Connecting the Dots
Jens H. van Dalfsen, PhD, a postdoctoral researcher in biological psychiatry, is the principal investigator of another UMCG group looking into the neurobiological mechanisms of major depressive disorder and treatment-resistant depression. His team’s strategy entails an elaborate coordination between the preclinical and clinical research settings.
For example, Sarah Massetti, a PhD candidate in biological psychiatry, is using blood samples collected in clinical trials to investigate the molecular mechanisms underpinning the neuroplasticity and immune-modulating effects produced by psychedelic compounds.
Another line of research spearheaded by Rutger Boesjes, a PhD candidate in biological psychiatry, is exploring the interactions between drugs like ketamine and the circadian system and how they might relate to antidepressant responses in animal models. It could be that the timing of administration of these drugs is relevant, he explained.
The Patient Factor
How psychedelics work and in whom is a big question for the UMCG team and across the research landscape.
“When researchers and the general public talk about psychedelics, they frequently refer to how they promote synaptic plasticity and new connections in the brain,” said van Dalfsen. “But traditional compounds also do that. So the ultimate question that we’ve been exploring is whether findings reflect an actual pharmacological effect or if expectancy also plays a role. In other words: How can we explain why psychedelics might or might not be effective in treatment-resistant patients?” he explained.
This is where the connection to the clinical experience becomes paramount and Joost Breeksema, PhD, comes in.
Breeksema divides his time between UMCG research and his role as executive director and co-founder of the Open Foundation, a nonprofit dedicated to advancing scientific psychedelic research. The work he’s doing outside the university is helping to frame the investigations of the wider group.
So far he has conducted two qualitative studies.
One was an off-label study in which patients with treatment-resistant depression were administered esketamine.
The other was a randomized clinical trial in which participants were blinded to a single 10- or 25-mg dose of psilocybin versus a 1-mg psilocybin microdose placebo that is too small to invoke any effects.
A key insight was the degree to which participants were unprepared for the intensity of their experiences, especially with regards to ketamine. Breeksema said the sessions might not have been so intense or negative for some participants had they been informed beforehand to expect the drugs could provoke “quite overwhelming experiences” and had they been accompanied by an experienced guide providing reassurance and support.
The format for the psilocybin trial met part of this criteria. Participants received a micro (placebo), medium, or high dose in a single session accompanied by two trained therapists. They then engaged in two sessions afterward to process their experiences. A single psilocybin experience appeared to be not enough or too much depending on the dose they were assigned and if they had prior experience with the compound.
Trial participants also felt they needed more help making sense of the experience. “This is a common and important theme,” said Breeksema. “Think about it. If you’ve been depressed for 10, 15 years and … you uncover something and break through something that’s been stuck, you need to process it.”
Jeanine Kamphuis, PhD, a psychiatrist and senior researcher at UMCG and one of the trial study co-authors, explained that they want to find a way to identify who will be too overwhelmed by these experiences if the dose should be adjusted or if some time needs to pass between dosing sessions. They also want to spend more time preparing patients for these sessions.
She emphasized that the studies have provided a reality check. “These are not wonder pills or wonder experiences. And in these types of patients, they’re not intended for a personal growth experience,” she said. “You have a patient who is sitting in front of you who seeks therapy and relief from very severe mood complaints, and the suffering is high,” she said, adding that expectancy bias further complicates patient participation and, likely, outcomes.