Theophylline for Depression Study (T-DEP)

Pilot Randomized Controlled Trial of Theophylline for Attenuation of Lipopolysaccharide-Induced Depressive Symptoms

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.

Study Overview

• Status: Withdrawn
• Conditions: Depression
• Intervention / Treatment: Drug: Theophylline ER; Biological: Lipopolysaccharide (LPS); Other: PO placebo; Other: IV placebo

• Study Type: Interventional
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095
      • UCLA Cousins Center for Psychoneuroimmunology

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Factorial Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / 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	Biological: Lipopolysaccharide (LPS); Purified bacterial wall component as an inflammatory challenge; Other: PO placebo; Capsules of methylcellulose
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

What is the study measuring?

Primary Outcome Measures

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

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in tension/anxiety from baseline	Short Form of the Profile of Mood States (POMS-SF) Tension Subscale with higher scores indicating more severe tension/anxiety (range 0-24)	At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in depressive symptoms from baseline	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	At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration
Change in feelings of social disconnection from baseline	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	At baseline and then at 2, 4, and 6 hours after LPS (or saline) administration
Change in fatigue from baseline	Short Form of the Profile of Mood States (POMS-SF) Fatigue Subscale with higher scores indicating more severe fatigue (range 0-20)	At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in confusion from baseline	Short Form of the Profile of Mood States (POMS) Confusion Subscale with higher scores indicating more severe confusion (range 0-20)	At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in verbal memory from baseline	Verbal memory measured using computerized tests from CNS Vital Signs™	At baseline and then 3 hours after LPS (or saline) administration
Change in visual memory from baseline	Visual memory measured using computerized tests from CNS Vital Signs™	At baseline and then 3 hours after LPS (or saline) administration
Change in executive function from baseline	Executive function measured using computerized tests from CNS Vital Signs™	At baseline and then 3 hours after LPS (or saline) administration
Change in attention from baseline	Attention measured using computerized tests from CNS Vital Signs™	At baseline and then 3 hours after LPS (or saline) administration

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Subjective Sensitivity to Social Rejection	Cyberball Social Exclusion Task	2 hours after LPS (or saline) administration
Negative Bias in Facial Emotion Recognition	Emotional Face Recognition Task	2 hours after LPS (or saline) administration
Reward	Reward Learning Task	2 hours after LPS (or saline) administration
Change in proinflammatory cytokines from baseline	Plasma proinflammatory cytokines (interleukin-1 receptor antagonist, interleukin-6, tumor necrosis factor-α, and soluble tumor necrosis factor receptor)	At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in kynurenine Metabolites from baseline	Plasma tryptophan, kynurenine, quinolinic acid, and kynurenic acid	At baseline and then at 1, 1.5, 2, 3, 4, 5, and 6 hours after LPS (or saline) administration
Change in gene expression from baseline	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).	At baseline and 30 minutes after LPS (or saline) administration

Collaborators and Investigators

• Sponsor: University of California, Los Angeles

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2023
• Primary Completion (Anticipated): June 1, 2025
• Study Completion (Anticipated): June 1, 2025

Study Registration Dates

• First Submitted: March 10, 2020
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 16, 2020

Study Record Updates

• Last Update Posted (Actual): November 5, 2021
• Last Update Submitted That Met QC Criteria: November 3, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Depression; Depressive Disorder; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Purinergic Antagonists; Purinergic Agents; Bronchodilator Agents; Anti-Asthmatic Agents; Respiratory System Agents; Phosphodiesterase Inhibitors; Purinergic P1 Receptor Antagonists; Theophylline
• Other Study ID Numbers: 20-000005

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No