The search for biomarkers has been one of the leading endeavours in biological psychiatry; nevertheless, in spite of hundreds of publications, hardly any marker has proved useful in clinical practice. To study how biomarker research has progressed over the years, we performed a systematic review of the literature to evaluate (a) the most studied peripheral molecular markers in major psychiatric disorders, (b) the main experimental design features of studies in which they are proposed as biomarkers and (c) whether their patterns of variation are similar across disorders. An automated search revealed that, out of the six molecules most commonly present as keywords in articles studying plasmatic markers of schizophrenia, major depressive disorder or bipolar disorder, five (BDNF, TNF-alpha, IL-6, C-reactive protein and cortisol) were the same across the three diagnoses. An analysis of the literature on these molecules showed that, whilst 66% of original articles compared their levels between patients and controls, only 35% were longitudinal studies, and only 10% presented an evaluation of diagnostic efficacy, a pattern that has not changed significantly over two decades. Interestingly, these molecules varied similarly across the three disorders, suggesting them to be nonspecific systemic consequences of psychiatric illness rather than diagnostic markers. On the basis of this, we discuss how research fragmentation between diagnoses and publication practices rewarding positive findings may be directing the biomarker literature to nonspecific targets, and what steps could be taken to increase clinical translation in the field.