Pentoxifylline as an Adjunctive in Treatment of Negative Symptoms in Chronic Schizophrenia

The Phosphodiesterase Inhibitor Pentoxifylline as an Adjunctive in Treatment of Negative Symptoms in Chronic Schizophrenia: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

The aim of this study to evaluate the efficacy and safety of pentoxifylline, the novel phosphodiesterase inhibitor, as an adjunctive to risperidone in alleviating the negative symptoms of schizophrenia.

Study Overview

• Status: Completed
• Conditions: Schizophrenia
• Intervention / Treatment: Drug: Placebo oral tablet; Drug: Pentoxifylline

Detailed Description

there is some evidence for the role of phosphodiesterase (PDE) signaling system in pathophysiology of schizophrenia making this system a potential target for therapeutic agents. PDEs are a family of enzymes that hydrolyse cyclic nucleotides and thus play a key role in regulating intracellular levels of the second messenger cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate. Pentoxifylline (PTX) is a methylated xanthine derivative and a PDE inhibitor that is FDA-approved for the treatment of patients with intermittent claudication on the basis of chronic occlusive arterial disease of the limbs. It is known to inhibit platelet aggregation, increase erythrocyte flexibility or deformability, and reduce blood viscosity. The rationale for its use in schizophrenia is that it competitively inhibits PDEs, resulting in increased cAMP levels, the activation of protein kinase A (PKA), the inhibition of IL and TNF-α synthesis, and reduced inflammation. Furthermore, there is growing evidence to support the inflammatory hypothesis of schizophrenia, the investigators will also explore whether cytokine levels mediate the response from pentoxifylline treatment.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Egypt
  • Shibīn Al Kawm, Egypt
    • Faculty of medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Ages between 18-40 years
• Males & females
• patients between the ages of 18 and 53 who met the diagnostic criteria for schizophrenia according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (20), with a minimum disease duration of two years.
• stable on risperidone for a minimum of 8 weeks
• clinically stable for at least 4 weeks prior to study.
• willing to give informed consent.
• able to take medication orally.

Exclusion Criteria:

• Acute, unstable, significant or untreated medical illness beside schizophrenia;
• Pregnant or breast-feeding females;
• History of substance abuse or dependence in the past 3 months.
• Known contraindication to pentoxifylline treatment.
• Any serious or life-threatening medical conditions or neurological problem, severe extrapyramidal symptoms, history of abnormal bleeding, presence of hypothyroidism, renal disease, cardiovascular problems, rising liver transaminases to 3 times the upper limit of normal or higher

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Control group; Equivalent Placebo will be given	Drug: Placebo oral tablet; Placebo tablets PLUS Risperidone 2 mg tablet up to 6 mg/day
Experimental: Pentoxifylline group; Pentoxifylline will be given orally at 800 mg a day for 8 weeks	Drug: Pentoxifylline; Pentoxifylline tablet PLUS Risperidone 2 mg tablet up to 6 mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-induced change in total score on Positive and Negative Syndrome Scale (PANSS)	PANSS total score will be used to examine treatment-induced change in psychaopthology. The PANSS is a 30-item rating scale used to assess symptoms of psychopathology. We will use the total PANSS score as the primary outcome measure which reflects total level of psychopathology including the positive and negative symptoms as well as general psychopathology.This measure will be administered at baseline, week 8 and week 16 of the study to assess if pentoxifylline treatment results in a significant reduction in PANSS total score as opposed to placebo.	Baseline to week 8 of the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment-induced changes in plasma level of cytokines	Cytokine levels will assessed at baseline and week 8 of the study to examine treatment-induced changes in neuroinflammation.	Baseline and week 8 of the study

Collaborators and Investigators

• Sponsor: Sadat City University

Publications and helpful links

General Publications

• Abdallah MS, Mosalam EM, Hassan A, Ramadan AN, Omara-Reda H, Zidan AA, Samman WA, El-Berri EI. Pentoxifylline as an adjunctive in treatment of negative symptoms in chronic schizophrenia: A double-blind, randomized, placebo-controlled trial. CNS Neurosci Ther. 2022 Nov 7. doi: 10.1111/cns.14010. Online ahead of print.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2019
• Primary Completion (Actual): September 30, 2021
• Study Completion (Actual): September 30, 2022

Study Registration Dates

• First Submitted: September 15, 2019
• First Submitted That Met QC Criteria: September 16, 2019
• First Posted (Actual): September 18, 2019

Study Record Updates

• Last Update Posted (Actual): October 25, 2022
• Last Update Submitted That Met QC Criteria: October 23, 2022
• Last Verified: October 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Mental Disorders; Schizophrenia Spectrum and Other Psychotic Disorders; Schizophrenia; 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: 4/2021NEUR1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Sharing Supporting Information Type: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF)

Drug and device information, study documents

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