Inflammation and Depression in People With HIV

Sponsor

Emory University (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05849038

Collaborator

National Institute of Mental Health (NIMH) (NIH)

150

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

1.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The purpose of this 10-week, double-blind, placebo-controlled study is to determine whether inflammation impacts reward and motor neural circuitry to contribute to depressive symptoms like anhedonia and psychomotor slowing in people with Human Immunodeficiency Virus (HIV) and depression. Sixty male and female patients with HIV who have depression, anhedonia and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either the anti-inflammatory drug baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study. The total length of participation is about 5 months.

Condition or Disease	Intervention/Treatment	Phase
HIV Depression Anhedonia	Drug: Baricitinib Other: Placebo	Phase 2

Detailed Description

Risk of depression is substantially higher in people with HIV (PWH) than the general population, and depression in PWH confers worse outcomes regarding treatment adherence, morbidity and mortality. Increased inflammation is one biological pathway that is linked to greater risk for depression in PWH and limits options for effective antidepressant therapy. Chronically elevated inflammation is associated with impairments within reward and motor neural circuits that contribute to symptoms of anhedonia (an inability to experience pleasure) and psychomotor slowing, which are overrepresented in PWH. The purpose of this 10-week, double-blind, placebo-controlled study is to provide mechanistic information on whether inflammation impacts corticostriatal reward and motor circuitry to contribute to anhedonia and psychomotor slowing in PWH with depression using the anti-inflammatory drug baricitinib.

This study will utilize an FDA-approved medication, baricitinib, to establish whether the effects of inflammation on reward and motor circuits are a mechanism of anhedonia and motor slowing in PWH with depression, while advancing avenues for new therapies.

Sixty male and female patients with HIV who have depression and high inflammation and are stable on effective treatment for their HIV will be randomized to receive either baricitinib or a placebo for 10 weeks. Participants will complete lab tests, medical and psychiatric assessments, neurocognitive testing, functional MRI (fMRI) scans, and optional spinal taps as part of the study. The total length of participation is about 3.5 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

150 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Triple (Participant, Care Provider, Investigator)

Primary Purpose:

Treatment

Official Title:

The Role of Inflammation in Central Nervous System (CNS) Mechanisms of Anhedonia and Psychomotor Slowing in Depressed People With HIV

Anticipated Study Start Date :

Jun 1, 2023

Anticipated Primary Completion Date :

Nov 1, 2027

Anticipated Study Completion Date :

Nov 1, 2027

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Baricitinib Participants will be randomized to receive 10 weeks of treatment with baricitinib.	Drug: Baricitinib Patients will receive baricitinib at a dose of 2 mg oral daily.
Placebo Comparator: Placebo Participants will be randomized to receive 10 weeks of treatment with placebo.	Other: Placebo A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 1 placebo tablet matching the baricitinib tablet.

Arm

Intervention/Treatment

Experimental: Baricitinib

Participants will be randomized to receive 10 weeks of treatment with baricitinib.

Drug: Baricitinib

Patients will receive baricitinib at a dose of 2 mg oral daily.

Placebo Comparator: Placebo

Participants will be randomized to receive 10 weeks of treatment with placebo.

Other: Placebo

A placebo is a sugar pill that has no therapeutic effect and will be administered orally. Participants will receive 1 placebo tablet matching the baricitinib tablet.

Outcome Measures

Primary Outcome Measures

Change in corticostriatal functional connectivity (FC) in reward circuit [Baseline visit, week 2, and week 10 after study medication]
Patients will undergo resting-state and task-based functional magnetic resonance imaging (fMRI) to calculate functional connectivity (FC) between the ventral striatum (VS) and ventromedial prefrontal cortex (vmPFC). FC is measured as continuous Z scores reflecting the correlation of activity between the brain regions. Higher FC Z scores reflect stronger connectivity.

Secondary Outcome Measures

Effort Expenditure for Reward Task (EEfRT) [Baseline visit, week 2 and week 10]
The EEfRT is a widely used, multi-trial task in which participants are given an opportunity on each trial to choose between two different task difficulty levels in order to obtain monetary rewards. EEfRT will be used as an objective measure of motivation and will be administered following MRI scans during the study. The EEfRT is reported as the percent of high effort trials selected. A higher percentage reflects higher motivation for effort expenditure.
Snaith Hamilton Pleasure Scale-Clinician Administered (SHAPS-C) [Baseline visit, week 1, week 2, week 4, week 6, week 10]
The Snaith-Hamilton Pleasure Scale-Clinician (SHAPS-C) is a clinician administered tool to assess symptoms of anhedonia. The SHAPS-C uses 14 question each rated on a Likert scale of 1-4, with higher scores reflecting greater pathology.
Motivation and Pleasure Scale-Self-Report (MAP-SR) [Baseline visit, week 1, week 2, week 4, week 6, week 10]
The Motivation and Pleasure-Self-Report (MAP-SR) will be used to capture self-reported aspects of anhedonia and reduced motivation. The scale uses 18 question each rated on a Likert scale of 0-4, with higher scores reflecting greater pathology.
Anhedonia subscale of Inventory of Depressive Symptoms-Self Rated (IDS-SR) [Baseline visit, week 1, week 2, week 4, week 6, and week 10]
Anhedonia will be assessed from a subscale of the Inventory of Depressive Symptomatology- Self-Report (IDS-SR). Scores on this 3-question scale range from 0-9 with higher scores reflecting greater anhedonia.
Finger Tapping Task (FTT) [Baseline visit, week 2 and week 10]
Finger Tapping Task (FTT) uses a specially adapted tapper that the subject taps as fast as possible using the index finger during 5 consecutive 10-second trials, calculated as mean and total number of taps for preferred and non-preferred hands.
Trail Making Task A (TMT-A) [Baseline visit, week 2 and week 10]
Trail Making Task A (TMT-A) measures psychomotor processing speed using a series of non-sequentially arranged numbers. The participant tracks the numbers in order as quickly as possible using paper and pencil.
Retardation Rating Scale (RRS) [Baseline visit, week 1, week 2, week 4, week 6, and week 10]
Retardation Rating Scale (RRS) is a 14-item, clinician-administered scale used to assess psychomotor retardation related to motility or mental activity.

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 65 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

HIV infected on continuous antiretroviral therapy (ART) with plasma HIV RNA <200 copies/ml for at least 12 months (on at least two previous clinic visits and confirmed at screening).
Current CD4+ > 350 cells/microliter for at least twelve months (on at least two previous clinic visits and confirmed at screening).
A primary diagnosis of DSM-V major depression, current, or Bipolar, depressed type as diagnosed by the SCID-V.
Score of ≥15 on the 9-item Patient Health Questionnaire (PHQ-9).
Off all antidepressant or other psychotropic therapy (e.g. mood stabilizers, antipsychotics, and sedative hypnotics) for at least 4 weeks (8 weeks for fluoxetine) or on a stable psychotropic regimen for at least 4 weeks prior to baseline visit.
Significant anhedonia as reflected by a score ≥ 2 on item #1 of the PHQ-9.
CRP≥3mg/L.
Women of reproductive age will have a negative serum pregnancy test at study entry and agree to contraception while on study drug.

Exclusion Criteria:

< 18 years of age or > 65 years of age
Pregnancy or breastfeeding
Significant hematological abnormalities at screening (ANC < 1500, Hgb<10, platelet< 100,000)
History of progressive multifocal leukoencephalopathy
Untreated latent tuberculosis infection (which will be screened for prior to entry)
Immunosuppressive medications (including corticosteroids) and anticoagulants (aspirin acceptable)
History of deep venous thrombosis
Cardiovascular disease:

Coronary artery disease or history of myocardial infarction
Congestive heart failure with left ventricular ejection fraction ≤40% per American Heart Association guidelines152
Stroke history

Hematologic malignancies including lymphoma and leukemia
Major surgery within 8 weeks prior to screening or will require major surgery during the study
Current or recent (<4 weeks prior to randomization) clinically serious viral (including COVID-19), bacterial, fungal, or parasitic infection or any other active or recent infection
Symptomatic herpes simplex at the time of randomization
Symptomatic herpes zoster infection within 12 weeks prior to randomization.
History of disseminated/complicated herpes zoster (for example, ophthalmic zoster or CNS involvement).
Positive test for hepatitis B virus (HBV) defined as:

positive for hepatitis B surface antigen (HBsAg), or
positive for hepatitis B core antibody (HBcAb) and positive for hepatitis B virus deoxyribonucleic acid (HBV DNA)

Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV ribonucleic acid [RNA]-positive).
Cirrhosis of the liver from any cause
Any of the following specific abnormalities on screening laboratory tests:

ALT or AST >2 x upper limits of normal (ULN)
alkaline phosphatase (ALP) ≥2 x ULN
total bilirubin ≥1.5 x ULN (with the exception of patients on atazanavir, who must have total bilirubin <2 x ULN)

Chronic kidney disease with eGFR <40 mL/min/1.73 m2 (note that dose of baricitinib will be reduced to 1 mg daily in participants with GFR between 40 and 60).
History of any (non-mood-related) psychotic disorder; active psychotic symptoms of any type; substance abuse/dependence within 6 months of study entry (as determined by Severe combined immunodeficiency (SCID).
A positive urine drug screen for illicit drugs at any time during the study excluding marijuana.
An active suicidal plan as determined by a score >3 on item #3 on the Hamilton Rating Scale for Depression (HAM-D).
An active eating disorder or antisocial personality disorder.
<24 on the Mini-Mental State Exam.
Chronic use of non-steroidal anti-inflammatory agents (NSAIDS) (excluding 81mg of aspirin), glucocorticoid containing medications or minocycline within 2 weeks of baseline or at any time during the study.
Any contraindication for MRI scanning.
Failure of more than 2 antidepressant trials (at least 6 weeks at recommended dose) in the current episode or 5 antidepressant trials lifetime.
BMI >40 (to exclude severe obesity).
History of an autoimmune disorder