EMA has published the 3rd revision of the Guideline on clinical investigation of medicinal products in the treatment of depression. This document updates and replaces the previous guideline (EMA/CHMP/185423/2010 Rev. 2). The main focus is on major depressive episodes that occur in the context of MDD. Bipolar and related disorders are separated from depressive disorders in DSM-5 and possible extrapolations in alignment with the bipolar guidance document will also be addressed.
Up to two thirds of MDD patients do not achieve remission following an initial adequate trial of antidepressant therapy. Despite many approved antidepressants there is a need for new medicinal products with better efficacy (e.g. faster onset of action, higher rates of response and remission) and improved safety profile. The typical design to demonstrate efficacy and safety of an antidepressant remains a randomized, double-blind, placebo controlled, parallel group study comparing change in the primary endpoint. The results must be robust and clinically meaningful. This requires incorporation of rates of response/remission to adequately assess clinical relevance, in addition to statistically significant results. It has to be shown that the initial response to treatment is maintained in at least one study following an adequate design. The emergence of new antidepressants with rapid onset of effect and recent clinical developments of psychedelics require separate design strategies. The requirements for clinical trials in partial and non-responders (i.e. treatment resistant depression) with MDD are revisited.
Nearly 70% of patients with MDD experience residual symptoms with first line standard of care. These may include anxiety, impaired cognition, fatigue and sleep disturbance. A separate claim in specific domains or symptom clusters within MDD (e.g. cognitive dysfunction either as specific claim or additional claim on top of MDD treatment) will need a solid justification for the therapeutic rationale. Specific studies should be performed.
The update specifically addresses:
- Several aspects for trial designs in difficult to treat patients (partial responders or non-responders to treatment) including the definition and identification of those patients, the role of augmentation and combination strategies
- Clinical development requirements for new rapid acting therapies
- Issues to consider for the development of psychedelic medications
- Clinical development requirements to target sub-domains of depression
- Requirements for clinical trials in children and adolescents and possible extrapolation from adult data
- Sex-related differences and considerations in MDD
The need to monitor the degree of suicidal thoughts and behaviour and their change (improvement or worsening) with antidepressant therapy by use of validated instruments is confirmed.
MDD is one of the most common and disabling psychiatric disorders and the fourth leading cause of global disease burden. An estimated 3.8% of the population worldwide is affected by MDD, including 5.0% of adults (4% among men and 6% among women), and 5.7% of adults older than 60 years. Approximately 280 million people in the world have depression. Depression is about 50% more common among women than among men. Worldwide, more than 10% of pregnant women and women who have just given birth experience depression. MDD is not a benign disorder. More than 700 000 people die due to suicide every year (World Health Organization webpages, accessed 2023), and MDD is a leading precipitating factor for suicide. Depression frequently occurs with comorbid psychiatric disorders. For preschool children MDD is very rare (point prevalence is thought to be 0.5%), in adolescents the prevalence is estimated to be approximately 8%. Meta-analytic analyses suggest a higher prevalence of MDD in adolescents than in the general global population, but the paucity of youth-specific epidemiologic studies of MDD across regions warrants further investigation. Signs and symptoms of MDD are similar to the adult population; however, differential diagnosis in this population is difficult particularly with dysthymic disorder or bipolar disorder.
Despite the many treatment options currently available for MDD, up to 50% of patients do not adequately respond to the first antidepressant prescribed and up to two thirds do not achieve remission, even if there is good compliance and the treatment has been taken for a sufficient length of time at an adequate dosage. In clinical practice, treatment algorithms have been established including re-evaluation of the initial diagnosis and, when no correctable cause is found, optimization of the initial regimen or switching to other antidepressants or augmentation strategies (e.g. combination therapy, lithium and other mood stabilizers, atypical antipsychotics, etc.) or monotherapy with second generation antipsychotics have been considered as psychopharmacologic options. However, treatment approaches are not standardised. The approval of a treatment for TRD in an add-on setting with conventional SSRIs or SNRIs after at least two treatment failures has resulted in adjunctive treatment trials being considered a valid approach for TRD.
It has been shown that many patients without adequate treatment suffer from a tendency of higher frequency of major depressive episodes together with an increased severity. Therefore, pharmaceutical companies are encouraged to foster development of new antidepressants and to focus not only on the treatment of acute symptoms and maintenance of the effect during the index episode, but also to explore the potential of their compounds in preventing new episodes called recurrence prevention. However, prevention of a new episode (recurrence prevention) is not a mandatory part of a registration package for treatment of episodes of MDD, but is considered as an additional claim.