A growing body of evidence has highlighted the role of inflammation and phosphodiesterases (PDE)-related pathways in the pathogenesis of neuropsychiatric illnesses such as depression/mood disorders. Herein, we aimed to evaluate the therapeutic benefits of pentoxifylline (PTX) in the treatment of therapy-resistant depression (TRD) in adult patients with bipolar depression.

Depression, which affects an estimated 300 million people worldwide, is the main cause of mental health-related illness burden. Depression keeps people from attaining their full potential, depletes human capital, and is linked to suicide and other forms of mortality. Despite the fact that depressive disorders have a better prognosis than primary psychotic illnesses like schizophrenia, 20%-40% of patients treated with antidepressants do not respond to their initial treatment regimens, and up to 15% do not respond to multiple antidepressant regimens and modalities, such as electroconvulsive shock (ECT) therapy. Since the treatment resistance has been shown to increase the likelihood of full symptomatic recurrence, worsen the treatment course and quality of life; therefore, there is a critical need for innovative treatment techniques for patients who have failed to respond to traditional treatments. Inflammation is one factor that has gotten a lot of attention lately as an etiologic mechanism of treatment-resistant depression (TRD). Increased levels of (pro) inflammatory markers such as tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1, and IL-6 are reported in a considerable percentage of patients with major depressive disorders with or without other comorbidities, including bipolar depression and TRD patients. Also, clinical factors connected to antidepressant response are linked to the reduction of inflammatory cytokines.

Moreover, cytokine antagonists, such as the chimeric anti-TNF-alpha antibody infliximab, has shown antidepressant efficacy. Hence, given the elevated levels of inflammatory activity in TRD patients, new treatments with anti-inflammatory effect might be an effective approach to treat these patients. Pentoxifylline (PTX) is a methylated xanthine derivative that has been used to treat peripheral vascular disease for more than two decades. PTX has anti-inflammatory and phosphodiesterase (PDE) inhibitory effects that enables it to inhibit PDEs competitively. Subsequently, it can increase cAMP levels, activate protein kinase A (PKA), inhibit ILs and TNF-α production, and reduce inflammation. Therefore, PTX-decreased inflammatory activity, may give rapid symptomatic alleviation for medically healthy individuals with TRD depression.

Inclusion Criteria:

• Provide written, voluntary informed consent prior to study enrollment.
• Male or female between the ages of 18 to 65.
• Meets the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-IV) criteria for bipolar I or II, currently experiencing a major depressive episode. A Mini-International Neuropsychiatric Interview (MINI) conducted by physician was used to confirm the diagnosis.
• Meets the criteria for treatment resistant depression (TRD) defined by failure to respond to of at least two treatment trials (antidepressant regimen or electroconvulsive therapy) during the current depressive episode.
• Prior to taking part in the trial, all patients were requested to be antidepressant free for 4 weeks or to be on a fixed psychotropic therapeutic regimen for at least 4 weeks.

Exclusion Criteria:

• Current psychotic symptoms or perceptual problems.
• The presence of a contraindication to PTX, such as a drug allergy or xanthine derivative allergy.
• Patients with substance dependence or abuse.
• Patients with concurrent active medical condition (congestive heart failure, abnormal electrocardiogram, malignancy, schizophrenia, neurological disease).
• Patients with inflammatory disorders and/or auto-immune conditions (rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis, lupus)