Table 1.

Innovation in psychopharmacology proceeds bottom-up more frequently than top-down in the levels of evidence

Level I: Double-blind randomized trials	Ia: Placebo-controlled
	Ib: Non placebo-controlled
Level II: Open randomized trials
Level III: Naturalistic studies	IIIa: Nonrandomized, controlled studies
	IIIb: Large nonrandomized, uncontrolled studies (n > 100)
	IIIc: Medium-sized nonrandomized, uncontrolled studies (100 > n > 50)
Level IV: Small naturalistic studies (nonrandomized, uncontrolled, (50 > n > 10)
Level V: Case series (n < 10), Case report (n = 1), Expert opinion
Adapted by us from principles of Evidence-based Medicine [9]
In terms of the timeline of how the discovery process proceeds, this schema is inverted. Everything begins at level V with novel observations and clinical innovation, and proceeds upwards. Putting emphasis on the utility of controlled studies should not lead to the conclusion that research simply consists of doing controlled studies.