Four in 10 kids who get a diagnosis of either depression or attention-deficit hyperactivity disorder (ADHD) end up getting both diagnoses sometime in their young lives. That means a lot will spend some part of their adolescence taking two psychiatric medications: methylphenidate (better known by its commercial name, Ritalin) and fluoxetine (better known as Prozac, the only of the new-generation antidepressants approved for kids as young as 8 years old). A new study conducted on rats suggests that taking that combination of drugs may change the adults they will become in ways that are distinctly troubling.

Taking Ritalin and Prozac together during adolescence appears to set in motion subtle changes in brain function that, in adulthood, makes an individual more sensitive to reward as well as to stress, and more likely to exhibit the pessimism and hopelessness seen in depression, concluded the study, published this week in the Journal of Neuroscience.

The study’s findings suggest “that combining methyphenidate and fluoxetine early in life may lead to lifelong behavioral and chemical abnormalities,” wrote the authors, from Florida State University and Cal State San Bernardino. Specifically, the combination of the stimulant drug methyphenidate and the serotonin-boosting antidepressant fluoxetine appears to act on the brain in much the same way as does cocaine.

In children’s developing brains, the researchers demonstrated that that combination turns on and off production of certain proteins in the ventral tegmental area, a key node in the brain’s reward circuitry. If those production processes get knocked out of whack during adolescence, the result can be subtle changes in an adult’s ability to regulate mood and to moderate reward-seeking behavior such as eating, drug-taking or sexual activity.


“This is not necessarily maladaptive and may not represent enhanced addiction potential,” the authors cautioned. But adult rats who got the Ritalin-plus-Prozac combo as pups were more likely than those who had no early exposure to psychotropic drugs to prefer highly sugared water to the plain stuff, and to stay longer in a compartment where they had gotten a dose of cocaine--evidence they were waiting around hoping for another. In assessing a rat’s propensity to addiction, those are troubling signs.

These effects were not the result of massive doses, either. In the study, researchers gave pre-adolescent rat pups two doses daily of the attention-deficit hyperactivity disorder drug and the antidepressant for 15 days, at dosages roughly the equivalent to what human children being treated with those medications would receive. The researchers also tested the long-term effects on rat pups of Prozac-only, Ritalin-only and saline solution-only.

The rat pups who got Prozac only also seemed more sensitive to rewards as adults--but on the plus side, they were also more resilient to stress than those who got none. The rats who got Ritalin-only as pups demonstrated not only less inclination toward sugar water, but a “significant aversion to cocaine” as adults--a sign that treating attention-deficit hyperactivity disorder may head off drug abuse later. But they also showed greater sensitivity to stress later on.

But while Ritalin and Prozac seemed to effect long-term changes in both positive and negative directions, something about the combination of the two seemed particularly worrisome, the authors said. “These results underscore the complexity of drug effects in the immature brain, and detailed assessments of these phenomena are needed.”


Will the many kids who now take both medications respond the same? That’s not clear. The subjects in this experiment were not only rats, they were rats that were developing normally and were by all appearances free of depression or attention-deficit hyperactivity disorder symptoms. Children with mood and behavioral problems that may reflect neurobiological differences might well need those differences corrected if they are to become healthy adults. There are a lot of “ifs” involved in applying these findings directly to humans.