The theory has bidirectional ambiguity. It is not clear whether the level of serotonin caused depression or the depression caused the lower levels of serotonin. Antidepressant drugs increase levels of serotonin in the brain immediately. However, most people do not report feeling better for 3-4 weeks after taking the drugs. If depression was only about serotonin levels, it should not have taken so long for improvements in the mood to take place. Additionally, antidepressants only seem to be effective for about 60% of people. If depression was caused by a lack of serotonin, antidepressants should have been effective for everyone.
According to Lacasse and Leo (2005), taking the alleged effectiveness of SSRIs as evidence for the serotonin hypothesis is an example of backward reasoning. Assumptions about the causes of depression are based on how people respond to a treatment, which is logically problematic.
Kirsch et al. (2002) found that there was a publication bias in research on the effectiveness of SSRI in depression. If the results of all studies were pooled out, it would seem that the placebo effect accounted for 80% of the anti-depressant response. Of the studies funded by pharmaceutical companies, 57% failed to show a statistically significant difference between an anti-depressant and a neutral placebo. This study hence casts doubt on the serotonin hypothesis.