Matheson et al. Study

Convergent increases in serotonin 1B receptor binding following ketamine and electroconvulsive therapy: a multi-centrecenter bayesian re-analysis of PET data

Granville J. Matheson et al.

Molecular Psychiatry. 2026. https://doi.org/10.1038/s41380-026-03704-2

Research Question

Do ketamine and electroconvulsive therapy (ECT) produce convergent changes in serotonin 1B receptor (5-HT1BR) binding, and can these changes be distinguished from placebo? 

Brief Background

• The serotonin 1B receptor (5-HT1BR) is an inhibitory receptor located both presynaptically on serotonin terminals as an autoreceptor and on non-serotonergic neurons as a heteroreceptor. It helps regulate serotonin release across cortical and limbic regions 
• Prior PET studies have suggested reduced 5-HT1BR binding in major depressive disorder, particularly within the hippocampus, anterior cingulate cortex, and ventral striatal–ventral pallidal reward circuitry; however, these studies generally involved small samples. 
• Ketamine and ECT have different primary mechanisms but may converge on serotonergic signaling. Preclinical findings indicate that both treatments can increase extracellular serotonin, potentially producing delayed, homeostatic changes in 5-HT1BR expression or activity. 
• [¹¹C]AZ10419369 PET estimates 5-HT1BR binding potential, not serotonin concentration. Increased binding may reflect greater receptor density, altered receptor affinity or conformational state, reduced competition from endogenous serotonin, or a combination of these processes. 

Study Location

Multi-center re-analysis of PET data collected at three centers:

• Karolinska Institutet (KI), Stockholm, Sweden

• Nippon Medical School (NMS), Tokyo, Japan

• Neurobiology Research Unit at Rigshospitalet (NRU), Copenhagen, Denmark

Study Sponsor

This work was supported by Hjärnfonden (PS2020-0016), Vetenskapsrådet (2020-06356, 2024-03534), Region Stockholm (clinical research appointment), NIH grants P50MH090964 and R01EB024526, and OpenNeuroPET, funded through BRAIN Initiative grant 1R24MH120004-01A1 and Novo Nordisk Foundation grant NN20OC0063277.

Inclusion Criteria

The combined dataset included healthy volunteers and patients with major depressive disorder (MDD). All patients met DSM-IV or DSM-5 criteria for a major depressive episode.

Within-subject treatment samples:

• Ketamine/placebo cohort: outpatients with SSRI-treatment-resistant depression, defined as failure to respond to at least 4 weeks of SSRI treatment at adequate doses during the current depressive episode. Patients were psychotropic medication-free at PET; those receiving antidepressants at inclusion completed a supervised washout of at least five drug half-lives before baseline PET.
• ECT cohort: hospitalised patients with severe major depressive episodes warranting ECT. Patients were receiving concurrent medication in steady state at the time of PET, with no medication changes between PET measurements; none of the medications acted on 5-HT1BR. No formal treatment-resistance criterion was applied.

Exclusion Criteria

Key exclusion criteria common to both treatment studies were:

• Psychotic disorder
• Substance abuse
• Organic brain disorder
• Pregnancy

How Many Participants

Treatment completers with usable pre- and post-treatment PET data:

• Ketamine: 19
• Saline placebo: 10
• ECT: 13

Study Intervention

This study re-analysed previously collected data; it did not administer new treatments.

Original ketamine/placebo study:

• Randomised, double-blind allocation to a single intravenous infusion of racemic ketamine 0.5 mg/kg or saline
• PET performed 1-3 days before and 24-72 hours after infusion

Original ECT study:

• Open-label ECT series of 7-16 treatments, administered 2-3 times per week
• PET performed before treatment and up to one week after the ECT series
• No sham-ECT control was included

The re-analysis applied SiMBA with the simplified reference tissue model to quantify and analyse the PET data simultaneously, borrow information across individuals and regions, and harmonise measurements across centers.

Follow-Up

The analysis used the original studies' pre- and post-treatment PET measurements. Post-treatment PET occurred 24-72 hours after the ketamine or saline infusion and up to one week after completion of the ECT series. No longer-term clinical or PET follow-up was reported in this re-analysis.

Endpoints

Primary analytical focus:

• Global within-individual change in 5-HT1BR binding after ketamine, saline placebo, and ECT
• Whether ketamine- and ECT-associated changes could be statistically distinguished from placebo and from one another

Secondary aims:

• Regional specificity of treatment effects
• Differences in 5-HT1BR binding between patients with MDD before treatment and healthy controls
• Association between change in 5-HT1BR binding and change in depressive symptoms
• Effect of adding data from other studies and center on precision of treatment-effect estimates

Results

Global treatment-associated changes in 5-HT1BR binding:

• Ketamine: +6.4% (95% credible interval [CI], 3.1% to 9.6%; posterior probability of direction [pd] > 0.999)
• ECT: +9.3% (95% CI, 4.3% to 14.2%; pd > 0.999)
• Placebo: -0.7% (95% CI, -4.6% to 3.1%; pd = 0.632)
• ECT-associated changes were slightly larger than ketamine-associated changes (pd = 0.973)

Difference-in-difference comparisons with placebo:

• Ketamine versus placebo: +7.1% (95% CI, 2.2% to 12.3%; pd = 0.996)
• ECT versus placebo: +10.0% (95% CI, 4.0% to 16.3%; pd > 0.999)

The ECT-placebo comparison used the saline-placebo arm of the ketamine study because the ECT study did not include sham ECT. It therefore assumed that placebo-associated changes would be similar for sham ketamine and sham ECT; center and treatment effects were also partially confounded.

Regional and clinical findings:

• No region was clearly statistically differentiable from the mean treatment effect for ECT or ketamine.
• For ECT, the hippocampus showed the largest proportional change relative to the mean ECT effect (+6.2%; pd = 0.937), while the frontal cortex showed the smallest (-3.9%; pd = 0.907).
• Estimated regional heterogeneity was greater for ECT than ketamine: SD of regional deviations in change in log BPND was 0.044 for ECT and 0.013 for ketamine; pd = 0.90 that ECT produced more regionally heterogeneous effects.
• Changes in binding were not associated with individual symptom improvement beyond the average change in symptom scores.

MDD versus healthy volunteers:

• No evidence of a global difference: -1.9% (95% CI, -7.3% to 4.1%; pd = 0.754).
• Age-by-MDD interaction: 3.0% greater reduction per decade (95% CI, -5.8% to 0.0%; pd = 0.972), suggesting lower binding among older patients with MDD relative to older controls.
• Exploratory regional analysis suggested lower amygdala binding in MDD: -6.3% (95% CI, -11.7% to -0.3%; pd = 0.985). The authors advised cautious interpretation.

Other Relevant Information

• 5-HT1BR functions as an inhibitory auto- and heteroreceptor; presynaptic autoreceptors are located on axon terminals in serotonin projection regions and regulate extracellular serotonin.
• [11C]AZ10419369 PET cannot distinguish binding to 5-HT1BR autoreceptors from heteroreceptors, or determine whether binding changes reflect receptor density, receptor affinity state, or competition from endogenous serotonin.
• Because acute serotonin release would be expected to decrease rather than increase binding potential, and PET was performed days after treatment, the authors considered receptor-level changes more plausible than sustained increases in extracellular serotonin.
• The authors proposed that increased binding could reflect receptor upregulation or a greater proportion of receptors in an active conformation, potentially as a homeostatic response to treatment-induced serotonin release.

Limitations

• This was a re-analysis of previously collected data, and the biological conclusions depend on the assumptions of the SiMBA model; independent replication with new data is needed.
• Sample sizes were determined by available data from the original studies; no prospective power calculation was performed for this re-analysis.
• The only experimental placebo group was the saline arm of the ketamine trial. The ECT-placebo comparison was cross-center and assumed that sham-ECT and sham-ketamine placebo effects on 5-HT1BR binding would be similar.
• ECT, ketamine and placebo were administered at separate locationsat KI, so center and treatment effects were partially confounded despite within-individual estimates and model-based harmonisation.
• The ketamine study was randomised and double-blind, whereas the ECT study was open-label and had no sham-ECT control.
• The treatment cohorts differed clinically: ketamine/placebo participants were medication-free outpatients with SSRI-resistant depression, while ECT participants were medicated inpatients with severe depressive episodes.
• The ketamine study included results following a single intravenous infusion of racemic ketamine compared to an acute, multi-treatment course of ECT. Current standard of care for ketamine infusion therapy similarly includes and acute, multi-treatment typically consisting of 6 to 8, twice weekly consecutive treatments. The results presented here may therefore under-represent biological changes to ketamine in a more clinically relevant treatment context.
• PET cannot determine the cellular source or precise biological meaning of increased [11C]AZ10419369 binding.
• Binding changes were not associated with individual symptom improvement, leaving their relationship to therapeutic efficacy uncertain.

Summary and Implications

This study showed global increases in 5-HT1BR binding after exposure to both ketamine and ECT. The estimated increases were distinguishable from saline placebo, although the ECT comparison was exploratory because it relied on the placebo arm of a different study conducted at another center. The magnitude of binding change was not associated with individual symptom improvement, however, the sample sizes in the treatment conditions were small.

The convergent findings support a possible shared downstream serotonergic response to two rapid-acting treatments with different primary mechanisms. The authors interpret the increased binding as more consistent with receptor-level adaptation than persistent elevation of extracellular serotonin, but PET cannot establish whether the signal reflects autoreceptors or heteroreceptors, receptor number or density, affinity state, or endogenous neurotransmitter competition. The results also do not preclude changes to subcellular neuronal morphology, such synaptic architecture, which these treatments are known to influence or changes to the glial contribution of the tripartite synapse. The clinical relevance of the finding therefore remains unresolved and requires further mechanistic study and independent replication.

Comments

Ketamine and ECT have markedly different proximal mechanisms of action. Ketamine is generally understood to initiate its antidepressant effects through NMDA-receptor antagonism, altered glutamate release, and increased AMPA-receptor signaling, followed by activation of neuroplasticity-related pathways such as BDNF–TrkB and mTOR. ECT begins with an electrically induced generalized tonic-clonic seizure that produces widespread changes in neuronal activity, network connectivity, neurotransmitter systems, and neurotrophic signaling. No single mechanism fully explains the clinical effects of either treatment.