A rich discussion emerged on the Exponential Do community Slack earlier this week inspired by a new paper published in Molecular Psychiatry. I asked one of the members involved in the discussion, Josh Hardman, founder and editor of Psychedelic Alpha, to share his views with us. Here’s Josh:

A new paper published in Molecular Psychiatry has caused quite a stir among researchers, practitioners, and reporters alike: according to Altmetric, it’s been cited in nearly 170 news articles and over 4,000 tweets since its publication on Wednesday.

The systematic review claims to debunk the serotonin theory of depression which holds that depression is caused by low levels of serotonin; a ‘chemical imbalance’. Instead, the authors argue that depression is caused by difficult life events.

Space does not allow us to delve into some of the methodological issues and more substantive debates around this paper (readers should see Science Media Centre for expert reactions in this vein) but it does afford us the chance to briefly explore the implications of its ‘findings’ and their largely uncritical depiction by media outlets.

The authors’ ‘finding’ that low serotonin does not cause depression is, prima facie, a pretty uncontroversial argument. While the first sentence of the publication claims that such a theory of depression “is still influential,” it’s not clear that this is the case among experts: you would be hard pressed to find a psychiatrist, for example, that subscribed to the notion. While it may remain undeniably salient among the public and perhaps even general practitioners, it is certainly not accepted among experts - most of whom subscribe to the biopsychosocial model knowing that depression is a heterogeneous disorder with several potential underlying causes.

It appears the authors are hoping that by debunking the chemical imbalance theory of depression they might restore agency to individuals who may otherwise be pessimistic about their ability to self-regulate their mood, perhaps believing that their mental health is biologically predestined.

Journalists, meanwhile, appear to have taken the high-level ‘finding’ that the serotonin theory of depression is unfounded and, by some leap, concluded that this undercuts the efficacy of SSRI antidepressants (given that their mechanism of action is thought to involve acting on the serotonin system). It’s not surprising that journalists came to this conclusion, as the authors of the paper invoke significant doubt around SSRIs by implying that they may work “via an amplified placebo effect or through their ability to restrict or blunt emotions in general.”

Many journalists leapt at the double whammy this narrative presents: an on-trend ‘gotcha’ piece pointed toward the undeniably concerning levels of antidepressant prescriptions, which are presumably welcomed by the big pharma companies that market them; and the ability to push a kind of mental health Brexit where readers feel empowered to take back control of their mental health, now that they know it’s not their biological destiny to be depressed.

But, this logical leap from discrediting the serotonin theory of depression to implying that serotonergic antidepressants are, by extension, ineffective is entirely unfounded. In order to arrive at such a conclusion, one has to conflate the clinical effects of a drug on a disease with its mechanism of action: and that is certainly not a wise thing to do, given that we have many drugs that ‘work’ without us understanding why.

UCL’s Dr Michael Bloomfield pithily captured this point in his response to the publication:

“Many of us know that taking paracetamol [AKA acetaminophen] can be helpful for headaches and I don’t think anyone believes that headaches are caused by not enough paracetamol in the brain. The same logic applies to depression and medicines used to treat depression.”

Even the history of psychiatric drugs is itself riddled with examples of serendipitous discovery of therapeutic benefits unrelated to any mechanistic understanding. Iproniazid, originally developed as a tuberculosis treatment in the 1950s, was found to improve mood and invoke joy, and later sparked the development of modern day antidepressants.

While not a descendent of those discoveries, psychedelics, whose presumed mechanism starts with binding to a subtype of serotonin receptor known as 5-HT2A receptors, represent a promising new avenue of treatment in psychiatry and yet another example of drugs with largely unknown mechanisms.  

Why does it matter?

What’s at stake here is not academic one upmanship or pedantry, but rather the consequences of individuals responding to sloppy journalism by withdrawing from medications that may very well help them, especially in the most severe cases of depression.

For context, I spend most of my time exploring the potential of psychedelics as a novel class of therapeutics over at Psychedelic Alpha. I am hopeful that psychedelic therapies prove to be safe and efficacious because, like many of you, I believe that the current state of care is wholly inadequate. The first line of treatment in many Western countries is SSRIs, which fail to confer a meaningful benefit to a large portion of those that use them, and produce significant side effects for many others.

But, we must remember that despite a lack of clarity around their mechanism of action, there is an evidence base that supports the use of such medicines. To suggest otherwise is irresponsible.

What’s more, the authors’ assertion that depression is, in fact, caused by ‘life events’ represents little more than the substitution of one crude, over simplistic model for another. Of course difficult life events have the capacity to trigger a depressive episode, but they do not, in themselves, explain the heterogeneous nature of the disease. Perhaps what the authors are looking for is the biopsychosocial model, after all?

Josh Hardman spends most of his time exploring the world of psychedelic medicine. He shares weekly updates on the space via the Psychedelic Alpha Bulletin, and works with a group of subject-matter experts to maintain a number of free resources to help individuals and organisations make sense of this burgeoning field. Josh is keen to balance the natural excitement around new treatment modalities with an appreciation for the broader social and economic realities that might influence their rationale and reach. When he’s not reading or writing about developments in the psychedelics space, Josh can usually be found listening to podcasts (including EV, of course) while wandering aimlessly around various North London parks.

*With thanks to Michael Haichin for comments.