Key points are not available for this paper at this time.
The comorbidity between chronic illnesses and depression is well known to all psychiatrists working in general hospitals. A large body of research indicates a bidirectional relationship: each condition can exacerbate the other, leading to worse outcomes compared to conditions without comorbidity (Katon 2011;Berg et al 2023;Herrera et al 2021;Moussavi et al. 2007;Read et al 2017;Handajani et al 2024;Kim et al 2021). At first glance, the comorbidity between depression and cancer may seem comparable to that seen in other chronic conditions. Yet, a more nuanced reality emerges.First, this is a phenomenon of considerable scope; however, it is not a distinctive characteristic of cancer (Bortolato et al. 2017). According to authoritative large cohort studies, reviews, and metaanalyses, the prevalence of major depressive disorder among people with cancer is estimated within a broad range but is reasonably around 10-15%, varying according to cancer type and the diagnostic tools used (Linden et al. 2012;Smith 2015;Krebber et al. 2014), which is roughly three to four times the rate observed in the general population (Horwath et al. 2002;Kasyanov et al. 2025). However, this prevalence is lower than that observed in conditions such as myocardial infarction, in which up to one in three individuals experiences depression (Wium-Andersen et al. 2020;Ogunmoroti et al. 2022;Bobo et al. 2020), or diabetes, where approximately one in five individuals is affected (Zhao et al. 2019;Meng et al. 2018;Alzoubi et al. 2018;Beran et al. 2022).Research on cancer stage as a predictor of depression has produced contradictory findings. Some studies report an association between depression and advanced or terminal stages of cancer (Meyer et al. 2015); however, systematic reviews indicate that although advanced or metastatic disease often correlates with a higher burden of depressive symptoms, the effect is modest as a direct determinant and less consistent than psychological or social variables, such as a history of previous depressive episodes or the presence of concurrent stressors (Riedl et al. 2022;Grassi et al. 2023;Rodríguez-González et al. 2023). Observational studies and meta-analyses suggest that depressive symptoms are more frequent during active treatment phases, but findings are heterogeneous and frequently confounded by multiple factors (Riedl Singer et al. 2010).Based on the current literature, chemotherapy agents and oncological drugs can be broadly classified into high-and moderate-risk categories with respect to depressive disorders. High-risk agents include interferon-α, for which the strongest evidence regarding depression risk derives mainly from non-oncological studies (Machado et al. 2017;Ehret et al. 2014), and corticosteroids used in combination therapies, which are associated with an increased risk of mania and mixed states during treatment and depressive episodes following discontinuation (Faggiano et al. 2022;Vardy et al. 2022;Konig et al. 2024). Agents considered to carry a moderate risk include platinumbased compounds (Vaishnav Qazi et al. 2024), andmethotrexate (Van Lint et al. 2022).The apparently lower frequency of the association between cancer and depression compared to what is observed in other chronic diseases does not diminish the importance of comorbidity; rather, the specificity of the depression/cancer relationship becomes evident when the connection between cancer and quality of life is analyzed. A study by our group measured the impact of cancer on quality of life in a consecutive sample of 150 individuals with solid tumors and compared it with the impact of other chronic diseases on quality of life in standardized case-controls studies (Aviles Gonzales et al. 2021). The research surprisingly revealed that not only is the impact of solid tumors on quality of life no greater than that of other chronic diseases, but also that diseases with a less fatal outcome, such as multiple sclerosis (Carta et al 2012) and even fibromyalgia (Carta et al 2018), compromise quality of life on average more than solid tumors. The impact was calculated as the difference in the score obtained on the SF-12 scale by individuals with the condition in question, compared to a sample of the same age and sex drawn from the database of an epidemiological study on the well-being of the general Italian population (Carta et al. 2014). Therefore, all the studies cited by Aviles Gonzales et al. (2021) were conducted using a case-control design with controls matched by sex and age to cases, drawn each time from the same database (Aviles Gonzales et al. 2021). Obviously, some solid tumors have a greater impact than others. In the cited study, the sample comes consecutively from the two regional reference centers in Sardinia, so the proportion of the different tumors is approximately the same as that present in the community.The relatively low impact (compared to other diseases) of cancer on quality of life might be explained by the fact that, today, suffering from an oncological condition is probably less stigmatizing than it was a few decades ago (Xu et al 2025;Ernst et al 2017;Zamanian et al 2022), and that treatments and prognosis have improved, including for symptoms such as pain and/or functional disability (Shrestha et al 2019: Poço Gonçalves et al 2021;Ehrhardt et al 2023). We are increasingly hearing entrepreneurs, politicians, and ordinary citizens speak openly in the media about their experiences after a cancer diagnosis, whereas only a few years ago this was kept secret. Difficulties persist for those who experience ongoing symptoms or live in sociocultural contexts in which stigma is still present. But, paradoxically, despite the relatively high prevalence, one of the greatest challenges concerns depressive disorder. In fact, the same study that highlighted the relatively low impact of cancer on the quality of life of those affected (Aviles Gonzales et al. 2021) also calculated how the onset of a depressive episode can further reduce the quality of life in people with cancer, and how this compares with other chronic diseases. In other words, we measured the difference in the SF-12 score between those who have cancer or another chronic illness without depression and those who have the same illness but also present depression. It emerges that, in the case of solid tumors, comorbidity with depression reduces quality of life by an average of 10 SF-12 points, which is about three times more than what is observed in other chronic conditions. In cancer, even if the frequency of depression is not very high, when depression is present as a comorbidity, the impact is devastating. The interest of the study by Aviles-Gonzales and colleagues lies in the fact that the comparison between cancer and other chronic diseases was conducted using the same methodology and a shared database derived from a national community survey, allowing the generation of age-and sex-matched control groups for each condition. More broadly, however, the negative impact of depression on cancer outcomes and quality of life is well established in the international literature (Caruso et al. 2017;Geue et al. 2018;Yen et al. 2022;Akechi et al. 2022;Ohi 2023;Osmani et al. 2023).Living with cancer requires maintaining a delicate balance that hinges, on one hand, on renewed hope for survival made possible by improved treatments, and, on the other, on the acceptance of life's end as a real possibility, albeit one moderated by therapeutic advances and hope. The onset of a depressive episode can profoundly disrupt this balance, often more severely than in other medical conditions. The combined effects of pain, functional impairment, and stigma, worsened by depression, may lead to a significant loss of hope. In such circumstances, the end of life may appear as inevitable and catastrophic, while the prospect of survival may be perceived instead as a source of anxiety, associated with fears of disability and external dependency.The dramatic impact of depressive disorders on quality of life raises significant questions for both research and clinical practice.1) Is the impact of depressive comorbidity so substantial that it may lead to a worsening of disease progression and even premature death? 2) What mechanisms can be investigated? 3) Is there a bidirectional relationship, namely, can depression increase the risk of cancer? 4) Can depression prevention and early intervention improve outcomes?We will attempt to propose some answers based on current knowledge. Even in cancer, depression is associated with disease worsening and increased risk of death. A landmark meta-analysis unequivocally revealed, across a large sample of studies, that a diagnosis of depression is linked to a higher mortality rate. This holds true whether depression emerges before or after the cancer diagnosis (Pinquart however, when mortality not directly related to cancer is also included (for instance, suicide), the risk exceeds 2 (Ko et al 2019;Sancassiani et al 2023;Lan et al 2024;Li et al 2025).Robust evidence found the consequences that depression can exert during the progression of cancer, and how these consequences may serve as mediating factors leading to premature death. For the sake of simplicity, we distinguish between psychosocial and behavioral consequences on the one hand, and biological, somatic consequences on the other; from a psychosomatic perspective, this distinction is artificial, yet we adopt it for clarity.Among the former, it has been demonstrated that depression leads to poor adherence to treatment (Mausbach et al 2015;Sancassiani et al 2023;de Souza et al 2014;Chabrier et al 2013). Depression also reduces energy and motivation, which may result in malnutrition, a sedentary lifestyle, and consequently a general weakening of the organism (Li et al 2025;Yao et al 2025;Jin et al 2025). Individuals with depressive disorders may increase their consumption of alcohol, tobacco, or other risky behaviors (Duffy et al 2006;McCarter et al 2018;Trudel-Fitzgerald et al 2022). The loss of social support can further worsen psychological well-being and disease management (Hermann et al 2024;Wondimagegnehu et al 2019;Marzorati et al 2025).Among so-called somatic consequences, the most significant of which are: As can be seen, rather than a clear distinction between psychosocial and somatic consequences, it would be more accurate to speak of two different perspectives from which to observe the same psychosomatic impact.The themes of death and depression suggest a psychosomatic perspective that does not exclude a spiritual dimension. It is therefore legitimate to ask whether death wish associated with depression might develop in parallel with the mechanisms responsible for regulating tumor cells. While this question may be relevant from a spiritual standpoint, it also opens the possibility of exploring pathogenic processes. Consequently, one might ask whether, in the absence of an initial tumor, depression, through its physiological effects and the accompanying death wish, could facilitate the onset of cancer. This remains a hypothesis, but it may offer a fruitful direction for both clinical and theoretical investigation.It's now widely understood that even people suffering from depression (initially without cancer) are also at increased risk of developing cancer (Oerlemans et The association between depression and lung cancer weakens after adjusting the data for factors such as tobacco use, suggesting that lifestyle (influenced by depression) may play an important mediating role. In this case, it can be stated that the increase in smoking associated with depression is the main cause of the higher incidence of lung cancer among individuals with depression (van Tuijl et al., 2023). This same model could be useful to explain the depression-cancer association in other organs / anatomical sites. For example, in the Emilia Romagna cohort (Grassi et al., 2021), an elevated risk was also observed for stomach and pancreatic cancer. It would be interesting to investigate whether alcohol consumption plays a similar role in these tumors.Regarding the second model, an example can be drawn from the fact that mood disorders (Paksarian et al 2020; and stabilizing neurosteroids (progestins and their derivatives), in favor of the former (Russart and Nelson 2018;Hardoy et al 2006). Other research findings suggest that a genetic predisposition to mood disorders may be associated with a genetic risk for breast cancer (Ren et al 2022). These data do not challenge the hypotheses concerning the impact of light pollution on both conditions (it is perhaps a sensitivity to rhythm dysregulation that is inherited). However, the underlying biological mechanisms deserve further investigation.Dorsal raphe neurons, which produce serotonin, display rhythmic electrical activity linked to the sleep-wake cycle (Urbain et al 2006;Kocsis et al 2006). Serotonin is a wakefulness-associated neurotransmitter and promotes cell proliferation. This has also been demonstrated in normal, noncancerous cells (such as epithelial, intestinal, and stam cells) (Sha et al 2021; Benninghoff et al 2012).Serotonin may exert a pro-oncogenic role in various types of cancer (Sarrouilhe et al 2015). Some examples include Serotonin stimulates the proliferation of breast cancer cells, which in turn can also produce serotonin themselves (Jayachandran et al 2023;Gwynne et al 2021); Serotonin enhances prostate cancer cell proliferation through the 5-HT1A or 5-HT2B receptors (Siddiqui et al 2006).Intestinal serotonin (produced by enterochromaffin cells) has been linked to colon cancer cell proliferation (Yu et al 2023). A role for the stress response has also been hypothesized along of a brain-gut axis (Di et al 2019;Chen et al 2024).Given these premises, it is legitimate to ask whether serotonergic antidepressants may represent a risk factor. Considering all cancer types as a whole, current data suggest that the use of serotonergic medications is not associated with a significant increase in cancer risk, although the available studies are not methodologically robust (Ma et al 2025;Liu et al 2020;Chen et al 2020). However, when specifically addressing breast cancer, serious concerns arise. A study involving 23,669 breast cancer patients found that SSRI users had higher breast cancer-specific mortality (HR = 1.27; 95% CI 1.16-1.40), which was even higher among long-term SSRI users (HR = 1.54; 95% CI 1.03-2.29). In this case as well, the co-occurrence of depression, although accounted for in the statistical analysis, still leaves room for interpretative ambiguity (Busby et al 2018).The data presented highlight the importance of psychosocial interventions in preventing the development of depression. A study conducted by our group found that strong psychological and spiritual support, as well as a supportive network of friends, were associated with optimal adherence to cancer treatments and better clinical outcomes (Sancassiani et al 2023). Psychosocial interventions and a good social networks are also protective factors against the onset of depressive episodes (Buntrock et al. 2024;Gariépy et al 2016). When antidepressant use was necessary, research on noncancer depression, showed that psychosocial interventions were associated with lower dosages and shorter treatment durations (Breedvelt et al 2021;Breedvelt, Warren et al 2021). Therefore, support, even from a single person with whom to share fears and concerns, can play a crucial role, in fact consistent with research on perceived social support in oncology, the perceived availability of at least one emotionally available significant other with whom patients can openly share their fears and concerns functions as an important protective factor against depressive symptoms in people living with cancer (Ng et al., 2015;Naseri Zamanian et al., 2021). Even the simple possibility of sharing the fear of death can be a protective factor for both the person suffering from cancer and the caregiver (An et al 2020;Haaksman et al 2024).This concept has also been elegantly expressed through art. In Giovan Battista Caracciolo's renowned painting Christ in the Garden of Gethsemane (https://www.meisterdrucke.ie/fine-art-prints/Giovanni-Battista-Caracciolo/1014752/Christ-on-the-Mount-of-Olives.html), "Battistello" portrays the precise moment in which Christ experiences anguish and fear in the face of imminent death, while simultaneously receiving consolation from an angel. As the Gospel of Luke states: "Then an angel appeared to him from heaven and strengthened him" (Luke 22:43). The painting thus conveys two essential elements: on the one hand, the fear of death, restored to its profoundly human dimension; on the other, the presence of someone, the angel, who consoles, shares that fear, and thereby makes it possible to accept it.To prevent a person with cancer from being aware of the possibility of death, and to deny them dialogue and the sharing of fears, can exacerbate the fear of death as an burden that be rather than anxiety, of improved treatments, and the possibility of death to a This that, even in the of cancer, the possibility of death not be or as that the to one does the and in the face of of of death in has the of and According to in the death has a In death is as a social and to that control life in to death as a and shared a as As a death is and becomes a moment rather than an or spiritual one that in death is perceived as an that be no it is to a often on and the et that, within the of death anxiety, which into an with and now perceived as with of the possibility of death in cancer dialogue about may the fear of death as a that be rather than as a social fact, yet as an essential of and from fear one may lies at the of our and When the life of the the with death For the with a and spiritual life was a for in within life is understood as a for the et al or such as the of death as a for the of or as a of when it is no possible to live an of yet it also a for social demonstrated within the of was associated with an increased risk of depression among of the in this how the of death can be an essential moment in the of (Carta et al the media that death as an and a social well as the social importance of death and this has not yet in our The experience of cancer can be with hope to the of but it also requires that can to not only the fear of possible death is by but also of the social of the consistent with our who have this experience or can more be a of reference for those who are through A with from this perspective of depressive episodes is be to of stress and to dysregulation of social the of the sleep-wake cycle may serve as an early accurate to patients and their is A crucial is also the of and the of often individuals are on their to clinical and other support plays a significant role. including may be not for individuals who or a social It may be to have with to or spiritual it is to these a depressive episode is it is important to in that of are not be when however, the most medications be and, treatment not be with to For this or other interventions that may the of treatment are It be in that depression is a disorder and therefore requires therapeutic not to treatment interventions have also been and to be in et al. et al. et al. et al. 2024).This has considered treatment and prevention of the disease as a social both in of the importance of the as a of and a for and as a social for This does not deny the of disease in a does it this with an of the role of and but rather, it into
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