Tretinoin Mental Health and Mood Impact: What the Evidence Actually Shows

Does topical tretinoin carry a psychiatric warning?

Not on the labels. The Renova (tretinoin cream 0.02%) label has no boxed warning, and its adverse reactions section describes reactions limited primarily to the skin: peeling, dry skin, burning, stinging, erythema and pruritus, with about 4% of patients discontinuing because of adverse reactions [1]. Depression, anxiety and suicidality are not listed there [1]. No single-ingredient topical tretinoin label in the FDA label database carries a boxed warning, including Retin-A and Retin-A Micro.

Topical tretinoin and oral isotretinoin (Accutane-type capsules) are different drug products. Isotretinoin has a boxed warning and a REMS; topical tretinoin has neither.

Where the depression link comes from

A review of retinoic acid neurobiology sets out why the question exists: retinoic acid binds specific receptors in the brain, animal studies have linked isotretinoin administration to behavior changes and inhibited hippocampal neurogenesis, and human evidence for a retinoid-depression link comes from case reports, health database studies and a small preliminary PET study [3]. That PET study found decreased orbitofrontal metabolism in people given isotretinoin, the oral drug, not a topical cream [3]. The review proposes that retinoids could play a role in affective disorders; it does not show that topical tretinoin does [3].

How much tretinoin gets into the blood?

The Renova label says transdermal absorption from various topical tretinoin formulations ranged from 1% to 31% of the applied dose, depending on whether it was applied to healthy skin or dermatitic skin [1]. In healthy men, absorption of a 0.05% tretinoin cream was less than 2% after a single application (seven men) and after 28 days of daily application (another seven men), and bioavailability was lower after repeated use; endogenous tretinoin concentrations did not differ significantly between single and repeated use [1]. No percutaneous absorption study was run with the 0.02% Renova cream itself [1].

Acne itself carries a mood burden

A questionnaire study of 3,775 adolescents aged 18 to 19 found that among those with very much acne, suicidal ideation was reported by 25.5% of girls versus 11.9% of those with none or little acne, and by 22.6% of boys versus 6.3% [2]. After adjustment for symptoms of depression, ethnicity and family income, substantial acne remained associated with suicidal ideation (odds ratio 1.80, 95% CI 1.30 to 2.50) [2]. The design was cross-sectional, so it shows an association and cannot determine whether acne caused the mental health problems or which came first. The authors suggested that adverse events such as suicidal ideation and depression that have been associated with acne therapies may reflect the burden of substantial acne rather than the medication [2].

What the Renova label says to expect on the skin

In the label's double-blind, vehicle-controlled studies involving 339 patients who applied Renova 0.02% cream, 32% of all study patients had skin irritation that was severe, led to temporary discontinuation, or led to use of a mild topical corticosteroid [1]. About 7% had irritation severe enough to warrant short-term use of a mild topical corticosteroid, versus less than 1% of controls, and about 4% discontinued because of adverse reactions [1]. The label notes that tretinoin has been reported to cause severe irritation on eczematous skin, and says that if the degree of local irritation warrants, patients should be directed to use less medication, apply it less often, stop temporarily or stop altogether and consider additional appropriate therapy [1].