Vol.:(0123456789) 1 3 Journal of Neural Transmission https://doi.org/10.1007/s00702-019-02014-y PSYCHIATRY AND PRECLINICAL PSYCHIATRIC STUDIES - REVIEW ARTICLE Genetic endophenotypes for insomnia of major depressive disorder and treatment‑induced insomnia Ibrahim Mohammed Badamasi 1  · Munn Sann Lye 2  · Normala Ibrahim 3  · Johnson Stanslas 1 Received: 18 December 2018 / Accepted: 11 May 2019 © Springer-Verlag GmbH Austria, part of Springer Nature 2019 Abstract Major depressive disorder (MDD) is primarily hinged on the presence of either low mood and/or anhedonia to previously pleasurable events for a minimum of 2 weeks. Other clinical features that characterize MDD include disturbances in sleep, appetite, concentration and thoughts. The combination of any/both of the primary MDD symptoms as well as any four of the other clinical features has been referred to as MDD. The challenge for replicating gene association fndings with phenotypes of MDD as well as its treatment outcome is putatively due to stratifcation of MDD patients. Likelihood for replication of gene association fndings is hypothesized with specifcity in symptoms profle (homogenous clusters of symptom/individual symptoms) evaluated. The current review elucidates the genetic factors that have been associated with insomnia symptom of MDD phenotype, insomnia symptom as a constellation of neuro-vegetative cluster of MDD symptom, insomnia symptom of MDD as an individual entity and insomnia feature of treatment outcome. Homozygous CC genotype of 3111T/C, GSK3B- AT/TT genotype of rs33458 and haplotype of TPH1 218A/C were associated with insomnia symptom of MDD. Insomnia symptom of MDD was not resolved in patients with the A/A genotype of HTR2A-rs6311 when treated with SSRI. Homozy- gous short (SS) genotype-HTTLPR, GG genotype of HTR2A-rs6311 and CC genotype of HTR2A-rs6313 were associated with AD treatment-induced insomnia, while val/met genotype of BDNF-rs6265 and the TT genotype of GSK-3beta-rs5443 reduced it. Dearth of association studies may remain the bane for the identifcation of robust genetic endophenotypes in line with fndings for genotypes of HTR2A-rs6311. Keywords Endophenotype · Genetic polymorphism · Major depressive disorder · SSRI · Antidepressants · Insomnia Introduction Major depressive disorders (MDD) are the fourth largest global disease burden afecting over 4% of adults globally (Ferrari et al. 2013). MDD is defned as at least 2 weeks of low mood and/or loss of interest in addition to a combina- tion of disturbances in appetite, sleep, psychomotor agitation or retardation, lethargy, diminished decision-making ability as well as feeling of worthlessness, poor concentration or suicidal ideation features (American Psychiatric Association 2013). Impairment in social, occupational and general func- tioning is also characteristically associated with depression (American Psychiatric Association 2013). Currently, evalu- ations of symptom severity and its associated changes dur- ing treatment are done using validated instruments. A major challenge in polythetic ailment such as MDD has been in the array of symptoms, some of which are polar opposites of one another, which could potentially contribute in making such a diagnosis. Such diagnostic heterogeneity is a key limiting factor for the evaluation of etiological as well as predictive factors for MDD and its treatment outcome (Trivedi et al. 2016; Trivedi 2013; Kapur et al. 2012; Morgan and Gartleh- ner 2011; Cipriani et al. 2005, 2009; Krueger and Bezdjian 2009; Olbert et al. 2014; Strauss and Smith 2009; Westen et al. 2004). Diferent analytical approaches have indicated that clini- cal features of MDD can be categorized into three clusters, * Johnson Stanslas rcxjs@upm.edu.my 1 Pharmacotherapeutics Unit, Department of Medicine, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia 2 Department of Community Health, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia 3 Department of Psychiatry, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Serdang, Malaysia