and MPFC over 4 weeks. We will follow outcomes for 12 weeks. Outcomes include treatment retention, craving, self-reported MA or stimulant use, urine drug screen results, depressive symptoms, anxiety symptoms, sleep quality, quality of life, response inhibition, and functional connectivity. Magnetic resonance imaging (MRI) to measure functional connectivity and a flanker task to measure response inhibition will be completed at baseline and four weeks. More detail is provided in the outcome measures section. Subjects will also complete the Big Five Inventory at baseline, a measure of personality characteristics, to explore how these relate to outcomes including retention in treatment and the study.

MR Image Acquisition: MRI will be completed at baseline and after the last TMS session. The MRI sessions will be conducted using research dedicated MRI scanners at each site. Anatomical images will include volumetric T1 and T2 weighted images with a 1.0 mm isotropic spatial resolution. Resting state fMRI will be performed to collect 20 minutes worth of data.

Statistical Analysis:

Retention in the Study and Psychosocial Treatment: We will describe the proportion of subjects who complete the 4-week TMS treatment period and complete each subsequent monthly follow-up visit. We will use Kaplan-Meier curves to describe retention in the study and in psychosocial treatment. If non-retention is common enough, we will use Cox regression to explore baseline measures as predictors of retention. We anticipate that multivariate analysis will not be feasible with the sample size.

Symptoms and Impulse Control Measures: Primary analyses for other measures will focus on changes over the 4-week TMS treatment period. Changes in symptoms evaluated weekly or biweekly (e.g. craving, depression, affect, anxiety, sleep) will be assessed using generalized linear mixed models with appropriate distributions. We anticipate a Poisson distribution for days of MA or other stimulant use and will use a binomial distribution with a logit link to evaluate changes in positive urine drug screens. Time will be the primary variable of interest to assess the slopes of change during treatment. Paired t-tests or Wilcoxon signed-rank tests will be used to evaluate changes in measures completed at baseline and after 4 weeks of treatment. We will compare measures at baseline and 4 weeks to those at 8 weeks and 12 weeks similarly, but in separate analyses since decay in effects may occur after TMS ends.

Functional Connectivity Analysis: fMRI functional connectivity analysis will be performed using a standard analysis pipeline. Functional images will undergo pre-processing including brain extraction, motion correction, spatial smoothing (6 mm FWHM), and temporal filtering (.008 Hz \< f \< 0.08 Hz). Following preprocessing, the fMRI signal will be corrected for potential sources of noise using image-based estimates and motion correction parameters. The resulting corrected time-series will be used for all functional connectivity analyses. Functional connectivity will be measured by extracting time-series data from the pre-processed imaging data for the regions of interest (ROIs). Multiple ROIs will be examined and will be defined as spheres (6mm radius) based on coordinate locations previously published by Yeo and colleagues. Specifically, we will focus on connectivity in the cingulo-opercular network involved in cognitive control and salience (DLPFC - anterior insula; DLPFC - anterior cingulate) and reward processing/motivation circuit (MPFC - ventral striatum). Analyses will be averaged across right and left hemispheres but we will also explore differences between right and left hemispheres. The time series from the ROIs will be cross-correlated with the time-series from the other ROIs to determine the strength of functional connectivity between regions. The resulting Pearson's r will be converted to Fisher's z scores to improve normality for the statistical analysis. We will treat each ROI pair connection (DLPFC - anterior insula, DLPFC - anterior cingulate, MPFC - ventral striatum) as a dependent variable. Primary analyses will use paired t-tests or Wilcoxon signed-rank tests to compare connectivity at baseline vs. after TMS treatment. We will explore correlates of connectivity and changes using Pearson or Spearman correlations and linear regression or mixed models.

Exploratory Analysis: Follow-up exploratory voxel-wise analyses will be conducted for functional connectivity, which will provide thousands of individual predictors. This will help confirm findings in large parcel ROI based analysis. We will use the same statistical models as used for the ROI based analysis described above but at the voxel level. Voxel-wise data creates a high-dimensional problem in which the number of predictors far exceeds the number of participants. Machine learning methods, such as random forest will be used to handle the high-dimensional sub-analyses. Random forest requires a minimum of data assumptions, automatically accounts for non-linear and interaction effects, and it has proven useful in identifying useful predictors in high-dimensional contexts.

Comparison with Historical Controls: We will compare retention in psychosocial treatment programs and positive urine drug screens from chart review with a historical control group of patients with MA use disorder matched on age, sex, site, and psychosocial treatment modality. Treatment retention will be compared using a log-rank test. Positive urine drug screens in each week of follow-up will be compared using generalized estimating equation models with a logit link, clustered on subject, with participation in the TMS study as the variable of interest.

Eligibility criteria: Inclusion Criteria:

* Diagnosed with an active methamphetamine use disorder
* Is engaged in psychosocial treatment or articulates a plan to engage in psychosocial treatment for methamphetamine use disorder during the study period
* Age 18 to 60 years
* Able to consent for treatment and research participation
* English-speaking
* Receiving care from UIHC's Addiction Medicine service. This includes patients in the Crisis Stabilization Unit, seen by the inpatient consultation service, enrolling in partial hospitalization or intensive outpatient treatment, or seen in the outpatient Addiction Medicine clinics.

Exclusion Criteria:

* Age less than 18 years
* Patients that are excluded during TMS assessment including: patients with epilepsy or seizure disorder, patients with implanted ferromagnetic equipment in their face or skull near the stimulation target.
* Current medical treatment with clozapine or stimulants.
* Current diagnosis of bipolar disorder, schizoaffective disorder, schizophrenia, that is deemed by research team psychiatrists not to have been drug-induced. Psychotic disorder not associated with drug use per the MINI International Neuropsychiatric Interview. Psychosis NOS, in remission, or drug-induced psychotic episodes are not exclusion criteria since these may be related to methamphetamine misuse.
* Lacks the mental capacity to provide informed consent (i.e. not able to demonstrate understanding of the risks and benefits of participation)
* Has a court appointed guardian.
* Unstable medical illness.
* Current diagnosis of neurological disorder or neurocognitive disorder.
* Prior neurosurgical procedure.
* History of seizure.
* History of ECT treatment within the past three months.
* History of any previous TMS treatment.
* Known inability to complete the protocol, as assessed by asking them if they are able to make it to all visits for this study without assistance.

MRI Exclusion criteria:

* Implanted device including pacemaker, coronary stent, defibrillator, or neurostimulation device that is not MRI-compatible
* Metal in body including bullets, shrapnel, metal slivers
* Claustrophobia
* Uncontrolled high blood pressure
* Atrial fibrillation
* Significant heart disease
* Hemodynamic instability
* Kidney disease
* Pregnant

Primary outcomes:
measure: Retention in the study
timeFrame: Baseline to 12 weeks (continuous)
measure: Retention in psychosocial treatment
timeFrame: Baseline to 12 weeks (continuous--assessed weekly)
Secondary outcomes:
measure: Functional connectivity of the dorsolateral prefrontal cortex and anterior insula
timeFrame: Baseline, 4 weeks
measure: Functional connectivity dorsolateral prefrontal cortex and anterior cingulate cortex
timeFrame: Baseline, 4 weeks
measure: Functional connectivity of the medial prefrontal cortex and ventral striatum
timeFrame: Baseline, 4 weeks
measure: Flanker Inhibitor Control and Attention Test, Age 12+
timeFrame: Baseline, 4 weeks
measure: Kirby Delay Discounting Questionnaire, 27 item
timeFrame: Baseline, 4 weeks
measure: Number of days of stimulant use in the past week
timeFrame: Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Urine drug screen positive for stimulant
timeFrame: Baseline, 1 week, 2 weeks, 3 weeks, 4 weeks
measure: Brief substance craving scale
timeFrame: 12 weeks
measure: Brief Addiction Monitor Use Subscale
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Brief Addiction Monitor Risk Factors Subscale
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Brief Addiction Monitor Protective Factors Subscale
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Brief Addiction Monitor Satisfaction with Progress Toward Achieving Recovery Goals
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Quality of Life Enjoyment and Satisfaction Questionnaire-Short Form
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Patient Health Questionnaire--8 item scale
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Generalized Anxiety Disorder 7-item scale
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Assessment of Recovery Capital
timeFrame: Baseline, 4 weeks, 8 weeks, 12 weeks
measure: Positive and Negative Affect Scale Positive Affect Score
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Positive and Negative Affect Scale Negative Affect Score
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Pittsburgh Sleep Quality Index
timeFrame: Baseline, 2 weeks, 4 weeks, 8 weeks, 12 weeks
measure: Difficulties in Emotion Regulation Scale--Short Form
timeFrame: Baseline, 4 weeks
measure: UPPS-P Impulsive Behavior Scale, 59-item revised version
timeFrame: Baseline, 4 weeks
Other outcomes:
Locations:
city: Iowa City
country: United States
facility: University of Iowa
state: Iowa
Study officials:
affiliation: University of Iowa
name: Ryan Carnahan, PharmD, MS
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Iowa
name: Alison C Lynch, MD, MS
role: PRINCIPAL_INVESTIGATOR
References:
citation: Courtney KE, Ray LA. Methamphetamine: an update on epidemiology, pharmacology, clinical phenomenology, and treatment literature. Drug Alcohol Depend. 2014 Oct 1;143:11-21. doi: 10.1016/j.drugalcdep.2014.08.003. Epub 2014 Aug 17.
citation: Ma T, Sun Y, Ku Y. Effects of Non-invasive Brain Stimulation on Stimulant Craving in Users of Cocaine, Amphetamine, or Methamphetamine: A Systematic Review and Meta-Analysis. Front Neurosci. 2019 Oct 18;13:1095. doi: 10.3389/fnins.2019.01095. eCollection 2019.
citation: Zhang JJQ, Fong KNK, Ouyang RG, Siu AMH, Kranz GS. Effects of repetitive transcranial magnetic stimulation (rTMS) on craving and substance consumption in patients with substance dependence: a systematic review and meta-analysis. Addiction. 2019 Dec;114(12):2137-2149. doi: 10.1111/add.14753. Epub 2019 Aug 16.
citation: Makani R, Pradhan B, Shah U, Parikh T. Role of Repetitive Transcranial Magnetic Stimulation (rTMS) in Treatment of Addiction and Related Disorders: A Systematic Review. Curr Drug Abuse Rev. 2017;10(1):31-43. doi: 10.2174/1874473710666171129225914.
citation: Liang Y, Wang L, Yuan TF. Targeting Withdrawal Symptoms in Men Addicted to Methamphetamine With Transcranial Magnetic Stimulation: A Randomized Clinical Trial. JAMA Psychiatry. 2018 Nov 1;75(11):1199-1201. doi: 10.1001/jamapsychiatry.2018.2383.