Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, debilitating, and multi-faceted illness. Heterogenous onset and clinical presentation with additional comorbidities make it difficult to diagnose, characterize, and successfully treat. Current treatment guidelines focus on symptom management, but with no clear target or causative mechanism, remission rates are low, and fewer than 5% of patients return to their pre-morbid activity levels. Therefore, there is an urgent need to undertake robust clinical trials to identify effective treatments. This review synthesizes insights from clinical trials exploring pharmacological interventions and dietary supplements targeting immunological, metabolic, gastrointestinal, neurological, and neuroendocrine dysfunction in ME/CFS patients which require further exploration. Additionally, the trialling of alternative interventions in ME/CFS based on reported efficacy in the treatment of illnesses with overlapping symptomology is also discussed. Finally, we provide important considerations and make recommendations, focusing on outcome measures, to ensure the execution of future high-quality clinical trials to establish clinical efficacy of evidence-based interventions that are needed for adoption in clinical practice.

Although historic documents posit schizophrenia to the beginnings of mankind, its diagnosis remains poorly defined, currently relying on unspecific clinical symptoms; and controversies still maintain its origin under intense debate. This review aimed at quantitatively assessing the preferential forefronts of clinical trials towards the treatment of schizophrenia from inception till present, according to clinicaltrials.gov database registry. Towards that end study status and study phase classifications were used as criteria for progress in the field. Study groups by sex and age together with countries and organisms involved in the studies were used as indicators of the populations studied and as evidence of main promoter institutions, in both, pharmacological and drug-free protocols. The findings clearly show a decline of active clinical research with small synthetic compounds and limited numbers of novel initiatives, mostly based on drug-free alternatives with expected reduced secondary effects. A paucity of sex- and age-oriented designs is detected, and it is proposed that future clinical trials should set their basis on data obtained from patient-derived induced pluripotent stem cells, brain organoid systems and human brain circuitry platforms. Only individual precision medical approaches may turn effective for the treatment of this complex and highly incapacitating disease.