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Peripheral Serotonin and CYP2D6: Candidate Biomarkers of Antidepressant Treatment Response

Holck, Amanda LU (2026) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Background and aim
Many patients with depressive disorders do not improve with first-line treatment with selective serotonin inhibitors (SSRIs). Adverse drug reactions (ADRs) are common. However, there are no reliable methods to predict treatment response.
The general aim of this thesis was to investigate the role of peripheral serotonin and the polymorphic CYP2D6 gene as potential biomarkers of treatment response, including ADRs and suicidality, in depressive disorders.

Methods
The thesis includes material from two clinical cohorts and one systematic review. In the first cohort (paper I) plasma serotonin was analysed at baseline and at week 8 in 26 participants with major depressive disorder that were treated with... (More)
Background and aim
Many patients with depressive disorders do not improve with first-line treatment with selective serotonin inhibitors (SSRIs). Adverse drug reactions (ADRs) are common. However, there are no reliable methods to predict treatment response.
The general aim of this thesis was to investigate the role of peripheral serotonin and the polymorphic CYP2D6 gene as potential biomarkers of treatment response, including ADRs and suicidality, in depressive disorders.

Methods
The thesis includes material from two clinical cohorts and one systematic review. In the first cohort (paper I) plasma serotonin was analysed at baseline and at week 8 in 26 participants with major depressive disorder that were treated with SSRIs. Paper II is a systematic review that examines the association between peripheral serotonin levels and treatment response to antidepressants. Papers III and IV are based on the Genes, Depression and Suicidality (GEN-DS) cohort, a cross-sectional observational study where 415 patients with depressive disorders were subjected to rigorous diagnostic and anamnestic interviewing and genotyped for CYP2D6.

Results
Paper I: Higher baseline serotonin was associated with SSRI treatment response. Treatment was associated with a decrease of serotonin.
Paper II: Several studies reported that higher baseline serotonin was associated with better response to SSRIs, but no studies showed an association between serotonin levels and response to non-SSRIs.
Paper III: Patients with CYP2D6 phenotypes with lower metabolizing effect did not report significantly more ADRs. This result remained unchanged when phenoconversion due to CYP2D6-inhibiting comedication was considered.
Paper IV: A history of suicide attempts was not overrepresented among CYP2D6 ultra-rapid metabolizers.

Conclusion
Peripheral serotonin levels may be associated with treatment response specifically to SSRI treatment in depressive disorders, but more studies are needed. The CYP2D6 polymorphism did not predict the occurrence of ADRs in a naturalistic setting. CYP2D6 UM phenotype was not associated with suicide attempts, and further studies of single-gene associations with suicidal behaviours are likely not warranted. (Less)
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author
supervisor
opponent
  • Professor Landén, Mikael, Gothenburg University, Gothenburg, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Depression, Biomarkers, Treatment response, Serotonin, CYP2D6, Pharmacogenetics, Adverse drug reactions, Suicide attempt
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2026:17
pages
111 pages
publisher
Lund University, Faculty of Medicine
defense location
Konferensrum 12, Avdelningen för psykiatri, Baravägen 1 Lund. Join by Zoom: https://lu-se.zoom.us/j/65087344980?pwd=dD0mwa2ObWpMP3rI8mNamXaNxMqyqh.1
defense date
2026-02-20 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-815-3
project
Peripheral Serotonin and CYP2D6: Candidate Biomarkers of Antidepressant Treatment Response
language
English
LU publication?
yes
id
bf755e45-ad17-4c56-bc7c-b500d84286aa
date added to LUP
2025-12-10 10:34:50
date last changed
2026-01-29 13:51:26
@phdthesis{bf755e45-ad17-4c56-bc7c-b500d84286aa,
  abstract     = {{Background and aim<br/>Many patients with depressive disorders do not improve with first-line treatment with selective serotonin inhibitors (SSRIs). Adverse drug reactions (ADRs) are common. However, there are no reliable methods to predict treatment response.<br/>The general aim of this thesis was to investigate the role of peripheral serotonin and the polymorphic CYP2D6 gene as potential biomarkers of treatment response, including ADRs and suicidality, in depressive disorders. <br/><br/>Methods<br/>The thesis includes material from two clinical cohorts and one systematic review. In the first cohort (paper I) plasma serotonin was analysed at baseline and at week 8 in 26 participants with major depressive disorder that were treated with SSRIs. Paper II is a systematic review that examines the association between peripheral serotonin levels and treatment response to antidepressants. Papers III and IV are based on the Genes, Depression and Suicidality (GEN-DS) cohort, a cross-sectional observational study where 415 patients with depressive disorders were subjected to rigorous diagnostic and anamnestic interviewing and genotyped for CYP2D6.  <br/><br/>Results<br/>Paper I: Higher baseline serotonin was associated with SSRI treatment response. Treatment was associated with a decrease of serotonin.<br/>Paper II: Several studies reported that higher baseline serotonin was associated with better response to SSRIs, but no studies showed an association between serotonin levels and response to non-SSRIs. <br/>Paper III: Patients with CYP2D6 phenotypes with lower metabolizing effect did not report significantly more ADRs. This result remained unchanged when phenoconversion due to CYP2D6-inhibiting comedication was considered.<br/>Paper IV: A history of suicide attempts was not overrepresented among CYP2D6 ultra-rapid metabolizers.<br/><br/>Conclusion<br/>Peripheral serotonin levels may be associated with treatment response specifically to SSRI treatment in depressive disorders, but more studies are needed. The CYP2D6 polymorphism did not predict the occurrence of ADRs in a naturalistic setting. CYP2D6 UM phenotype was not associated with suicide attempts, and further studies of single-gene associations with suicidal behaviours are likely not warranted.}},
  author       = {{Holck, Amanda}},
  isbn         = {{978-91-8021-815-3}},
  issn         = {{1652-8220}},
  keywords     = {{Depression; Biomarkers; Treatment response; Serotonin; CYP2D6; Pharmacogenetics; Adverse drug reactions; Suicide attempt}},
  language     = {{eng}},
  number       = {{2026:17}},
  publisher    = {{Lund University, Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Peripheral Serotonin and CYP2D6: Candidate Biomarkers of Antidepressant Treatment Response}},
  url          = {{https://lup.lub.lu.se/search/files/239717511/Amanda_Holck_Thesis_compilation.pdf}},
  year         = {{2026}},
}