In the mid-1990s, child mental health researchers at top New York institutions injected grade-school boys with fenfluramine, also known as the diet drug "fen-fen," a substance that was later banned by the Food and Drug Administration, due to its links to valvular heart disease and pulmonary hypertension. The boys were all Black or Hispanic by design: Eligible participants were required to be African American or Hispanic because they were deemed to be at higher risk for developing disruptive behaviors.
The standard explanation is that ketamine blocks NMDA receptors. These receptors bind glutamate, which is a chemical messenger found throughout the brain and body. By blocking NMDA receptors, ketamine increase "brain-derived neurotrophic factor" (BDNF), a protein which I refer to as "Miracle-Grow for the brain." BDNF promotes neuroplasticity-which is the growth of new connections (synapses) in the brain. This has traditionally been viewed as the primary mechanism responsible for ketamine's therapeutic benefits. But ketamine does so much more!
Before treatment began, participants underwent neuroimaging. Instead of relying on a single modality, the researchers fused structural connectivity (how regions are physically wired) with functional connectivity (how regions co-activate at rest). The goal was not to throw every possible feature at a black box, but to learn a constrained pattern-what the authors call structure-function "covariation"-that carries the most predictive signal for outcome. In other words, the model tries to find the smallest set of connections that meaningfully forecasts symptom change.
Yes, there has been a shocking lack of progress in developing transformative psychiatric medicine (We need new drugs for mental ill-health, 5 February), but this may be because in mental health, drugs are not always the answer (see, for example, Richard P Bentall's Doctoring the Mind). Huge progress has been made in the effectiveness of talking therapies for example, free effective treatment for post-traumatic stress disorder (PTSD) is available to all UK army veterans through the charity PTSD Resolution.
Statistics show that about one-third of people with depression achieve remission-meaning their symptoms are gone-with traditional antidepressant medications. This matched my experience treating people, and I had grown to accept that this was as good as it gets. Although I wasn't thrilled with the fact that many people continued to struggle with significant symptoms of persistent depression, it seemed this was as good as we could do.
That sounds impressive; however, the devil is in the details that the popular media completely ignored. For example, only 11 of those studies were focused on depression. The authors concluded that exercise had a medium effect on depression. It is impossible to know how a "medium" effect compares with drug therapy since the studies were not head-to-head comparisons. The study also reported that exercise benefited many other health conditions, including HIV or kidney disease, various mental disorders, and cancers.
Even as new GLP-1 agonists with brand names like Wegovy and Zepbound make it easier to achieve weight loss, and selective serotonin reuptake inhibitors ( SSRIs) like Prozac and Zoloft provide a hedge against depression, there is growing interest in an old idea: psychedelics. The drugs are not being researched as a diversion from life, but instead as a therapeutic intervention to help us handle life's challenges in more creative ways.
