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Cilostazol (PLETAL) for depression

Updated: Nov 20, 2021

Cilostazol (PLETAL)

Pronounced: sye LOE sta zol / PLAY tal

FDA-approved for: Intermittent claudication

Used off-label for: Depression (investigational)

Cilostazol (PLETAL)  for depression mnemonic by Jason Cafer MD

Cilostazol (Pletal) is a phosphodiesterase III (PDE3) inhibitor approved for treatment of intermittent claudication due to occlusive peripheral arterial disease. Claudication is pain/cramping in the lower leg induced by exercise due to inadequate blood flow. With cilostazol, subjects with intermittent claudication could walk 333 meters compared to 237 meters with placebo (Money et al, 1998).

By inhibiting PDE3, cilostazol increases cyclic adenosine monophosphate (cAMP) levels, which inhibits platelet aggregation and causes vasodilation. Cilostazol also has antiproliferative effects on smooth muscle cells.

Phosphodiesterase (PDE) inhibitors are a class of drugs known for promoting blood vessel dilation. Examples of nonselective PDE inhibitors are caffeine, theophylline, and pentoxifylline (Trental). Pentoxifylline—the only other medication approved for claudication—improves capillary blood flow by increasing the deformability of red blood cells. Pentoxifylline is less effective than cilostazol in reducing claudication.

Cilostazol is the only commonly used selective PDE3 inhibitor. The other PDE3 inhibitors are approved to treat congestive heart failure (CHF) as inotropic agents (drugs that increase the force of cardiac contractions) but were found to increase mortality in CHF. Cilostazol has a much weaker inotropic effect but still has a black box warning contraindicating its use in CHF of any severity.

Fatty meals increase absorption of cilostazol, raising plasma levels by about 90%. It should not be taken with food.

Cilostazol and its metabolites have a half-life of about 12 hours. It is dosed twice daily.

Side effects of cilostazol may include headache, diarrhea, palpitations, dizziness, and peripheral edema. Resting heart rate increases by 5 to 7 beats per minute. Premature ventricular contractions (PVCs) may be seen on ECG. Based on findings with dogs, cardiovascular toxicity might be possible with long-term use.

Potential relevance to psychiatry: Cilostazol has anti-inflammatory and neurotrophic effects. Improvement was seen when cilostazol was given adjunctively to antidepressants in patients with major depressive disorder in a pilot, proof-of-concept study (Abdallah et al, 2021). The authors concluded that cilostazol is safe and effective short-term adjunctive therapy for depression. Side effects were minimal. Cilostazol was chosen because it increases cAMP levels. cAMP is downregulated in depression and upregulated by antidepressants (Reierson et al, 2011).

Cilostazol (PLETAL) interactions for depression by Dr Jason Cafer MD

Dosing: For claudication, give 100 mg BID >30 minutes before or 2 hours after food. Consider reducing to 50 mg BID if taken with inhibitors of 3A4 or 2C19. For depression, 50 mg BID was used in the pilot study.

For explanations of visual mnemonics, check out Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots

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