The European Medicines Agency (EMA) has updated its general guidelines on the development of medicinal products for Major Depressive Disorder (MDD) to include a section on psychedelic therapy.
With up to two-thirds of MDD patients not responding to current therapies, there is an urgent need for new and innovative treatments.
The area of psychedelic research has in recent years produced increasing clinical evidence that points towards these therapies as being potentially efficacious treatments for the condition.
The guidelines – previously updated in 2002 and 2013 – now include a section on these therapies in light of this research.
The update specifically addresses topics such as trial designs in difficult-to-treat patients, clinical development requirements for new rapid-acting therapies, clinical development requirements to target sub-domains of depression, requirements for clinical trials in children and adolescents as well as extrapolation from adult data, and gender and drug metabolism differences in patient populations.
The section on psychedelics addresses, in particular, issues concerning the development of psychedelic medicines and the “new paradigm of psychedelic-associated psychotherapy in the field of MDD”.
The guidelines read: “Psychedelics are currently being recognised in psychiatry as potential treatment options to treat various medical conditions including depression.
“Psychedelic-assisted psychotherapy faces several challenges mainly related to standardisation, training, monitoring and safety that need to be addressed in specific study designs.”
Psychedelic clinical trials
The document highlights that the effects of psychedelic agents present a number of challenges for the design, conduct and interpretation of clinical trials.
Such challenges include:
Placebos and comparators
The psychoactive of psychedelics are very noticeable, making the choice of comparator and blinding difficult during clinical trials.
Expectancy and unblinding
With increasing headlines and discussion around the potentially beneficial effects of psychedelic therapies, positive expectations can sometimes lead to “overestimation bias” as well as disappointment for patients if expectations are not met – which the guidelines highlight can lead to the worsening of symptoms for patients.
The guidelines read: “Different strategies such as low dose or active placebo, i.e. alternative substances with a distinct mechanism of action but with a similar psychoactive effect have been considered to make it more difficult to guess the treatment arm. The use of independent and blinded external raters could help to mitigate the effects of unblinding and expectancy.”
Dosing
The document highlights the vital need for the dose-effect relationship of psychedelics to be characterised, emphasising the need for individualised dosing due to “individual variability in drug metabolism, age, sex, or personality…”.
Effect maintenance
The guidelines highlight the current lack of knowledge on the sustainability of the action and the long-term effects of psychedelics – emphasising that “the ability to change the perception of reality can have unknown implications for depressed patients (anxiety with derealisation, negative trips).”
Psychotherapy
With the majority of clinical trials investigating psychedelics administering the treatments alongside psychotherapy, the guidelines note that clinical trials will have to demonstrate that the effect of the psychedelic-assisted therapy is not due to psychotherapy alone.
The guidelines read: “The framework of operation (protocol) as well as preparatory and post-dose integration sessions and whether this needs to be adapted to the type of psychedelic need to be clearly defined.
“Type, length and frequency of psychotherapy and training need to be standardised to the maximum possible effect, despite ethnic and cultural differences.”
Read the full guidelines here: https://www.ema.europa.eu/en/documents/scientific-guideline/draft-guideline-clinical-investigation-medicinal-products-treatment-depression-revision-3_en.pdf
