Research Article: Fluoxetine disrupts motivation and GABAergic signaling in adolescent female hamsters
Get Article Here: http://www.sciencedirect.com/science/article/pii/S0278584616300380
Journal: Progress in Neuropsychopharmacology and Biological Psychiatry
Publication Dates: Online, April 8, 2016; Print, TBD
In this paper, we show preclinical evidence of harmful effects of antidepressant use during adolescence and young adulthood. The practice of prescribing antidepressants to depressed patients under the age of 25 years is controversial because they are more susceptible to the side effects and less likely to experience the benefits than older patient populations are. Furthermore, antidepressant resistance is a major problem at all ages. The consequences of this practice need to be determined with urgency because there are millions of antidepressant users worldwide who are under age 25 years, and 3.5 million of them are Americans. Moreover, population studies indicate that teenagers’ use of antidepressants has increased during the past three decades. A relatively short period of decreased use occurred between 2004 and 2006 when the U.S. Food and Drug Administration and European Medicines Agency issued strong warnings about antidepressant use by persons up to age 24 years.
It appears that antidepressant use rebounded in recent years. A study by Bachmann and colleagues (2016), published in the European Journal of Neuropsychopharmacology reports increases in antidepressant use by 0- to 19-year-olds in Denmark, Germany, Netherlands, UK, and USA between 2006 and 2012. The increases ranged from 26% (USA) to 60% (Denmark). Investigations into adverse responses to antidepressants were prompted in the USA and Europe by anecdotal reports of increases in suicidal and aggressive behaviors by teenagers after they took these psychotropic medicines. The warnings issued by regulatory agencies resulted from subsequent population studies that confirmed higher risks of suicidal thinking and behavior, as well as worsening of the symptoms of depression and anxiety in children and adolescents.
Despite the detrimental effects that antidepressants have in some humans, previous animal studies have encountered difficulty is demonstrating elevated depression-related behavior during adolescence. A few such studies have shown that initial antidepressant administration elevates anxiety during adolescence, but many antidepressants also have that effect in adult humans and laboratory animals. Of course, there are no rodent models of suicidal thinking or behavior.
What makes our study different from relevant previous studies? Before digging into our findings, bear in mind that our work is different in three ways.
- First, we used hamsters* as the model species, whereas virtually all studies of this kind have used rats or mice.
- Second, we used females, whereas most biomedical studies of any kind have used males.
- Third, we studied effects of the prototypical antidepressant, fluoxetine, per se. In other words, no additional impactful treatment or condition was imposed to generate adverse responses. With other adolescent animal models, paradoxical depression-related effects have been induced only by combining antidepressant treatment with surgical trauma or by abruptly withdrawing treatment.
Thus, our results have broad potential implications for antidepressant users who are teenagers or young adults.
*Although hamsters cannot be left unattended on elevated behavioral apparatuses because they leap off without warning, that’s not suicidal behavior. They just aren’t very bright. In fact, the male hamster’s brain is about the same size as one of its testicles. So, they are not too bright, but prolific breeders.
Now for the results. Initial antidepressant treatment during adolescence, but not during adulthood, paradoxically increased depression-related behavior in female hamsters. It also induced antidepressant resistance that persisted into young adulthood. Although, fluoxetine increased anxiety-related behavior in both age groups, this paradoxical response has been shown in adolescent and adult rats or mice by others. Our work, however, is the first to show that this detrimental effect was twice as strong in adolescents as in adults.
Fluoxetine’s effects on GABA-A receptor signaling in the brain were also dependent on the age of the hamsters. For certain aspects of GABA-controlled electrical activity and gene expression, adolescents and adults exhibited opposite responses. These findings are interesting because antidepressants of different classes are known to influence GABA-A receptor signaling. Importantly, GABA-A receptors contribute to paradoxical emotional effects of other drugs (e.g., anxiolytics), particularly in females at hormonal transitions (e.g., puberty).
Finally, we draw three conclusions from this work. First, disruption of GABA-A receptor signaling potentially mediates paradoxical responses and resistance to antidepressants during adolescence. Second, more studies of this kind using female animal models are needed. Third, more studies of this kind using alternative model species (e.g., hamsters) are needed.