Theophylline for Depression Study

Study Overview
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Brief Summary
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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.

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

Conditions
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Depression

Intervention / Treatment
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* Drug: Theophylline ER
* Other: PO placebo
* Biological: Lipopolysaccharide (LPS)
* Other: IV placebo


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PO theophylline & IV LPS<br>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<br>* Capsules of theophylline ER<br>Biological: Lipopolysaccharide (LPS)<br>* Purified bacterial wall component as an inflammatory challenge<br>|
| Experimental: PO placebo & IV LPS<br>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<br>* Capsules of methylcellulose<br>Biological: Lipopolysaccharide (LPS)<br>* Purified bacterial wall component as an inflammatory challenge<br>|
| Experimental: PO theophylline & IV placebo<br>PO theophylline 400 mg/day for 2 weeks followed by a single IV bolus of 0.9% saline | Drug: Theophylline ER<br>* Capsules of theophylline ER<br>Other: IV placebo<br>* Normal (0.9%) saline<br>|
| Placebo Comparator: PO placebo & IV placebo<br>PO methylcellulose (placebo) daily for 2 weeks followed by a single IV bolus of 0.9% saline | Other: PO placebo<br>* Capsules of methylcellulose<br>Other: IV placebo<br>* Normal (0.9%) saline<br>|

What is the study measuring?
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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 |