Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)

Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose r...

Celý popis

Uloženo v:

Podrobná bibliografie
Vydáno v:	Molecular psychiatry Ročník 25; číslo 7; s. 1592 - 1603
Hlavní autoři:	Fava, Maurizio, Freeman, Marlene P, Flynn, Martina, Judge, Heidi, Hoeppner, Bettina B, Cusin, Cristina, Ionescu, Dawn F, Mathew, Sanjay J, Chang, Lee C, Iosifescu, Dan V, Murrough, James, Debattista, Charles, Schatzberg, Alan F, Trivedi, Madhukar H, Jha, Manish K, Sanacora, Gerard, Wilkinson, Samuel T, Papakostas, George I
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	England Nature Publishing Group 01.07.2020
Témata:	Adult Antidepressants Antidepressive Agents - therapeutic use Blood pressure Depression - drug therapy Depressive Disorder, Treatment-Resistant - drug therapy Double-Blind Method Double-blind studies Female Glutamic acid receptors (ionotropic) Humans Infusions, Intravenous Intravenous administration Ketamine Ketamine - administration & dosage Ketamine - therapeutic use Male Mental depression Midazolam Middle Aged N-Methyl-D-aspartic acid receptors Placebos Treatment Outcome Treatment resistance
ISSN:	1359-4184, 1476-5578, 1476-5578
On-line přístup:	Získat plný text
Tagy:	Přidat tag Žádné tagy, Buďte první, kdo vytvoří štítek k tomuto záznamu!

Abstract	Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.
AbstractList	Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555. Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18-70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = -0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555. Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient antidepressant effects when administered intravenously (IV) at subanesthetic doses (0.5 mg/kg over 40 min). However, the optimal antidepressant dose remains unknown. We aimed to compare to active placebo the rapid acting antidepressant properties of a broad range of subanesthetic doses of IV ketamine among outpatients with treatment-resistant depression (TRD). A range of IV ketamine doses were compared to active placebo in the treatment of adult TRD over a 3-day period following a single infusion over 40 min. This was an outpatient study conducted across six US academic sites. Outpatients were 18–70 years old with TRD, defined as failure to achieve a satisfactory response (e.g., less than 50% improvement of depression symptoms) to at least two adequate treatment courses during the current depressive episode. Following a washout period, 99 eligible subjects were randomly assigned to one of the five arms in a 1:1:1:1:1 fashion: a single intravenous dose of ketamine 0.1 mg/kg (n = 18), a single dose of ketamine 0.2 mg/kg (n = 20), a single dose of ketamine 0.5 mg/kg (n = 22), a single dose of ketamine 1.0 mg/kg (n = 20), and a single dose of midazolam 0.045 mg/kg (active placebo) (n = 19). The study assessments (HAM-D-6, MADRS, SDQ, PAS, CGI-S, and CGI-I) were performed at days 0, 1, 3 (endpoint), 5, 7, 14, and 30 to assess the safety and efficacy. The overall group × time interaction effect was significant for the primary outcome measure, the HAM-D-6. In post hoc pairwise comparisons controlling for multiple comparisons, standard dose (0.5 mg/kg) and high dose (1 mg/kg) of intravenous ketamine were superior to active placebo; a low dose (0.1 mg/kg) was significant only prior to adjustment (p = 0.02, p-adj = 0.14, d = −0.82 at day 1). Most of the interaction effect was due to differences at day 1, with no significant adjusted pairwise differences at day 3. This pattern generally held for secondary outcomes. The infusions of ketamine were relatively well tolerated compared to active placebo, except for greater dissociative symptoms and transient blood pressure elevations with the higher doses. Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Trial Registration: NCT01920555.HighlightsQuestion: What is the optimal, rapid antidepressant dose of intravenous (IV) ketamine, an NMDA receptor antagonist?Findings: Our results suggest that there is evidence for the efficacy of the 0.5 mg/kg and 1.0 mg/kg subanesthetic doses of IV ketamine and no clear or consistent evidence for clinically meaningful efficacy of lower doses of IV ketamine. Most of the effect was due to differences at day 1.Meaning: Our results suggest that there is a range of effective, subanesthetic doses of IV ketamine in TRD.
Author	Chang, Lee C Judge, Heidi Papakostas, George I Schatzberg, Alan F Trivedi, Madhukar H Sanacora, Gerard Ionescu, Dawn F Debattista, Charles Jha, Manish K Freeman, Marlene P Fava, Maurizio Hoeppner, Bettina B Cusin, Cristina Murrough, James Mathew, Sanjay J Iosifescu, Dan V Wilkinson, Samuel T Flynn, Martina
Author_xml	– sequence: 1 givenname: Maurizio surname: Fava fullname: Fava, Maurizio email: mfava@mgh.harvard.edu organization: Massachusetts General Hospital, Boston, MA, USA. mfava@mgh.harvard.edu – sequence: 2 givenname: Marlene P surname: Freeman fullname: Freeman, Marlene P organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 3 givenname: Martina surname: Flynn fullname: Flynn, Martina organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 4 givenname: Heidi surname: Judge fullname: Judge, Heidi organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 5 givenname: Bettina B surname: Hoeppner fullname: Hoeppner, Bettina B organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 6 givenname: Cristina surname: Cusin fullname: Cusin, Cristina organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 7 givenname: Dawn F surname: Ionescu fullname: Ionescu, Dawn F organization: Massachusetts General Hospital, Boston, MA, USA – sequence: 8 givenname: Sanjay J surname: Mathew fullname: Mathew, Sanjay J organization: Baylor College of Medicine/Michael E. Debakey VA Medical Center, Houston, TX, USA – sequence: 9 givenname: Lee C surname: Chang fullname: Chang, Lee C organization: Baylor College of Medicine/Michael E. Debakey VA Medical Center, Houston, TX, USA – sequence: 10 givenname: Dan V orcidid: 0000-0002-2512-2835 surname: Iosifescu fullname: Iosifescu, Dan V organization: Icahn School of Medicine at Mount Sinai, New York, NY, USA – sequence: 11 givenname: James surname: Murrough fullname: Murrough, James organization: Icahn School of Medicine at Mount Sinai, New York, NY, USA – sequence: 12 givenname: Charles surname: Debattista fullname: Debattista, Charles organization: Stanford University School of Medicine, Stanford, CA, USA – sequence: 13 givenname: Alan F surname: Schatzberg fullname: Schatzberg, Alan F organization: Stanford University School of Medicine, Stanford, CA, USA – sequence: 14 givenname: Madhukar H orcidid: 0000-0002-2983-1110 surname: Trivedi fullname: Trivedi, Madhukar H organization: University of Texas Southwestern, Dallas, TX, USA – sequence: 15 givenname: Manish K surname: Jha fullname: Jha, Manish K organization: University of Texas Southwestern, Dallas, TX, USA – sequence: 16 givenname: Gerard surname: Sanacora fullname: Sanacora, Gerard organization: Yale University, New Haven, CT, USA – sequence: 17 givenname: Samuel T surname: Wilkinson fullname: Wilkinson, Samuel T organization: Yale University, New Haven, CT, USA – sequence: 18 givenname: George I surname: Papakostas fullname: Papakostas, George I organization: Massachusetts General Hospital, Boston, MA, USA
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30283029$$D View this record in MEDLINE/PubMed
BookMark	eNp9kUtrFzEQwINU7EM_gBcJeKlgNO_sHqX1BQVB6nnJZic1f7PJmmQL_Qp-alOsFw8ehnn9ZpjHKTpKOQFCzxl9w6gY3lbJxEAJZQOhXGmiHqETJk03lBmOui3USCQb5DE6rfVA6X1SPUHHgvKhy3iCfl3mfY5A5hjS8hpv0TqYM3E5tZJjhB5bcgVSbLoJ6Qa3EmzE2ePQAXsLKe8V_4Bm15AA24rtctiTa-EWcPsOxW53He1lYNsKqZECNdRmU8MLbN2pISd8fv318tVT9NjbWOHZgz5D3z68v774RK6-fPx88e6KOC1YI9Yq46gfQDjwXlgtHfPezZp6bQR3mtNFgRgXq7lUI_VczUrPTpgZ5AhCnKHzP323kn_uUNu0huogRpugbzNxxjTjclCyoy__QQ95L6lPN_F-SiOlUfz_FJPKjIbf93rxQO3zCsu0lbDacjf9_YX4DX30jr4
CitedBy_id	crossref_primary_10_1080_17512433_2021_1933434 crossref_primary_10_1176_appi_ajp_20240378 crossref_primary_10_1002_da_22975 crossref_primary_10_1016_j_euroneuro_2024_11_008 crossref_primary_10_1038_s41467_023_42141_5 crossref_primary_10_1098_rstb_2023_0225 crossref_primary_10_1038_s41380_020_0740_6 crossref_primary_10_1016_j_amp_2022_05_008 crossref_primary_10_1192_bjo_2025_10823 crossref_primary_10_1038_s41398_022_01803_6 crossref_primary_10_1523_JNEUROSCI_1545_24_2025 crossref_primary_10_3389_fpsyt_2023_1283733 crossref_primary_10_1016_j_clinph_2021_08_021 crossref_primary_10_1124_pharmrev_120_000056 crossref_primary_10_1177_2045125320968331 crossref_primary_10_1038_s41380_020_0798_1 crossref_primary_10_1177_02698811251350267 crossref_primary_10_1016_j_ejphar_2025_177470 crossref_primary_10_3389_fpsyt_2021_662963 crossref_primary_10_1016_j_expneurol_2021_113963 crossref_primary_10_1038_s41380_021_01377_7 crossref_primary_10_1016_j_neuint_2025_105961 crossref_primary_10_1016_j_nbd_2024_106573 crossref_primary_10_1146_annurev_med_051322_120608 crossref_primary_10_1016_j_nsa_2024_104049 crossref_primary_10_1016_j_fct_2022_113508 crossref_primary_10_1007_s00406_020_01103_4 crossref_primary_10_3389_fpsyt_2024_1209419 crossref_primary_10_1038_s41380_022_01465_2 crossref_primary_10_1007_s00213_024_06599_5 crossref_primary_10_7759_cureus_91829 crossref_primary_10_1016_j_jpsychires_2021_05_014 crossref_primary_10_1016_j_ajp_2025_104502 crossref_primary_10_3390_brainsci15090971 crossref_primary_10_1007_s00406_021_01264_w crossref_primary_10_1038_s41398_022_02192_6 crossref_primary_10_1038_s41380_025_03198_4 crossref_primary_10_1007_s00210_022_02229_z crossref_primary_10_1097_JCP_0000000000001946 crossref_primary_10_3389_fpsyt_2023_1135828 crossref_primary_10_1007_s12325_021_01732_8 crossref_primary_10_1038_s41398_024_02973_1 crossref_primary_10_1038_s41398_022_02249_6 crossref_primary_10_1016_j_encep_2021_08_011 crossref_primary_10_1016_j_psycr_2024_100228 crossref_primary_10_1177_24705470211020446 crossref_primary_10_1002_cpt_3555 crossref_primary_10_1111_jne_13194 crossref_primary_10_1016_j_neuropharm_2019_107684 crossref_primary_10_1038_s41467_024_45157_7 crossref_primary_10_1016_j_neuropharm_2022_109219 crossref_primary_10_1097_MS9_0000000000003232 crossref_primary_10_1177_02698811251332831 crossref_primary_10_1016_j_jad_2020_10_007 crossref_primary_10_3389_fnmol_2022_892345 crossref_primary_10_1089_psymed_2024_0040 crossref_primary_10_1177_02698811241227026 crossref_primary_10_1016_j_jad_2025_120337 crossref_primary_10_1016_j_jad_2023_05_024 crossref_primary_10_54033_cadpedv22n7_044 crossref_primary_10_1007_s00406_024_01920_x crossref_primary_10_1016_j_bpsgos_2023_01_005 crossref_primary_10_1016_j_phrs_2022_106620 crossref_primary_10_1177_0706743720970860 crossref_primary_10_3390_ph16010031 crossref_primary_10_1080_14740338_2022_2049754 crossref_primary_10_1038_s41386_021_01242_9 crossref_primary_10_1016_j_drudis_2019_07_007 crossref_primary_10_1016_j_jad_2024_08_050 crossref_primary_10_1093_ijnp_pyaf007 crossref_primary_10_1186_s12888_024_05951_5 crossref_primary_10_1176_appi_ajp_2021_21020197 crossref_primary_10_3389_fpsyt_2021_513068 crossref_primary_10_1016_j_dscb_2025_100286 crossref_primary_10_1016_j_neuropharm_2022_109351 crossref_primary_10_1016_j_pnpbp_2019_109750 crossref_primary_10_4103_ija_ija_75_25 crossref_primary_10_1016_j_bcp_2022_114963 crossref_primary_10_1177_20451253211056743 crossref_primary_10_1007_s40263_021_00885_y crossref_primary_10_1038_s41398_021_01674_3 crossref_primary_10_3390_biomedicines11102664 crossref_primary_10_1080_02791072_2023_2248989 crossref_primary_10_1038_s41586_021_03769_9 crossref_primary_10_2196_34711 crossref_primary_10_31083_j_jin2205116 crossref_primary_10_1016_j_ajp_2021_102976 crossref_primary_10_1080_14740338_2021_1949454 crossref_primary_10_1016_j_jaclp_2024_03_008 crossref_primary_10_1007_s00228_023_03605_1 crossref_primary_10_1186_s43045_024_00420_x crossref_primary_10_1007_s43440_021_00232_4 crossref_primary_10_1176_appi_ajp_20230902 crossref_primary_10_1016_j_pbb_2024_173917 crossref_primary_10_1097_ACO_0000000000001039 crossref_primary_10_1177_02698811221140011 crossref_primary_10_1002_da_22875 crossref_primary_10_12788_acp_0048 crossref_primary_10_1002_wps_21120 crossref_primary_10_1016_j_psc_2023_02_012 crossref_primary_10_1016_j_neuropharm_2022_109250 crossref_primary_10_1038_s41380_022_01757_7 crossref_primary_10_1038_s41398_020_00897_0 crossref_primary_10_1016_j_jad_2019_09_017 crossref_primary_10_1080_14740338_2022_2047928 crossref_primary_10_1093_ijnp_pyae024 crossref_primary_10_2147_JPR_S389564 crossref_primary_10_1016_j_isci_2023_108527 crossref_primary_10_1124_molpharm_124_000890 crossref_primary_10_1016_j_brainres_2023_148375 crossref_primary_10_1080_19490976_2024_2310603 crossref_primary_10_1038_s41398_019_0624_1 crossref_primary_10_1016_j_neuropharm_2022_109383 crossref_primary_10_1073_pnas_2305772120 crossref_primary_10_1016_j_jad_2024_03_137 crossref_primary_10_3389_fpsyt_2025_1610335 crossref_primary_10_1016_j_pmip_2024_100119 crossref_primary_10_1016_j_psc_2023_02_003 crossref_primary_10_1016_j_jad_2023_07_048 crossref_primary_10_1016_j_jad_2025_04_077 crossref_primary_10_1080_14740338_2020_1776699 crossref_primary_10_1038_s41386_022_01266_9 crossref_primary_10_1038_s41380_023_02397_1 crossref_primary_10_1113_JP280706 crossref_primary_10_3390_ijms222313070 crossref_primary_10_1016_j_pbb_2024_173736 crossref_primary_10_36290_aim_2023_058 crossref_primary_10_3389_fpsyt_2024_1398859 crossref_primary_10_1002_phar_2664 crossref_primary_10_1177_2042098620937899 crossref_primary_10_1007_s40473_019_00184_3 crossref_primary_10_3389_fnbeh_2021_759466 crossref_primary_10_1186_s12888_024_06203_2 crossref_primary_10_1177_02698811211021588 crossref_primary_10_1007_s11126_020_09830_6 crossref_primary_10_1093_ijnp_pyab088 crossref_primary_10_1093_ijnp_pyac055 crossref_primary_10_1016_j_neuropharm_2025_110650 crossref_primary_10_3389_fpsyt_2020_595584 crossref_primary_10_1155_2023_3371272 crossref_primary_10_1016_j_jphs_2024_01_008 crossref_primary_10_1186_s12871_024_02681_9 crossref_primary_10_1016_j_pbb_2020_172870 crossref_primary_10_1080_02791072_2024_2421895 crossref_primary_10_1016_j_ibneur_2022_09_001 crossref_primary_10_1016_j_pnpbp_2020_110041 crossref_primary_10_1016_j_jad_2024_08_123 crossref_primary_10_1002_wps_21056 crossref_primary_10_1016_j_jpsychires_2021_07_048 crossref_primary_10_1038_s41380_021_01082_5 crossref_primary_10_1186_s12888_022_04388_y crossref_primary_10_1016_j_jad_2024_09_150 crossref_primary_10_1016_j_pnpbp_2025_111503 crossref_primary_10_1080_1028415X_2021_1888205 crossref_primary_10_1016_j_bpsc_2023_09_003 crossref_primary_10_1038_s41398_023_02564_6 crossref_primary_10_1016_j_pneurobio_2021_102140 crossref_primary_10_1038_s41467_020_20190_4 crossref_primary_10_1016_j_neuropharm_2022_109297 crossref_primary_10_3389_fpsyt_2020_549903 crossref_primary_10_1016_j_euroneuro_2021_04_024 crossref_primary_10_1177_20451253231151327 crossref_primary_10_1038_s41398_024_03180_8 crossref_primary_10_1016_j_gene_2021_145920 crossref_primary_10_1080_09540261_2020_1854194 crossref_primary_10_1176_appi_ajp_2020_20081251 crossref_primary_10_1176_appi_ajp_20230025 crossref_primary_10_1038_s41380_021_01093_2 crossref_primary_10_1016_j_encep_2020_08_006 crossref_primary_10_1016_j_pnpbp_2020_110060 crossref_primary_10_1016_j_pbb_2020_172856 crossref_primary_10_1016_j_neuropharm_2019_05_016 crossref_primary_10_1007_s00406_023_01570_5 crossref_primary_10_12788_acp_0112 crossref_primary_10_1016_j_jns_2022_120152 crossref_primary_10_1016_j_jad_2024_08_222 crossref_primary_10_3390_ijms232012196 crossref_primary_10_1038_s41398_024_03176_4 crossref_primary_10_1016_j_euroneuro_2021_04_010 crossref_primary_10_1136_bmj_2022_073823 crossref_primary_10_1016_j_psychres_2024_115949 crossref_primary_10_1097_PRA_0000000000000589 crossref_primary_10_3928_00485713_20200113_01 crossref_primary_10_1017_ipm_2021_47 crossref_primary_10_1523_JNEUROSCI_1316_22_2022 crossref_primary_10_1038_s41380_020_0845_y crossref_primary_10_1016_j_jad_2022_07_004 crossref_primary_10_1007_s00115_021_01260_4 crossref_primary_10_1016_j_jad_2023_07_007 crossref_primary_10_1186_s12888_023_05365_9 crossref_primary_10_1001_jamapsychiatry_2025_0900 crossref_primary_10_1159_000539714 crossref_primary_10_1038_s41386_023_01629_w crossref_primary_10_3390_jpm13050773 crossref_primary_10_1016_j_psychres_2024_115765 crossref_primary_10_3390_ph13060116 crossref_primary_10_1176_appi_focus_19203 crossref_primary_10_1186_s12888_022_03789_3 crossref_primary_10_1097_JCP_0000000000001524 crossref_primary_10_1055_a_2179_8884 crossref_primary_10_1177_02698811251340925 crossref_primary_10_1089_psymed_2023_0035 crossref_primary_10_1038_s41380_021_01246_3 crossref_primary_10_1016_j_neubiorev_2022_104762 crossref_primary_10_1016_j_jad_2025_04_165 crossref_primary_10_1038_s41398_024_03027_2 crossref_primary_10_3390_ijms26146673 crossref_primary_10_1038_s41398_025_03255_0 crossref_primary_10_1038_s44184_024_00091_w crossref_primary_10_1111_pcn_13870 crossref_primary_10_3928_00485713_20200109_02 crossref_primary_10_1007_s11920_019_1108_y crossref_primary_10_3390_ph17121627 crossref_primary_10_1016_j_ajp_2024_104090 crossref_primary_10_1007_s12021_025_09725_6 crossref_primary_10_1007_s43440_020_00097_z crossref_primary_10_1177_02698811211026426 crossref_primary_10_1016_j_jad_2022_08_050 crossref_primary_10_1097_JCP_0000000000001898 crossref_primary_10_1093_ijnp_pyaa089 crossref_primary_10_1007_s13205_024_04104_5 crossref_primary_10_1093_ijnp_pyaa087 crossref_primary_10_1016_j_jad_2024_01_165 crossref_primary_10_1093_ijnp_pyab050 crossref_primary_10_1016_j_jad_2023_07_103 crossref_primary_10_1016_j_bpsgos_2025_100503 crossref_primary_10_1016_j_jad_2023_10_120 crossref_primary_10_1016_j_pnpbp_2024_111107 crossref_primary_10_1016_j_psychres_2024_116273 crossref_primary_10_1080_14728222_2023_2225216 crossref_primary_10_1080_14737175_2024_2373302 crossref_primary_10_1111_cns_14464 crossref_primary_10_1016_j_pbb_2023_173556 crossref_primary_10_3389_fphar_2024_1394730 crossref_primary_10_1001_jamanetworkopen_2023_28817 crossref_primary_10_3390_ijms21217951 crossref_primary_10_1016_j_encep_2022_08_011 crossref_primary_10_1007_s00228_021_03216_8 crossref_primary_10_1016_j_jatmed_2024_07_001 crossref_primary_10_1111_jcpt_13041 crossref_primary_10_1038_s41386_019_0317_8 crossref_primary_10_1038_s41380_023_01945_z crossref_primary_10_3389_fnins_2021_609485 crossref_primary_10_3928_00485713_20240613_01 crossref_primary_10_1016_j_ajp_2024_104076 crossref_primary_10_1016_j_conctc_2019_100432 crossref_primary_10_1186_s12871_024_02436_6 crossref_primary_10_1016_j_ajp_2022_103189 crossref_primary_10_1007_s00406_024_01865_1 crossref_primary_10_1038_s41380_025_03100_2 crossref_primary_10_1111_pcn_13734 crossref_primary_10_1016_j_psychres_2024_115987 crossref_primary_10_1038_s41386_025_02085_4 crossref_primary_10_1038_s41380_022_01447_4 crossref_primary_10_1016_j_euroneuro_2022_09_004 crossref_primary_10_1177_20451253211011021 crossref_primary_10_1007_s00406_024_01925_6 crossref_primary_10_1177_02698811231161627 crossref_primary_10_1016_j_jad_2022_07_030 crossref_primary_10_1038_s41398_020_0733_x crossref_primary_10_1007_s43440_024_00637_x crossref_primary_10_1007_s00406_024_01770_7
ContentType	Journal Article
Copyright	Springer Nature Limited 2018.
Copyright_xml	– notice: Springer Nature Limited 2018.
DBID	CGR CUY CVF ECM EIF NPM 3V. 7TK 7X7 7XB 88E 88G 8AO 8FE 8FH 8FI 8FJ 8FK ABUWG AFKRA AZQEC BBNVY BENPR BHPHI CCPQU DWQXO FYUFA GHDGH GNUQQ HCIFZ K9. LK8 M0S M1P M2M M7P PHGZM PHGZT PJZUB PKEHL PPXIY PQEST PQGLB PQQKQ PQUKI PRINS PSYQQ Q9U 7X8
DOI	10.1038/s41380-018-0256-5
DatabaseName	Medline MEDLINE MEDLINE (Ovid) MEDLINE MEDLINE PubMed ProQuest Central (Corporate) Neurosciences Abstracts Health & Medical Collection ProQuest Central (purchase pre-March 2016) Medical Database (Alumni Edition) Psychology Database (Alumni) ProQuest Pharma Collection ProQuest SciTech Collection ProQuest Natural Science Collection Hospital Premium Collection Hospital Premium Collection (Alumni Edition) ProQuest Central (Alumni) (purchase pre-March 2016) ProQuest Central (Alumni Edition) ProQuest Central UK/Ireland ProQuest Central Essentials Biological Science Collection ProQuest Central Natural Science Collection ProQuest One Community College ProQuest Central Korea Health Research Premium Collection Health Research Premium Collection (Alumni) ProQuest Central Student SciTech Premium Collection ProQuest Health & Medical Complete (Alumni) ProQuest Biological Science Collection Health & Medical Collection (Alumni) Medical Database Psychology Database Biological Science Database ProQuest One Academic ProQuest One Academic (New) ProQuest Health & Medical Research Collection ProQuest One Academic Middle East (New) ProQuest One Health & Nursing ProQuest One Academic Eastern Edition (DO NOT USE) ProQuest One Applied & Life Sciences ProQuest One Academic (retired) ProQuest One Academic UKI Edition ProQuest Central China ProQuest One Psychology ProQuest Central Basic MEDLINE - Academic
DatabaseTitle	MEDLINE Medline Complete MEDLINE with Full Text PubMed MEDLINE (Ovid) ProQuest One Psychology ProQuest Central Student ProQuest One Academic Middle East (New) ProQuest Central Essentials ProQuest Health & Medical Complete (Alumni) ProQuest Central (Alumni Edition) SciTech Premium Collection ProQuest One Community College ProQuest One Health & Nursing ProQuest Natural Science Collection ProQuest Pharma Collection ProQuest Central China ProQuest Central ProQuest One Applied & Life Sciences ProQuest Health & Medical Research Collection Health Research Premium Collection Health and Medicine Complete (Alumni Edition) Natural Science Collection ProQuest Central Korea Health & Medical Research Collection Biological Science Collection ProQuest Central (New) ProQuest Medical Library (Alumni) ProQuest Biological Science Collection ProQuest Central Basic ProQuest One Academic Eastern Edition ProQuest Hospital Collection Health Research Premium Collection (Alumni) ProQuest Psychology Journals (Alumni) Biological Science Database ProQuest SciTech Collection Neurosciences Abstracts ProQuest Hospital Collection (Alumni) ProQuest Health & Medical Complete ProQuest Medical Library ProQuest Psychology Journals ProQuest One Academic UKI Edition ProQuest One Academic ProQuest One Academic (New) ProQuest Central (Alumni) MEDLINE - Academic
DatabaseTitleList	MEDLINE MEDLINE - Academic ProQuest One Psychology ProQuest One Psychology
Database_xml	– sequence: 1 dbid: NPM name: PubMed url: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed sourceTypes: Index Database – sequence: 2 dbid: BENPR name: ProQuest Central url: https://www.proquest.com/central sourceTypes: Aggregation Database
DeliveryMethod	fulltext_linktorsrc
Discipline	Biology
EISSN	1476-5578
EndPage	1603
ExternalDocumentID	30283029
Genre	Journal Article Research Support, N.I.H., Extramural
GrantInformation_xml	– fundername: NIDA NIH HHS grantid: HHSN271201100006I – fundername: NCATS NIH HHS grantid: UL1 TR001863 – fundername: NIMH NIH HHS grantid: R01 MH102279 – fundername: NIMH NIH HHS grantid: HHSN271201100006I – fundername: NIDA NIH HHS grantid: HHSN271201100006C
GroupedDBID	--- -Q- 0R~ 123 29M 2WC 36B 39C 4.4 406 53G 70F 7X7 88E 8AO 8FI 8FJ 8R4 8R5 AACDK AANZL AASML AATNV AAYZH ABAKF ABAWZ ABBRH ABDBE ABDBF ABFSG ABIVO ABJNI ABLJU ABRTQ ABUWG ABZZP ACAOD ACGFS ACKTT ACPRK ACRQY ACSTC ACUHS ACZOJ ADBBV AEFQL AEJRE AEMSY AENEX AEVLU AEXYK AEZWR AFBBN AFDZB AFHIU AFKRA AFRAH AFSHS AGAYW AGHAI AGQEE AHMBA AHSBF AHWEU AIGIU AILAN AIXLP AJRNO ALFFA ALIPV ALMA_UNASSIGNED_HOLDINGS AMYLF ATHPR AXYYD AYFIA AZQEC B0M BAWUL BBNVY BENPR BHPHI BKKNO BPHCQ BVXVI CAG CCPQU CGR COF CS3 CUY CVF DIK DNIVK DPUIP DU5 DWQXO E3Z EAD EAP EBC EBD EBLON EBS ECM EE. EIF EIOEI EJD EMB EMK EMOBN EPL EPS ESX F5P FDQFY FEDTE FERAY FIGPU FIZPM FSGXE FYUFA GNUQQ HCIFZ HMCUK HVGLF HZ~ IAO IHR INH INR IPY ITC IWAJR JSO JZLTJ KQ8 M1P M2M M7P NPM NQJWS O9- OK1 OVD P2P PHGZM PHGZT PJZUB PPXIY PQGLB PQQKQ PROAC PSQYO PSYQQ Q2X RNS RNT RNTTT ROL SNX SNYQT SOHCF SOJ SRMVM SV3 SWTZT TAOOD TBHMF TDRGL TEORI TR2 TSG TUS UKHRP ~8M 3V. 7TK 7XB 8FE 8FH 8FK K9. LK8 PKEHL PQEST PQUKI PRINS Q9U 7X8 PUEGO
ID	FETCH-LOGICAL-c631t-aa57c0f8e3ceff3a64c1ffcb60f6732c620d5e39da624590f25b56bc37be49e33
IEDL.DBID	M7P
ISICitedReferencesCount	313
ISICitedReferencesURI	http://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=Summon&SrcAuth=ProQuest&DestLinkType=CitingArticles&DestApp=WOS_CPL&KeyUT=000541097500021&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
ISSN	1359-4184 1476-5578
IngestDate	Fri Sep 05 10:19:46 EDT 2025 Mon Oct 06 18:25:35 EDT 2025 Mon Oct 06 18:28:14 EDT 2025 Mon Jul 21 06:08:09 EDT 2025
IsDoiOpenAccess	false
IsOpenAccess	true
IsPeerReviewed	true
IsScholarly	true
Issue	7
Language	English
LinkModel	DirectLink
MergedId	FETCHMERGED-LOGICAL-c631t-aa57c0f8e3ceff3a64c1ffcb60f6732c620d5e39da624590f25b56bc37be49e33
Notes	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ORCID	0000-0002-2512-2835 0000-0002-2983-1110
OpenAccessLink	https://www.nature.com/articles/s41380-018-0256-5.pdf
PMID	30283029
PQID	2414579724
PQPubID	44096
PageCount	12
ParticipantIDs	proquest_miscellaneous_2116124854 proquest_journals_2476744752 proquest_journals_2414579724 pubmed_primary_30283029
PublicationCentury	2000
PublicationDate	2020-07-01
PublicationDateYYYYMMDD	2020-07-01
PublicationDate_xml	– month: 07 year: 2020 text: 2020-07-01 day: 01
PublicationDecade	2020
PublicationPlace	England
PublicationPlace_xml	– name: England – name: New York
PublicationTitle	Molecular psychiatry
PublicationTitleAlternate	Mol Psychiatry
PublicationYear	2020
Publisher	Nature Publishing Group
Publisher_xml	– name: Nature Publishing Group
References	30617276 - Mol Psychiatry. 2020 Jul;25(7):1604. doi: 10.1038/s41380-018-0311-2.
References_xml	– reference: 30617276 - Mol Psychiatry. 2020 Jul;25(7):1604. doi: 10.1038/s41380-018-0311-2.
SSID	ssj0014765
Score	2.6975722
Snippet	Numerous placebo-controlled studies have demonstrated the ability of ketamine, an NMDA receptor antagonist, to induce rapid (within hours), transient...
SourceID	proquest pubmed
SourceType	Aggregation Database Index Database
StartPage	1592
SubjectTerms	Adult Antidepressants Antidepressive Agents - therapeutic use Blood pressure Depression - drug therapy Depressive Disorder, Treatment-Resistant - drug therapy Double-Blind Method Double-blind studies Female Glutamic acid receptors (ionotropic) Humans Infusions, Intravenous Intravenous administration Ketamine Ketamine - administration & dosage Ketamine - therapeutic use Male Mental depression Midazolam Middle Aged N-Methyl-D-aspartic acid receptors Placebos Treatment Outcome Treatment resistance
Title	Double-blind, placebo-controlled, dose-ranging trial of intravenous ketamine as adjunctive therapy in treatment-resistant depression (TRD)
URI	https://www.ncbi.nlm.nih.gov/pubmed/30283029 https://www.proquest.com/docview/2414579724 https://www.proquest.com/docview/2476744752 https://www.proquest.com/docview/2116124854
Volume	25
WOSCitedRecordID	wos000541097500021&url=https%3A%2F%2Fcvtisr.summon.serialssolutions.com%2F%23%21%2Fsearch%3Fho%3Df%26include.ft.matches%3Dt%26l%3Dnull%26q%3D
hasFullText	1
inHoldings	1
isFullTextHit
isPrint
link	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMwpV1Lb9QwELb6QuICpbwK7cpIHIqE1azfPiGgrbjsalW10t4iP6VCSUoTKvUv8KsZO9m9lQsXS4kTK_Jj5puZLzMIvXeVA5geJTFeaMINmDvWJkcs01FInSNboRSbUPO5Xi7NYnS4dSOtciUTi6AOrc8-8mPKc9oZrgT9dPOL5KpRObo6ltDYRNs5SwIr1L3FOooAr4hicIkc7dR8FdVk-rgD4a0zJUuTrPWJeBhhFk1z9vR_v3EXPRkxJv48bIpnaCM2e-jRUHXy_jn6A6DZXUfiAGGGj7iwslxLRtL6dYR7oe0iAS2WKxjhUtgDtwlfZUfwXUnqin_E3v4EhIpth234Dtoxy008_M51D4_iNYWdgEWfUWrT4zXvtsFHF-cnH16gy7PTi6_fyFiSgXjJpj2so1C-SjoyH1NiVnI_Tck7WSWpGPWSVkFEZoKVlAtTJSqckM4z5SI3kbGXaKtpm_ga4WnwPmeDt0F6HqdBm0CFBYTiHDUy2X10sJrkejxXXQ14gwtlFOUPdK8WYB-9W3fDgclRENtEmJ8aLF5AdVwLGOLVsM71zZDZo2ZVyYdm3vx78LfoMc1md2HtHqCt_vZ3PEQ7_q6_6m4naFMtVWn1BG1_OZ0vzuFqRmeTsjuhnS9mfwF_NOxJ
linkProvider	ProQuest
linkToHtml	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1LaxRBEG5CVPTiW5MYtQUFBZvM9mu6DyJiDAnJLiIr5Db2E2KSmWRnEtm_4I_xN1rds7O3eMvB6_TQNNVF1VePrg-h17awANODJNoJRbiGcMeYaIlhKgipUmXLZ7KJcjJRh4f66wr6M7yFSW2Vg03Mhto3LuXItyhPY2d4KejHs3OSWKNSdXWg0OjVYj_Mf0HI1n7Y24b7fUPpzpfp512yYBUgTrJRB0cRpSuiCsyFGJmR3I1idFYWUZaMOkkLLwLT3kjKhS4iFVZI61hpA9chJUDB5N_gEAklqogxHS-rFnBEkQM8kaqrig9VVKa2WnAWKrWAKZJQBhFXI9rs2Xbu_W8yuY_uLjA0_tQr_QO0EuqH6FbPqjl_hH5DUGBPArGAoP17nLvObEMWTfknAb75pg0EvHRiaMKZuAQ3ER-lRPdlHlqLj0NnTgGBY9Ni43-C909-AffP1ebwK1626JNZaBMKrzu87Cuu8dvpt-13j9H3axHEE7RaN3VYQ3jknUvT7o2XjoeRV9pTYQCBWUu1jGYdbQ6XWi3sRlsBnuKi1CXlVywPF76OXi2XwSCkKo-pA8ingogeUCtXArZ42utVddZPLqlYkee96Y1_b_4S3d6djg-qg73J_jN0h6YUQ-5Q3kSr3ewiPEc33WV31M5eZP3H6Md1K9dfkYNFvA
linkToPdf	http://cvtisr.summon.serialssolutions.com/2.0.0/link/0/eLvHCXMw1V1Lb9QwELaq8hAX3o9CASOBBFKtzfoV-4AQYllRFa1WqEi9BT-lQknKJhTtX-An8esYO8neyq0HrnFkWfZ45puZzzMIPbeFBZgeJNFOKMI1uDvGREsMU0FIlTJbPjebKBcLdXSkl1voz_gWJtEqR52YFbVvXIqRTyhPZWd4KegkDrSI5Wz-5vQHSR2kUqZ1bKfRi8hBWP8C9619vT-Ds35B6fz94bsPZOgwQJxk0w6WJUpXRBWYCzEyI7mbxuisLKIsGXWSFl4Epr2RlAtdRCqskNax0gauQwqGgvq_VKai5Zk2uNxkMGC5Ijt7ImVaFR8zqkxNWjAcKtHBFEmIg4jz0W22cvMb__P-3ETXB2yN3_aX4RbaCvVtdKXvtrm-g36Ds2BPArGArP0ezmw025CBrH8S4Jtv2kDAeqfOTTg3NMFNxMcpAH6Wi9nib6Ez3wGZY9Ni478CKkj2AvfP2NbwK95Q98kqtAmd1x3e8I1r_PLw0-zVXfT5QjbiHtqumzo8QHjqnUtV8I2XjoepV9pTYQCZWUu1jGYH7Y4HXA36pK0AZ3FR6pLyc4bHw99BzzbDoChS9sfUAfanAk8f0CxXAqa438tYddpXNKlYkevA6Yf_nvwpugoyVX3cXxw8Qtdoijxk4vIu2u5WP8NjdNmddcft6km-Chh9uWjZ-gv6tE6N
openUrl	ctx_ver=Z39.88-2004&ctx_enc=info%3Aofi%2Fenc%3AUTF-8&rfr_id=info%3Asid%2Fsummon.serialssolutions.com&rft_val_fmt=info%3Aofi%2Ffmt%3Akev%3Amtx%3Ajournal&rft.genre=article&rft.atitle=Double-blind%2C+placebo-controlled%2C+dose-ranging+trial+of+intravenous+ketamine+as+adjunctive+therapy+in+treatment-resistant+depression+%28TRD%29&rft.jtitle=Molecular+psychiatry&rft.au=Fava%2C+Maurizio&rft.au=Freeman%2C+Marlene+P&rft.au=Flynn%2C+Martina&rft.au=Judge%2C+Heidi&rft.date=2020-07-01&rft.pub=Nature+Publishing+Group&rft.issn=1359-4184&rft.eissn=1476-5578&rft.volume=25&rft.issue=7&rft.spage=1592&rft.epage=1603&rft_id=info:doi/10.1038%2Fs41380-018-0256-5&rft.externalDBID=HAS_PDF_LINK
thumbnail_l	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/lc.gif&issn=1359-4184&client=summon
thumbnail_m	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/mc.gif&issn=1359-4184&client=summon
thumbnail_s	http://covers-cdn.summon.serialssolutions.com/index.aspx?isbn=/sc.gif&issn=1359-4184&client=summon