Current Management of Depression in Cancer Patients

In their paper, Schwartz and colleagues review the risk factors fordepression and suicide in patients with cancer and argue convincingly thatscreening for depression can be simply and quickly performed. They alsodelineate the efficacy and potential adverse effects of psychotherapeutic orpsychopharmacologic treatments for these patients. Buttressing theidentification and treatment of depression in the cancer patient are vital,ongoing scientific developments that flow from an increased understanding ofinteractions among the brain, endocrine system, and immune system. This rapidlyevolving body of neurobiological knowledge has catalyzed fundamental changes inhow we conceptualize depression in cancer patients and has importantramifications regarding the treatment and prevention of depressive syndromes inthis setting.

HPA Axis Hyperactivity

Indeed, recent advances in biological psychiatry have included discoveries ofneurochemical, neuroendocrine, and neuroanatomic alterations in patients withmajor depression. Such findings include hypothalamic-pituitary-adrenal axishyperactivity, alterations of the hypothalamic-pituitary-thyroid axis,diminished serotonergic neurotransmission, structural and functional brainabnormalities, impaired sleep architecture, and activation of the immunesystem.[1]

Although few of these biological alterations have been systematicallyinvestigated in medically ill patients, certain effects have been observed incancer patients with comorbid depression—notably hyperactivity of thehypothalamic-pituitary-adrenal (HPA) axis,[2-4] as manifested by nonsuppressionof plasma cortisol concentrations following dexamethasone administration, andincreased immune activity, as manifested by elevated levels of proinflammatorycytokines [4].

HPA axis hyperactivity in patients with cancer and comorbid depression islikely due, at least in part, to central nervous system (CNS) hypersecretion ofcorticotropin-releasing factor (CRF). The preeminent CNS stress hormone, CRF islocated in neurons both inside and outside the hypothalamus. Within thehypothalamus, CRF-containing neurons that project from the paraventricularnucleus to the median eminence[5] control the secretion of adrenocorticotropichormone (ACTH) and beta-endorphin from the anterior pituitary[6]; ACTH, in turn,stimulates cortisol secretion from the adrenal cortex. In addition to itsneuroendocrine role in extrahypothalamic circuits throughout the nervous system,CRF also coordinates behavioral, autonomic, and immune responses to stress.

Whether HPA axis hyperactivity (and other neurochemical/neuroendocrineperturbations) influences immune function, cancer progression, and survival iscurrently a matter of intense scrutiny and debate. Spiegel and colleagues haverecently documented that women with metastatic breast cancer who exhibit areduced diurnal variability in cortisol secretion have not only diminishednatural killer cell function, but also increased mortality over a 6-yearfollow-up period.[7]

Proinflammatory Cytokines

Patients with cancer may also be susceptible to depressive syndromes broughton by inflammation secondary to tissue damage (eg, following surgery, or duringchemotherapy and/or radiation treatment) and the associated release ofproinflammatory cytokines. These cytokines, such as interleukin (IL)-1, IL-6,and tumor necrosis factor (TNF), are produced by activated immune cells thatregulate immune responses involved in host defense[8,9] and have profoundneuroendocrine and behavioral consequences. For example, they have the capacityto directly stimulate the HPA axis, resulting in the release of CRF.[10-12]

Moreover, with regard to mood disorders, proinflammatory cytokines can alsoinduce "sickness behavior," a syndrome whose symptoms—includingfatigue, anorexia, anhedonia, decreased psychomotor activity, and thedisappearance of body care activities—overlap with those of majordepression.[13,14] In one study, plasma concentrations of IL-6 were markedlyelevated in cancer patients with depression, compared to cancer patients withoutdepression and healthy controls.[4] Whether through the release ofproinflammatory cytokines or via stress-induced CRF hypersecretion, HPAhyperactivity in patients with cancer and depression may exert untoward effectson immunologic function.

Prophylactic Antidepressant Administration

Given the elevations of IL-6 plasma concentrations in patients with cancerand major depression, and noting Yirmiya’s 1996 report of the reduction ofsickness behavior in animals treated with antidepressants prior to immune systemactivation,[14] we conducted a double-blind, randomized, placebo-controlledtrial in patients with malignant melanoma receiving high doses of the cytokineinterferon alfa-2b (Intron A).[15] We sought to determine whether administrationof the selective serotonin-reuptake inhibitor paroxetine (Paxil) wouldeffectively diminish the induction of depressive symptoms in this population.

Among malignant melanoma patients receiving placebo, 45% developed symptomssufficient to meet DSM-IV criteria for major depression. However, in the groupof patients who received paroxetine, beginning 2 weeks prior to the initiationof interferon alfa-2b administration (and throughout the first 3 months ofinterferon alfa-2b therapy), the development of major depression wassignificantly reduced (fourfold, to 11%). In comparison to placebo-treatedpatients, the paroxetine-treated patients experienced significantly reducedelevations of depression, anxiety, and neurotoxicity symptoms. In addition,paroxetine treatment significantly decreased the likelihood that interferonalfa-2b would have to be discontinued due to severe depression or neurotoxicity(Figure 1).[15]

Conclusions

In certain instances, prophylactic antidepressant treatment of cancerpatients may not only reduce the incidence of depressive symptoms, but alsoprevent other symptoms associated with immune system activation such ascognitive dysfunction and pain, and thus improve compliance with immunotherapyand long-term survival.

Certainly, this century will bring further evolution of concepts regardingthe diagnosis, pathophysiology, and treatment/prevention of depression in thepatient with cancer. For example, investigators will undoubtedly seek todetermine whether psychiatric interventions that reduce HPA axis hyperactivityand normalize immune function will enhance long-term survival through increasedcompliance or via other, as yet undiscovered, neurobiological pathways.

References:

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2. Joffe RT, Rubinow DR, Denicoff KD, et al: Depression and carcinoma of thepancreas. Gen Hosp Psychiatry 8:241-245, 1986.

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4. Musselman DL, Miller AH, Porter MR, et al: Increased plasma interleukin-6concentrations in cancer patients with depression. Am J Psychiatry. In press.

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13. Kent S et al: Sickness behavior as a new target for drug development.Trends in Pharmacological Science 13:24-28, 1992.

14. Yirmiya R: Endotoxin produces a depressive-like episode in rats. BrainRes 711:163-174, 1996.

15. Musselman DL, Lawson DH, Gumnick JF, et al: Paroxetine for the preventionof depression induced by high-dose interferon alfa. N Engl J Med 344:961-966,2001.