The association of FKBP5 gene polymorphism with genetic susceptibility to depression and response to antidepressant treatment- a systematic review

Zhang, Ying; Yue, Weihua; Li, Jie

doi:10.1186/s12888-024-05717-z

Table 1 Basic characteristics of the studies

From: The association of FKBP5 gene polymorphism with genetic susceptibility to depression and response to antidepressant treatment- a systematic review

First author	Year	Country	Study design	Research Subjects	Ethnic	Sample Size	Gender (M/F)	Age, years (range, mean)	Sample resource	Diagnostic criteria
Yang dong	2013	China	Case-control study	MDD	Han	263	Response 89/92	31 ± 11	Outpatient	DSM-IV
Yang dong	2013	China	Case-control study	MDD	Han	263	Non-response 29/18	31 ± 10	Outpatient	DSM-IV
Yu yan	2012	China	Case-control study	Depression	Han	254	126/128	31 ± 11	Outpatient	DSM-IV
Binder, E. B.	2004	Germany	Case-control study	Unipolar depression	Caucasians	Original sample 294	122/172	47.65 ± 14.5	Inpatient	DSM-IV
				BD		Original sample 294	122/172	47.65 ± 14.5
				PDD		replication sample 85	29/56	50.5 ± 12.48
Brent, D.	2010	United States	cohort study	MDD for adolescents	European origin	155	46/109	15.7 ± 1.6	-	DSM-IV
Cattaneo, A.	2013	Europe	Open, partially randomized, multicenter pharmacogenetics study	Moderate-to-severe unipolar depression	White Europeans	74	31/43	38.3 ± 10.9	Outpatient	ICD-10
Cattaneo, A.	2013	Europe		Moderate-to-severe unipolar depression	White Europeans	74	31/43	38.3 ± 10.9	Outpatient	DSM-IV
Dam, H.	2019	Denmark	Case-control study	Unipolar depression	85% Danish	718	227/491	-	Danish Psychiatric Biobank	ICD-10
Ellsworth, K. A.	2013	United States	Case-control study	Depression	Mayo: 337 Non-Hispanic White、96 African Americans、96 Han Chinese Americans	529	-	-	Mayo PGRN-AMPS	DSM-IV
Ellsworth, K. A.	2013	United States	Case-control study	Depression	STAR*D replication sample: Non-Hispanic White	960	-	-	STAR*D	DSM-IV
Fabbri, C.	2018	Europe	Open multicenter study	ES1: MDD	345 Caucasians	357	103/254	51.25 ± 14.51	Inpatient、Outpatient	DSM-IV
				ES2: Moderate-to-severe depression	208 Caucasians	218	72/146	47 ± 12.56	-
				ITAS: Non-psychotic MDD	-	96	32/64	57.34 ± 15.97	Outpatient
				STAR*D replication sample response: -	-	1409	565/844	42.94 ± 13.49	STAR*D
				STAR*D replication sample remission: -	-	620	264/356	43.11 ± 12.95	STAR*D
Gawlik M	2006	Germany	Case-control study	Recurrent depression	Caucasians	57	32/25	48.1	-	ICD-10
Gawlik M	2006	Germany	Case-control study	BD	Caucasians	191	122/69	48.1	-	ICD-10
Ising, M.	2019	Germany	Naturalistic Open Label Longitudinal Treatment Study	Moderate-to-severe depressive disorder	-	297	Response 96/77	48.8 ± 14.0	Inpatient	ICD-10
Ising, M.	2019	Germany	Naturalistic Open Label Longitudinal Treatment Study	Moderate-to-severe depressive disorder	-	297	Non-response 61/63	47.0 ± 13.4	Inpatient	ICD-10
Kirchheiner, J.	2008	Germany	cohort study	Unipolar depression	Caucasians	179	61/118	45.92 ± 11.73	Inpatient	ICD-10
Kirchheiner, J.	2008	Germany	cohort study	BD	Caucasians	179	61/118	45.92 ± 11.73	Inpatient	DSM-IV
Lekman, M.	2008	United States	Case-control study	Non-psychotic MDD	1256 Non-Hispanic White	1523(1809 for genetic analysis)	-	-	STAR*D outpatient sample	DSM-IV
Lekman, M.	2008	United States	Case-control study	Non-psychotic MDD	267 Black	1523(1809 for genetic analysis)	-	-	STAR*D outpatient sample	DSM-IV
Nobile, B.	2020	France	Prospective cohort study	MDD	Caucasians	496	192/304	48.05 ± 14.75	Outpatient	DSM-IV
Papiol, S.	2007	Spain	Prospective cohort study	Depression	Spanish	159	35/124	39.5 ± 12.2	Outpatient	DSM-IV
Perroud, N.	2011	Switzerland	Partially randomized study	Moderate-to-severe depressive disorder	95 European origin	131	53/78	36.65 ± 10.69	Outpatient	ICD-10
Perroud, N.	2011	Switzerland	Partially randomized study	Moderate-to-severe depressive disorder	95 European origin	131	53/78	36.65 ± 10.69	Outpatient	DSM-IV
Sarginson, J. E.	2010	United States	RCT	MDD in the elderly	226 Caucasians	246	Paroxetine 57/65	72.25 ± 5.13	Outpatient	DSM-IV
Sarginson, J. E.	2010	United States	RCT	MDD in the elderly	226 Caucasians	246	mirtazapine 63/61	71.91 ± 5.67	Outpatient	DSM-IV
Stamm, T. J.	2016	Germany	RCT	MDD	Central European origin	298	111/187	44.35 ± 12.04	Inpatient	DSM-IV
Szczepankiewicz, A.	2014	Poland	Case-control study	BD	Polish	528	221/307	44.36 ± 13.9	Inpatient	DSM-IV
Szczepankiewicz, A.	2014	Poland	Case-control study	MDD	Polish	218	50/168	45.5 ± 14.0	Inpatient	DSM-IV
Tsai, S. J.	2007	China	Prospective cohort study	MDD	Ethnic Chinese	125	56/69	42.1 ± 16.2	Outpatient	DSM-IV
Tsai, S. J.	2007	China	Prospective cohort study	PDD	Ethnic Chinese	125	56/69	42.1 ± 16.2	Outpatient	DSM-IV
Yang, C.	2021	China	Case-control study	Depression	Han	181	TRDI:47/34	46.0 ± 12.7	Inpatient、Outpatient	DSM-IV
Yang, C.	2021	China	Case-control study	Depression	Han	181	MDNTR:24/76	42.8 ± 10.2	Inpatient、Outpatient	DSM-IV
Zobel, A.	2010	Germany	Case-control study	Recurrent unipolar depression	Caucasians	268	98/170	48.92 ± 14.0	Inpatient	DSM-IV

First author	Assessment Scale	AD	SNPs	Genotype method	Definition of treatment response	Assessment time	Results
Yang dong	HAMD-17	escitalopram	rs3800373	PCR-LDR	Response: HAMD score reduction rate < 50%	Week 6	rs3800373、rs1360780 unable to predict treatment response to antidepressants
	HAMD-17	Paroxetine	rs1360780		Response: HAMD score reduction rate < 50%
	TESS	Venlafaxine	rs1360780		No response: HAMD score reduction rate ≥ 50%
	TESS	Duloxetine	rs1360780		No response: HAMD score reduction rate ≥ 50%
Yu yan	HAMD-17	-	rs3800373	PCR-LDR	-	-	Lack of association between rs3800373、rs1360780 and susceptibility to depression
	HAMA		rs1360780
	BPRS		rs1360780
Binder, E. B.	HAMD-21	SSRIs	rs3800373	MALDI-TOF-MS Real-time PCR	Response: a decrease > 50% in the HAMD score at week 5	Week 2、5	rs1360780 TT genotype responded faster and better to antidepressants, rs3800373 CC genotype responded better to treatment than other genotype carriers, and there was no difference in the frequency of individual SNPs or haplotypes between depressed patients and healthy controls
	HAMD-21	TCAs	rs1360780		Response: a decrease > 50% in the HAMD score at week 5
	MADRS	mirtazapine	rs4713916		Remission: HAMD ≤ 10
	MADRS	Reboxetine			Remission: HAMD ≤ 10
Brent, D.	CDRS	Fluoxetine	rs1360780 rs3800373	fluorescence polarization method	Response: a decrease > 50% in the CDRS score and a score < 40 at week 12	Week 6、12	rs1360780 TT and rs3800373 GG genotypes were associated with higher and earlier occurrence of suicidal events, and there was no significant relationship between genotype and treatment response
	CGI	Paroxetine
	C-SSRS	citalopram
		Venlafaxine
Cattaneo, A.	MADRS HAMD-17	escitalopram	-	Real-time PCR	Response: a reduction in MADRS > 50% at week 12	Week 8、12	Successful antidepressant response is associated with reduced levels of FKBP5, a gene that does not predict response to antidepressants
Cattaneo, A.	BDI	Nortriptyline	-	Real-time PCR	Response: a reduction in MADRS > 50% at week 12	Week 8、12
Dam, H.	-	-	rs1360780	Real-time PCR	-	-	rs1360780 is not associated with susceptibility to depression and the CC genotype has a higher family history of depression
Dam, H.	-	-	rs1360780	TaqMan	-	-
Ellsworth, K. A.	QIDS-16	citalopram	384个SNPs	Sanger	Response: ≥ 50% reduction in QIDS score	Mayo: Week 8 STAR*D: Week 6	rs1360780、rs3800373 and rs4713916 were not associated with SSRI treatment outcomes in MDD, and rs352428 was associated with 8-week treatment response in the Mayo study and 6-week treatment response in the STAR*D replication study
	HAMD	escitalopram		Illumina/Affymetrix	Remission: a QIDS score of ≤ 5 at the last visit
				TaqMan	Remission: a QIDS score of ≤ 5 at the last visit
Fabbri, C.	HAMD-21	Venlafaxine	rs9296157 rs9470080 rs1043805 rs3800373 rs1360780 rs4713916 rs3800373 rs352428	Real-time PCR	Response: a decrease of at least 50% in the HDRS-21 or the MADRS or the QIDS-C at week 4 or 6	Week 4	rs3800373 in ES1 the CC genotype had a high risk of treatment non-response, in ES2 and ITAS the AA genotype and A allele had better response and remission. rs1360780 in ES2 the CC genotype and C allele were associated with better response and remission to venlafaxine and a reduced risk of TRDA, in ITAS the CC genotype and C allele were associated with better response and remission. In STAR*D replication samples rs9368882 was associated with level 1 remission
	MADRS	citalopram				Week 12
	HAMD-21	bupropion-SR				Week 8
	QIDS	Sertraline			Remission: HDRS ≤ 7 or MADRS < 10 or QIDS-C ≤ 5	Week 2、4、6、9、12
	QIDS	escitalopram			Remission: HDRS ≤ 7 or MADRS < 10 or QIDS-C ≤ 5	Week 2、4、6、9、12
Gawlik M	-	-	rs4713916 rs1360780 rs3800373	PCR	-	-	FKBP5 polymorphisms and haplotypes are not associated with the inheritance of affective disorders
Gawlik M	-	-	rs4713916 rs1360780 rs3800373	TaqMan	-	-
Ising, M.	HAMD-21	SSRIs	rs1360780	Illumina Beadchip technology	Response: a reduction of the HAMD-21 score of at least 50%	Week 6	Successful antidepressant treatment outcomes were accompanied by reduced expression of FKBP5 gene and FKBP51 protein, with the rs1360780 T allele showing a better treatment response
		TCAs		Illumina Beadchip technology
		SNRIs		Real-time PCR
		NaSSA		TaqMan
		Other		TaqMan
Kirchheiner, J.	HAMD-21	SSRIs	rs3800373 rs1360780	Real-time PCR	Response: HDRS decreased by ≥ 50% at day 21	Week 3	A higher proportion of rs3800373 AA genotype carriers were diagnosed with bipolar disorder, and patients carrying rs1360780 CC genotype or rs3800373 AA genotype were poorly treated with antidepressants, with a closer association with venlafaxine treatment efficacy
		mirtazapine		Real-time PCR
		Venlafaxine		TaqMan
		TcAs
		Other
Lekman, M.	QIDS	citalopram	rs1360780 rs4713916 rs3800373	Illumina	Remission: QIDS-C16 ≤ 5	Week 2、4、6、9、12、14	rs1360780 was significantly associated with disease status in non-Hispanic whites but not in blacks. rs1360780 and rs4713916 were strongly LD in non-Hispanic whites but not in blacks.When all races were analyzed together rs4713916 was significantly associated with remission, but not with response, and this association was primarily caused by non-Hispanic whites. No correlation was detected between rs3800373、 rs1360780 and antidepressant response
Lekman, M.	QIDS	citalopram	rs1360780 rs4713916 rs3800373	TaqMan	Response: QIDS-C16 reduced by ≥ 50%	Week 2、4、6、9、12、14
Nobile, B.	HADS	Tianeptine	rs3800373 rs7757037 rs737054 rs1360780 rs9470080 rs6902321	Real-time PCR	TESI: having a MADRS-SI score of 0 or 1 at baseline, followed by a score > 1 at least once during the follow-up	Week 2、4、6	rs6902321 TT genotype is significantly associated with treatment-triggered suicidal ideation, and no SNP is associated with TWOSI
Nobile, B.	MADRS-SI	Tianeptine	rs3800373 rs7757037 rs737054 rs1360780 rs9470080 rs6902321	TaqMan	TWOSI: the worsening of pre-existing SI when starting a new antidepressant drug	Week 2、4、6
Papiol, S.	HAMD-21	citalopram	rs1360780	Applied Biosystems SNaP-Shot	Response: HDRS at 4th week ≤ 50%	Week 4、8、12	rs1360780 TT genotype has poor antidepressant response to citalopram, and FKBP5 genotype is not a predictor of treatment outcome
Papiol, S.	HAMD-21	citalopram	rs1360780	TaqMan	Remission: HDRS at 12th week ≤ 7	Week 4、8、12
Perroud, N.	MADRS	Paroxetine	rs1360780	-	Increasing suicidal ideation: Any 1-point increase which reached a level of 2 at least on the 10th suicidal item of the MADRS	Assessed every 2 weeks for 30 weeks	Carriers of the rs1360780 T allele have a higher risk of increased suicidal ideation on treatment, and there is no association between rs1360780 and drug blood levels
		Venlafaxine
		clomipramine
		nefazodone
Sarginson, J. E.	HAMD-17	Paroxetine	rs1360780 rs3800373	TaqMan	Remission: HDRS-17 ≤ 7 or HDRS-21 ≤ 10	Week 1–4、6、8	No association between rs1360780, rs3800373 and clinical outcomes and no prediction of remission or time to remission
Sarginson, J. E.	HAMD-21	mirtazapine	rs1360780 rs3800373	TaqMan	Response: 50% reduction in HDRS-21	Week 1–4、6、8
Stamm, T. J.	HAMD-21	Venlafaxine	rs1360780	Real-time PCR	Remission: HDRS-21 < 10	Week 2、4、6、8、10、12、14	The rs1360780 TT genotype showed superior treatment response under all treatment conditions, and the effect of genotype on treatment outcome did not differ significantly between antidepressants. Standardized, quality-controlled treatment can compensate to some extent for the "genetic disadvantage" of C-allele carriers
		Sertraline		Real-time PCR
		Amitriptyline		TaqMan
		Reboxetine		TaqMan
Szczepankiewicz, A.	-	-	rs1360780 rs755658 rs9470080 rs4713916 rs7748266 rs9296158 rs9394309 rs3800373	TaqMan	-	-	Associations between rs1360780, rs9470080, rs4713916, rs9296158 and rs9394309 and MDD but not bipolar disorder
Tsai, S. J.	HAMD-21	Fluoxetine	rs1360780	PCR	Response: ≥50% reduction in HAMD at week 4	Week 4	No association between rs1360780 genotype and short-term antidepressant treatment response and lifetime depressive episodes
Yang, C.	HAMD-17	-	rs1043805 rs3800373 rs9296158 rs7748266 rs1360780 rs2766537 rs9394309 rs9470080 rs2817035	MALDI-TOF MS	TRDI: CRP 0. 85 − 10 mg/L;Insufficient response to ≥ 1 antidepressants, at least 6w and adequate dose; Current antidepressant treatment ≥ 2w	-	No association of SNPs and haplotype combinations of FKBP5 with MDD or antidepressant treatment response
Zobel, A.	HAMD	citalopram	rs3800373 rs755658 rs1360780 rs1334894 rs4713916	TaqMan	-	Week 4	rs3800373 AA, rs4713916 GG (related to clinical diagnosis) showed less reduction in cortisol secretion in the Dex/CRH test after 4 weeks of citalopram treatment

Note: ES: European sample; ITAS Italian sample STAR*D Sequenced Treatment Alternatives to Relieve Depression Mayo PGRN-AMPS: Mayo Clinic Pharmacogenomics Research Network-Antidepressant Medication Pharmacogenomic Study; MDD: Major Depressive Disorder; BD: Bipolar disorder; PDD: Persistent depressive disorder; TRDI: antidepressant treatment resistance and increased inflammatory activity; MDNTR: major depression without treatment resistance; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ICD-10: international Classification of diseases-10
Note: AD: antidepressive drugs；SNPs：single nucleotide polymorphisms；HAMD：Hamilton depression scale；HDRS：Hamilton Depression Rating Score；HADS：Hospital Anxiety and Depression Scale；MADRS：Montgomery-Asberg Depression Rating Scale；QIDS：Quick Inventory of Depressive Symptomatology；BDI：Beck Depression Inventory；CDRS：Children’s Depression Rating Scale；CGI：Clinical Global Impressions scale；C-SSRS：Columbia-Suicide Severity Rating Scale；BPRS：Brief Psychiatric Rating Scale；HAMA：Hamilton Anxiety Scale；TESS：Treatment Emergent Symptom Scale；SSRIs：selective serotonin reuptake inhibitor；TCAs：Tricyclic Antidepressive Agents；SNRIs：serotonin-norepinephrine reuptake inhibitor；NaSSA：Noradrenergic and specific serotonergic antidepressant；TESI：treatment-emergent suicidal ideation；TWOSI：treatment worsening of suicidal ideation；TRDI: antidepressant treatment resistance and increased inflammatory activity;

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