The Neural Underpinnings of Depression and Cannabis Use in Young People Living With HIV

Study Overview
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Brief Summary
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To elucidate mechanisms of substance use disorders (SUD) and comorbid mental illnesses in people living with HIV (PLWH), the investigators propose to investigate reward and pain circuitry in cannabis use and depression comorbidity, two highly prevalent conditions in PLWH. The study will take place in our health system in The Bronx-a persistent epicenter of the HIV epidemic due to profound poverty and health disparities. The focus is on young adults (ages 18-34) to minimize HIV chronicity effects and due to the high rates of SUD and reduced adherence to HIV treatments in this age group; among >31,000 diagnosed young PLWH in The Bronx in 2019, less than 70% had suppressed (<200 copies/mL) viral load (VL).

Detailed Description
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We propose to investigate reward and pain circuitry in cannabis use and depression comorbidity, two highly prevalent conditions in PLWH. We will focus on young adults (ages 18-34) to minimize HIV neuronal chronicity effects and in light of the high rates of substance use and reduced adherence to HIV treatment in this age group. Our proposed model is: 1) Both reward dysfunction (deficits in reward learning, expectancy, attainment, positive prediction errors) and pain hypersensitivity (pain sensitivity, aversion, negative prediction errors) contribute to cannabis use and depression comorbidity in young PLWH. 2) The habenula (Hb), a small limbic hub, plays a pivotal regulatory role in these processes by inhibiting ventral tegmental area (VTA) reward signals to the nucleus accumbens (NAc) following pain and loss. 3) THC, a major component of cannabis, exerts its psychoactive analgesic effects by binding to cannabinoid 1 receptors in the reward and pain systems, including the anterior cingulate (ACC), periaqueductal gray (PAG), thalamus, amygdala, VTA, NAc, and Hb, creating temporary relief of mood and pain symptoms but resulting in long-term alterations in reward circuitry that exacerbate depression and substance use. 4) Capitalizing on improvements in fMRI resolution, our novel imaging methods overcome prior technical constraints to study the Hb and other small structures critical to reward and pain processing.We will test the overall hypothesis that cannabis use and depression in young PLWH have an additive effect, inducing both reward deficits and pain hypersensitivity, and that this pattern will predict worse outcomes at 1 year follow-up. Investigators will utilize a 2×2 factorial design: 1) 70 depressed cannabis users; 2) 70 depressed cannabis non-users; 3) 70 non-depressed cannabis users; and 4) 70 non-depressed cannabis non-users. To capture a wide range of illness severity, investigators will include subthreshold depression and cannabis use on ≥20 days of the past 30 days. Comprehensive clinical evaluations, a computerized reward task, and blood tests for CD4+ count, VL, and serum THC will be performed at baseline, 6- and 12 months. fMRI (resting-state, RFT, RPET, pain task) and cognitive tests will be done at baseline.

Official Title
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The Neural Underpinnings of Depression and Cannabis Use in Young People Living With HIV

Conditions
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Hiv, Depression, Cannabis Use Disorder

Intervention / Treatment
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* Other: MRI study - everyone scanned.


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: HIV seropositivity confirmed with lab report, medical records, or HIV testing. Between the ages of 18-34 years Fluency in English or Spanish Ability to provide informed consent and perform study procedures, including estimated full-scale IQ >75 to ensure that participants are able to understand the study. Cannabis users: To capture a wide range of cannabis use frequency, meeting DSM-5 criteria for CUD will not be required. However, in order to ensure sufficient exposure, cannabis use will be significant (self-reported use on ≥20 of the prior 30 days and positive THC urine toxicology). Depressed: In order to capture a wide range of depression illness severity, we will allow participants with subthreshold depression, defined as a raw severity score of ≥12 on the Montgomery Asberg Depression Rating Scale (MADRS). Exclusion Criteria: Perinatally acquired HIV infection, as early neurodevelopmental alterations and HIV legacy effects may exist in this group Pregnancy or lactation Current Substance Use Disorder other than cannabis or nicotine Certified for or self-reported medical cannabis use, or intent to become certified Current cocaine use by self-report or urine toxicology CNS disease or injury, or neuro-degenerative disease Unique pain syndromes (e.g. multiple sclerosis, rheumatoid arthritis); Severe medical illness such as end-stage renal disease, heart failure, cirrhosis, or cancer MRI contraindication such as claustrophobia, metallic ink tattoos, or pacemaker. Depressed cannabis non-users: At baseline, all participants will be psychotropic-medication-free for ≥1 month prior to study enrollment (or ≥3 months for medications with longer half-lives). Benzodiazepines and sleeping aids taken on an as-needed basis will be allowed, however we will require a 4-day abstinence period before the scan. Exclusionary are participants with a DSM-5 diagnoses of bipolar disorder, psychotic disorders, autism spectrum disorders, and all non-cannabis substance-related disorders will be exclusionary. disorder (PTSD) are not uncommon among depressed individuals and will be Anxiety disorders, obsessive-compulsive disorder (OCD), and post-traumatic stress are allowed as long as depressive symptoms are primary. atypical of depression. • Suicidal ideations (SI) without a specific plan (defined as passive SI) are common in depression and will be allowed. However, if SI constitutes an imminent risk to self or others (defined as active SI), the participant will be withdrawn from the study and emergency procedures will be initiated immediately, including ER admission. Depressed cannabis users: • Exclusion criteria will be the same as depressed cannabis non-users except for cannabis use. Non-depressed cannabis users: • Will have no major psychiatric conditions other than cannabis use/disorder. Non-depressed cannabis non-users: • Exclusion criteria will be the same as for non-depressed cannabis users; in addition participants will not report cannabis use in the prior 90 days and have a urine toxicology test negative for cannabis.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 34 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Intervention Model: Single Group Assignment
Interventional Model Description: 2x2 neuroimaging study
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: PLWH<br>All participants will undergo neuroimaging and behavioral tests. | Other: MRI study - everyone scanned.<br>* This is an observational study without an intervention.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Addiction Severity Index (ASI) | Tool widely used in the evaluation of substance use treatment. It looks at history, frequency, and consequences of alcohol and drug use. | Baseline | 
| Montgomery Asberg Depression Rating Scale (MADRS) Scale 0-60 higher more severe | Measures the severity of depressive episodes in patients with mood disorders | Baseline | 
| Temporal Experience of Pleasure Scale (TEPS) 25 to 120 higher more pleasure | Self-report measure allowing the assessment of anticipatory and consummatory pleasure | Baseline | 
| neural circuitry underling reward and pain | fMRI based tasks to measure brain activation during reward and pain processes | Baseline | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Daily Sessions Frequency Age Quantity of Cannabis Use Inventory (DFAQ- CU) Score range 0 to 185. The higher the score, the greater the usage of cannabis. | Measures cannabis consumption | Baseline | 
| Daily sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ- CU) Score range 0 to 185. The higher the score, the greater the usage of cannabis. | Measures cannabis consumption | 6 months | 
| Daily sessions, Frequency, Age of Onset, and Quantity of Cannabis Use Inventory (DFAQ- CU) Score range 0 to 185. The higher the score, the greater the usage of cannabis. | Measures cannabis consumption | 12 months | 
| Time Flowback (TLFB) Higher the score the greater the use. | Tool to obtain a variety of quantitative estimates of marijuana, cigarette, and other drug use. | Baseline | 
| Time Flowback (TLFB) Higher the score the greater the use. | Tool to obtain a variety of quantitative estimates of marijuana, cigarette, and other drug use. | 6 month | 
| Time Flowback (TLFB) Higher the score the greater the use. | Tool to obtain a variety of quantitative estimates of marijuana, cigarette, and other drug use. | 12 month | 
| THC Metabolite, Serum | Suggests use of, or exposure to, a product containing THC. | Baseline | 
| THC Metabolite, Serum | Suggests use of, or exposure to, a product containing THC. | 6 month | 
| THC Metabolite, Serum | Suggests use of, or exposure to, a product containing THC. | 12 month | 
| Fagerstrom test of nicotine dependence | Examines physical intensity of addiction to nicotine | Baseline | 
| Fagerstrom test of nicotine dependence | Examines physical intensity of addiction to nicotine | 6 month | 
| Fagerstrom test of nicotine dependence | Examines physical intensity of addiction to nicotine | 12 month | 
| Beck Depression Inventory-II (BDI-II) Score 0-63 higher the score greater the depression | Designed to assess the presence and severity of depressive symptoms | Baseline | 
| Beck Depression Inventory-II (BDI-II) Score 0-63 higher the score greater the depression | Designed to assess the presence and severity of depressive symptoms | 6 month | 
| Beck Depression Inventory-II (BDI-II) Score 0-63 higher the score greater the depression | Designed to assess the presence and severity of depressive symptoms | 12 month | 
| Snaith-Hamilton Pleasure Scale (SHAPS) Score 0-42 greater the score greater the pleasure. | Measures anhedonia, the inability to experience pleasure. | Baseline | 
| Snaith-Hamilton Pleasure Scale (SHAPS) Score 0-42 greater the score greater the pleasure. | Measures anhedonia, the inability to experience pleasure. | 6 month | 
| Snaith-Hamilton Pleasure Scale (SHAPS) Score 0-42 greater the score greater the pleasure. | Measures anhedonia, the inability to experience pleasure. | 12 month | 
| AUDIT-C The higher the score the greater the alcohol use disorder. | Identify persons who are hazardous drinkers or have active alcohol use disorders | Baseline | 
| AUDIT-C The higher the score the greater the alcohol use disorder. | Identify persons who are hazardous drinkers or have active alcohol use disorders | 6 month | 
| AUDIT-C The higher the score the greater the alcohol use disorder. | Identify persons who are hazardous drinkers or have active alcohol use disorders | 12 month | 
| CUPIT The higher the score the more problematic the use. | Measures risky and problematic cannabis use. | Baseline | 
| CUPIT The higher the score the more problematic the use. | Measures risky and problematic cannabis use. | 6 month | 
| CUPIT The higher the score the more problematic the use. | Measures risky and problematic cannabis use. | 12 month | 
| Pittsburgh sleep quality index Scores 0-24 higher the score greater sleep dysfunction | Assesses sleep quality and disturbances over a month period | Baseline | 
| Pittsburgh sleep quality index Scores 0-24 higher the score greater sleep dysfunction | Assesses sleep quality and disturbances over a month period | 6 month | 
| Pittsburgh sleep quality index Scores 0-24 higher the score greater sleep dysfunction | Assesses sleep quality and disturbances over a month period | 12 month | 
| Addiction Severity Index (ASI) | Tool widely used in the evaluation of substance use treatment. It looks at history, frequency, and consequences of alcohol and drug use. | 6 months | 
| Addiction Severity Index (ASI) | Tool widely used in the evaluation of substance use treatment. It looks at history, frequency, and consequences of alcohol and drug use. | 12 months | 
| Montgomery Asberg Depression Rating Scale (MADRS) Scale 0-60 higher more severe | Measures the severity of depressive episodes in patients with mood disorders | 6 months | 
| Temporal Experience of Pleasure Scale (TEPS) 25 to 120 higher more pleasure | Self-report measure allowing the assessment of anticipatory and consummatory pleasure | 6 months | 
| Brief Pain Inventory (BPI) The higher the score the greater the pain severity and impairment on functioning. | Assesses the severity of pain and its impact on functioning. | 6 months | 
| Brief Pain Inventory (BPI) The higher the score the greater the pain severity and impairment on functioning. | Assesses the severity of pain and its impact on functioning. | 12 months | 
| Temporal Experience of Pleasure Scale (TEPS) 25 to 120 higher more pleasure | Self-report measure allowing the assessment of anticipatory and consummatory pleasure | 12 months | 
| Pain Anxiety Symptom Scale (PASS-20) Range 0-100 higher the more anxiety symptoms | Measures fear and anxiety responses specific to pain. | 6 months | 
| HIV RNA test 20 to 10,000,000 copies/mL higher the amount the more infectious | HIV RNA test detects HIV and not antibodies | Baseline | 
| CD4+ CD8+ | Monitors the immune system | Baseline | 
| CD4+ CD8+ | Monitors the immune system | 6 months | 
| CD4+ CD8+ | Monitors the immune system | 12 months | 
| Montgomery Asberg Depression Rating Scale (MADRS) Range 0-60 higher more severe | Measures the severity of depressive episodes in patients with mood disorders | 12 months | 
| Brief Pain Inventory (BPI) The higher the score the greater the pain severity and impairment on functioning. | Assesses the severity of pain and its impact on functioning. | Baseline | 
| Pain Anxiety Symptom Scale (PASS-20) Range 0-100 higher the more anxiety symptoms | Measures fear and anxiety responses specific to pain. | 12 months | 
| Pain Anxiety Symptom Scale (PASS-20) Range 0-100 higher the more anxiety symptoms | Measures fear and anxiety responses specific to pain. | Baseline | 
| HIV Visual Analogue Scale (HIV-VAS) 0-30 higher score worse pain | The VAS asks individuals to mark a line at the point along a continuum showing how much of each drug they have taken in the last 4 weeks. | 12 month |