CNECT Blog

ECT, Ketamine, and the serotonin 1B receptor - Evidence of a potential convergent mechanism of action

Fri, 25 Sep 2026 14:10:59 GMT

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.

"CREST - MST" Study

Thu, 13 Aug 2026 14:12:08 GMT

Confirmatory efficacy and safety trial of magnetic seizure therapy versus right unilateral ultra-brief electroconvulsive therapy in depression (CREST–MST): a randomised, double-blind, non-inferiority trial in Canada and the USA

Daniel M. Blumberger et al.

Lancet Psychiatry. 2026;13:376–386.

Research Question

Is magnetic seizure therapy (MST) non-inferior to right unilateral ultra-brief pulse-width electroconvulsive therapy (RUL-UB ECT) for the treatment of major depressive disorder (MDD), while causing fewer cognitive adverse effects?

Study Location

Multicentre randomised controlled trial conducted at three academic centres:

Centre for Addiction and Mental Health (Toronto, Canada)
University of Texas Southwestern Medical Center (Dallas, USA)
University of California, San Diego (USA)

Study Sponsor

This study was funded by a grant from the NIMH (R01MH112815).

Inclusion Criteria

Participants:

Aged 18 years or older
Diagnosed with non-psychotic major depressive disorder
Baseline Hamilton Rating Scale for Depression (HRSD-24) score ≥21
Considered suitable candidates for convulsive therapy (ECT and MST)
Able to maintain stable antidepressant treatment during the study period

Exclusion criteria

Recent substance dependence in the last 3 months
Significant neurological disease or dementia
Major unstable medical illness
Intracranial metal implants
Requirement for anticonvulsants or high-dose benzodiazepines (>2 mg lorazepam equivalent daily)

How Many Participants

292 participants assessed for eligibility
239 participants randomised
236 participants received treatment
119 participants received RUL-UB ECT
117 participants received MST
219 participants completed a full course of treatment or achieved remission

Study Intervention

Participants were randomly assigned to receive either MST or RUL-UB ECT until remission, withdrawal, or completion of 21 treatments.

MST characteristics

Twin magnetic coils placed over the frontal midline (Fz position)
Stimulation delivered at 100 Hz
Progressive escalation of train duration
Mean number of treatments: 14.2

RUL-UB ECT characteristics

Right unilateral ultra-brief pulse-width stimulation
Treatment administered at six times seizure threshold
Mean number of treatments: 11.4

Follow-Up

Participants were assessed:

At baseline
Every three or four treatments
At treatment completion
Six months after treatment completion

Endpoints

Coprimary outcomes

Remission of depression (HRSD-24)
Worsening of autobiographical memory (25% reduction from baseline on Autobiographical Memory Test [AMT])

Secondary outcomes

Response rates
Suicidal ideation remission
Anxiety symptoms
Quality of life
Subjective adverse effects
Neurocognitive performance
Time to reorientation after treatment

Results

Depression outcomes

Remission rates:
RUL-UB ECT: 27.8%
MST: 22.5%
Absolute difference: 5.3% (non-inferiority margin was 15%)
MST met criteria for non-inferiority.

Response rates

RUL-UB ECT: 48%
MST: 47%

Suicidal ideation remission

RUL-UB ECT: 48%
MST: 48%
Non-inferiority established.

Cognitive outcomes

Autobiographical memory worsened (binary outcome defined as a worsening from baseline of at least 25% in the AMT total score) in:

17.3% of RUL-UB ECT patients
2.7% of MST patients (p = 0.0003)

Compared with ECT, MST was associated with better outcomes in:

Global cognition (MoCA)
Verbal learning and memory
Attention
Executive function
Verbal fluency
Time to reorientation after treatment

Adverse effects

Compared with MST, RUL-UB ECT was associated with higher rates of:

Memory impairment
Jaw pain
Headache
Confusion

However, MST was associated with more post-treatment breathing difficulties.

There were:

13 serious adverse events overall
No treatment-related deaths
No suicide-attempt-related outcomes

Other Relevant Information

Approximately 82% of participants had failed at least two antidepressant trials.
Around one-third had previously received repetitive transcranial magnetic stimulation (rTMS).
Most participants were treated as outpatients.
Participants with psychotic depression were excluded.

Limitations

Target recruitment was not achieved.
The COVID-19 pandemic disrupted recruitment and treatment delivery.
The trial excluded psychotic depression.
Participants were younger than those typically treated with ECT.
Electrode placement was not changed to bilateral treatment in ECT non-responders, reducing generalisability to routine clinical practice.

Summary and Implications

This trial demonstrated that MST produced antidepressant effects that were statistically non-inferior to RUL-UB ECT while causing substantially fewer cognitive adverse effects. Although remission rates (approximately 20-30%) were lower than anticipated in both groups, MST appeared to better preserve autobiographical memory and was associated with reduced transient cognitive side-effects while maintaining efficacy.

The findings suggest that MST could become an important alternative for patients who might otherwise decline ECT because of concerns regarding memory impairment and other cognitive adverse effects. Wider implementation will depend upon regulatory approval, clinician training, and further studies examining long-term outcomes and optimisation of treatment protocols.

Comments

Magnetic seizure therapy (MST) has been in development for over two decades and this study was the largest randomised controlled trial to-date. Rather than passing electrical current diffusely through the brain, MST induces therapeutic seizures using strong focused magnetic stimulation, which results in highly focalised brain stimulation compared with ECT, which instead generally stimulates the whole brain. This approach theoretically can preserve efficacy while reducing cognitive adverse effects, particularly by minimising stimulation of memory related brain regions. The current results suggested broadly similar antidepressant effects of MST compared to right unilateral ultrabrief ECT (RUL UB ECT), the type of ECT which shows the slowest antidepressant effects, though has the best cognitive side-effect profile relative to other types of ECT.

There are several considerations related to this study and its primary findings, both clinically and from a research perspective.

Both ECT and MST were well-tolerated by participants
While the study results support the utility of MST as a potential viable alternative to RUL UB ECT, for example, in people who refuse ECT and are non-psychotic, it does not support the use of MST as an alternative to ECT as treatment is most typically given in clinical practice. This is due to both how ECT was administered (i.e., with no change of electrode placement allowed due to minimal response and treatment continuing to up to 21 treatments) and the study population (mostly outpatients, overall younger relative to a more typical ECT population and all with non-psychotic depression).
The low remission rates with both treatments generally do not support the use of both treatment approaches in this sample with these clinical characteristics (see above).
It is also important to note that while the overall remission rates were broadly similar at post treatment, MST overall required a higher number of required treatments (mean 14.2 MST vs 11.2 ECT treatments) for participants to either achieve remission or complete the entire treatment protocol of up to 21 treatments. Thus, when considering whether to refer patients for MST, clinicians and patients would need to weigh the necessity for speed of antidepressant effects against risk for adverse cognitive effects.
Last, due to the choice of the primary cognitive outcome measure in the study, the Autobiographical Memory Test (AMT), unfortunately, the cognitive results from this study with MST cannot be directly compared with other seminal studies of ECT, which predominantly have used the Columbia Autobiographical Memory Questionnaire – Short Form (C-AMI-SF). Retrograde autobiographical memory side effects are the most persistent adverse cognitive effect of ECT, while other adverse cognitive side effects are mostly transient. To establish whether MST definitively has a more favourable cognitive profile compared to RUL-UB-ECT and other forms of ECT, longer term follow-up data using the C-AMI-SF would be required.

When ECT Becomes Palliative Care: What a Cohort Study Reveals

Wed, 13 May 2026 13:08:02 GMT

Gregg A. Robbins-Welty et al.
Journal of the Academy of Consultation-Liaison Psychiatry. 2025;66:215–223.

DOI: 10.1016/j.jaclp.2024.12.001

“Patients who receive PECT experience reduced suffering and improved QOL. PECT may be helpful in scenarios of life-threatening psychiatric illnesses, terminal medical illnesses with comorbid treatment-refractory psychiatric illnesses, and diagnostic uncertainty with MNCD.”

Research Question

What are the indications, outcomes, and treatment characteristics of palliative electroconvulsive therapy (PECT) in patients with serious medical illness?

Study Location

Single-site retrospective cohort study at Duke University.

Inclusion Criteria

Patients with serious medical illness who:

received an ECT consultation between 2018 and 2023, and
had either palliative care involvement or DNAR status.

How Many Patients

31 patients met inclusion criteria.

21 patients received ECT
10 patients did not proceed with ECT.

Study Intervention

Patients underwent electroconvulsive therapy according to clinical indication.

Common indications included:

Catatonia (64.5%)
Treatment-resistant depressive disorder (35.5%)

ECT characteristics:

Mean acute course: 15 treatments
Mean maintenance course: 26 treatments
Most patients received ECT with palliative intent (81%)
Surrogate decision-makers consented in 76.2% of cases

Medical comorbidities frequently complicated management but often did not preclude ECT.

Follow-Up

Retrospective chart review covering treatment episodes from 2018–2023.

Endpoints

Primary descriptive outcomes included:

Psychiatric symptom improvement
Functional improvement
Cognitive outcomes
Quality of life (QOL)
Safety and complications
Diagnostic clarification

Results

All 21 patients who received ECT experienced psychiatric symptom improvement.
Catatonia patients demonstrated a mean Bush-Francis Catatonia Rating Scale improvement of 17 points (range 8-30; n = 14).
Patients with persistent major neurocognitive disorder (MNCD) demonstrated a mean Montreal Cognitive Assessment (MoCA) improvement of 5 points (range 0-17; n = 8).
Five patients previously diagnosed with were reclassified as depression-related cognitive dysfunction.

ECT improved:

communication (71.4%)
oral intake/hydration (66.7%)
activities of daily living/function (57.1%)
ECT was associated with reversal of life-threatening weight loss in approximately 20% of some patients.
ECT-related complications were uncommon:
one aspiration pneumonia
one episode of bradycardia
No deaths were attributed to ECT.

Other Relevant Information

Many patients had severe medical comorbidities including cancer, heart failure, cirrhosis, COPD, and failure to thrive.
Some patients required ICU-level monitoring during ECT.
Catatonia was frequently under-recognized and misdiagnosed as dementia.
Palliative care consultations were commonly triggered by psychiatric complications such as inability to eat, failure to thrive, or goals-of-care decisions around ECT.
The study highlights the importance of collaboration between consultation-liaison psychiatry and palliative care.

Limitations

Small sample size.
Single-center retrospective design.
Potential selection bias.
Reliance on chart documentation and subjective review of clinical improvement.

Summary and Implications

Palliative ECT appears to be a safe and effective intervention for selected patients with severe psychiatric illness in the setting of serious medical disease. In this cohort, ECT consistently improved psychiatric symptoms, cognition, communication, oral intake, and overall quality of life, while causing few complications.

ECT may also assist diagnostically, particularly in distinguishing depression-related cognitive dysfunction and catatonia from irreversible dementia. The study supports closer collaboration between palliative care and consultation-liaison psychiatry and suggests that ECT should be considered as a palliative intervention when severe psychiatric symptoms contribute substantially to suffering or functional decline.

Comments

Electroconvulsive therapy (ECT) is often framed as a treatment aimed at full remission: for instance, resolving catatonia, lifting severe depression, or stabilizing psychosis. But on medical inpatient units, in the intensive care unit, and alongside palliative care teams, the goal is sometimes different. In such settings, it may be clinically appropriate to prioritize the relief of suffering, restoration of communication, and improvement in eating and drinking. This study addresses that under-discussed clinical reality by describing “palliative ECT” for patients with limited medical prognosis.

Consider ECT as a palliative intervention when the goal is relief of suffering and restoration of function, even if full remission is unlikely. For select patients, ECT may be indicated to improve communication, eating and drinking, basic functioning, and time spent out of the hospital.
When “dementia” is diagnosed in the setting of rapid decline, withdrawal, poor intake, or immobility, keep catatonia and severe depression with cognitive impairment high on the differential—this cohort included multiple cases where cognition improved substantially after ECT.
Medical complexity should trigger careful planning (including higher-acuity monitoring when needed), not automatic exclusion; complications were uncommon and no deaths were attributed to ECT in this series.
Strong collaboration between patients, surrogate decisionmakers, consultation-liaison psychiatry, palliative care, anesthesia, and the ECT service is essential for shared decision-making aligned with patient goals.