Part 3
If you’re currently taking an antidepressant, please don’t stop or change your dose based on this article. Talk to your prescriber first. This piece is about the research behind the theory, not medical advice for your situation.
What Actually Helps (And Where This Is All Headed)
If depression isn’t a chemical deficiency, what do you do with that? Say the pill isn’t fixing what you thought it was fixing. Then what?
Three Things Are Always Happening at Once
One detail from Moncrieff’s conversation with Dr. Bruce Wampold on Making Therapy Better stands out, because it quietly explains why antidepressant trials are so hard to interpret in the first place.
Wampold pointed out that people in clinical trials often see a psychiatrist every week or two, just to check in. In real-world practice, appointments that frequent are rare. Many people go months between visits with barely more than a prescription refill.
Moncrieff’s answer reframed the whole conversation. There’s actual research showing that the number of appointments someone has predicts their outcome, and the effect is bigger than the gap between drug and placebo.
She breaks it down into three things happening simultaneously in anyone’s depression:
- Natural history. Most people recover from depression eventually, medication or not. Emotions fluctuate. A bad period tends to lift on its own over time.
- Human contact. Simply having someone supportive, attentive, and consistently checking in produces a measurable effect on its own, separate from anything pharmacological.
- Specific interventions. Certain therapies, along with things like exercise and mindfulness, have shown real benefit in the research, though not necessarily by the mechanisms we’ve assumed.
All three are tangled together in every clinical trial, in every patient’s experience, in every “the medication is working” moment. Untangling which part is actually doing the work is far harder than the tidy chemical imbalance story ever let on.
“An awful lot of the outcome of people with depression can be attributed to their interaction with someone who is supportive and caring,” Moncrieff said, “and keeping an eye out for them.”
Rethinking Depression as a Signal, Not a Malfunction
Wampold raised something the show has explored before with evolutionary psychiatrists: the idea that depression might be an evolved response, a forced slowdown that pushes you to examine your life and recalibrate. Grief works the same way. It’s not a glitch. It’s what happens when something significant changes and your mind needs time to process it.
Moncrieff largely agrees, though she frames it a bit differently. Her take isn’t so much that depression serves a specific evolutionary function. It’s that emotional sensitivity in general is part of what makes us the kind of creatures we are.
We notice things. It matters to us when someone is unkind, when we fail at something we care about, when a relationship ends. That sensitivity, she argues, is a sign of intelligence, not a defect to medicate away.
“Emotions in that sense are a signal to us,” she said. “If we just try and numb or obliterate them, we may prevent people from making important changes in their lives that are actually going to lead them in a better direction.”
That reframing has real teeth. Depression is often grief, Moncrieff points out, and not only for the death of a loved one. Losing a job, a relationship, an identity you’d built your life around can trigger the same process. Numbing that response doesn’t resolve what caused it. It just makes it harder to hear.
The Part That Should Worry You More Than Serotonin Does
If there’s a genuinely alarming section of this conversation, it’s not about the past. It’s about where psychiatric drug development is headed next.
Moncrieff sees the field circling toward some familiar dangers. New opioid-type medications are in development or already reaching the licensing stage. A new drug with effects similar to benzodiazepines has recently been approved. None of these, she notes, have been adequately tested for dependence potential, something they’re very likely to carry.
Psychedelics Were Supposed to Be Different
Psychedelic-assisted therapy started from a more promising place, in Moncrieff’s view. The original model wasn’t about ongoing use. It was one or two guided doses alongside a therapist, followed by real psychotherapeutic processing to help someone integrate what they experienced and apply it to their life.
That model, she says, is theoretically sound. It doesn’t pretend psychedelics are inert. It just centers the insight and the human support around the drug experience, rather than the drug itself.
But she’s watched that model start to erode. At a recent conference on ketamine and esketamine, she noticed something telling: the researchers presenting on psychedelic-assisted psychotherapy trials had clearly put real effort into the therapy component. Nearly everyone else at the conference had moved on entirely, focused only on receptor mechanisms and dosing frequency, with psychotherapy barely mentioned.
The financial incentive points in an uncomfortable direction. One or two guided psychedelic sessions with a therapist isn’t a repeatable revenue stream. Regular ketamine infusions, on the other hand, are. That’s already the pattern taking shape in the U.S., and it concerns Moncrieff for a specific reason: we already know sustained ketamine use carries real physical risk, and likely psychological risk as well.
“It’s not very profitable to give someone one or two doses of psychedelics and a few sessions of therapy,” she said. “It’s much more profitable to have people coming back on a regular basis.”
Why the Field Keeps Missing the Point
Here’s the thread that ties all three parts of this series together. Moncrieff doesn’t think a more precise biological explanation for depression is coming, not because the science isn’t advanced enough yet, but because she doesn’t believe depression is fundamentally a brain disease to begin with.
Something is always happening in the brain, she’d be the first to say that. But she doesn’t see that as evidence of a specific pathology waiting to be found and targeted. She sees it as biology reflecting an experience, the way biology reflects any intense emotional state, joy included.
That’s a very different premise than the one modern psychiatric drug development keeps building on. And as long as the field keeps searching for the next specific biological switch to flip, whether it’s serotonin, glutamate, or whatever comes after ketamine, Moncrieff thinks it’s chasing something that was never really there.
Where This Actually Leaves You
None of this means medication has no place, and it doesn’t mean therapy is automatically superior in every case. What it means is that the story you were probably told, low serotonin, corrected by a pill, was never supported by the evidence. And building treatment decisions on a story that isn’t true has real costs, for how hopeful people feel about recovery and for how honestly they can weigh their own options.
Depression, in Moncrieff’s framing, isn’t a malfunction. It’s a response. Sometimes proportionate, sometimes overwhelming, always shaped by the life it’s responding to.
That reframe isn’t a smaller or lesser explanation than the biological one. If anything, it’s more hopeful. A chemical imbalance is something that happens to you. A response to your life is something you can understand, work through, and in time, move past, often with real help from other people along the way.
“It’s a human state that we can influence,” Moncrieff said. “It may not be easy, it may take time, it may take help from other people, but we can influence our emotional states. And not only that, we can learn from them.”
