The clinical guidelines that underpin the use of drugs for mental disorders are informed by evidence from randomised controlled trials (RCTs). RCTs are performed to obtain marketing authorisation from regulators. The methods used in these RCTs could be appropriate for early phases of drug development because they identify drugs with important harms and drugs that are efficacious for specific health problems and populations. RCTs done before marketing authorisation do not tend to address clinical questions that concern the effectiveness of a drug in heterogeneous and comorbid populations, the optimisation of drug sequencing and discontinuation, or the comparative benefits and harms of different drugs that could be used for the same health problem. This Review proposes an overview of some shortcomings of RCTs, at an individual level and at the whole portfolio level, and identifies some methods in planning, conducting, and carrying out analyses in RCTs that could enhance their ability to support therapeutic decisions. These suggestions include: identifying patient-important questions to be investigated by psychopharmacological RCTs; embedding pragmatic RCTs within clinical practice to improve generalisability to target populations; collecting evidence about drugs in overlooked populations; developing methods to facilitate the recruitment of patients with mental disorders and to reduce the number of patients who drop out, using specific methods; using core outcome sets to standardise the assessment of benefits and harms; and recording systematically serious objective outcomes, such as suicide or hospitalisation, to be evaluated in meta-analyses. This work is a call to address questions relevant to patients using diverse design of RCTs, thus contributing to the development of a patient-centred, evidence-based psychiatry.