Treatment of Bipolar Depression With Pentoxifylline (PTX-BD)

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

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.

Study Overview

• Status: Completed
• Conditions: Bipolar Depression
• Intervention / Treatment: Drug: Pentoxifylline 400 MG

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Early Phase 1

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Toronto, Ontario, Canada, M5T 2S8
      • Toronto Western Hospital

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:

1. 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.
2. Male or female between the age of 18 to 65, inclusive.
3. 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.
4. Patient must present with a moderate to severe depressive episode, as determined by the MADRS score greater than 21.
5. Patient must be receiving guideline-concordant pharmacotherapy without changes in the last month.

Exclusion Criteria:

1. Currently exhibiting symptoms of mania, as determined by the Young Mania Rating Scale (YMRS) score greater than 11.
2. Current symptoms of psychosis or perceptual disturbances of any kind per investigator discretion
3. History of neurological disorders
4. Presence of active suicidality, as determined by the MADRS suicidality item (Item #10) score greater than 4
5. 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.
6. Renal impairment, assessed as creatinine clearance less than 80ml/min
7. Abnormal liver function, assessed as ALT or AST ≥ 3 x ULN or bilirubin ≥ 2 x ULN
8. Severe myocardial infarction
9. Patients with standard contraindications to magnetic resonance imaging (MRI), such as non-MRI compatible implanted metallic devices
10. Patients with a history of cerebrovascular disease or history of intercranial hemorrhage.
11. Laboratory biochemical evidence of abnormal bleeding and/or coagulopathy
12. Pregnant or breastfeeding women. Patients who are sexually active must agree to use a highly effective contraceptive method
13. Use of prohibited concomitant medications

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Health Network, Toronto
• Investigators: Principal Investigator: Joshua D Rosenblat, MD, MSc, Psychiatry

Study record dates

Study Major Dates

• Study Start (Actual): July 12, 2021
• Primary Completion (Actual): November 3, 2021
• Study Completion (Actual): November 29, 2021

Study Registration Dates

• First Submitted: June 2, 2020
• First Submitted That Met QC Criteria: June 3, 2020
• First Posted (Actual): June 4, 2020

Study Record Updates

• Last Update Posted (Actual): April 15, 2022
• Last Update Submitted That Met QC Criteria: April 13, 2022
• Last Verified: April 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Behavioral Symptoms; Mental Disorders; Mood Disorders; Bipolar and Related Disorders; Depression; Depressive Disorder; Bipolar Disorder; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Enzyme Inhibitors; Platelet Aggregation Inhibitors; Protective Agents; Antioxidants; Phosphodiesterase Inhibitors; Free Radical Scavengers; Radiation-Protective Agents; Pentoxifylline
• Other Study ID Numbers: 20-5219

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