"Merck’s behavioral psychopharmacology screening program finally identified one highly promising new antidepressant. Code named MK-202, the chemical increased lever-pressing work output under a range of conditions, in seemingly more adaptive ways than amphetamine. For instance, in the “strained fixed-ratio” test, designed to measure “an animal’s ability to handle an overly large workload with inadequate motivation,” MK-202 performed better than dextroamphetamine. Here, hungry rats were given a drop of condensed milk only after pressing a lever two hundred times in response to a light signal. However, in the middle of their heavy and under-rewarded task a second light would turn on intermittently, and if they immediately responded by pressing a second lever they would get a milk drop instantly. Thus, this experiment measured both willingness to do “a particularly long and tedious job” as well as “alertness” to a second stimulus, according to Merck researchers. The rats on amphetamine performed well on the repetitive task but tended to miss the second stimulus; not so the rats on MK-202. Given the similarity between the rat’s situation and the repetitive work that most people must endure to make a living, a drug that increased lever pressing without producing unresponsiveness would seem a likely antidepressant—provided we accept that inefficiency in unrewarding jobs indicates psychiatric depression."

"This implicit identification of impaired work efficiency with depressive illness, inscribed in the use of amphetamine-boosted lever pressing as the benchmark that subsequent antidepressants had to meet, applied to the highest level executive type of work also. (The business world is called a “rat race” with reason!) This is evident from another test, designed to measure a rat’s capacity to perform complex tasks. Here, to get a reward, rats had to press a lever rapidly when a white light was on, slowly when a red light was on, and not at all when both lights were on. The rats on amphetamine pressed their levers fast no matter what lights were on, but the rats on MK-202 only pressed fast when high speed was rewarded. In these and a half a dozen other experiments with trained rats subject to diabolically ingenious “reinforcement schedules” (that is, particular programs of reward and punishment), MK-202 outperformed amphetamine for boosting work output, maximizing reward, and minimizing punishment, particularly when tasks were both difficult and unrewarding. A more promising antidepressant drug candidate could hardly be imagined, and in January 1960 the behavioral psychopharmacology unit passed it on for human testing as an antidepressant, with its highest
recommendation."