Suicide and cancer: Where do we go from here?

2.1. Search limits 

To clarify the state of the art on the topic of suicide in cancer patients, we conducted a detailed search of the published medical literature with a review of the Medline (PubMed) databases. Articles were included in the review based on the following criteria: (1) publication between January 1980 and March 2009; (2) subjects older than 18 years (adults); and (3) specific focus on cancer patients. Exclusion criteria were the following: (1) articles not written in English; and (2) articles with a primary focus on euthanasia or physician-assisted suicide, because of the particular legal and social constraints. Conversely, we chose to include papers focused on suicidal ideation and desire for hastened death in cancer patients, because these topics are inherent to suicidal intent [3].

For our purposes, we used various combinations of the following keywords: “cancer”, “suicide”, “suicidal ideation”, and “suicidality”.

2.2. Selection process 

A first search was performed to extract records concerning suicide in the general population. This was done to underline complete definitions and characteristics of suicide and to highlight discrepancies and convergences between suicide in the general and in the cancer population.

Another search was performed to identify articles focused specifically on suicide in cancer patients. In this second stage, we selected only papers that strictly adhered to the keywords “cancer” and “suicide”. The criterion of “adherence to the keywords” of a paper was defined as the presence of these two keywords in either the text or the abstract. A paper was considered for inclusion if all of the criteria listed above were fulfilled. We also considered cross-references and review articles reported in the different papers collected. Historically important and conceptually related articles were also included. A paper was considered as “conceptually related” to the issue of suicide in patients with cancer if it contained a source of information (i.e. data, models or hypotheses) on a topic reported in the literature related to the above-mentioned keywords (e.g. depression, hopelessness, pain).

All articles cited in this manuscript were judged by I.S. and G.S. to be relevant and to meet the scientific and conceptual criteria listed.

2.3. Study definitions 

Suicide is a broad term that includes a range of suicidal behaviours and thoughts. Study definitions are listed and described in Box 1.

Study definitions.

	Suicide:
	The intentional taking of one's own life, resulting from a positive act (which directly causes death) or negative act (i.e. the person does not do what is necessary to escape death) [141].
	Suicide attempt:
	Self-injurious behaviour associated with the intent of dying [142].
	Suicidal ideation:
	Thoughts about suicide, which may be as detailed as a formulated plan, without the suicidal act itself [143].
	Desire for hastened death:
	Broad construct underlying requests for assisted suicide, euthanasia and suicidal thoughts [99], [109].
	Parasuicide:
	An apparent attempt at suicide, commonly called “suicidal gesture”, in which the aim is not death (e.g. a sublethal drug overdose) [144].

4.1. What is the real prevalence and phenomenology of suicidal behaviours in the general population? 

Suicide is a complex phenomenon with ethical, sociological and psychiatric implications. It is a major public health concern worldwide, affecting both developing and industrialised countries and all age groups and social classes. Although suicide is not considered a mental illness, it comprises a set of complex behavioural patterns that lie on a continuum of severity, ranging from parasuicide to completed or attempted suicide, suicidal plans and intermittent thoughts [9]. From a phenomenological point of view, attempted suicide is behaviourally similar to completed suicide because it includes having suicidal intent and doing something that one believes will cause death but does not result in death, typically due to factors beyond the attempter's control [10]. Suicidal ideation is a broad term (see Box 1) that refers to a wide range of thoughts or fantasies about killing oneself which may or not lead to the suicidal act [11]. Thus, suicidal ideation can range from transient and intermittent thoughts about death to more severe rumination and creation of a plan to take one's life. To prevent suicide, understanding these thoughts and behaviours is of utmost importance to mental health practitioners and requires greater knowledge about its epidemiology, aetiology and treatment.

It has been estimated that over one million people worldwide commit suicide every year and 10–20 million people attempt suicide [12]. In Europe alone there are 700,000 suicide attempts a year and approximately 45,000 completed suicides; and suicide is one of the leading causes of death among people under 35 [13]. Furthermore, from 2 to 25% of the general population experiences suicidal ideation. Therefore, suicidal ideation and suicide attempts are pervasive phenomena that are far more common that completed suicide. However, it is difficult to obtain a true estimate of the prevalence of attempted suicide and ideation in the general population because most of these data come from retrospective reports of public health services. Moreover, many suicide attempts remain undocumented, often because they are not severe enough to require medical treatment [9]. Therefore, the lack of systematic recording procedures makes it almost impossible to understand the epidemiology of suicidal attempts so that researchers have to rely on self-report data of suicidal behaviour, which may be subject to a significant reporting bias [14].

4.2. Who is at higher risk of suicide? 

Since preventing suicidal behaviours depends in part on understanding their aetiologies, many epidemiological studies have investigated a range of putative causal or risk factors to develop prevention strategies focused specifically on higher risk groups [15]. Despite some inconsistencies, more than 60 different risk factors for suicide have been described [16]. Specific subgroups of the general population appear to be at higher risk of suicide: males, people who are separated, divorced or widowed, or who are unemployed, and people with a history of psychiatric disorders, substance abusers, and, importantly, people with physical illnesses [17].

One of the well-known risk factors for suicidal behaviour is a previous attempt [9], [18]. Studies also consistently report suicidal ideation as another predictor of suicide [19], [20], which emphasizes the need for in-depth studies of suicidal thoughts and their triggers.

In primary care settings, major depression is one of the main risk factors for suicidal ideation [21] along with anxiety disorders and substance abuse [22], [23]. Although researchers have attempted to define risk factors related to suicidal ideation and to predict the development of suicidal behaviour over time, it is still unclear what compels an individual to move from ideation to overt suicidal behaviour. The few existing studies suggest that the more severe and pervasive suicidal ideation is, the more likely the ideation will progress to a suicidal act [24]. However, a retrospective study [25] reported that only 16% of suicide attempters had specific suicidal plans and that the majority of patients (84%) had fleeting, intermittent and transient (although disturbing) thoughts of suicide. Thus, the course and nature of suicidal ideation, as well as the possibility of an effective intervention to prevent suicidal behaviour, must still be clarified. Unfortunately, suicidal ideation is often at risk to be undetected by primary care physicians [26]. This is particularly striking because suicidal ideation is also associated with functional impairment, psychiatric comorbidity, increased health service use and subjective distress in primary care patients [22], [23].

4.3. Are psychiatric disorders necessary and sufficient causes of suicide? 

Although the aetiology of suicide is not fully understood, numerous studies have shown that the presence of a psychiatric disorder is one of the strongest predictors of suicide attempts and suicide deaths [18], [27], [28]. Studies suggest that about 90% of individuals who kill themselves have a diagnosable mental illness [19], [29]. Mood disorders, in particular, are the most consistent and powerful predictors of suicidal behaviour, with evidence that from 49 to 61% of suicide completers had a diagnosis of major depression [9], [19], [30]. Also, the presence of comorbid disorders is associated with a higher risk of suicide attempts [31].

Although mood disorders are a well-known risk factor for completed and attempted suicide, they might not be sufficient to discriminate attempters from non-attempters. Indeed, recent epidemiological studies suggest that depression predicts the onset of suicidal ideation but has lower predictive power in detecting suicide attempts [32], [33]. It can be speculated that acting out a suicidal behaviour requires additional precipitating events or conditions, such as contingent and overwhelming stressors. Also, genetic and environmental factors may play a key role. Indeed, family and genetic studies suggest that the co-occurrence of suicidal ideation among family members might be explained by the presence of mental disorders. On the contrary, the tendency to act is more likely to be the result of a genetic component (“diathesis” or vulnerability), which is thought to be related to the presence of impulsive-aggressive traits [34], [35]. Consistently with this hypothesis, mental disorders characterized by anxiety/agitation (e.g. post-traumatic stress disorder) and poor impulse control (e.g. bipolar disorder, substance abuse disorder) are the strongest predictors of committing suicide versus ideation [31]. However, it is possible that the association between suicidal behaviour and these psychiatric disorders is mediated by depression [31].

Considering this evidence, it appears that a psychiatric disorder is not a sufficient cause but is highly predictive of suicide. Also, given the high comorbidity among mental disorders, it still has to be clarified which mental disorders are uniquely predictive of suicide and which aspects of suicidal behaviour can be predicted [31].

4.4. Why do people commit suicide? The role of depression and cognition 

In the literature on the general population, suicide appears to be a multidetermined event. Indeed, despite increasing awareness of its prevalence, the question “why do people commit suicide?” still remains unanswered. Suicide is commonly thought to be the final effect of particularly traumatic or distressing events and/or to indicate that a person has a severe psychiatric disease. The “escape model of suicide” [31], [36] argues that people commit suicide in an effort to escape intolerable distress. Furthermore, according to Baumeister's [37] “self-awareness model”, suicide is the result of the desire to alleviate aversive self-awareness and the related self-blame that stems from unfavourable comparisons with others. Thus, suicide attempts may result from the escalation of efforts to lessen painful self-awareness. By matching the two models, it can be hypothesized that people commit suicide to escape internal and/or external stressors, and the more conscious the person is of these, the greater the risk of suicide. Furthermore, as self-criticism and self-blame are two depressive symptoms (see Table 1), these theories may help explain the link between depression and suicide. If upcoming research will confirm our hypothesis, depression will be recognized as the factor linking self-awareness and suicide.

Table 1. Depressive symptoms for depressive disorders diagnoses according to DSM-IV-TR.

	Symptoms	Description
	Depressed mooda,b	Significant unpleasant mood with feelings of sadness or emptiness and/or appearance of tearfulness
	Anhedoniaa	Significantly reduced level of interest or pleasure in most or all activities
	Appetitea,b or weight changea	Substantial increase or decrease in appetite nearly every day or unintentional weight loss or gain (e.g. 5% or more change of weight in a month when not dieting)
	Sleep disturbancea,b	Difficulty falling or staying asleep (insomnia) or sleeping more than usual (hypersomnia)
	Increased or decreased psychomotor activitya	Behaviour that is agitated or slowed down. Others should be able to observe this
	Decreased energya,b	Feeling fatigued, or having less energy
	Guilt feelings or feelings of worthlessnessa	Feelings or thoughts of worthlessness or excessive guilt (not about being ill)
	Decreased concentrationa,b	Diminished ability to think, concentrate or make decisions
	Suicidal ideationa	Frequent thoughts of death or suicide (with or without a specific plan), or suicidal attempt or suicidal acts
	Low self-esteemb	Feelings of being uninteresting or incapable
	Hopelessnessb	Feelings of discouragement and pessimism, i.e., no hope for the future

DSM-IV-TR: Diagnostic and statistical manual of mental disorders, 4th ed. [text revised] [145].

a Major and minor depressive disorder symptom. b Dysthymic disorder symptom.

Research also consistently suggests that cognitive symptoms of depression must be taken into account as factors contributing to suicide [38]. Some cognitive styles are related to depression and might increase vulnerability to suicidality [39]. In particular, internal negative attributional style [40], hopelessness [41] and rumination [42] have been found to be the main cognitive predictors for suicidal risk. An internal negative attributional style is the tendency to attribute negative outcomes to the self [43]; these may overlap and explain the tendency toward self-blame. Rumination is defined as an inflexible and perseverative cognitive style characterized by repetitive focus on the causes, meanings and consequences of one's depressed mood [42]. It may predict suicidal ideation because it interferes with effective problem solving [44] and emotional regulation [39]. Also, repetitive and ruminative thinking may increase suicidal ideation because it focuses the individual's attention on painful symptoms of depression [39].

Among these cognitive styles, hopelessness has the clearest relationship with suicidal behaviour. Although it partially overlaps with depression, studies have shown that hopelessness or helplessness is an independent risk factor for the development of suicidal behaviour [45], [46], [47]. According to the diathesis-stress-hopelessness model, hopelessness is the reaction of individuals with poor problem-solving ability when faced with life stressors [48]. Furthermore, suicidal ideation is considered an extreme of the hopelessness dimension, and some formulations of this model have suggested that problem-solving ability may have a mediating role in the development of suicidal ideation from hopelessness [47], [49]. On the other hand, the role of depression was pointed out by animal studies which reported that in rats hopelessness subsequent to chronic and severe distress was prevented by treatment with antidepressant drugs [50].

Overall, the role of cognition in suicide is not fully understood and studies on the topic are sparse [51]. The cognitive risk factors described above appear to be related to deficits in managing negative life events and emotional distress. In particular, the importance of problem solving ability in the development and prediction of hopelessness and depression has been pointed out [47], [48]. This leads to the issue of the role of distress as a risk factor for suicide in people with physical illnesses.

4.5. What is the role of physical illness in determining suicidal risk? 

As mentioned before, physical illness is one of the most consistent risk factors for suicide [52]. Indeed, chronic illness has been identified as the motivating factor in approximately 25% of all suicides [53], and the percentage may rise with age [54]. Some forms of physical illness are per se associated with increased rates of suicidal ideation [26], [54], [55]. This association can likely be explained by considering that pain and physical suffering, as well as the prospective of a limited lifestyle due to the physical illness, lead to thoughts that life is not worth living [26]. Indeed, a life-threatening illness has widespread ramifications, which affect the individual's physical, emotional, social and spiritual well-being. Consistently with Baumeister's model, for some patients living with such an illness may increase their awareness that their lives are lacking in meaning and purpose, leading to a sense of demoralization and despair [56]. Finally, consistently with models that consider diathesis-stress or vulnerability to suicide, research has confirmed the association between suicide and physical and emotional distress in patients with medical illnesses, showing that the risk of suicide increases when a patient has a physical illness, especially if it is comorbid with depression [5].

Thus, physical illness seems to play a key role in suicidal risk due to increased vulnerability to physical and psychological stressors. Therefore, patients with a chronic and devastating illness, such as cancer, may be particularly at risk for suicide.

5.1. Prevalence of cancer suicide 

Cancer is a devastating illness with substantial physical and psychological distress and increased risk of suicide [4], [57], [58], [59]. Several studies across different countries have demonstrated that cancer is a risk factor for suicide [60], [61], [62]. In particular, cancer is associated with an increased rate of suicidal acts [4], [63], [64], [65], [66], [67], [68], [69], [70], suicidal attempts [71], [72] and suicidal ideation [5], [11], [72]. As for suicidal acts, with respect to the general population cancer patients show an increased risk of between 1.3 and 2.6 [4], [64], [65], [66], [67], [69], [71], [73], [74], [75]. However, the real occurrence of suicide in cancer patients is considered to be underreported because of methodological issues regarding the validity of suicide statistics [65]. Epidemiological studies on suicide or suicidal ideation in cancer patients are summarized in Table 2.

Table 2. Epidemiology of suicide or suicidal ideation in cancer patients.

	Authors	Reference number	Sample	Period	Methods	Risk of suicide	Main findings
	Bjorkenstam et al. (2005)	[4]	1,031,919 European (Sweden) cancer patients	From 1965 to 1999	Register-based retrospective cohort study	Increased	Cancer patients showed higher risk of committing suicide than general population.
	Miller et al. (2008)	[60]	1408 Americans aged 65 or older enrolled in a pharmaceutical insurance program	From 1994 to 2002	Population-based study	Increased	The suicidal risk in the elderly was significantly higher among patients with cancer than other medical illnesses.
	Misono et al. (2008)	[61]	3,594,750 American cancer patients	From 1973 to 2002	Retrospective cohort study	Increased	Patients with cancer had nearly twice the incidence of suicide as the general population.
	Muff Christensen et al. (2006)	[62]	European (Denmark) patients with a diagnosis of non-melanoma skin cancer	From 1971 to 1999	Retrospective cohort study	Increased	More cancer suicides than in the general population were found among women, not men.
	Allebeck et al. (1989)	[63]	424,217 European (Sweden) cancer patients	From 1962 to1979	Register-based retrospective cohort study	Increased	Suicide rate increased among cancer patients.
	Tanaka et al. (1999)	[64]	23,979 Asian (Japan) cancer outpatients	From 1978 to 1994.	Observational follow-up study	Increased	Suicide risk increased significantly within the first 5 years following cancer diagnosis and decreased after 5 years. The highest suicide mortality was observed between the third and fifth months after cancer diagnosis.
	Hem et al. (2004)	[65]	490,245 European (Norway) cancer patients	From 1960 to 1999	Register-based retrospective cohort study	Increased	589 suicides were observed. Risk was highest in the first months after diagnosis. There was a significant decrease in the suicide risk over decades.
	Crocetti et al. (1998)	[66]	27,123 European (Italy) cancer patients	From 1985 to 1989	Register-based retrospective cohort study	Increased	Cancer patients showed a higher suicidal risk than the general population in the first 6 months after diagnosis.
	Levi et al. (1991)	[67]	24,166 European (Switzerland) cancer patients	From 1976 to 1987	Register-based retrospective cohort study	Increased	The risk of suicide was high during the first year after the cancer diagnosis and decreased over 5 years from the diagnosis.
	Innos et al. (2003)	[68]	65,419 European (Estonia) cancer patients	From 1983 to 2000	Register-based retrospective cohort study	Increased	An increased suicide risk was found in men, especially 3–6 months after the diagnosis.
	Yousaf et al. (2005)	[69]	564,508 European (Denmark) cancer patients	From 1971 to 1999	Observational follow-up study	Increased	1,241 deaths due to cancer suicide were observed. The suicide risk was highest in the first 3 months for men and between months 3 and 12 for women.
	Schairer et al. (2006)	[70]	723,810 American (USA) breast cancer	From 1953 to 2002	Register-based retrospective cohort study	Increased	836 breast cancer patients committed suicide. Risk was elevated throughout follow-up, including for 25 or more years after diagnosis.
	Allebeck and Bolund (1991)	[71]	59,845 European (Sweden) patients	From 1975 to 1985	Observational follow-up study	Increased	Cancer patients showed more than twofold excess mortality from suicide and a moderately increased rate of suicide attempts.
	Druss and Pincus (2000)	[72]	7589 American (USA) adults in the general population	From 1988 to1994	National survey	Increased	Cancer was associated with a more than fourfold increase in the likelihood of a suicide attempt.
	Miccinesi et al. (2004)	[73]	90,197 European (Italy) cancer patients	From 1985 to1999	Register-based retrospective cohort study	Decreased	A decreasing suicide rate was observed in the follow-up period.
	Storm et al. (1992)	[74]	296,331 European (Denmark) cancer patients	From 1971 to 1986	Register-based retrospective cohort study	Increased	Higher suicide risk was observed in both sexes.
	Fox et al. (1982)	[75]	144,530 American (USA) cancer patients	From 1940 to 1973	Register-based retrospective cohort study	Increased	Suicide risk was higher in cancer patients than in the general population, especially soon after diagnosis but only among men.
	Kondrichin and Lester (2001)	[77]	General population; individuals from the WHO statistics annual in 37 European nations	1990	Ecological study	Increased	A positive association between cancer mortality and suicide was found across the 37 European nations studied.
	Kendal (2007)	[78]	1.3 million American cancer patients	From 1973 to 2001	Register-based retrospective cohort study	Increased	The suicide rate was higher in patients with head and neck cancer or myeloma, advanced illness, little social support, and limited treatment options.
	Dormer et al. (2008)	[80]	121,533 Australian cancer patients	From 1981 to 2002	Register-based retrospective cohort study	Increased	Higher suicide risk was observed 3 months after diagnosis. A second peak occurred 12–14 months after diagnosis.
	Rasic et al. (2008)	[100]	36,984 American (Canada) individuals from the general population;. 863 patients were diagnosed with cancer	From 2001 to 2002	Register-based retrospective cohort study	Increased	Cancer was associated with suicidal ideation in the 55–74-year-old age group, but this relationship was found to be mediated by psychiatric disorders and social support.

Clinical and sociodemographic risk factors for suicide have been identified in cancer patients. These include gender, age, clinical stages, cancer sites, time since diagnosis, occurrence of pain and depression [65], [66].

5.2. Risk factors of suicide in oncological patients 

Studies on cancer patients have consistently found that male cancer patients commit suicide more often than females [65], [76], [77]. In fact, it seems that the highest-risk patient is male, with head and neck cancer, advanced disease, little social or cultural support, and limited treatment options [78]. Another factor associated with increased suicide risk in cancer patients is aggression and the disruption of the therapeutic alliance with the medical staff. In fact, the sudden development of hostility toward doctors or nurses may be a sign of impending suicide [79]. As aggression and alcoholism are more common in males than in females, this might partially explain the higher suicidal rates in male patients.

Another consistent finding is that patients with non-localized disease at diagnosis are at higher suicidal risk than patients with localized cancer [67], [74]. As for age, several studies have described little, but significant, variation in the suicide rate across age groups [4], [66], [71], [75], [80], with a peak for people aged 40–46 and over 60 [80]. Notably, a population-based retrospective study of men aged 65 years and older in South Florida [81] showed that 20% of all suicides were cancer-related and that the risk of committing suicide was fourfold higher in men with prostate cancer in this sample, possibly because of issues about sexuality, sense of maleness and self-esteem, with deleterious consequences on mood. Some clinical correlates of suicide were also identified, such as comorbid anxiety symptoms, depressive symptoms, pain related to cancer and marital status.

Variations in suicidal rates according to type of cancer have also been reported [4]. As aforementioned, suicidal rates are higher in patients with head and neck cancer as well as cancer of the larynx and tongue, upper digestive tract, pancreas and lungs [68], probably because these types of cancer cause difficulties in vital functions, like breathing and eating, and are associated with severe pain and substantial physical and social impairments. Thus, it has been argued that physical and social impairments caused by specific cancers, rather than by a cancer diagnosis per se, are triggers of suicide [71]. Also, aspects such as survivorship, impact on quality of life and pain vary according to the type of cancer. For instance, cancers with a lower than 5-year survival rate are associated with a higher suicide rate [4].

Notably, the time after diagnosis is often associated with increased risk of cancer suicide, which is higher in the first year after diagnosis, especially in the first 3–5 months [64], [69], [82], and declines thereafter [74]. However, for some cancer sites there is also evidence of increased long-term suicide risk many years after diagnosis [70]; thus, the suicidal risk may be present even many years after the diagnosis.

As the highest suicide rates are reported in the first 3 months following diagnosis, this appears to be a critical window of opportunity for treatment strategies. A recent retrospective cohort study in cancer patients in Australia [80] found a suicide peak in the first month after diagnosis, a second but smaller peak at 12–14 months (possibly due to recurrence of disease, occurrence of metastases, or failure of treatment), and a higher suicide rate in patients with poorer prognosis. This can probably be explained by considering that patients who receive a diagnosis of cancer are forced to face a life-threatening experience, leading to painful emotional reactions [80]. Specifically, the periods after the diagnosis and following discharge from the hospital appear to be at highest risk of suicide [83] because of the emotional impact and the difficult psychological adjustment outside the support of the hospital environment [64], [73]. Consistently, patients who committed suicide within 1 year after the diagnosis were shown to have rapidly progressing cancer [82]. With these findings in mind, it can be assumed that the prognostic status of cancer at the time of the diagnosis and the impact of recurrence or treatment failure are among the key factors predicting risk of suicide in cancer patients.

Finally, the increased risk of suicide in cancer patients is higher if it is comorbid with a psychiatric disorder [6] and pain [5], [11], [84]. Risk factors for suicide in cancer patients are summarized in Table 3.

Table 3. Risk factors for suicide in cancer patients.

	Risk factors for suicide	Reference number
	Sociodemographic factors
	Middle or older age	[4], [64], [66], [71], [75], [80], [81]
	Gender: male	[65], [76], [77], [78]
	Marital status: single, divorced or widowed	[81]
	Race: black	[70]
	Psychiatric disorders
	Pre-existing psychopathology	[6], [60], [62]
	Depression	[3], [4], [6], [57], [79], [81], [88], [89], [90], [93], [94], [95], [96]
	Anxiety	[81], [100]
	Aggression	[79]
	Family mental disorders or family history of suicide	[5], [57], [91]
	Psychosocial factors
	Poor social support	[64], [57], [73], [78]
	Loss of independence, feeling of being a burden	[6], [79]
	Medical factors
	Pain	[5], [6], [11], [79], [81], [84]
	Advanced disease	[64], [78], [80], [82]
	Poor prognosis	[4], [69], [70], [80]
	Survival rate lower than 5 years	[4]
	Non-localized cancer	[67], [69], [74]
	Short time since diagnosis disclosure	[75]
	1–5 months	[64], [65], [66], [68], [69], [74], [80], [82], [83]
	Within 5 years	[61], [64]
	Physical symptoms	[6], [71], [79]
	Cancer sites (head and neck, gastrointestinal, urogenital)	[4], [61], [68], [74], [78]
	Other factors
	Previous suicide attempt	[5], [57]
	Suicidal thoughts	[11], [57], [97]

5.3. Psychological and psychiatric risk factors of suicide in oncological patients 

The literature on the general population tends to consider suicide as a manifestation of failure to cope with chronic and severe distress. Perhaps more than any other stressor, a serious medical illness like cancer forces the individual to confront severe and unavoidable distress and to deal with issues of mortality [85]. Consistently, the existing “psychological autopsy” studies on cancer patients (i.e. based on interviews with relatives, friends, and next-of-kin of the person who committed suicide) have concluded that several physical and psychological stressors such as pain, physical impairment, depression, loss of independence and loss of autonomy are the main causes of cancer suicides [6], [57].

Thus, cancer suicides tend to be seen as a more rational or justifiable choice in the face of severe psychological and physical stressors and pain [86]. Consequently, one issue is whether cancer suicides differ from other suicides [87]. Studies have consistently reported that the major risk factor in cancer suicides, as well as in those in the general population, is depression [3], [6], [88], which is one of the earliest report in oncological literature [89]. Among the depressive disorders, major depression may be the most important factor in suicidality, as reported in a retrospective survey on 1713 cancer patients who committed suicide in Japan [90]. Thus, depression is a leading cause of suicide in both cancer and non-cancer populations. However, it is well known that cancer patients are at higher risk for depression that the general population [2], [3], [91], not only because of a secondary reaction to the diagnosis but also because of immunological disturbances [92] (see Section 5.5). Thus, depression might be significant in explaining the link between cancer and suicide.

Although depression is associated with suicide in individuals both with and without cancer [6], with no quantitative differences between the two populations [93], suicidality in cancer patients is supposed to be underlain by broader multidimensional factors such as different types of depressive thoughts [90] (see next paragraph). Therefore, an interesting topic for future research in the area of cancer suicides might be the qualitative, rather than the quantitative, differences between people with and without cancer who have depressive disorders.

An alternative explanation is that cancer represents an independent risk factor for suicidality over and above depressive symptoms, as has been argued for other general medical illnesses [72]. Interestingly, studies show that patients with head and neck cancer diagnosed after biopsy investigation had significantly higher depression scores even before receiving the diagnosis [94]. Therefore, putative biological mechanisms, rather than the mere reaction to the cancer diagnosis, may explain increased depression risk [4]. A recent study [95] found that the use of antidepressants reduced the suicide rate in patients with head and neck cancer, particularly in the first 3 months following diagnosis. Therefore, early prophylaxis with antidepressants may be one avenue to prevent suicide. Thus, prevention, recognition and treatment of major depression are particularly crucial in cancer patients, especially in neck and head cancer patients who are at higher risk of suicide.

Actually, in cancer patients vulnerability to suicide appears to be linked to multiple risk factors, many of which are linked to depression [79], [96]. Targeting mood disorders represents an optimal area for further research, because it is amenable to preventive interventions. In fact, the literature on depression suggests that also in cancer patients pharmacotherapeutic and psychotherapeutic interventions are effective in ameliorating psychopathological outcomes and in providing relapse prevention [92].

5.4. Suicidal ideation and desire for hastened death in cancer patients 

One way of preventing suicidal acts in cancer patients is to have a profound awareness of the type of thoughts that lead to a suicide attempt [11], [97]. According to several studies [3], [98], [99], [100], patients with terminal cancer constitute a subgroup that is particularly prone to suicidal ideation. Consistently, a number of studies have reported that suicidal ideation is relatively infrequent in non-terminal cancer patients [5], [101]; indeed, it is present in only about 8% [11]. These data are surprisingly inconsistent with clinician's impressions, because non-terminal cancer patients frequently express suicidal thoughts. In fact, this gap may be due to the methods used to collect the subjective reports [5]. For instance, the different and personal meanings underlying suicidal ideas may not be considered [5], [102]. One of the most frequent concerns leading to suicidal thoughts is that of losing autonomy and becoming a burden to the family [79], [103]. Also, it must be considered that poor physical functioning and hopelessness are strongly associated with suicidal ideation in cancer patients [3].

Furthermore, it has been argued that the intention to commit suicide in cancer patients may be manifested as treatment refusal [5]. Indeed, among the possible explanations to non-compliance with treatment, suicidal intention should be considered in patients who express the desire for hastened death. Unfortunately, the literature on suicidal ideation in cancer patients often mixes suicidal thoughts with the desire for hastened death, and, although the two phenomena appear to overlap, the two constructs may be partially distinct. To the best of our knowledge, no studies have sought to quantify the extent to which desire for hastened death expressed by refusing treatment is a predictor of suicide. Consistently with this hypothesis, desire for hastened death may be associated with depression and hopelessness. Indeed, Breitbart et al. [3] studied 92 terminally ill cancer patients to assess the prevalence of desire for hastened death and to identify its correlates and found that patients with major depression were fourfold more likely to report a desire for hastened death than those who were not depressed, especially if depression was associated with hopelessness. Indeed, nearly two thirds of the patients with both depression and hopelessness had a greater desire for hastened death. However, disentangling the phenomena of depression and hopelessness is particularly difficult in cancer patients with suicidal ideation. Especially in terminally ill patients, confusion may arise between a hopeless prognosis and a hopeless (i.e. pessimistic) cognitive style [3]. On the other hand, hopelessness is a symptom of depression even though they are only moderately associated [3].

These results are in line with other studies that found a strong association between desire for hastened death and major depression in terminally ill cancer patients [104] and a sense of hopelessness or despair [105]. Indeed, there are reports in the literature that desire for hastened death is linked to depression, debilitating progression of the disease, perception of chronic and progressive loss of social support and autonomy, pain [106], shortness of breath and disturbing medical information [107], [108]. In 44 terminal-stage cancer patients, Brown et al. [109] found that all patients who reported desire for a rapid death (i.e. 23% of the sample) were diagnosed with major depression. Another study showed that the desire to hasten death in terminally ill patients was related to depression, high pain ratings and lack of family support [99]. Finally, depression but not pain differentiated patients requesting hastened death and those who did not make such a request [110]. Conversely, a study on 48 patients with metastatic cancer found that somatic symptom burden, more than pain and depression, correlated with desire for a hastened death [111].

Depression is associated with suicidal ideation in oncological patients as well as in the general population [112], and this link could be mediated by a decline in physical functioning, as demonstrated in cancer patients with major depression [93]. Suicidal ideation is a core symptom of major depression, and the two are highly correlated [113]. Nevertheless, many individuals with suicidal ideation also have subthreshold depressive syndromes [72]. Although these are very frequent in cancer patients, they are often underdiagnosed and untreated [92]. Indeed, the use of categorical diagnoses of depressive syndromes in cancer patients may make it impossible to identify a wide range of subsyndromal depressive syndromes and to predict suicidal ideation and behaviour [72].

Furthermore, depressive symptoms may fluctuate widely at the time of disclosure of the cancer diagnosis and before treatment [88]. To investigate this issue, longitudinal studies are needed. Akechi et al.’s [88] longitudinal study of patients with advanced unresectable lung carcinoma showed that depressive disorders which developed during the course of the illness predicted suicidal ideation, whereas depressive disorders already existing at baseline did not. Overall, these data suggest that depression may predict suicidal ideation/desire for hastened death. Risk factors of suicidal ideation in cancer patients are summarized in Table 4.

Table 4. Risk factors for suicidal ideation in cancer patients.

	Risk factors for suicidal ideation	Reference number
	Depression	[3], [11], [88], [99], [107], [108], [110], [112]
	Hopelessness	[3], [111]
	Poor social support	[99]
	Sense of loss of autonomy, feeling of being a burden	[79], [103], [104]
	Pain	[11], [99], [104]
	Advanced disease	[104]
	Fearful medical information	[105], [106]
	Physical symptoms	[3], [105], [106], [109]

5.5. Neurobiology of suicidality in cancer patients: toward a better understanding of the mechanisms involved in cancer suicides 

Neurobiological studies on suicide suggest that suicidal intent and suicidal act are strongly and positively correlated because both are related to biological abnormalities involving the serotoninergic system [114]. Studies on the general population corroborate the hypothesis of a diathesis or predisposition to suicidal behaviour [115], [116]. However, although studies do not universally agree [115], suicide seems to be associated with hyperactivity of the HPA axis, which can predict suicide in depressed patients [117]. Thus, a physical illness that affects the immunological system, like cancer, might trigger both depression and suicidal ideation and thus explain the higher risk of suicide in oncological patients. Indeed, immune dysregulations have been described in cancer, where a persistent humoral immune response exacerbates activation of the innate immune response and inflammatory pathways, which concur in promoting the development of cancer [118], [119]. Since chronic inflammation, in particular the release of pro-inflammatory cytokines, is strongly associated with processes that contribute to the onset and progression of cancer, the association between depression and cancer seems to directly involve immune dysregulation and pro-inflammatory cytokine up-regulation. In fact, the predominant activation of innate immune cells has also been described in depressive disturbances [92]. Two well-known physiological correlates of depression are a decrease in cell-mediated immune functions and alterations in the activity of the HPA axis, which is associated with levels of pro-inflammatory cytokines. From studies on the general population we know that these physiological correlates of depression may affect health status adversely. Thus, although depression can be a secondary manifestation of cancer, from a biological point of view a depressive state may favour the development of cancer, as reported by Reiche et al. [120] in a study on how stress and depression influence the risk and the progression of cancer through neuroendocrine-immune-mediated mechanisms. In particular, depressed subjects show a reduction of both viral and antigen specific measures of cell-mediated immunity [121] and a reduced ability of the T cells to mount an antigen-specific response, such as that necessary to combat viruses, bacteria and tumours [122], [123]. Therefore, depressive symptoms appear to be associated with poor cellular immune functions across several domains. These data have been confirmed also in cancer patients. In women with cancer, severity of depression may reduce the number of leukocytes over short periods of time [124], and depressive symptoms are predictors of both lower white blood cell counts and natural killer cell number [124], [125]. Similarly, cytokine dysregulation has been largely associated with depression [126], [127]; and serum levels of pro-inflammatory cytokines, including IL-1_, TNF-_, IL-6 and IL-18, are all elevated in depressed patients [128], [129], [130]. Indeed, several studies investigating the interactions between immunity and depressive symptoms have suggested that a dysfunction of the innate immune system is a relevant factor contributing to the onset and maintenance of the depressive disorder [131]. The relationship appears to be reciprocal in the sense that immune activation may alter mood and a depressed state may affect immune functioning [132], [133]. In particular, exposure to certain cytokines, such as IL-1, leads to a complex constellation of symptoms similar to those of a depressive state (i.e. anhedonia, decreased sexual/social activity, sleep abnormalities, decreased feeding and motor behaviour, anxiety and diminished intracranial self-stimulation) [132], [133], [134]. In addition, cytokine exposure leads to neuroendocrine changes analogous to those observed in individuals with depression such as increased corticotropin-releasing factor, adrenocorticotropic hormone and corticosterone levels [135], alterations of the monoaminergic system [132] and decreases in the brain-derived neurotrophic factor [136]. Another possible effect of cytokine release is an increase in HPA activity [132], suggesting a cross-sensitization between stress and cytokine production [133]. Moreover, it has been hypothesized that the inflammatory response, together with the stress response, is involved in the survival of the organism and the species. Therefore, immune disturbances, such as a chronic inflammatory state, may affect several aspects of an individual's well being and may be linked to the pathogenesis of several common diseases, including cancer and depression [137]. Cytokines are crucial in inflammatory responses, and a disturbance at the neuroendocrine–immune interface may imply a cytokine network imbalance, leading to an excessive production of pro-inflammatory cytokines. Accordingly, further evidence of the link between depression, cancer and immune dysregulation is that cytokines can be considered reliable biomarkers for depression in cancer, as in the case of IL-6 in which plasma concentrations are significantly increased in depressed patients with cancer [137]; interestingly, pharmacological doses of cytokines in cancer patients have an effect on the maintenance of depression [138]. Thus, there is preliminary evidence for a relationship between depressive symptoms and dysregulation of the immune system in cancer patients. Since both depression and cancer may affect immunity, this link deserves to be further explored in order to understand the phenomenon of suicide in oncological patients. Indeed, more research is needed to clarify the link between immune function and suicide in cancer. Overall, these observations imply that studying the association between cancer and suicide may involve both biological and clinical issues. In this regard, the role of depressive disorders, which play a part in the described pathogenic mechanisms including immune dysregulation, seems to be of particular interest in cancer suicide.