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| PMID |
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| TITLE |
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| Genetic and Phenotypic Associations With Sustained Antidepressant Use in Major Depressive Disorder. |
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| ABSTRACT |
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| IMPORTANCE |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. |
| OBJECTIVE |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. |
| DESIGN, SETTING, AND PARTICIPANTS |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. |
| EXPOSURES |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups. |
| MAIN OUTCOMES AND MEASURES |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups. Associations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants. |
| RESULTS |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups. Associations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants. Of 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10-8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10-5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10-4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10-3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10-8). |
| CONCLUSIONS AND RELEVANCE |
NlmCategory: UNASSIGNED |
| Antidepressant treatment remains a trial-and-error process: one-third of people with major depressive disorder (MDD) report inefficacy of first-line medications. Predictors of prescription patterns are needed to improve prescribing precision. To investigate phenotypic and genetic heterogeneity of MDD subgroups defined by antidepressant prescription patterns. This was a retrospective cohort study of Australian Genetics of Depression Study (2017-2018) adult participants (aged ≥18 years) with lifetime MDD who filled 1 or more prescriptions of the 10 most commonly used antidepressants across 4.5 years (2013-2017). Data were analyzed from August 2024 to October 2025. Treatment complexity was assessed as number of different antidepressant classes in prescriptions filled in 4.5 years. Sustained-use 360 groups were defined as 360 or more cumulative days (in 4.5 years) of a single antidepressant. Participants with genome-wide genotypes were contrasted across mutually exclusive sustained-use 360 groups. Associations of 44 self-reported phenotypes and polygenic scores (PGSs) for 15 traits with sustained-use 360 subgroups. Genome-wide association studies (GWASs) were conducted for selective serotonin reuptake inhibitor (SSRI) or SSRI/serotonin-norepinephrine reuptake inhibitor sustained use contrasted to other participants. Of 12 074 participants (9041 [75%] female with a mean [SD] age of 41.8 [14.6] years; 3022 [25%] male with a mean [SD] age of 47.7 [14.6] years) with 1 or more prescriptions and lifetime MDD, 8898 had genotyping data. High treatment complexity was significantly associated with 37 of 44 self-reported phenotypes (eg, higher rates of smoking, recurrent MDD, suicidal ideation, chronic pain, and circadian and atypical depression subtypes) and higher PGSs for psychiatric traits (MDD PGS: β, 0.04; 95% CI, 0.03-0.06; P = 1.2 × 10-8; ADHD PGS: β, 0.03; 95% CI, 0.02-0.05; P = 2.1 × 10-5 ; bipolar disorder PGS: β, 0.03; 95% CI, 0.01-0.04. P = 1.2 × 10-4 ; neuroticism PGS: β, 0.02; 95% CI, 0.01-0.04; P = 1.3 × 10-3). A total of 5453 (61%) met criteria for an exclusive antidepressant sustained-use 360 group. These groups had distinct phenotypic profiles, including associations with body mass index, suicidal ideation, and co-occurring conditions. GWASs identified novel loci, including an immune-related gene SLAMF3/LY9, for which single-nucleotide variant rs4656934 was associated with reduced odds of sustained SSRI use (G allele; odds ratio, 0.81; 95% CI, 0.75-0.87; P = 3.5 × 10-8). This study found that phenotypic factors were associated with sustained antidepressant use and treatment complexity. PGSs for traits studied were associated with treatment complexity but showed little association with sustained-use 360 groups. These findings support further research to guide treatment selection and to identify patients at risk of difficult-to-treat depression, informing precision psychiatry and early intervention in MDD. |
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| DATE PUBLISHED |
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| HISTORY |
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| PUBSTATUS |
PUBSTATUSDATE |
| medline |
2026/01/28 13:18 |
| pubmed |
2026/01/28 13:18 |
| entrez |
2026/01/28 11:34 |
| pmc-release |
2026/01/28 |
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| AUTHORS |
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| NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
| Walker A |
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Walker |
Alicia |
A |
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Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom. |
| Mitchell BL |
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Mitchell |
Brittany L |
BL |
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School of Biomedical Sciences, Queensland University of Technology, Brisbane, Queensland, Australia. |
| Lin T |
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Lin |
Tian |
T |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. |
| Crouse JJ |
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Crouse |
Jacob J |
JJ |
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Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia. |
| Albiñana C |
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Albiñana |
Clara |
C |
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Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom. |
| Yap CX |
|
Yap |
Chloe X |
CX |
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Mater Research Institute, The University of Queensland, Brisbane, Queensland, Australia. |
| Lynall ME |
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Lynall |
Mary Ellen |
ME |
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Department of Psychiatry, University of Cambridge, Cambridge, United Kingdom. |
| Lind PA |
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Lind |
Penelope A |
PA |
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Psychiatric Genetics, Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Cipriani A |
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Cipriani |
Andrea |
A |
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NIHR Oxford Health Clinical Research Facility, Oxford Health National Health Service Foundation Trust, Oxford, United Kingdom. |
| Byrne EM |
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Byrne |
Enda M |
EM |
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Child Health Research Centre, The University of Queensland, Brisbane, Queensland, Australia. |
| Medland SE |
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Medland |
Sarah E |
SE |
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School of Psychology and Counselling, Queensland University of Technology, Brisbane, Queensland, Australia. |
| Martin NG |
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Martin |
Nicholas G |
NG |
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Genetic Epidemiology, Queensland Institute of Medical Research Berghofer Medical Research Institute, Brisbane, Queensland, Australia. |
| Taquet M |
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Taquet |
Maxime |
M |
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Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, United Kingdom. |
| Hickie IB |
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Hickie |
Ian B |
IB |
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Brain and Mind Centre, The University of Sydney, Sydney, New South Wales, Australia. |
| Wray NR |
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Wray |
Naomi R |
NR |
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Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. |
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| INVESTIGATORS |
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| JOURNAL |
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| VOLUME: |
| ISSUE: |
| TITLE: JAMA psychiatry |
| ISOABBREVIATION: JAMA Psychiatry |
| YEAR: 2026 |
| MONTH: Jan |
| DAY: 28 |
| MEDLINEDATE: |
| SEASON: |
| CITEDMEDIUM: Internet |
| ISSN: 2168-6238 |
| ISSNTYPE: Electronic |
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| MEDLINE JOURNAL |
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| MEDLINETA: JAMA Psychiatry |
| COUNTRY: United States |
| ISSNLINKING: 2168-622X |
| NLMUNIQUEID: 101589550 |
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| PUBLICATIONTYPE TEXT |
| Journal Article |
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