Acne Drug Makes Mice Depressed

AUSTIN, Tex., Sept. 22 -- The widely used acne drug Accutane (isotretinoin) appears to cause depression in mice, according to researchers here and in England.

The finding -- even though it is an animal study -- is likely to revive debate over the drug, which has been linked to adolescent depression, suicidal ideation, and psychosis in case reports since the mid-1980s. Its teratogenic effects are well known.

But more rigorous examinations of the psychiatric effects of the drug in humans have had mixed results, with some studies showing a link to depression and others not, according to Michelle Lane, Ph.D., of the University of Texas at Austin.

Part of the problem is that acne itself can lead to a range of depressive symptoms, especially in severe cases, Dr. Lane and colleagues reported in the current issue of the journal Neuropsychopharmacology.

"Humans have self-image and social stresses which can contribute to the development of depression," Dr. Lane said, so she and colleagues at the University of Bath in England turned to mice.

"Mice lack these confounding variables, allowing us to examine the effect of the drug itself on behavior," Dr. Lane said.

On the other hand, "you can't ask a mouse if it's depressed," said co-author Sarah Bailey, Ph.D., of the University of Bath.

Instead, the researchers looked for symptoms of depression, anxiety, and motor impairment in a series of experiments comparing adolescent mice treated with the active ingredient in Accutane, 13-cis-retinoic acid, with mice given a control substance.

The treated mice were injected intraperitoneally with 13-cis-retinoic acid at 1 mg/kg of body weight -- a dose that resulted in plasma serum levels comparable to those seen in adolescents taking Accutane, the researchers said.

Mice with depressive symptoms -- when faced with a stressful situation -- tend to spend more time immobile than do normal mice, Dr. Lane and colleagues said.

In these experiments, the researchers tested mice in two stressful situations -- one in which they were suspended by their tails for several minutes and one in which they were forced to swim in a tank of water.

In both situations, the treated mice spent significantly more time immobile than did control animals, the researchers found: When the two tests were analyzed together, the main effect of group was F(1,21) = 4.8, which was significant at P<0.039.

The researchers also tested the mice for anxiety, using what's called an open-field test, in which mice have the option of remaining hidden in corners or venturing out into an open area of the test apparatus. Mice that are anxious spend less time in the open.

In these experiments, though, there was no significant difference between treated mice and controls. There was also no difference in their motor behavior. Both groups traveled the same amount in the test apparatus.

Finally, the researchers tested the animals' motor co-ordination and found that mice treated with 13-cis-retinoic acid tended to have better co-ordination than controls. They fell off a rotating rod less often -- but not a significant advantage (P=0.07).

The retinoids are known to play a key role in embryonic development and there is increasing evidence that they also affect the functions of the adult brain, Dr. Lane said. "For example," she said, "there is some evidence that high dietary vitamin A may cause psychiatric symptoms such as hysteria."

But, she added, this is the first study to link depression in mice to a retinoid compound.

"Without more research it is difficult to say for sure whether the same link (to depression) applies to people taking the drug," Dr. Bailey said. "This laboratory evidence provides a useful model for future research into Accutane and understanding how this family of compounds affects the brain."

This research was supported by a University of Texas at Austin.