Discussion
To our knowledge this is the first large-scale multicenter, prospective, double-blind randomized clinical trial (RCT) to assess whether PGx-guided selection of treatment is more effective than unguided treatment in improving MDD patients’ response and poor drug tolerability. Our results show that achievement of sustained response within the 12-week follow-up period (primary outcome of the study) did not differ between the two groups. Positive results were found within 12 weeks of treatment based on the double-blind evaluation of patient-rated improvement (PGI-I), especially when the 17 subjects randomized to the PGx-guided group but being prescribed a drug regime not in accordance with the test results were excluded. Positive results were also observed within the first 6 weeks of treatment according to HDRS-17 change (single-blind).
Proper randomization and blinding are necessary because performing a genetic test has the potential to affect the attitude of the patient towards the post-test medication, resulting in increased adherence, as has been recently shown for other medical conditions [
38]. In our study, we ensured double-blinding by using the patient rating of improvement (PGI-I scale), collected by blinded phone interviews, as the primary variable. The treating psychiatrists, which selected the drug regiment for patients either in the PGx-guided or TAU groups, could not be blinded and therefore phone interviews by independent raters were considered as the best option to guarantee double-blinded assessments. The present study has been conducted with conditions representative of real-world clinical practice. Most subjects enrolled were not drug-naïve (having received up to 15 previous courses of different psychiatric medication for the current depressive episode), and a substantial percentage of them displayed concurrent psychiatric disorders such as anxiety and substance abuse, while 17.8% displayed a depression of mild severity. In contrast, Phase III clinical trials of antidepressant efficacy commonly tend to employ more stringent inclusion/exclusion criteria, typically excluding subjects with comorbidities, those with HDRS-17 baseline severity of <19 and those with a current episode lasting more than 24 months [
39]. In this regard, efficacy of antidepressant medication compared with placebo increases with severity of the disorder and tends to be smaller in patients with mild to moderate depression [
39,
40]. In our study, comorbidities were not excluded and patients were selected according to a CGI-S score ≥ 4, which may explain the finding of a 17.8% of subjects with HDRS-17 score below 14 at randomization (baseline), the depression severity cutoff used in the STAR-D study [
41]. Furthermore, our study included patients who had failed multiple previous treatments (65% of the population could be regarded as refractory).
A recent systematic review indicated that, up until now, only a handful of studies have examined the effects of combinatorial pharmacogenomics testing on clinical outcomes of adult MDD patients [
17]. Of these, only two were randomized clinical trials, and none were multi-centric studies. In the first one, Winner and colleagues found a statistical trend for better outcomes in a trial conducted in 51 study subjects (26 pharmacogenetic-guided versus 25 unguided) with baseline HDRS-17 scores ≥14 [
18]. Conversely, Singh [
19] used a pharmacogenetic report to adjust drug dosages in 148 MDD patients (74 guided versus 74 unguided) and showed patients in the guided group had a 2.52-fold increased likelihood of remission. Of note, the latter included subjects with HDRS-17 scores over 18 only, and excluded smokers, patients with psychiatric comorbidities, and those receiving known inducers/inhibitors of CYP2C19, CYP2D6 and ABCB1. Although with promising results, both studies were conducted in populations of patients of modest size and thus additional data was needed to firmly establish the utility of pharmacogenetic testing for the treatment of MDD.
Therefore, regardless of the high heterogeneity of the AB-GEN full study population in terms of depression severity, length of diagnosis and comorbidities, statistically significant differences were observed in the PGx-guided treatment group versus the unguided group, although effect sizes were modest. The definition of sustained response in this study required at least obtaining significant differences already at 8 weeks, which may be too short a follow-up period, especially in a design seeking to demonstrate superiority against treatment as usual (opposed to trials intending to prove non-inferiority). The statistically significant increase in response rate in the PGx-guided group during the study period and the difference observed against the control group at 12 weeks raise the question of whether a longer follow-up time could confirm a difference in sustained response.
The effects of PGx-guided treatment on response (PGI-I) and HDRS-17 change were more consistent and clinically relevant in subjects with 1 to 3 unsuccessful previous drug trials, where a 2.39-fold increase in the odds of response was found. Hence, our results suggest that use of pharmacogenetic information to guide treatment adjustments would be justified if the traditional first line of treatment fails. Our results are in agreement with previous studies reporting that pharmacogenetic tools are effective in patients that failed a previous medication trial [
18,
19,
42]. Moreover, the results of this study are consistent with previous data from a retrospective naturalistic study also conducted with Neuropharmagen [
20]. However, our results also indicate that pharmacogenetics tools may be of little benefit to those patients with large numbers of unsuccessful medication attempts. We hypothesize this could be due to those patients having less untested therapeutic alternatives remaining, and thus the reduction in uncertainty caused by the test would be smaller. Future studies should attempt to assess this hypothesis.
Remarkably, the present study is also the first prospective multicenter double-blind RCT indicating that the use of a pharmacogenetic test report improves medication tolerability as suggested by a statistically significant reduction in the burden of side-effects. Non-adherence is a global challenge for psychiatry and has been linked to poorer outcomes, while improved tolerability facilitates long-term adherence. In the present study, a very small correlation was found between the change in HDRS-17 and the change in side effect burden on the same visits, suggesting that the improved tolerability is not the cause of the improvement in depression severity during the 12-week follow-up period.
The pharmacogenetic tool used in this study also allows physicians to check for potential drug-drug, drug-medical condition and drug-lifestyle factor interactions. Therefore, we compared those patients whose treating psychiatrists had consulted for interaction alerts to those whose treating psychiatrist had not, within the PGx group. A slight increase in response rate was observed in the former group, yet the opposite trend was observed regarding the reduction in HDRS-17, the differences being not significant in either case. Also, it must be noted that the number of subjects displaying real interactions was not determined, and could differ between the two subgroups, thus compromising their comparability. Therefore, no conclusions could be drawn regarding whether the addition of interaction alerts to pharmacogenetic information had a significant impact.
Personalization of psychiatric treatments using pharmacogenetic information is emerging as a valuable tool to identify in advance which medications will be more effective, which will require dose adjustments or which may cause meaningful adverse reactions. Besides a clinically-demonstrated effect on efficacy and tolerability, for pharmacogenetic data to represent a real benefit for psychiatric patients it needs to be seamlessly integrated into clinical practice. Drug response and tolerability profiles depend on the combined effects of different genes as well as environmental and clinical factors. In this regard, the translation of the combined effect of different genes into actionable recommendations has been previously shown to outperform the effect of single genes [
43]. The Neuropharmagen web-based platform uses a proprietary combinatorial approach to translate pharmacogenetic as well as pharmacological information into clinical actionable recommendations. In the case of drug-metabolizing enzymes polymorphisms, international guidelines (Clinical Pharmacogenetics Implementation Consortium genotype-driven dose adjustments, FDA-approved drug labelling) are included in the recommendations when available.
A number of barriers have been noted for the widespread adoption of precision medicine, such as insufficient evidence generation, data sharing and slow uptake of genomic information into clinical care [
44]. In this regard, a multi-centric, double-blinded RCT design such as the one used in our study represents the gold standard for evidence generation, while having performed the study in a naturalistic scenario allows to account for the limitations in sharing and uptaking of pharmacogenetic data in a real-life scenario.
Acknowledgements
The authors thank Fernando Rico-Villamoros, MD (Cociente, S. L., Madrid, Spain) for help in preparing the study protocol; Adknoma Health Research SL (Barcelona, Spain), the Medical Statistics Core Facility IDIBAPS-Hospital Clinic (Barcelona, Spain) and Trialance Sccl (Barcelona, Spain) for providing contract research organization services. We express our thanks to the medical doctors, investigators and nurses of the different hospitals, and to the patients for their participation.
AB-GEN Collaborative Group:
Enric Álvarez
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain, & Mental Health Department, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain.
Fermín Mayoral-Cleries
Department of Psychiatry, Hospital Universitari de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Carretera de la Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barcelona, Spain.
Javier Quintero
Departament de Ciències Clíniques, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Diego J. Palao
UGC de Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain
Luis Javier Irastorza
Department of Psychiatry, Hospital Infanta Leonor, Madrid, Spain
Rafael Navarro
Servei de Salut Mental, Parc Taulí-Hospital Universitari, Departament de Psiquiatria, Universitat Autònoma de Barcelona, Sabadell, Barcelona, Spain.
María Luisa Barrigón
Departamento de Psiquiatría, Fundación Jiménez Díaz, IIS FJD, Madrid, Spain.
Marina Garriga
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Columbia University, New York, USA
Lucía Villoria
Departamento de Psiquiatría, Fundación Jiménez Díaz, IIS FJD, Madrid, Spain. Virginia Soria
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM, Spain & Servei de Psiquiatria, Hospital de la Santa Creu i Sant Pau, Institut d’Investigació Biomèdica Sant Pau (IIB Sant Pau), Universitat Autònoma de Barcelona, Barcelona, Spain.
José M. Rodao
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Departament of Psychiatry, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Universidad de Alcalá, Madrid, Spain.
Juan Castaño
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Institut de Neuropsiquiatria i Addiccions (INAD), Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Departament de Psiquiatria, Universitat Autònoma de Barcelona, Barcelona, Spain.
Jordi Blanch
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Columbia University, New York, USA.
Cristobal Díez-Aja
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Institut de Neuropsiquiatria i Addiccions (INAD), Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Departament de Psiquiatria, Universitat Autònoma de Barcelona, Barcelona, Spain.
Mercè Brat
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Columbia University, New York, USA.
José M. Mongil
Department of Psychiatry, Instituto de Investigación Hospital 12 de Octubre (i+12), Madrid, Spain.
Juan Miguel Garrido
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Columbia University, New York, USA.
Fernando Mora
Departament de Ciències Clíniques, Facultat de Medicina, Universitat de Barcelona, Barcelona, Spain.
Pedro M. Holgado
Department of Psychiatry, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Instituto Biomédico Galicia Sur, Vigo, Spain.
Roberto Sánchez-González
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Institut de Neuropsiquiatria i Addiccions (INAD), Hospital del Mar, Institut Hospital del Mar d’Investigacions Mèdiques (IMIM), Departament de Psiquiatria, Universitat Autònoma de Barcelona, Barcelona, Spain.
Alexandra Bagney
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Department of Psychiatry, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Instituto Biomédico Galicia Sur, Vigo, Spain.
Eva Aguilar
UGC de Salud Mental, Hospital Regional Universitario de Málaga, Instituto de Investigación Biomédica de Málaga (IBIMA), Málaga, Spain.
María Paz García-Portilla
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Área de Psiquiatría, Facultad de Medicina, Universidad de Oviedo, Instituto Universitario de Neurociencias del Principado de Asturias (INEUROPA), Oviedo, Spain.
Gemma Safont
Psychiatric Hospitalization Unit, Hospital General de Jerez de la Frontera, Jerez de la Frontera, Cádiz, Spain.
Joana Bauzà
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Mental Health Department, Hospital de Mataró, Consorci Sanitari del Maresme, Mataró, Spain.
Mercedes Martín-del Moral
Department of Psychiatry, Hospital Álvaro Cunqueiro, Complejo Hospitalario Universitario de Vigo, Instituto Biomédico Galicia Sur, Vigo, Spain.
Nazaret Cantero
Department of Psychiatry, Hospital Universitari de Bellvitge, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Carretera de la Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barcelona, Spain.
Miquel Bernardo
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Spain & Columbia University, New York, USA.
Núria Rissech
AB-Biotics, S. A, Barcelona, Spain.
Marta Puigmulé
AB-Biotics, S. A, Barcelona, Spain.
Miquel Àngel Bonachera
AB-Biotics, S. A, Barcelona, Spain.
Competing interests
VP has received grants and served as consultant, advisor or CME speaker for AB-Biotics, AstraZeneca, Bristol-Myers Squibb, Glaxo-Smith-Kline, Pfizer, Janssen, Lundbeck, Medtronic, Otsuka, and the Spanish Ministry of Economy and Competitiveness (Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM). AS and JE are employees of and minor stock shareholders in AB-Biotics. MT is employee of AB-Biotics. JSR has received grants and served as consultant, advisor or CME speaker for Lundbeck, Janssen and Otsuka. JB1 has received grants and served as consultant, advisor or CME speaker for AB-Biotics, Adamed, Almirall, AstraZeneca, Bristol-Myers Squibb, Ferrer, Glaxo-Smith-Kline, Hoffman-La Roche, Janssen-Cilag, Eli Lilly, Lundbeck, Merck, Novartis, Organon, Otsuka, Pfizer, Pierre-Fabre, Sanofi-Aventis, Servier, Schering-Plough and Shire, and research funding from the Spanish Ministry of Economy and Competitiveness (CIBERSAM, Instituto de Salud Carlos III, ISCIII), Spanish Ministry of Health, Social Services and Equality (Plan Nacional sobre Drogas) and the European Union’s 7th Framework Program (EU FP7). EB has received grants from Janssen, Otsuka and Servier. EV has received grants and served as consultant, advisor or CME speaker for AB-Biotics, Actavis, Allergan, AstraZeneca, Bial, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Elan, Eli Lilly, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, Shire, Solvay, Sunovion, Takeda, Telefonica, the Brain & Behavior Research Foundation (NARSAD), CIBERSAM, the EU FP7 (ENBREC), and the Stanley Medical Research Institute. JMO has received grants and served as consultant, advisor or CME speaker for AstraZeneca, Bristol-Myers Squibb, Glaxo-Smith-Kline, Pfizer, Janssen, Lundbeck, Otsuka, Eli Lilly, Novartis, and Sanofi-Aventis. RRJ has received grants and served as consultant, advisor or CME speaker for ISCIII, Fondo de Investigación Sanitaria (FIS), CIBERSAM, Madrid Regional Government (S2010/BMD-2422 AGES), Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Ferrer, Juste. JMV has received grants and served as consultant, advisor or CME speaker for Janssen-Cilag, Pfizer, Bristol-Myers Squibb, Otsuka, Glaxo-Smith-Kline, AstraZeneca, Sanofi-Aventis, Novartis, Lundbeck and Ferrer. JG has received grants and served as consultant, advisor or CME speaker for Janssen-Cilag, Lundbeck, Pfizer and BioClever 2005. JCC has received grants and served as consultant for Lundbeck/Otsuka. PAS has received grants or served as consultant for Adamed, AstraZeneca, Brainpharma, Bristol-Myers Squibb, Esteve, Ferrer inCode, Glaxo-Smith-Kline, Janssen-Cilag, Eli Lilly, Lundbeck, Otsuka, Pfizer, Rovi, Servier, the Spanish Ministry of Health, Social Services and Equality (Plan Nacional sobre Drogas), CIBERSAM, and the EU FP7. AI has served as speaker or advisor for Bristol-Myers Squibb, Ferrer, Lundbeck, Otsuka and Servier. JDA is funded by the Instituto de Salud Carlos III through a ‘Juan Rodés’ research fellowship (JR14/00011) and has received lecture honoraria from Pfizer, Glaxo-Smith-Kine and Lundbeck. JMM1 has received grants and served as consultant, advisor or CME speaker for AB-Biotics, Ferrer, Glaxo-Smith-Kline, Janssen, Lundbeck, Medtronic, Otsuka, and CIBERSAM. EA1 has received grants and served as consultant, advisor or CME speaker for AB-Biotics, Eli Lilly, Lundbeck, Pfizer, Sanofi-Aventis, Bristol-Myers Squibb, Servier and Otsuka. FMC has served as consultant for Janssen-Cilag. JQ has received grants, served as consultant or CME speaker for Janssen, Otsuka, Shire, Mutua Madrileña & Grunethal. DJP has received grants and served as consultant for Lundbeck/Otsuka. MG has received grants and served as consultant, advisor or CME speaker for Ferrer, Janssen, Lundbeck and the Spanish Ministry of Economy and Competitiveness (ISCIII). VS has received grants and served as consultant or CME speaker for Servier, Rovi, Lundbeck, Pfizer and the Spanish Ministry of Science and Innovation. CDA has received grants and served as consultant, advisor or CME speaker for Lundbeck, Rovi, Eli Lilly and Pfizer. JMM2 has received grants and served as CME speaker for Janssen-Cilag, Pfizer, Otsuka, AstraZeneca, Sanofi-Aventis, Lundbeck and Ferrer. FM has received grants and served as consultant, advisor or CME speaker for AstraZeneca, Ferrer, Janssen, Glaxo-Smith-Kline, Pfizer, Otsuka and Lundbeck. PMH has received grants and served as consultant, advisor or CME speaker for Janssen-Cilag, Lundbeck, Otsuka, Boehringer Ingelheim. EA2 has received grants and served as CME speaker for Janssen-Cilag and Otsuka. MPGP has received grants or served as consultant for Lundbeck/Otsuka, ISCIII, CIBERSAM, Janssen-Cilag, Eli Lilly, Lundbeck, Otsuka, Pfizer, Servier, Roche and Rovi. MB has received grants and served as consultant, advisor or CME speaker for AB-Biotics, Adamed, Almirall, Amgen, Boehringer, Eli Lilly, Ferrer, Forum Pharmaceuticals, Gedeon Richter, Hersill, Janssen-Cilag, Lundbeck, Otsuka, Pfizer, Roche, Servier and has obtained research funding from the Ministry of Education, Culture and Sports, ISCIII, CIBERSAM, the Government of Catalonia, Secretaria d’Universitats i Recerca del Departament d’Economia i Coneixement (2014SGR441), European Group for Research In Schizophrenia (EGRIS) Foundation, and the EU FP7. MP and NR are employees of AB-Biotics. MAB is employee of and stock shareholder in AB-Biotics. All other authors declare no conflicts of interests.