Treating the Mood Underneath the Pain: What Ketamine Might Actually Be Doing

A client finished a series of ketamine infusions for pain he had carried for six years. When I asked how it went, he didn't tell me the pain was gone. He said, "It's still there. It just doesn't run my life anymore." I have heard some version of that sentence enough times now to stop treating it as a curiosity.

That report does not fit a clean analgesia model. If ketamine were simply turning down a pain signal, you would expect patients to describe less pain, not the same pain with less power over them. What my client described sounds less like anesthesia and more like a change in his relationship to the pain. A 2023 cohort study suggests that distinction is not incidental. It may be most of the effect.

Voute and colleagues followed 329 patients receiving racemic ketamine for treatment-resistant chronic pain and modeled what actually accounted for their relief. The result was striking: baseline depression mediated most of ketamine's pain relief, roughly 64.6% of it. Ketamine dose was not associated with the degree of pain reduction. Anxiety was not the driver. Depression was.

In this population, who got better tracked with depression, and the amount of ketamine given did not. A higher dose did not buy more relief. A heavier depression burden at baseline predicted more room for it to move.

Here is the discipline the finding requires. This is a cohort study, not a randomized trial, and a mediation analysis on observational data cannot establish causation. Baseline depression could be a marker for something else: central sensitization, sleep disruption, or the affective weighting the brain assigns to a chronic nociceptive signal. Depression and chronic pain share circuitry, and a statistical mediator is not the same thing as a mechanism.

What the study earns is a reframe, not a protocol. It is a strong signal that we should stop treating ketamine-for-pain and ketamine-for-mood as separate lanes when the same patients so often sit in both. It also fits a broader pattern in this literature, where ketamine's analgesic and antidepressant effects can come apart under the right conditions.

If depression is doing a large share of the work, then the depression assessment is not a side task you clear before the "real" pain treatment. It is part of the primary assessment.

• Screen for depression at baseline with an instrument, not an impression. A PHQ-9 takes two minutes.
• Track mood across the series, not only pain scores. If pain drops and mood was never measured, you have missed the variable most likely to explain the change.
• Ask about suicidality directly. Chronic pain and depression each raise risk; together they compound it.
• Take what my client said seriously. "The pain is still there but it doesn't run my life" is a mood-and-function report, and it deserves to be documented as one.

Whose pain gets read as "real" and whose gets read as "in your head" has never been evenly distributed. Women, and Black patients especially, are more likely to have their pain attributed to psychological causes and undertreated because of it. So a finding that says "depression mediates the analgesia" can be bent into "it was never really pain." That is not what the data say. The data say pain and mood are entangled in this population and both deserve treatment.

Keep those two moves apart. A clinician who screens for depression in order to treat it is practicing well. A system that screens for depression in order to dismiss the pain is doing something else entirely.

The old question was "will ketamine fix this pain?" The question this cohort supports is "is there a mood component driving this presentation, and am I measuring it?" That is a smaller, more honest claim, and it is more useful at the point of care. It also sits alongside a live problem for anyone practicing in this space: the formal guidance for ketamine in chronic pain has not been meaningfully updated since 2018, which leaves the careful assessment work resting largely on the clinician.

In treatment-resistant chronic pain, a 2023 cohort found ketamine's pain relief was mediated almost entirely, about 65%, by its effect on depression, with no dose–response for pain itself. The honest answer is that for many patients the two are entangled, and the mood effect appears to carry much of the analgesia. This remains observational data, not proof of mechanism.

Yes. If depression accounts for most of the measurable pain relief, baseline and serial depression screening is part of the primary assessment, not an add-on. Use a validated instrument such as the PHQ-9, track it across the infusion series, and assess suicidality directly, given the compounded risk in pain-plus-depression presentations.

Not in this cohort. Ketamine dose was not associated with the degree of pain reduction; baseline depression was. That undercuts the intuition that escalating the dose reliably buys more analgesia, and it argues against dose-chasing as a first response when a patient plateaus. Individual response still varies, and this is one observational study.

Peter H. Addy, PhD, LPC, LMHC is a Portland-based licensed therapist and the founder of Psychedelic Affirming Education, an NBCC-approved continuing education provider for licensed mental health professionals and Oregon Psilocybin Services facilitators. His research background includes work at Yale School of Medicine on psychedelic substances.

Assessing mood and medical fitness before and during ketamine work is a trainable skill set, not a matter of clinical instinct. Our Comprehensive KAP Assessment Bundle (2 CE credits) covers the medical and psychological assessment that ketamine-assisted psychotherapy actually requires.