**4. Discussion**

The results of this project can contribute significantly to the knowledge about patients with SUD and DD both at a basic or theoretical level and for intervention and relapse prevention. All the results obtained from the two studies, but especially the relationships between the different variables evaluated (clinical characteristics, genetic polymorphisms, circadian rhythmicity, neurocognitive functioning and personality traits), will represent, in most cases, the first data obtained in the field both at national and international level. The adjuvant chronobiological therapy intervention will be the first study to be carried out with this type of patients and with an objective outpatient evaluation that provides us with information on patient compliance and changes in circadian rhythmicity. The consideration of sex in SUD and dual depression is a pending task due to the non-proportional prevalence of cases in the clinic, which we will carry out in a novel way both at the level of characterization and intervention.

Currently, both SUD and DD are disorders of high prevalence in drug dependence and mental health care worldwide, with difficulties in therapeutic managemen<sup>t</sup> and with high relapse rates. The search for biomarkers or endophenotypes likely to improve adherence and response to treatment is a relevant pending issue. Furthermore, exploring the option of improving the approach by means of chronobiological strategies will be a pioneering contribution that can be transferred to the clinical setting, as well as being disseminated at a social and media level.

Likewise, our research can provide recommendations in relation to considering aspects that benefit the evaluation and diagnosis protocols and/or the convenience of incorporating some strategies in the therapeutic managemen<sup>t</sup> of patients (i.e., cognitive rehabilitation), including the sex dimension. We also hope to delimit some cost-effective markers of adherence, prognosis and risk of relapse, as well as the existence of rhythmic characteristics in combination with modifiable genetic polymorphisms in case they are found to be altered. With all this, the present research will result in a contribution in line with the general objectives proposed by the WHO for mental illnesses [89] and specifically in the clinical managemen<sup>t</sup> of patients with addiction and DD [90]. Finally, the proposed intervention, if it proves to be useful, will be the first work carried out worldwide with a potential clinical sample (SUD and dual depression) that could unquestionably benefit from it.

From a social-impact point of view, since the Nobel medicine/physiology award of 2017 (Jeffrey C. Hall, Michael Rosbash and Michael W. Young) for research on the molecular mechanisms that control circadian rhythms, media interest in chronobiology has notably increased. DD is a health issue to which the media are beginning to be sensitive, especially promoted by the debate on the legal situation of cannabis and the coexistence of psychotic disorders among its consumers. The media have also recently echoed the impact that the coronavirus pandemic has generated on consumption patterns and increases in SUD. The dissemination of the results of study 1 will make visible the high presence of psychiatric comorbidity in SUD, as well as its personal and social impact, together with recommendations based on useful markers in clinical management. The data from the chronobiological intervention, if positive results are obtained, will undoubtedly be likely to be disseminated not only in our country but internationally.

**Author Contributions:** Conceptualization, A.A.; methodology, A.A. and J.F.N.; funding acquisition, A.A.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the gran<sup>t</sup> PID2020-117767GB-I00 of the Spanish Ministry of Science and Innovation (MCIN/AEI/10.13039/501100011033), the Generalitat of Catalunya (2017SGR-748) and by Consejería de Economía, Innovación, Ciencia y Empleo, Junta de Andalucía, Spain (Group CTS-195).

**Institutional Review Board Statement:** The study will be conducted according to the guidelines of the Declaration of Helsinki and was approved by Ethics Committee of the University of Barcelona (IRB00003099).

**Informed Consent Statement:** Informed consent will be obtained from all subjects involved in the two studies.

**Conflicts of Interest:** The authors declare no conflict of interest.
