Numerous pharmacological treatments for
mood disorders are currently available; however, rates of treatment resistance, relapse and recurrence remain high. Therefore, novel treatments acting outside of the conventionally targeted monoamine system are urgently needed to improve patient outcomes. Emerging and converging evidence suggests that immune dysfunction, oxidative stress, impaired cerebral blood flow (CBF) and decreased
neurotrophic factors all contribute to
mood disorder pathophysiology and are therefore treatment targets of interest.
Pentoxifylline (PTX) is a
phosphodiesterase inhibitor with potent anti-inflammatory and
antioxidant effects, with additional pleiotropic effects that lead to improved CBF and increases in
brain derived neurotrophic factor (
BDNF) levels. The direct effect of non-specific
phosphodiesterase inhibition may also improve alertness and cognitive function through enhancing second messenger systems. Replicated preclinical studies have demonstrated
antidepressant-like effects in animal models. Small preliminary clinical trials have demonstrated promising results for
antidepressant and procognitive effects, however, have yet to be replicated in larger
mood disorder samples. Only one randomized clinical trial (RCT) specifically assessed the effects of adjunctive PTX in
major depressive disorder (MDD), showing clinically and statistically significant
antidepressant effects compared to placebo. No studies have assessed PTX in
bipolar disorder (BD), where
inflammation and altered CBF have also been strongly implicated. Taken together, PTX presents as a promising pleiotropic agent with several potential novel mechanisms of action meriting further evaluation in clinical trials to evaluate target engagement,
antidepressant, procognitive and mood stabilizing effects.