Depresión en pacientes con cancer

Notas del editor

• #3: Depression is among the most common and prevalent psychiatric disorders studied in cancer patients with a prevalence between 15 to 50% (Massie, 2004) . Data accumulated in the last twenty years have specifically investigated the epidemiologic and pathogenesis of depressive disorders in cancer, the role of depression in influencing patients’ quality of life and in the lives of their families and the efficacy of psychiatric and psychosocial interventions (Rodin & Voshart, 1986; Mermelstein & Lesko, 1992; Sellick & Crooks, 1999; Chochinov, 2001). In fact, although it is understandable that a diagnosis of cancer, and related treatments are a source of profound distress and suffering, it is also important to distinguish between “normal” degrees of sadness and depressive disorders for which treatment should be instituted. Several phases during the cancer trajectory can be at risk for clinical depression, such as diagnosis, active treatment and end of treatment as well, recurrence and palliative care.
• #4: Many symptoms of depressive disorders are similar to those of cancer, including loss of appetite, loss of weight, insomnia, loss of interest and cognitive impairment, fatigue, and loss of energy. This makes the diagnosis of depression difficult in cancer patients. Some authors suggest including all of the symptoms in the assessment for depression, irrespective of the fact that these symptoms may be attributable to cancer (inclusive approach). It should be noted that certain symptoms (e.g., appetite-related symptoms and a diminished ability to think) seem to be useful in the diagnosis of depression, while others (e.g., sleep disturbances and fatigue) are not (Akechi et al. 2003). Other researchers have suggested the following approaches in assessing for depression in patients with cancer: replacing somatic symptoms with cognitive-affective items (substitute approach) (Endicott 1984); adding some new affective symptoms to the original criteria (alternative approach) (Von Ammon Cavanaugh 1995); or completely excluding somatic symptoms and using only affective symptoms to make the diagnosis (exclusive approach). An agreement on which method is the most specific has not been reached, although the exclusive approach has been reported to be the most valid and appropriate method of diagnosing major depression in cancer patients (Uchitomi et al. 2001).  
• #5: An important aspect regards the difference between major depression and other forms of depressive syndromes. Among them, demoralisation is considered a specific clinical condition that should be separated from adjustment disorder and major depression and which merits consideration in the spectrum of mood disorders that may occur in medically ill patients (Clarke et al. 2005; Grassi et al. 2007; Mangelli et al. 2005). According to Kissane (Kissane et al. 2001), the core symptoms of a demoralisation syndrome in medically ill patients, including patients with cancer, are presented in the slide and include: 1. affective symptoms of existential distress including hopelessness or loss of meaning and purpose in life; 2. cognitive attitudes of pessimism, helplessness, a sense of being trapped, personal failure, or lacking a worthwhile future; 3. absence of drive or motivation to cope differently; 4. associated features of social alienation or isolation and lack of support; 5. allowing for fluctuation in emotional intensity, these phenomena persist for more than 2 weeks; 6. a major depressive episode or other psychiatric disorder is not present as the primary condition. In oncology, demoralisation has been shown to occur in at least 20% of patients who did not meet the criteria for any DSM-IV diagnosis (Grassi et al. 2005b), indicating the need for more attention to the psychosocial concomitants of cancer.
• #7: Several causes or risk factors of depressive disorders among cancer patients have been pointed out, with an intersection between psychological, social and biological factors (Table 2) (Holland 1992). Such psychological types of risk factors may include: family history of depression; previous episodes of depression; and a tendency to consider stressful life events as uncontrollable (external locus of control). Poor support (e.g. family, friends) and diffuse (e.g. neighborhood, work) interpersonal ties represent possible social risk factors (Grassi et al., 1993; Grassi et al., 1997).
• #8: Among the biological factors, the site of cancer and chemotherapeutic drugs are the most common factors associated with depression. It has been shown that certain sites of cancer may influence depression. Pancreatic cancer has been indicated as a neoplastic disease frequently associated with depression (Boyd & Riba, 2007). At the same time, studies tend to indicate that people affected by depression are at higher risk of developing pancreatic cancer (Carney et al., 2003). Thirty five-forty percent of patients with pancreatic cancer report depressive symptoms (Kelsen et al., 1995). Head and neck, lung and gastrointestinal carcinomas are also associated with a higher risk of depression (Zabora et al., 2001).  Chemotherapeutic agents, such as methotrexate, vincristine, vinblastine, asparaginase, procarbazine, and interferon, have also been associated with depressive symptoms (Adams et al, 1984; Middleboe et al, 1994). Furthermore, the role of pro-inflammatory cytokines such as interleukin-1 (IL-1), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) have been implicated depression and cancer. Cancer patients with major depression have shown to report markedly higher plasma levels of interleukin-6, abnormal dexamethasone suppression test and higher cortisol concentrations than nondepressed patients (Soygur et al., 2007), with both IL-6 and cortisol variations being possible biological markers of depression in cancer patients (Jehn et al., 2006). Lastly, in a study of breast cancer patients Yoshikawa et al., (2006) showed that the left amygdala volumes in the subjects with a first minor and/or major depressive episode were significantly smaller than in those with no history of any depressive episode, suggesting that amygdala volume was associated with a first minor and/or major depressive episode after cancer diagnosis.
• #10: Assessment and treatment of depression among cancer patients is important. Several studies have indicated that depression is associated with maladaptive coping and abnormal illness behaviour, such as a tendency to react excessively in interpersonal relationships (irritability); to adopt a pessimistic attitude about the illness (hopelessness); and to focus attention on physical symptoms interpreting them as a sign of illness (anxious preoccupation) (Grassi et al. 1993; Grassi and Rosti 1996). Depression has been shown to have a negative influence on several dimensions of the patient’s quality of life (Parker et al. 2003). As discussed in more detail in the following sections as well as in Volume II, Chapter 9 “Depressive Disorders and Pain”, depression affects the patient’s perception of pain as well as suicide ideation. Researchers have also esamine biological effects associated with the relationship with breast cancer, for example, seem to have less response to chemotherapy agents (Walker et al. 1999), and some data has indicated a possible, yet not fully understood role, of depression in increasing the risk of recurrence and in reducing survival among breast cancer patients (Hjerl et al. 2003; Watson et al. 1999, 2005). It is possible that effects on adherence to treatment, maintenance of high-risk behaviour, and an hypothesised direct link between immunity and cancer (Reiche et al. 2005; Spiegel and Giese-Davis 2003) explain this relationship, although caution is needed in interpreting the data that are emerging in this area. Finally, depression reverberates within the family, so that both emotional distress and the rate of psychiatric diagnoses (e.g., major depression, general anxiety disorders) are higher among caregivers of cancer patients than in the general population (Couper et al. 2006; Heaven and Maguire 2003). In the case of the patient’s death, the risk of complicated or traumatic grief is higher in families that showed psychosocial disorders andmaladaptive coping before the loss (Kissane et al. 1997, 2003).
• #11: The literature on psychosocial treatment in cancer has increased with data indicating the need for adapting psychotherapy to the specific context of oncology (Bloch and Kissane, 2000) and to create new approaches to deal with the specific issues raised by cancer. With regard to the latter, significant steps have been made in psychosocial intervention in the advanced phases of cancer, where the need is great to maintain dignity and to enhance the spiritual aspects of dying (Breitbart, 2002; Chochinov et al., 2005). Counselling and communication skills are of paramount importance to recognize the conduce correct interview, to recognize the symptoms of depression and to provide help to cancer patients. Several studies have shown that psychological intervention provides a significant improvement of the patients’ quality of life, reduction of emotional symptoms, including depression, and of maladaptive coping styles (e.g. hopelessness and anxious preoccupation) (Sheard and Maguire, 1999). An accurate diagnosis and proper referral for psychological intervention are necessary steps to increase the likelihood of benefit and low drop-out among depressed cancer patients. In fact, psychotherapy (both in individual and group format) show the most effective results among cancer patients with well- defined depressive symptoms, while the effects of the interventions for patients with “normal” psychological distress are scarce or not evident at all (Fawzy, 1995; Coyne et al., 2006 ). Preliminary data on the effect of psychosocial intervention in increasing survival rates of cancer patients (Spiegel et al.1989) have not been confirmed by more recent studies (Goodwin et al., 2001; Kissane et al., 2007; Spiegel et al., 2007) which did not indicate an influence of psychotherapy in improving the patient’s cancer prognosis. As a general recommendation, the combination of psychological intervention and pharmacotherapy tailored according to the patient’s needs, should be considered as the best choice in treating depression in cancer settings. Positive effects in reducing psychiatric disorders, especially depression, has been reported by several authors when applying guidelines where screening, proper diagnosis and psychological and psychopharmacological approaches are available (Sharpe et al., 2004b; Akechi et al., 2007). Similar indications have been given by the recent NCCN guidelines for supportive care - distress management in the area concerning mood disorders (Holland et al., 2007; NCCN, 2008).
• #12: Psychopharmacology in oncology has extensively changed over the last ten years (Schwartz et al., 2002). Older generation antidepressants (ADs), such as tricyclics (TCAs), are less used than in the past, especially for the problematic side-effect profile in this population (dry mouth, constipation, sedation and confusion). A large experience has been accumulating in oncology on the use of more recent ADs, including selective serotonin reuptake inhibitors SSRIs, such as fluoxetine, citalopram, paroxetine and sertraline (Holland et al., 1999; Theobald et al., 2003; Pae et al., 2004; Torta et al., 2008), NRIs, such as reboxetine (Grassi et al., 2004), benzamides, such as amisulpride (Torta et al., 2007). Advantages and disadvantages should be balanced in an individualized way, both paying attention to the patient’s physical condition, the type of depression (agitated/slow), and the side effect profile, by taking advantage of it when appropriate on a case by case basis(e.g. increase of appetite determined by the drug mirtazapine in patients with poor appetite, increased intestinal motility determined by some SSRIs in patients taking opioids). The dual effect on mood and pain of duloxetine represents, among ADs, a new interesting possibility for treating depression in cancer patients. When tolerated, TCAs are useful in lower doses given in shorter intervals, for the treatment of both depressive symptoms and pain (Chaturvedi et al., 1995). Psychostimulants, such as dextroamphetamine, methylphenidate, and pemoline, in low doses have been considered for treating depressive symptoms in terminally ill patients because of the rapid onset of action, and the positive effect on attention, concentration, psychomotor activity, appetite, weakness and fatigue and opioid-induced sedation (Homsi et al., 2000). Recently, modafinil, a memory-improving and mood-brightening drug, has been used to counterbalance fatigue in cancer patients (Carroll et al., 2007) and to treat depression, as a possible alternative to classic psychostimulants, for its low potential abuse, and its relativelys afer side-effect profile (Konuk et al, 2006; Orr & Taylor, 2007). Drug Interactions Relevant to Cancer Patients Both TCAs and newer generation ADs (e.g. fluoxetine, venlafaxine) potentiate the analgesic effects of morphine. Attention should be paid when prescribing SSRIs in patients receiving tramadol, for its serotoninergic action and the risk of a serotoninergic syndrome. Desipramine inhibits morphine and methadone metabolism and may increase the plasma levels of these opioids. Methadone may inhibit the metabolism of desipramine. Propoxyphene can inhibit metabolism of doxepin and other TCAs, resulting in an elevation of serum levels. Antidepressants with anticholinergic side effects may aggravate certain symptoms, such as constipation, dryness of mouth, and confusion related to chemotherapy, narcotics or the advanced phase of illness.   Serious drug interactions may occur between antidepressants and certain chemotherapeutic agents. Fluoxetine may interact with procarbazine, resulting in an MAOI/fluoxetine-like interaction. If fluoxetine is used, there should be a 5-week washout period before starting procarbazine is .Cisplatin and lithium carbonate given together may increase the risk of renal toxicity. Recent reports indicate that some ADs may influence the metabolism of tamoxifen, a selective estrogen receptor modulator which is used in long-term treatment of breast cancer patients. The inhibitory effect on the cytochrome P450 CYP2D6 caused by some ADs, especially paroxetine, can reduce the active metabolite of tamoxifen endoxifen by 38-58%, thus reducing the effect of the drug in breast cancer patients (Jin et al., 2005) Several studies have also accumulated on the efficacy of ADs (e.g. venlafaxine, mirtazapine, paroxetine) in working as adjuvant drugs in the treatment of hot-flashes (De Sloover Koch & Ernts, 2004) and pruritus (Greaves, 2004) among cancer patients, independent of the action on mood.  
• #13: Depression is an important comorbid psychiatric disorder in patients with cancer. The report from the Institute of Medicine of the National Academies, “Cancer Care for the Whole Patient: Meeting Psychosocial Health Needs”, is an important roadmap for addressing the depression and anxiety that frequently develops in patients with cancer (Committee on Psychosocial Services to Cancer Patients/Families in a Community Setting et al. 2007). This Institute of Medicine report provides a blueprint for what should be standard psychosocial care for patients with cancer. It is important for psychiatrists to work with their medical colleagues to develop best practices to be used in screening for and detection of depression and other psychiatric problems in patients being treated in the oncology setting. In addition, evidence-based clinical trials are needed to determine which are the best treatments for depression for patients at all stages of disease and in all types of cancer. As new technologies are developed and more powerful chemotherapeutic and non-chemotherapeutic agents for the treatment of cancer are brought to clinical trials, we need to continue to enlarge our understanding of the impact of these treatments on the psychiatric care of patients and their families.