Since the development of selective serotonin reuptake inhibitors there has been a widening of the definition of depression and a decrease in the placebo-drug difference in controlled studies. In the early 1960s, ~33% of depressed patients improved with placebo and 66% with active compounds and current controlled studies suggest that the situation has certainly not improved. The Sequenced Treatment Alternatives to Relieve Depression Study found that response rates to new compounds after the failure of the first antidepressant are low. The monoamine hypothesis of depression was formulated in the mid 1960s based on the antidepressant efficacy of the monoamine reuptake inhibitors, monoamine oxidase inhibitors and the depressogenic effects of reserpine as a monoamine depleter. However, no monoamine-related finding has been found that is diagnostic for depression. A second major hypothesis regarding depression has been the stress cortisol hypothesis. However, blood cortisol levels are not diagnostic of depression. Every psychiatric clinician is convinced that there are patients for whom antidepressants have made the difference between life and death. However, physicians may generalize unjustifiably based on single dramatic cases to a much larger diagnostic group. Perhaps there are many causes of different types of human sadness, and perhaps only some of these involve mechanisms related to monoamines. Thus, Robert H. Belmaker, MD, suggests that perhaps only some kinds of depression are responsive to monoamine affecting antidepressants.