Defining Neurobiological Links Between Substance Use and Mental Illness
Study Details
Study Description
Brief Summary
Background:
Nicotine dependence leads to about 480,000 deaths every year in the United States. People with major depressive disorder (MDD) are twice as likely to use nicotine compared to the general population. They have greater withdrawal symptoms and are more likely to relapse after quitting compared with smokers without MDD. More research is needed on how nicotine affects brain function in those with MDD.
Objective:
To understand how nicotine affects symptoms of depression and related brain function.
Eligibility:
People aged 18 to 60 years with and without MDD who do not smoke cigarettes or use other nicotine products.
Design:
Participants will have 3 or 4 study visits over 1 to 4 months.
Participants will have 3 MRI scans at least 1 week apart. Each scan visit will last 5 to 7 hours. At each scan, they will have urine and breath tests to screen for recent use of alcohol, nicotine, and illegal drugs.
Before each scan, they will take 1 of 3 medications: nicotine, placebo, or mecamylamine. (Mecamylamine blocks the effects of nicotine.) Participants will receive each medication once. They will not know which medication they are receiving at each scan.
For each MRI scan, they will lie on a table that slides into a cylinder. Sometimes they will be asked to lie still. Sometimes they will complete tasks on a computer. Tasks may include identifying colors or playing games to win money. Each scan will take about 2 hours.
Participants will answer questions about their thoughts, feelings, and behaviors before and after each scan.
They will have a blood test after each scan.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
Study Description:
Tobacco smoking leads to 480,000 deaths and a loss of $300 billion a year in the U.S. Individuals with major depressive disorder (MDD) are more vulnerable for experiencing these burdens as they are twice as likely to use nicotine versus the general population. The current work will explain the neurobiological basis of this enhanced risk and will define potential targets for lessening the impact of nicotine on those with MDD. This research plan will take the innovative approach of evaluating nicotine s effects in non-smokers with and without MDD. In contrast to focusing on nicotine dependent individuals, which introduces confounds due to chronic use, this design will directly show the domains in which the neurobiological impact of nicotine is greater in those with MDD, providing a mechanistic framework for enhanced risk. This proposal also will evaluate two theories linking nicotine use with MDD by comparing the neurobiological consequence of nicotine with that of the nicotinic antagonist mecamylamine. This is relevant as it is postulated that nicotinic agonists and antagonists may both have anti-depressant effects that drive further use.
Objectives:
The primary objective is to determine the differential neurobiological impact of a nicotinic agonist and antagonist on those with and without current major depressive disorder. Whether such effects are linked with specific symptoms of MDD will be assessed as will the potential modifying influence of biological sex. Those with a lifetime history of MDD will be assessed as well given evidence that reduced reward responsivity is a trait that persists even when one no longer meets current MDD criteria.
Endpoints:
Brain function will be assessed in several ways: 1) Resting-state fMRI will determine pharmacologically mediated group-specific differences in functional brain organization and inherent dynamic functioning 2) Task-based fMRI will determine pharmacologically mediated group-specific differences in reward function, affective processing, and interceptive awareness. These same measures will further be assessed considering specific symptoms of MDD and biological sex.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Arm 1: Placebo Placebo patch + Placebo Pill |
Other: Placebo Nicotine Patch
Comparator
Drug: Mecamylamine
Study drug: 7.5 mg mecamylamine pill, which will be administered in a double blind, randomized manner.
|
| Experimental: Arm 2: Nicotine Patch Nicotine Patch + Placebo Pill |
Drug: Nicotine Patch
Study drug: 7.5 mg Nicotine Patch which will be administered in a double blind, randomized manner
Drug: Mecamylamine
Study drug: 7.5 mg mecamylamine pill, which will be administered in a double blind, randomized manner.
|
| Experimental: Arm 3: Mecamylamine Placebo Patch + Mecamylamine Pill |
Other: Placebo Nicotine Patch
Comparator
Drug: Mecamylamine
Study drug: 7.5 mg mecamylamine pill, which will be administered in a double blind, randomized manner.
|
Outcome Measures
Primary Outcome Measures
- 3. Task and Resting State Brain [At each scan visit]
Relate static and temporal dynamic resting state brain function to nicotinic effects.
- 1.Resting-fMRI [At each scan visit]
1.Determine the impact of nicotine agonism/antagonism on the brain s inherent function and organization at rest.
- 4.Nicotine effects and symptoms of MDD [At each scan visit]
Greater expression of MDD symptoms will related to a larger nicotine-induced impact within that domain.
- 2.Task-fMRI [At each scan visit]
2. Evaluate nicotine agonism/antagonism on: 1) different phases of reward processing, 2) brain/behavioral measures of attentional bias using the classic and emotional Stroop task, and 1.3. 3) interoceptive awareness. 4) confidence on value-based decisions, determine the influence of sex in the context of points 1-3.
Secondary Outcome Measures
- Determine the relationship between blood-based biomarkers, such as inflammatory makers/metabolomics and nicotinic effects [Ongoing]
Correlate levels of blood-based biomarkers with brain and behavioral measures and determine whether nicotine...
Eligibility Criteria
Criteria
- INCLUSION CRITERIA:
To be eligible for this study, an individual must meet all the following criteria assessed under the 06-DA-N415 protocol: Evaluation of potential research subjects - screening protocol for clinical studies (here referred to as the NIDA screening protocol). This is a protocol led by the Office of the Clinical Director (OCD) at the National Institute on Drug Abuse Intramural Research Program (NIDA IRP) to assess potential research participants eligibility for entering clinical protocols at the NIDA/IRP. Additional details can be found in the NIDA screening protocol documents. As routinely done at the NIDA IRP, the screening procedures and data collected under the NIDA screening protocol will capture information above and beyond what is necessary to determine eligibility for this protocol but allows the Investigators to assess the eligibility criteria for this protocol.
In order to be eligible to participate in this study, an individual must meet all of the following criteria:
All Participants:
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Able and willing to provide written informed consent, which includes agreement to all Lifestyle Considerations
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Both sexes and all ethnic origins, age between 18 and 60: Justification: Many neural processes change with age, and these changes could introduce unwanted variability in both behavioral and MRI signals.
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Be general healthy
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Absence of pregnancy and breastfeeding. Justification: study procedures and drugs used in the current protocol may complicate pregnancy or be transferred to nursing children. Assessment tool(s): Urine and/or serum pregnancy tests, and clinical interview. Urine pregnancy tests will also be conducted at the beginning of each imaging visit. 5) Have a Breath Alcohol Value of 0 on all study visit days involving scanning. Participant may be rescheduled if this value is greater than 0.
MDD Subjects:
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Meet DSM-5 diagnostic criteria for current MDD at screening
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Have a baseline (Hamilton Depression) HAM-D score indicative of current depression
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Absence of any psychotropic medication for at least 2 weeks except current stable SSRI/SNRI treatment is allowed (no changes in the last 2 months)
Remitted MDD Subjects:
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Meet DSM-5 diagnostic criteria for remitted MDD (full remission or past depression)
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Absence of any psychotropic medication for at least 2 weeks prior to scanning except current stable SSRI treatment is allowed, provided there are no changes in the 2 months prior to scanning
Control Subjects (without MDD):
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In addition to the absence of medical, neurological, and psychiatric illness listed above, control participants must not have current/lifetime MDD
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HAM-D score indicating no clinically-relevant depression
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Absence of any psychotropic medication for at least 2 weeks prior to scanning
EXCLUSION CRITERIA:
An individual who meets any of the following criteria will be excluded from participation in this study:
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Subjects with suicidal ideation where outpatient treatment is determined unsafe.
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Lifetime history or current diagnosis of any of the following psychiatric illnesses: organic mental disorder, schizophrenia, schizoaffective disorder, delusional disorder, psychotic disorders not otherwise specified, bipolar disorder, patients with mood congruent or mood incongruent psychotic features. The MAI and/or PI/LI will reserve the right to exclude based psychiatric history not explicitly described in this criterion
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Within the current/remitted MDD cohorts, simple phobia, social anxiety disorder, ADHD, and generalized anxiety disorders will be allowed cohort only if secondary to MDD;
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Within the control group, Current/lifetime MDD will be exclusionary for controls. The MAI will reserve the right to exclude on the basis of psychiatric history not explicitly described in this criterion
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Patients with a lifetime history of electroconvulsive therapy (ECT)
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Are cognitively impaired or learning disabled. Justification: Cognitive impairment and learning disabilities may be associated with altered brain functioning in regions recruited during laboratory task performance. Cognitive impairment may affect one s ability to give informed consent
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Heavy caffeine users (consume greater than 500 mg on a regular or daily basis. This is approximately five 8 fl oz cups of coffee). Participants will be asked to not deviate from their typical caffeine use on all scanning days.
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May not have used any nicotine product in the past year; must report fewer than 20 lifetime uses of nicotine
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Must have an expired carbon monoxide level of less than or equal to 5 ppm and no detected cotinine
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History of substance abuse in the past 6 months (other than caffeine)
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Current pharmacological treatment for opiate use disorder (i.e. use of methadone)
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Current use of illegal drugs other than marijuana as measured by urine drug screen. Marijuana will not be allowed in the 24 hours prior to scanning based on self-report. Study day can be rescheduled to accommodate.
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May not use anticholinergic drugs (i.e. scopolamine) in the week prior to any scanning visit. Scanning visit timing can be adjusted to accommodate.
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May not use drugs that directly enhance dopamine (i.e. methylphenidate) in the week prior to any scanning visit. Scanning visit timing can be adjusted to accommodate.
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Any past or present significant cardiovascular, cerebrovascular, or respiratory conditions, including arrhythmias, acute coronary syndrome, or ischemic heart disease
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Uncontrolled hypertension history of chronic low blood pressure, history of frequent fainting/near syncope episodes
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Endorsement of this question: Do you regularly get lightheaded or temporarily lightheaded when getting up out of a chair or from laying down?
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Body mass index (BMI) lower than 18.5 kg/m^2
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Contraindication to MRI as determined by MRI Safety Screening form
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Contraindication to mecamylamine which includes a coronary insufficiency or recent myocardial infarction; uremia; glaucoma; and co-administration with antibiotics or sulfonamides.
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Abnormal structural MRI, significant head trauma, current neurological illness including but not limited to frequent migraines, multiple sclerosis, movement disorder
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Lifetime history of significant seizure disorder
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Any other serious or unstable medical illness as defined by self-report, the evaluation of vital signs or other observation that in the view of the investigators would compromise the safety of an individual during participation
All data collected will be evaluated by members of the study team to decide if there is an existing medical illness that would compromise participation in this research
-Subjects that cannot speak English. Justification: To include non-English speakers, we would have to translate the consent and other study documents and hire and train bilingual staff, which would require resources that we do not have and could not justify, given the small sample size for each experiment. Additionally, the data integrity of some of the cognitive tasks and standardized questionnaires used in this study would be compromised as they have only been validated in English. Most importantly, ongoing communication regarding safety procedures is necessary when participants are undergoing MRI procedures. The inability to effectively communicate MRI safety procedures in a language other than English could compromise the safety of non-English speaking participants
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | National Institute on Drug Abuse | Baltimore | Maryland | United States | 21224 |
Sponsors and Collaborators
- National Institute on Drug Abuse (NIDA)
Investigators
- Principal Investigator: Amy Janes, Ph.D., National Institute on Drug Abuse (NIDA)
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 10000922
- 000922-DA