Serotonin 4 Receptor Brain Binding in Major Depressive Disorder and Association With Memory Dysfunction

Kristin Köhler-Forsberg; Vibeke H Dam; Brice Ozenne; Anjali Sankar; Vincent Beliveau; Elizabeth B Landman; Søren V Larsen; Asbjørn S Poulsen; Cheng-Teng Ip; Anders Jørgensen; Michal Meyer; Dea S Stenbæk; Hans R L Eiberg; Jacob Madsen; Claus Svarer; Martin B Jørgensen; Vibe G Frokjaer; Gitte M Knudsen

doi:10.1001/jamapsychiatry.2022.4539

. 2023 Feb 8;80(4):296–304. doi: 10.1001/jamapsychiatry.2022.4539

Serotonin 4 Receptor Brain Binding in Major Depressive Disorder and Association With Memory Dysfunction

Kristin Köhler-Forsberg ^1,^2,³, Vibeke H Dam ^1,², Brice Ozenne ^1,⁴, Anjali Sankar ¹, Vincent Beliveau ^1,⁵, Elizabeth B Landman ¹, Søren V Larsen ^1,², Asbjørn S Poulsen ¹, Cheng-Teng Ip ^1,^2,⁶, Anders Jørgensen ^2,³, Michal Meyer ⁷, Dea S Stenbæk ^1,⁸, Hans R L Eiberg ⁹, Jacob Madsen ¹⁰, Claus Svarer ¹, Martin B Jørgensen ^1,^2,³, Vibe G Frokjaer ^1,^2,³, Gitte M Knudsen ^1,^2,^✉

¹Neurobiology Research Unit, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

²Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

³Psychiatric Center Copenhagen, Rigshospitalet, Copenhagen, Denmark

⁴Department of Public Health, Section of Biostatistics, University of Copenhagen, Copenhagen, Denmark

⁵Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria

⁶Department of Clinical Pharmacology, H. Lundbeck A/S, Valby, Denmark

⁷Center for Referral and Diagnostics, Mental Health Services, Capital Region of Denmark, Copenhagen, Denmark

⁸Department of Psychology, University of Copenhagen, Copenhagen, Denmark

⁹Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark

¹⁰Department of Clinical Physiology and Nuclear Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark

Accepted for Publication: November 5, 2022.

Published Online: February 8, 2023. doi:10.1001/jamapsychiatry.2022.4539

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Corresponding Author: Gitte M. Knudsen, DMSc, University of Copenhagen, Chair of Center for Experimental Medicine Neuropharmacology, Inge Lehmanns Vej 6-8, Rigshospitalet (8057), 2100 Ø Copenhagen, Denmark (gmk@nru.dk).

Author Contributions: Prof Knudsen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Köhler-Forsberg and Dam contributed equally as co–first authors. Drs Frokjaer and Knudsen contributed equally as co–senior authors.

Concept and design: Köhler-Forsberg, Dam, A. Jørgensen, Meyer, Stenbæk, M.B. Jørgensen, Frokjaer, Knudsen.

Acquisition, analysis, or interpretation of data: Köhler-Forsberg, Dam, Ozenne, Sankar, Beliveau, Landman, Larsen, Poulsen, Ip, A. Jørgensen, Eiberg, Svarer, M.B. Jørgensen, Frokjaer, Knudsen.

Drafting of the manuscript: Köhler-Forsberg, Dam, Ozenne, Sankar, Beliveau, M.B. Jørgensen, Frokjaer, Knudsen.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Köhler-Forsberg, Dam, Ozenne, Sankar, Beliveau, Stenbæk, Svarer, Frokjaer.

Obtained funding: Köhler-Forsberg, M.B. Jørgensen, Frokjaer, Knudsen.

Administrative, technical, or material support: Köhler-Forsberg, Beliveau, Landman, Larsen, Ip, Eiberg, Madsen, M.B. Jørgensen, Knudsen.

Supervision: Köhler-Forsberg, Stenbæk, M.B. Jørgensen, Frokjaer, Knudsen.

Conflict of Interest Disclosures: Dr Köhler-Forsberg reported receiving grants from G.J. Foundation during the conduct of the study. Dr Landman reported receiving grants from Det Frie Forskningsråd during the conduct of the study. Dr Ip reported receiving personal fees from DeepPsy AG outside the submitted work. Professor M.B. Jørgensen reported receiving personal fees from Boehringer Ingelheim and H. Lundbeck A/S outside the submitted work. Dr Frokjaer reported receiving personal fees from H. Lundbeck A/S and Sage Therapeutics outside the submitted work. Professor Knudsen reported receiving personal fees from Sanos, Sage Biogen, and H. Lundbeck A/S outside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported by grant 4108-00004B from the Innovation Fund Denmark, grant R279-2018-1145 from The Lundbeck Foundation Alliance BrainDrugs, grants from the Research Fund of the Mental Health Services–Capital Region of Denmark, grant R149-A6325 from the Research Council of Rigshospitalet, grant 16-0058 from the Augustinus Foundation, grants from Savværksejer Jeppe Juhl og Hustru Ovita Juhls Mindelegat, and grants DFF-6120-00038 and DFF-1057-00052B from H. Lundbeck A/S and Independent Research Fund Denmark (Drs Köhler-Forsberg, Dam, Ozenne, Sankar, Beliveau, Landman, Larsen, Poulsen, Ip, M.B. Jørgensen, Frokjaer, and Knudsen).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Data Sharing Statement: See Supplement 2.

Additional Contributions: We thank all participants and their relatives for taking part in this study. We are grateful to all of the investigators involved; collaborating general practitioners; staff at the Center for Referral and Diagnostics, Mental Health Services, Capital Region of Copenhagen; and other collaborators who helped throughout the study. We especially acknowledge the following individuals for providing excellent laboratory and technical assistance: Lone Ibsgaard Freyr, MSc; Bente Dall, BSc; Gerda Thomsen, BSc; Svitlana Olsen, BSc; Agnete Dyssegaard, MSc; Arafat Nasser, PhD; Ida Marie Brandt, MSc; Anna Maria Florescu, MD; and Mads Heidemann, MSc. These individuals received no additional compensation, outside of their usual salary, for their contributions.

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Corresponding author.

PMCID: PMC9909578 PMID: 36753296

This case-control study compares levels of serotonin type 4 receptor as well as verbal memory, working memory, reaction time, emotion recognition bias, and negative social emotions in unmedicated patients with major depressive disorder vs individuals without this diagnosis.

Key Points

Question

Is the serotonin 4 (5-HT₄) receptor altered in depression, and is it associated with memory dysfunction?

Findings

In this case-control study of 90 patients with untreated major depressive disorder and 91 healthy individuals, patients had approximately 7.0% lower cerebral 5-HT₄ receptor binding. In patients, 5-HT₄ receptor binding was inversely associated with verbal memory performance.

Meaning

Findings of this study suggest that the 5-HT₄ receptor is a promising target for treatment of cognitive symptoms in major depressive disorder.

Abstract

Importance

The cerebral serotonin 4 (5-HT₄) receptor is a promising novel target for treatment of major depressive disorder (MDD), and pharmacological stimulation of the 5-HT₄ receptor has been associated with improved learning and memory in healthy individuals.

Objective

To map the neurobiological signatures of patients with untreated MDD compared with healthy controls and to examine the association between cerebral 5-HT₄ receptor binding and cognitive functions in the depressed state.

Design, Setting, and Participants

This case-control study used baseline data from the NeuroPharm clinical depression trial in Denmark. Adult participants included antidepressant-free outpatients with a current moderate to severe depressive episode and healthy controls. All participants completed positron emission tomography (PET) scanning with [¹¹C]SB207145 for quantification of brain 5-HT₄ receptor binding, but only the patients underwent cognitive testing. Data analyses were performed from January 21, 2020, to April 22, 2022.

Main Outcomes and Measures

The main study outcome was the group difference in cerebral 5-HT₄ receptor binding between patients with MDD and healthy controls. In addition, the association between 5-HT₄ receptor binding and verbal memory performance in the patient group was tested. Other cognitive domains (working memory, reaction time, emotion recognition bias, and negative social emotions) were assessed as secondary outcomes.

Results

A total of 90 patients with untreated MDD (mean [SD] age, 27.1 [8.2] years; 64 women [71.1%]) and 91 healthy controls (mean [SD] age, 27.1 [8.0] years; 55 women [60.4%]) were included in the analysis. Patients with current MDD had significantly lower cerebral 5-HT₄ receptor binding than healthy controls (−7.0%; 95% CI, −11.2 to −2.7; P = .002). In patients with MDD, there was a correlation between cerebral 5-HT₄ receptor binding and verbal memory (r = 0.29; P = .02).

Conclusions and Relevance

Results of this study show that cerebral 5-HT₄ receptor binding was lower in patients with MDD than in healthy controls and that the memory dysfunction in patients with MDD was associated with lower cerebral 5-HT₄ receptor binding. The cerebral 5-HT₄ receptor is a promising treatment target for memory dysfunction in patients with MDD.

Introduction

Serotonin (5-hydroxytryptamine [5-HT]) regulates a wide range of psychophysiological functions involved in mental health, such as mood, sleep, and cognition.^1,2,3 Although altered 5-HT neurotransmission is believed to play a role in major depressive disorder (MDD), the exact association between the 5-HT system and MDD pathology is not well understood.⁴ Major depressive disorder is highly heterogenous, with moderate treatment success rates⁵ and biomarkers that can help stratify patients into clinically meaningful groups having the potential to improve future clinical trials and, ultimately, patient care. Molecular neuroimaging is a particularly valuable tool for investigating disease brain mechanisms as it allows for in vivo assessment of 5-HT brain features in patients with MDD and healthy individuals.

A common but often underrecognized symptom in patients with MDD is the presence of cognitive disturbances, including impaired memory and learning capacity.⁶ While treatment with serotonergic drugs is often associated with improved cognitive performance in MDD,⁷ many patients still experience lingering cognitive symptoms after remission of the depressive episode.⁸ Treatments that target these cognitive symptoms thus play a central role in improved long-term outcomes for patients.⁹

The 5-HT 4 (5-HT₄) receptor has been proposed as a promising antidepressant target,¹⁰ particularly for the treatment of cognitive dysfunction.¹¹ The 5-HT₄ receptor is a G_s protein–coupled postsynaptic heteroreceptor that is predominantly expressed in limbic regions and prefrontal cortex.¹² Preclinical data support the involvement of the 5-HT₄ receptor in the treatment mechanisms of depression.¹³ For example, both short-term^14,15 and long-term¹⁶ administration of 5-HT₄ receptor agonists to rodents has been associated with rapid antidepressant and anxiolytic-like behavioral changes, hippocampal neurogenesis,¹⁷ and prophylactic antidepressant and anxiolytic properties.¹⁸ In humans, so far no direct evidence has been found of the antidepressant properties of 5-HT₄ receptor agonism. However, human study data have shown that striatal 5-HT₄ receptor binding is lower in healthy individuals with familial risk of mood disorders.¹⁹ Additionally, preclinical studies have shown that the 5-HT₄ receptor is critically involved in learning and memory functions,^20,21 likely by modulating synaptic plasticity in the hippocampus.²² These findings are supported by 2 independent neuroimaging studies that reported an association between 5-HT₄ receptor binding and verbal memory performance in healthy individuals.^23,24 Furthermore, recent studies^25,26 of acute and short-term administration of the partial 5-HT₄ receptor agonist prucalopride in healthy volunteers have found that pharmacological stimulation of the 5-HT₄ receptor specifically enhances memory and reward-learning behaviors, whereas performance on emotion processing tasks is unaltered.

In this study, we used data from the NeuroPharm depression trial to map the neurobiological signatures of patients with untreated MDD compared with healthy controls and to investigate whether such features were associated with cognitive dysfunction.²⁷ To our knowledge, the NeuroPharm trial was the first to investigate in vivo cerebral 5-HT₄ receptor in patients with untreated MDD in comparison to healthy controls as a primary outcome measure. Next, we examined the association between cerebral 5-HT₄ receptor binding and cognitive functions in the depressed state. We believe this study will help inform a future analysis of the association between 5-HT₄ receptor and treatment outcome in a longitudinal follow-up, which will be published separately. We hypothesized that cerebral 5-HT₄ receptor levels differ between patients with MDD and healthy individuals and that memory function is associated with cerebral 5-HT₄ receptor binding in patients with MDD.

Methods

Participants and Study Design

The NeuroPharm clinical depression trial included 100 antidepressant-free outpatients with MDD, who were recruited from the mental health system in the Capital Region of Denmark.²⁷ All participants provided written informed consent prior to inclusion. The study protocol was approved by the Health Research Ethics Committee of the Capital Region of Denmark, the Danish Data Protection Agency, and Danish Medicines Agency (H-15017713 and H-KF-2006-20) and extended to the present case-control study. We followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Among the 100 outpatients, 90 had available positron emission tomography (PET) neuroimaging data. To be included, patients had to be aged 18 to 60 years and have a score higher than 17, indicating a moderate to severe depressive episode, on the 17-item Hamilton Depression Rating Scale (HAMD-17).²⁸ Patients were screened with the Mini-International Neuropsychiatric Interview (Danish translation, version 6.0.0, of the DSM-IV).²⁹ All patients met the criteria for MDD according to the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code, and the MDD diagnosis was confirmed by a specialist in psychiatry. Personality disorders and anxiety disorders secondary to MDD were allowed in the patient population. Exclusion criteria were use of antidepressant drugs 2 months prior to inclusion; more than 1 attempt with an antidepressant treatment in the current episode; treatment with any form of psychotherapy during the study period; previous nonresponse or known contraindications to selective serotonin reuptake inhibitors (SSRIs); duration of the current depressive episode exceeding 2 years; acute suicidal ideation or psychosis; other primary Axis I psychiatric disorder; alcohol or substance use disorder or dependence; severe somatic illness; history of severe brain injury; nonfluency in Danish; current or planned pregnancy or breastfeeding; use of medical treatment affecting the central nervous system (eg, metoclopramide, ondansetron, and clonidine); or contraindications to PET or magnetic resonance imaging (MRI) scans, such as claustrophobia, non–MRI-compatible device, soft-tissue metal, and exposure to radiation (>10 mSv) during the past year.

Ninety-one healthy controls with no Axis I psychiatric disorder were included for comparisons and recruited from either a quality-controlled repository³⁰ or an online recruitment site. The healthy control group was age- and sex-matched as closely as possible to the patient group and met the same inclusion and exclusion criteria as those for the patients except the healthy individuals did not have a current diagnosis or a history of mental illness. Participants underwent PET scanning with the radioligand [¹¹C]SB207145, MRI, urine screening for pregnancy or toxicological purposes, and routine blood tests. In addition, patients underwent broad cognitive testing.

In this case-control study, we analyzed the primary outcome of the baseline program of the NeuroPharm trial; a detailed overview of the complete NeuroPharm trial is provided elsewhere.²⁷ Additional analyses of the secondary and exploratory aims in the same cohort have been published, including data on functional MRI,^31,32 electroencephalogram and event-related potential,^33,34 cognition,^35,36 oxidative stress,³⁷ and anxiety symptoms.³⁸

PET and MRI Procedures

Procedures for PET and MRI acquisition, preprocessing, and region-based PET quantification are described elsewhere.^27,39 Briefly, PET images were acquired during a 120-minute dynamic scan using a high-resolution research tomography PET scanner (CTI/Siemens) after injection of [¹¹C]SB207145. All 90 patients and 53 healthy controls were scanned with a 3-Tesla Prisma MRI scanner (CTI/Siemens). The other 38 controls were scanned with a Magnetom Trio 3-T MRI scanner (CTI/Siemens).³¹ The 3-dimensional T1-weighted MRI scan was coregistered to PET images to obtain structural information. The PET scans were motion corrected using the Air 5.2.5 method.⁴⁰ PVElab software (Neurobiology Research Unit, Copenhagen) was used to extract regions of interest,⁴¹ which were automatically delineated on the individual’s own MRI. The mean tissue time activity for hemisphere-averaged gray matter volumes was used for kinetic modeling using the Simplified Reference Tissue Model, with cerebellum (excluding vermis) as a reference region.³⁹ The calculated nondisplaceable binding potential (BP_ND) served as an outcome measure for the 5-HT₄ receptor binding. Additional details are provided in the eMethods in Supplement 1.

We also conducted exploratory voxel-based and vertex-based analyses. Parametric 5-HT₄ receptor BP_ND maps were generated using the PetSurfer⁴² processing stream FreeSurfer, version 7.1.1 (Laboratory for Computational Neuroimaging),⁴³ as described previously.¹² Briefly, PET and MR coregistration was estimated using linear registration between the structural MRI and the time-weighted mean of the dynamic PET images. Cortical vertex-wise and subcortical voxelwise time-activity curves (TACs) were obtained by resampling the dynamic PET data onto the common mean surface space and/or transforming them to the common MNI152 volume space using combined volume and surface registration.^44,45 Cortical and subcortical TACs were surface smoothed by a 2-dimensional 10-mm Gaussian filter (full width at half-maximum) and volume smoothed by a 3-dimensional 5-mm Gaussian filter (full width at half-maximum), respectively. Kinetic modeling of the parametric BP_ND was performed using the Multilinear Reference Tissue Model 2,⁴⁶ with cerebellar gray matter, excluding vermis, as a reference region. Cerebellar gray matter masks were obtained by taking the intersection of the cerebellar gray matter segmentation defined by PetSurfer and a cerebellar gray matter segmentation, excluding vermis, derived using SUIT, version 3.1 (Diedrichsenlab).⁴⁷ The reference region washout rate (k2) was computed using Multilinear Reference Tissue Model,⁴⁸ and the high-binding TAC was obtained from a volume-weighted mean of caudate and putamen. Multilinear Reference Tissue Model 2 was preferred over the Simplified Reference Tissue Model for vertex-space and voxel-space kinetic modeling because it is more robust to noise in TACs.

The vertex-wise cortical 5-HT₄ receptor binding maps and the voxelwise subcortical 5-HT₄ receptor BP_ND were available for 90 patients with MDD and 83 healthy controls. Reasons for exclusion were poor quality of T1-weighted MRI (n = 1 control); different PET scanner (n = 3 controls); and acquisition of fewer than 38 PET frames (n = 4 controls). The vertex-wise cortical 5-HT₄ receptor binding maps and the voxelwise subcortical 5-HT₄ receptor BP_ND were used for exploratory investigations of whole-brain differences in 5-HT₄ receptor binding between patients and healthy controls.

Cognitive Measures

Patients completed a battery of cognitive tests, including verbal memory function, assessed with the 26-item Verbal Affective Memory Test³⁶; working memory function, assessed with the Wechsler Adult Intelligence Scale, Third Edition, Letter-Number Sequencing task⁴⁹; psychomotor speed, assessed with a Simple Reaction Time task; affective bias in emotion recognition, assessed with the EMOTICOM Emotional Recognition Task⁵⁰; and experience of negative social emotions (guilt and shame), assessed with the EMOTICOM Moral Emotions Task.⁵⁰ An overview of all cognitive measures is provided in the eMethods in Supplement 1.

Statistical Analysis

We used a latent variable model (LVM) to evaluate global and regional differences in 5-HT₄ receptor BP_ND between patients and healthy controls. In general, the use of LVMs reduce multiple testing issues and may ease interpretation as they are able to summarize multiple measurements of related constructs, providing a single global estimate; in this case, a latent variable capturing the shared covariance in log-transformed 5-HT₄ receptor BP_ND estimates for these regions of interest: neocortex, hippocampus, putamen, and caudate nucleus.⁴¹ P values for the region-specific outcomes were adjusted for multiple comparisons using a single-step maximum test. We also performed a post hoc assessment of the correlation between the latent 5-HT₄ receptor BP_ND estimate and depression severity as indexed with the HAMD-17.

We used 5 LVMs to investigate the correlation between the latent variable capturing global 5-HT₄ receptor BP_ND and performance on individual cognitive tasks within the patient group. The primary cognitive outcome was verbal memory, while the secondary outcomes were working memory, reaction time, emotion recognition bias, and negative social emotions. Reported P values for the secondary cognitive outcomes were corrected for 4 tests using the Bonferroni-Holm method to control for the familywise error rate (adjusted P value). To assess the potential role of educational, depression, and anxiety³⁸ levels in the association between 5-HT₄ receptor BP_ND and cognitive scores, we conducted post hoc analyses in which years of education, HAMD-17 scores, and 10-item Generalized Anxiety Disorder (GAD-10) scores, respectively, were included as covariates in the models.

In all LVMs, the latent 5-HT₄ receptor BP_ND construct was adjusted for age, sex,⁵¹ serotonin transporter gene (5-HTTLPR) LALA vs non-LALA variant,⁵² and [¹¹C]SB207145-injected mass per kilogram,⁵³ while the LVM assessing group differences between patients and healthy controls also included MRI scanner type. In addition, the observed patient scores (ie, HAMD-17 scores or cognitive scores) were also corrected for age and sex. Misspecification of the LVM was considered by adding 1 mean parameter (eg, region-specific group outcome) or 1 covariance parameter (eg, covariance between caudate and putamen 5-HT₄ receptor BP_ND). Relevance of any LVM-1 parameter extension was tested using score tests: if any false discovery rate was an adjusted P < .05, the parameter with the smallest P value was included in the LVM.⁵⁴ The procedure was repeated until no additional parameter was found to be relevant.

Comparisons of 5-HT₄ receptor BP_ND estimates between patients and healthy controls were performed independently for the left and right hemispheres and the subcortical regions using generalized linear models implemented in the Permutation Analysis of Linear Models (PALM) package⁵⁵ in the FMRIB Software Library. Similar to the primary analysis (ie, the region-based LVM analysis), age, sex, 5-HTTLPR LALA vs non-LALA variant, [¹¹C]SB207145-injected mass per kilogram, and MRI scanner type were used as covariates.

Using a conservative approach,⁵⁶ significant clusters were identified with permutation testing using PALM with 5000 permutations, a cluster-forming threshold of P < .001, and a correction for familywise error (adjusted P value) across contrasts (-corrcon flag).⁵⁵ A level of adjusted P < .02 (ie, P < .05 Bonferroni-corrected for 3 regions: left hemisphere, right hemisphere, and subcortex) was used to identify significant clusters. As recommended,⁵⁵ -logp function was used for better visualization. Data analyses were performed from January 21, 2020, to April 22, 2022.

Results

A total of 90 patients with a current moderate to severe depressive episode and 91 healthy controls were included in the study. The patients had a mean (SD) age of 27.1 (8.2) years and consisted of 64 women (71.1%), as expected for the MDD group, and 26 men (28.9%). The controls had a mean (SD) age of 27.1 (8.0) years and consisted of 55 women (60.4%) and 36 men (39.6%). Table 1 provides information on demographic characteristics, clinical profile, and tracer data. Patients and healthy controls were comparable except for a minor difference in educational levels and [¹¹C]SB207145-injected mass per kilogram of body weight.

Table 1. Clinical Profile, Demographic Characteristics, and Cognitive and Radiotracer Data for Patients With MDD vs Healthy Controls .

	Patients with MDD		Healthy controls		P value
	No.	Mean (SD) [range]	No.	Mean (SD) [range]	P value
Sex
Female, No. (%)	64 (71.1)	NA	55 (60.4)	NA	.16^a
Male, No. (%)	26 (28.9)	NA	36 (39.6)	NA	.16^a
5-HTTLPR genotype LALA variant, No. (%)	90	25 (27.8)	91	27 (29.7)	.91^a
Single-episode as reference vs recurrent depression, No. (%)	90	37 (41.1)	NA	NA	NA
Age, y	90	27.1 (8.2) [18 to 57]	91	27.1 (8.0) [19 to 60]	.59^b
Years of education	75	11.6 (1.1) [5 to 12]	91	11.9 (0.5) [9 to 12]	.003^b
BMI	90	24.6 (5.6) [17.1 to 45.1]	91	23.6 (3.1) [18.3 to 36.9]	.94^b
Cerebellum AUC, kBq/mL	90	10.3 (2.6) [3.9 to 17.8]	85	10.3 (2.5) [3.2 to 16.2]	.73^b
Injected dose, MBq	90	577.2 (56.2) [263.0 to 615.0]	91	569.4 (76.3) [226.0 to 617.0]	.18^b
Injected mass/kg, μg/kg	90	0.01 (0.01) [0.004 to 0.08]	91	0.02 (0.01) [0.003 to 0.07]	.02^b
HAMD-17 score	90	22.8 (3.4) [18 to 31]	NA	NA	NA
GAD-10 score	90	23.8 (9.3) [7 to 47]	NA	NA	NA
MDI	88	34.5 (7.0) [16 to 49]	91	5.6 (4.2) [0 to 18]	<.001^b
Verbal memory score (0-26)^c	85	14.7 (4.1) [6 to 23]	NA	NA	NA
Working memory score (0-21)^d	82	11.6 (2.8) [6 to 18]	NA	NA	NA
Reaction time, ms^e	89	277.2 (60.8) [201 to 467]	NA	NA	NA
Emotion recognition bias, %^f	90	−6.1 (23.6) [−80 to 45]	NA	NA	NA
Negative social emotions (1-7)^g	89	4.3 (0.7) [3 to 6]	NA	NA	NA

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Abbreviations: AUC, area under the curve (calculated based on injected dose per kilogram of body weight); BMI, body mass index (calculated as weight in kilograms divided by height in meters squared); GAD-10, 10-item Generalized Anxiety Disorder; HAMD-17, 17-item Hamilton Depression Rating Scale; MDD, major depressive disorder; MDI, Major Depressive Inventory; NA, not applicable.

^{^a}

P value computed using a Fisher exact test.

^{^b}

P value computed using a Mann-Whitney test.

^{^c}

Verbal memory was indexed as the mean number of words remembered across learning, immediate recall, and delayed recall trials in the 26-item Verbal Affective Memory Test.

^{^d}

Working memory score was indexed as the raw score from the Letter-Number Sequencing task of the Wechsler Adult Intelligence Scale, Third Edition.

^{^e}

Reaction time was indexed as the response time in milliseconds on a Simple Reaction Time task.

^{^f}

Emotion recognition bias was indexed as the hit rate for happy faces minus the hit rate for sad faces in the EMOTICOM Emotional Recognition Task.

^{^g}

Negative social emotions were indexed as the mean rating of self-reported guilt and shame on a scale of 1 (not at all) to 7 (extremely) in the EMOTICOM Moral Emotions Task.

Nondisplaceable binding potential, indexed as area under the curve of the TAC from the cerebellum, did not differ between the patient and control groups. When cognitive data were compared between patients and a separate group of healthy controls³⁵ (n = 103) (eTable 1 in Supplement 1), the patients performed worse than the controls. The magnitude of the cognitive disturbances ranged from small to medium: verbal memory (Cohen d = 0.46), working memory (Cohen d = 0.68), reaction time (Cohen d = 0.75), emotion recognition bias (Cohen d = 0.51), and negative social emotions (Cohen d = 0.82).

Group Differences in 5-HT₄ Receptor Binding

The primary LVM analysis showed that patients with untreated MDD had significantly lower global 5-HT₄ receptor BP_ND compared with healthy controls (−7.0%; 95% CI, −11.2 to −2.7; P = .002), corresponding with 6% to 8% lower 5-HT₄ receptor BP_ND across regions (Figure 1A). A sensitivity analysis using simple linear regression models generated a similar outcome (eTable 2 in Supplement 1)_. The exploratory voxel-based and vertex-based analyses showed that patients with MDD had significantly lower cerebral 5-HT₄ receptor BP_ND than healthy controls in cortical clusters (Figure 1B and C; eTables 3 and 4 in Supplement 1). We did not find any differences between groups in 5-HT₄ receptor BP_ND in the subcortical regions. Within the patients, we found no correlation between global 5-HT₄ receptor BP_ND and HAMD-17 scores (r = −0.06; P = .60) (Figure 2A).

Figure 1. — A, β indicates role of group status in global (log-transformed) nondisplaceable binding potential (BP_ND); λ, loading; dashed line, additional shared correlations between caudate nucleus and putamen; and lower boxes, percentage difference in baseline 5-HT₄ receptor binding between patients and controls (P values and CIs were adjusted for 4 comparisons). B and C, Lateral, inferior, and medial renderings show clusters of lower 5-HT₄ receptor BP_ND in the left and right hemispheres in patients vs controls (adjusted P < .02). Color bar indicates corrected P values. Lower 5-HT₄ receptor BP_ND was observed in the following clusters: large temporo-parieto-occipital cluster, prefrontal clusters, temporal cluster, left precentral gyrus, left precuneus, left superior parietal cortex, and cluster encompassing the right isthmus of the cingulate and precuneus.

5-HT₄ Receptor Binding and Cognitive Performance in MDD

In patients with MDD, we observed a direct correlation between global 5-HT₄ receptor BP_ND and verbal memory performance (r = 0.29; P = .02) (Figure 2B). An association between global 5-HT₄ receptor BP_ND and scores on working memory did not survive correction for multiple comparisons (r = 0.25; P = .04; adjusted P = .16). We found no statistically significant association between global 5-HT₄ receptor BP_ND and reaction time (r = −0.14; P = .23), emotion recognition bias (r = −0.05; P = .69), or negative social emotions (r = −0.19; P = .11) (Table 2).

Table 2. Association Between Serotonin 4 Binding and Cognitive Performance in Patients^a.

	Hippocampus, λ₂	Caudate, λ₃	Putamen, λ₄	β	r	P value	Adjusted P value
Primary
Verbal memory^b	1.13	0.97	0.96	0.16	0.29	.02	NA
Secondary^c
Working memory^d	1.18	0.99	0.96	0.08	0.25	.04	.16
Reaction time^e	1.13	0.96	0.93	−1.03	−0.14	.23	.93
Emotion recognition bias^f	1.13	0.96	0.94	−0.14	−0.05	.69	>.99
Negative social emotions^g	1.13	0.97	0.95	−0.02	−0.19	.11	.43

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Abbreviation: NA, not applicable.

^{^a}

Latent variable models were used to assess the association between a latent variable capturing serotonin 4 receptor binding across the neocortex, hippocampus, caudate, and putamen. λ indicates the loading of each region onto the latent variable. Neocortex was used as a reference, with a loading of 1 in all models (λ₁), and therefore was not shown in the table. The latent construct was corrected for age, sex, 5-HTTLPR genotype LALA vs non-LALA variant, and injected mass per kilogram. The observed cognitive score was corrected for age and sex. The r indicates the estimated correlation coefficient between the latent variable and the observed cognitive performance.

^{^b}

Verbal memory was indexed with the 26-item Verbal Affective Memory Test.

^{^c}

For the secondary outcomes, both uncorrected P values and Bonferroni-Holm–corrected P values for 4 tests are presented.

^{^d}

Working memory was indexed with the Letter-Number Sequencing Task of the Wechsler Adult Intelligence Scale, Third Edition.

^{^e}

Reaction time was indexed with a Simple Reaction Time task.

^{^f}

Emotion recognition bias was indexed with the EMOTICOM Emotional Recognition Task.

^{^g}

Negative social emotions were indexed with the EMOTICOM Moral Emotions Task.

Associations between individual cognitive scores and regional 5-HT₄ receptor BP_ND are provided in eTable 5 in Supplement 1. Post hoc analysis showed that inclusion of educational level, HAMD-17 scores, or GAD-10 scores in the models did not change the main finding of an association between 5-HT₄ receptor BP_ND and verbal memory (eTable 6 in Supplement 1).

Discussion

In this case-control study, we analyzed the primary baseline outcomes from the NeuroPharm trial, which to our knowledge was the largest single-site clinical PET study of the serotonin system in MDD to date. We found that, overall, antidepressant-free patients with a moderate to severe depressive episode had approximately 7.0% lower cerebral 5-HT₄ receptor binding compared with healthy controls. While the cerebral 5-HT₄ receptor binding was not associated with the depressive symptom severity, cerebral 5-HT₄ receptor binding was directly associated with verbal memory function in patients with MDD.

The finding that patients with untreated MDD exhibited low 5-HT₄ receptor binding compared with healthy controls confirmed our hypothesis that cerebral 5-HT₄ receptor binding is pathologically altered in MDD. The finding also aligned with a previous study¹⁹ showing that, in healthy individuals, striatal and limbic 5-HT₄ receptor binding had an inverse association with the number of first-degree relatives with a history of mood disorders. Collectively, these findings suggested that low cerebral 5-HT₄ receptor binding represents a trait factor, such as a familial risk phenotype in MDD presenting prior to the onset of the depressive episode. We speculate that low 5-HT₄ receptor density is directly involved in risk or pathophysiological mechanisms in MDD, which so far has been only indirectly supported by preclinical studies that reported the antidepressant-like properties of 5-HT₄ receptor agonists.^14,15,17,18 Specifically, emerging evidence from studies in both rodent models and 5-HT₄ receptor knockout mice suggested that reduced 5-HT₄ receptor agonism (ie, any combination of low 5-HT₄ receptor binding and/or low levels of synaptic 5-HT) is a risk factor for depressive- and anxiety-like behavior¹¹ and that intervention with 5-HT₄ receptor agonists protects against stress.¹⁸ Meanwhile, it has also been shown in healthy individuals that 3 weeks of SSRI intake, which putatively increases 5-HT interstitial concentration in the brain, is associated with reduced 5-HT₄ receptor binding,⁵⁷ a finding supported by observations from rodent studies.^58,59,60 Thus, the lower cerebral 5-HT₄ receptor binding in high-risk individuals and in patients with MDD could also be due to a compensatory mechanism whereby brain 5-HT levels are elevated in an attempt to maintain euthymia that, in turn, plays a role in a downregulation of the 5-HT₄ receptor.

The vertex-based and voxel-based exploratory analyses revealed results that are in line with the results of the LVM analyses showing lower 5-HT₄ receptor binding in MDD. Specifically, there were differences in 5-HT₄ receptor binding between healthy individuals and patients with MDD in the prefrontal cortex and the isthmus of the cingulate; this finding is consistent with prevailing theories of frontolimbic functional alterations in MDD.^61,62 In support of this result, rodent models have suggested that focal overexpression of 5-HT₄ receptor in the prefrontal cortex (medial portion) alone is sufficient to produce an antidepressant- and anxiolytic-like behavioral phenotype.⁶³ The exploratory analyses also showed lower 5-HT₄ receptor binding in MDD in the inferior frontal, temporal, parietal, and occipital cortices. Along with the prefrontal cortex, these regions are parts of the neocortex. The observation of lower 5-HT₄ receptor binding in occipital cortex aligns with whole-brain studies of patients with MDD (wherein structural and functional alterations in occipital cortex are described^64,65,66) along with lower levels of γ-aminobutyric acid in the occipital cortex, which is well known to be modulated by the 5-HT₄ receptor.^13,67 Thus, the findings support that occipital cortex function through a modulation of the 5-HT₄ receptor may be pathologically affected in MDD.

We found that 5-HT₄ receptor binding was directly associated with verbal memory performance, which fits with the observation that intake of the partial 5-HT₄ receptor agonist prucalopride had improved memory function as an outcome, at least in healthy individuals,^11,26 and emphasized the potential of the 5-HT₄ receptor as a treatment target for learning and memory dysfunction in MDD and potentially the depressive symptoms. Since prucalopride frequently has adverse effects, such as headache and gastrointestinal issues, an alternative 5-HT₄ receptor agonist, such as PF-04995274, may prove effective for the treatment of depression; PF-04995274 is also being studied in ongoing clinical trials. An inverse association between 5-HT₄ receptor binding and memory was reported in 2 independent cohorts of healthy individuals,^23,24 suggesting that the relationship between memory and cerebral 5-HT₄ receptor binding differs qualitatively between the depressed and the healthy brain. It is possible that the association between 5-HT₄ receptor levels and verbal memory function follows an inverted U-shape wherein both very low and very high cerebral 5-HT₄ receptor levels are associated with poor memory performance. If so, this situation could help explain why the association in patients with pathologically lower 5-HT₄ receptor levels was direct. Taking into account the educational level or the severity of depressive or anxiety symptoms did not substantially change the association between memory dysfunction and 5-HT₄ receptor. This finding indicates that the association between verbal memory and 5-HT₄ receptor in MDD was independent from the previously reported association between anxiety and 5-HT₄ receptor in this patient cohort.³⁸

Strengths and Limitations

A major strength of the study is its inclusion of a large number of unmedicated patients with a moderate to severe depressive episode. A few limitations also deserve to be mentioned. The patients were relatively young, and we were unsure whether the results can be generalized to older patients. In addition, we could not directly compare the association between cognitive measures and 5-HT₄ receptor binding between healthy controls and patients with MDD since the healthy volunteers did not undergo the same cognitive tests. Consequently, with the exception of verbal memory (which has been studied in healthy populations^23,24), we were unable to assess whether the association between a given cognitive domain and 5-HT₄ receptor binding was specifically linked to or altered in the depressed state or whether the association reflected a general neurobiological mechanism that was unrelated to depressive pathology. Furthermore, as previous nonresponse to SSRIs was an exclusion criterion, the present findings may not generalize to individuals with MDD who did not previously respond to SSRIs. The extent to which the 5-HT₄ receptor plays a role in the broader spectrum of affective disorders with cognitive deficits (eg, bipolar disorder) also warrants an investigation in future studies.

Conclusions

In this case-control study, patients with MDD had lower cerebral 5-HT₄ receptor, and the lower the cerebral 5-HT₄ receptor, the worse the memory performance was regardless of overall symptom severity. Thus, the 5-HT₄ receptor is a promising treatment target in depression and may be particularly relevant in treatment of cognitive symptoms, including memory disturbances.

Supplement 1.

eMethods

eTable 1. Differences in Cognitive Scores Between Patients and Reference Healthy Control Group

eTable 2. Group Differences in Regional 5-HT4R Brain Binding

eTable 3. Clusters in the Left Hemisphere Showing Significantly Lower 5-HT4R BPND in Patients With MDD Relative to Healthy Controls

eTable 4. Clusters in the Right Hemisphere Showing Significantly Lower 5-HT4R BPND in Patients With MDD Relative to Healthy Control

eTable 5. Cognition and Regional 5-HT4R Brain Binding

eTable 6. Sensitivity Analyses for Association Between 5-HT4R and Cognitive Performance in Patients

eReferences

Click here for additional data file.^{(291.6KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(12.6KB, pdf)}

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplement 1.

eMethods

eTable 1. Differences in Cognitive Scores Between Patients and Reference Healthy Control Group

eTable 2. Group Differences in Regional 5-HT4R Brain Binding

eTable 3. Clusters in the Left Hemisphere Showing Significantly Lower 5-HT4R BPND in Patients With MDD Relative to Healthy Controls

eTable 4. Clusters in the Right Hemisphere Showing Significantly Lower 5-HT4R BPND in Patients With MDD Relative to Healthy Control

eTable 5. Cognition and Regional 5-HT4R Brain Binding

eTable 6. Sensitivity Analyses for Association Between 5-HT4R and Cognitive Performance in Patients

eReferences

Click here for additional data file.^{(291.6KB, pdf)}

Supplement 2.

Data Sharing Statement

Click here for additional data file.^{(12.6KB, pdf)}

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PERMALINK

Serotonin 4 Receptor Brain Binding in Major Depressive Disorder and Association With Memory Dysfunction

Kristin Köhler-Forsberg, PhD

Vibeke H Dam, PhD

Brice Ozenne, PhD

Anjali Sankar, PhD

Vincent Beliveau, PhD

Elizabeth B Landman, MD

Søren V Larsen, MD

Asbjørn S Poulsen, MD

Cheng-Teng Ip, PhD

Anders Jørgensen, PhD

Michal Meyer, BSc

Dea S Stenbæk, PhD

Hans R L Eiberg, MSc

Jacob Madsen, PhD

Claus Svarer, PhD

Martin B Jørgensen, MD, DMSc

Vibe G Frokjaer, MD, PhD

Gitte M Knudsen, DMSc

Key Points

Question

Findings

Meaning

Abstract

Importance

Objective

Design, Setting, and Participants

Main Outcomes and Measures

Results

Conclusions and Relevance

Introduction

Methods

Participants and Study Design

PET and MRI Procedures

Cognitive Measures

Statistical Analysis

Results

Table 1. Clinical Profile, Demographic Characteristics, and Cognitive and Radiotracer Data for Patients With MDD vs Healthy Controls .

Group Differences in 5-HT4 Receptor Binding

Figure 1. Latent Variable Model for Evaluating Global Serotonin 4 (5-HT4) Receptor Binding and Vertex-Based Group Differences for 5-HT4 Receptor Binding in Patients With Major Depressive Disorder (MDD) vs Healthy Controls .

Figure 2. Correlation of Latent Estimates of Serotonin 4 Receptor Binding with Depressive Symptoms and Verbal Memory.

5-HT4 Receptor Binding and Cognitive Performance in MDD

Table 2. Association Between Serotonin 4 Binding and Cognitive Performance in Patientsa.

Discussion

Strengths and Limitations

Conclusions

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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Cited by other articles

Links to NCBI Databases

Group Differences in 5-HT₄ Receptor Binding

Figure 1. Latent Variable Model for Evaluating Global Serotonin 4 (5-HT₄) Receptor Binding and Vertex-Based Group Differences for 5-HT₄ Receptor Binding in Patients With Major Depressive Disorder (MDD) vs Healthy Controls .

5-HT₄ Receptor Binding and Cognitive Performance in MDD

Table 2. Association Between Serotonin 4 Binding and Cognitive Performance in Patients^a.