Treatment of Bipolar Depression With Pentoxifylline

Study Overview
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Brief Summary
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Growing theoretical and clinical evidence has suggested that pentoxifylline may have an effect in improving depressive symptoms. Herein, we aim to evaluate the effect of pentoxifylline in patients with bipolar depression over an 8-week trial.

Detailed Description
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Growing evidence has demonstrated that inflammation and alterations in cerebral blood flow (CBF) contribute to the pathophysiology of bipolar depression (BD). Pentoxifylline is a phosphodiesterase inhibitor that improves CBF and has potent anti-inflammatory and antioxidant effects. We therefore hypothesize that pentoxifylline may have antidepressant effects in BD. We will conduct an 8-week, open-label, single-armed, feasibility study assessing clinical and neurobiological effects of adjunctive pentoxifylline in the acute treatment of BD. Feasibility will be determined by evaluating recruitment/retention rates, target engagement (e.g., changes in biomarkers with pentoxifylline treatment) and preliminary efficacy testing with 6 participants. Evaluating pentoxifylline's effects may further our understanding of BD pathophysiology and help identify novel treatment targets.

Official Title
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Pentoxifylline for Bipolar Depression: A Proof-of-Concept Feasibility Study

Conditions
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Bipolar Depression

Intervention / Treatment
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* Drug: Pentoxifylline 400 MG


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written, voluntary informed consent prior to study enrollment. Substitute decision makers will not be allowed to consent to study on a potential patients behalf. Male or female between the age of 18 to 65, inclusive. Meets DSM-5 criteria for Bipolar I or II Disorder, currently experiencing a Major Depressive Episode. Diagnosis will be confirmed using the Mini-International Neuropsychiatric Interview (MINI) conducted by a delegated physician or trained research study while assessing eligibility. Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21. Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month. Exclusion Criteria: Currently exhibiting symptoms of mania, as determined by the Young Mania Rating Scale (YMRS) score greater than 11. Current symptoms of psychosis or perceptual disturbances of any kind per investigator discretion History of neurological disorders Presence of active suicidality, as determined by the MADRS suicidality item (Item #10) score greater than 4 Presence of a contraindication to PTX, including a drug allergy or allergy to xanthine derivatives, low or labile blood pressure, acute myocardial infarction, cardiac arrhythmia, peptic ulcers, coronary artery disease or coagulation disorder. Renal impairment, assessed as creatinine clearance less than 80ml/min Abnormal liver function, assessed as ALT or AST ≥ 3 x ULN or bilirubin ≥ 2 x ULN Severe myocardial infarction Patients with standard contraindications to magnetic resonance imaging (MRI), such as non-MRI compatible implanted metallic devices Patients with a history of cerebrovascular disease or history of intercranial hemorrhage. Laboratory biochemical evidence of abnormal bleeding and/or coagulopathy Pregnant or breastfeeding women. Patients who are sexually active must agree to use a highly effective contraceptive method Use of prohibited concomitant medications

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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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Pentoxifylline<br> | Drug: Pentoxifylline 400 MG<br>* All patients will be provided with pentoxifylline 400 mg to be orally ingested twice daily for 8 weeks.<br>* Other names: Trental;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The recruitment rate | The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by recruitment rate | 8 weeks | 
| The retention rate | The feasibility of pentoxifylline as a treatment in bipolar disorder will be measured by retention rate of the study. | 8 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety will be assessed using patient-reported treatment emergent adverse events. |  | 8 weeks | 
| Change in depression severity using the Montgomery Asberg Depression Rating Scale (MADRS) | The MADRS is a clinician-rated scale measuring depression severity. It consists of 10 items, each scored from 0 (normal) to 6 (severe), for a total possible score of 60. A higher score is indicative of greater depressive severity Response rates are defined as ≥ 50% decrease and Remission ≤ 10 actual score. | 8 weeks | 
| Change in cerebral blood flow using ASL MRI imaging | Patients will complete an MRI sequence called arterial spin labelling (ASL) at baseline and week 8 to look at changes in cerebral blood flow before and after treatment. ASL does not use any contrast or radiation. | 8 weeks | 
| Change in inflammatory markers using blood serum and plasma | Blood will be collected in order to evaluate changes in inflammatory biomarkers associated with depressive disorders (e.g., TNF-alpha, IL-1 and IL-6). | 8 weeks | 
| Change in subjective measures of depression using 16-item Quick Inventory for Depressive Symptomology-Self Report (QIDS-SR16) Total Score | Patients will complete a brief self-reported scale that measures subjective symptoms of depression. In total there are 16 items, each scored from 0 to 3. The total score ranges from 0 to 27, with higher scores indicating worse depressive severity. | 8 weeks | 
| Changes in subjective measures of cognition using the Perceived Deficits Questionnaire for Depression-5 item (PDQ-5-D) | The PDQ-5 is a brief patient-rated scale to assess subjective cognitive dysfunction in people with depression. The PDQ originally is a 20-item questionnaire that generates a total score and 4 subscale scores in 4 cognitive domains: attention/concentration, retrospective memory, prospective memory, and planning/organization. The 5-item version (PDQ-D-5) is derived from the 20-item version and provides a validated measure of perceived cognitive deficits in depressive disorders. | 8 weeks | 
| Changes in psychomotor speed, concentration and memory using the Digit Symbols Substitution Task (DSST) | The DSST is used to evaluate psychomotor speed and concentration. It consists of multiple digits with unique symbols associated with each digit. Patients are asked to substitute each digit with the correct symbol in 90 seconds. Each correct symbol is counted to calculate the total score | 8 weeks | 
| Change in attention and concentration using the Trails Making Tests | Trail Making Test (TMT) is a cognitive test designed to assess attention and concentration through visuomotor tracking, executive function, and cognitive flexibility. It consists of two parts, A and B. In part A, a line is drawn between consecutive numbers. In part B a line is drawn alternating between numbers and letters. Score is calculated through total time to completion of each part, with higher times indicating impairment. | 8 weeks | 
| Change in verbal fluency using the FAS test | Change in verbal fluency (i.e., semantic and animal naming) will be measured by using the Controlled Oral Word Association Test. Scores will be assessed through the total number of words stated in a given letter or category in a time period of one minute. Number of repetitions and intrusions will also be measured. | 8 weeks |