Of Mice and Men:

New York Times: Why Test Animals to Cure Human Depression? With the recent furor about whether antidepressants can promote suicide, why not test them on animals to find a more definitive answer? The answer illustrates some fundamental differences between drug development in the rest of medicine and that in psychiatry, which treats ‘higher’ cognitive functions that by and large have no direct analogues in laboratory animals. For example, there really is not a good ‘animal model’ for human depression, which involves feelings of guilt and worthlessness that have no animal analogue of which we are aware. Indeed, after the serendipitous discovery that some compounds alleviated depression, animal testing was developed to help speed the discovery of subsequent antidepressants. All tests that assay antidepressant effectiveness in animals rely on one aspect of depression, of controversial value, which is called “learned helplessness” and is based largely on the work of Pennsylvania psychologist Martin Seligman. Essentially, animals treated with compounds that turn out to have human antidepressant properties struggle longer before giving up in any of several paradigms in which they are made helpless to fend off an adverse stimulus. Seligman insists that the antidepressant amelioration of learned helplessness represents a good animal analogue of depression and its treatment despite significant differences the actions of these compounds have in animals as opposed to humans, such as rapidity of onset and regions of the brain affected. Indeed, animals do not at all have a well-developed prefrontal cortex, that most recently evolved and most human of brain regions where the cognitive aspects of the depressive experience such as worthlessness, self-reproach and, yes, probably the helplessness and hopelessness reside. So it may be the case with antidepressants, as I have argued with other classes of psychoactive drug discovery driven by animal testing, that depending on such an imperfect ‘animal model’ restricts us to discovering only a small and imperfect subset of potentially therapeutic substances. [It is even worse with animal screening of potential antipsychotic medications; the target symptoms watched for are side effects, virtually ensuring that antipsychotic medications that were discovered with the aid of animal testing will be poorly tolerable!] One thing is certain with respect to depression at least; there is no ‘animal model’ for suicidal self-destruction per se, and thus no way to screen our medications for promotion of suicide, as the recent concerns emphasize. But since, as FmH readers know, I do not believe antidepressants actually promote suicide at all, not to worry about the lack of an animal test… [In a psychopharmacological stand-up comedy routine, the comedian would have Eli Lilly asserting that they had definitively proven that Prozac does not promote suicide, since no laboratory rats killed themselves after receiving large doses of the antidepressant…]