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Theophylline for Depression Study (T-DEP)

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ClinicalTrials.gov Identifier: NCT04309877
Recruitment Status : Not yet recruiting
First Posted : March 16, 2020
Last Update Posted : October 22, 2020
Sponsor:
Information provided by (Responsible Party):
Hyong Jin Cho, University of California, Los Angeles

Brief Summary:
Depression is very common and poses a huge disease burden. About 20% of the US population suffers from depression at least once in their lifetime. Inflammations that are hidden inside our body as a result of aging, obesity, chronic diseases, or certain treatments (e.g., interferon for hepatitis C) appear to cause depressive symptoms and even clinical depression. Individuals with such inflammations are more likely to suffer from depression and are less likely to respond to currently available antidepressant medications. This study will test theophylline, a medication currently used for asthma treatment, as a new way to mitigate depressive symptoms in response to such inflammations. This study begins with a 90-minute screening session to determine whether participants are eligible to join the main study. Those who meet the eligibility criteria will then join the main study, which will consist of taking theophylline or methylcellulose (i.e., oral placebo) for 2 weeks at home and an 8-hour session at the UCLA Medical Center. Approximately 20 healthy adults will be recruited for participation in the study. During the course of the study, participants will take theophylline or methylcellulose for 2 weeks at home and then will be injected either lipopolysaccharide (LPS) or saline (i.e., intravenous placebo) at the UCLA Medical Center. LPS is a bacterial substance that can initiate chemical reactions that are similar to those seen in individuals with mild sickness symptoms, such as a slight increase in body temperature, muscle aches, or tiredness. It is a safe way of investigating the body's response to inflammation and how these changes may alter cognitive, emotional, or neural function. It has been given thousands of times to healthy volunteers - both younger and older adults - without any serious side effects.

Condition or disease Intervention/treatment Phase
Depression Drug: Theophylline ER Other: PO placebo Biological: Lipopolysaccharide (LPS) Other: IV placebo Early Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Basic Science
Official Title: Pilot Randomized Controlled Trial of Theophylline for Attenuation of Lipopolysaccharide-Induced Depressive Symptoms
Estimated Study Start Date : March 2021
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: PO theophylline & IV LPS
Oral (PO) theophylline 400 mg/day for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight
Drug: Theophylline ER
Capsules of theophylline ER

Biological: Lipopolysaccharide (LPS)
Purified bacterial wall component as an inflammatory challenge

Experimental: PO placebo & IV LPS
PO methylcellulose (placebo) daily for 2 weeks followed by a single intravenous (IV) bolus of lipopolysaccharide (LPS) 0.8 ng/kg of body weight
Other: PO placebo
Capsules of methylcellulose

Biological: Lipopolysaccharide (LPS)
Purified bacterial wall component as an inflammatory challenge

Experimental: PO theophylline & IV placebo
PO theophylline 400 mg/day for 2 weeks followed by a single IV bolus of 0.9% saline
Drug: Theophylline ER
Capsules of theophylline ER

Other: IV placebo
Normal (0.9%) saline

Placebo Comparator: PO placebo & IV placebo
PO methylcellulose (placebo) daily for 2 weeks followed by a single IV bolus of 0.9% saline
Other: PO placebo
Capsules of methylcellulose

Other: IV placebo
Normal (0.9%) saline




Primary Outcome Measures :
  1. Change in depressed mood from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Short Form of the Profile of Mood States (POMS-SF) Depression Subscale with higher scores indicating more severe depressed mood (range 0-32)


Secondary Outcome Measures :
  1. Change in tension/anxiety from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Short Form of the Profile of Mood States (POMS-SF) Tension Subscale with higher scores indicating more severe tension/anxiety (range 0-24)

  2. Change in depressive symptoms from baseline [ Time Frame: At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration ]
    Montgomery-Asberg Depression Rating Scale (MADRS): a clinician-rated questionnaire of depressive symptoms with scores ranging from 0 to 60, with higher scores indicating more severe depressive symptoms

  3. Change in feelings of social disconnection from baseline [ Time Frame: At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration ]
    Feelings of Social Disconnection Scale: a self-report questionnaire of feelings of social disconnection with scores ranging from 0 to 28, with higher scores indicating more severe feelings of social disconnection

  4. Change in fatigue from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Short Form of the Profile of Mood States (POMS-SF) Fatigue Subscale with higher scores indicating more severe fatigue (range 0-20)

  5. Change in confusion from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Short Form of the Profile of Mood States (POMS) Confusion Subscale with higher scores indicating more severe confusion (range 0-20)

  6. Change in verbal memory from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
    Verbal memory measured using computerized tests from CNS Vital Signs™

  7. Change in visual memory from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
    Visual memory measured using computerized tests from CNS Vital Signs™

  8. Change in executive function from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
    Executive function measured using computerized tests from CNS Vital Signs™

  9. Change in attention from baseline [ Time Frame: At baseline and then 3 hours after LPS (or saline) administration ]
    Attention measured using computerized tests from CNS Vital Signs™


Other Outcome Measures:
  1. Subjective Sensitivity to Social Rejection [ Time Frame: 2 hours after LPS (or saline) administration ]
    Cyberball Social Exclusion Task

  2. Negative Bias in Facial Emotion Recognition [ Time Frame: 2 hours after LPS (or saline) administration ]
    Emotional Face Recognition Task

  3. Reward [ Time Frame: 2 hours after LPS (or saline) administration ]
    Reward Learning Task

  4. Change in proinflammatory cytokines from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Plasma proinflammatory cytokines (interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-α, and soluble tumor necrosis factor receptor)

  5. Change in kynurenine Metabolites from baseline [ Time Frame: At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration ]
    Plasma tryptophan, kynurenine, quinolinic acid, and kynurenic acid

  6. Change in gene expression from baseline [ Time Frame: At baseline and 30 minutes after LPS (or saline) administration ]
    Genome-wide transcriptional profiling with focus on the percentage increase from baseline to 30 minutes after LPS (or saline) administration in activities of transcription factors related to immune activation, sympathetic activation, and glucocorticoid insensitivity: respectively, nuclear factor kappa-B (NF-kB), cAMP response element-binding protein (CREB), and glucocorticoid receptor (GR).



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • in good general health (as evaluated during the phone and in-person screening sessions)
  • aged 18-65 years
  • if female, using adequate birth control

Exclusion Criteria:

  • history of hypersensitivity to xanthine derivatives (a contraindication to theophylline treatment)
  • pregnant or planning to become pregnant in the next 6 months
  • current breastfeeding
  • chronic diseases such as cardiovascular disease, hepatic impairment, peptic ulcer disease, and seizure disorders
  • current use of prescription medications such as steroids, non-steroid anti-inflammatory drugs, immune modifying drugs, opioid analgesics, and psychotropics
  • Axis I psychiatric disorders including current major depressive disorder
  • current depressive symptoms assessed by the Patient Health Questionnaire (PHQ-9 ≥ 5)
  • heavy smoking (1 pack or more per day)
  • excessive caffeine use (>600 mg/day)
  • Body-mass index > 35 due to the effects of obesity on cytokine activity
  • evidence of recreational drug use from urine test
  • evidence of pregnancy from urine test
  • evidence of clinically significant rhythm abnormality on a resting electrocardiogram (ECG)
  • clinically significant abnormalities on screening laboratory tests

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04309877


Contacts
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Contact: Ariya Mahbod, MD 310-267-4389 Amahbod@mednet.ucla.edu

Locations
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United States, California
UCLA Cousins Center for Psychoneuroimmunology
Los Angeles, California, United States, 90095
Sponsors and Collaborators
University of California, Los Angeles
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Responsible Party: Hyong Jin Cho, Associate professor, University of California, Los Angeles
ClinicalTrials.gov Identifier: NCT04309877    
Other Study ID Numbers: 20-000005
First Posted: March 16, 2020    Key Record Dates
Last Update Posted: October 22, 2020
Last Verified: October 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Depression
Depressive Disorder
Behavioral Symptoms
Mood Disorders
Mental Disorders
Theophylline
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Phosphodiesterase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Vasodilator Agents
Purinergic P1 Receptor Antagonists
Purinergic Antagonists
Purinergic Agents
Neurotransmitter Agents