The Pros and Cons of Premedicating Patients Undergoing Chemotherapy

Question:

"In cancer treatment, should patients undergoing chemotherapy be premedicated with anti-anxiety medications or antidepressants (with or without symptoms of anxiety or depression) to help them feel more responsive to chemotherapy by reducing inflammation in the body? Discuss the pros and cons of this idea."

Charles Raison, MD:

This question comes from an attendee at our West Coast Treating the Whole Patient: The Mind-Body Connection in Psychiatric Disorders conference in August and it shows great understandings of the implications of my section of the meeting, which focused on the role of inflammatory pathways in major depression. The gist of the issue comes down to this: If cancer and its treatment induce inflammation, and inflammation promotes depression, then pretreating cancer patients prior to chemotherapy initiation might block negative mood effects of the treatment. On the other hand, if inflammation is required to kill the cancer, then perhaps such a strategy might come at too high a cost. Who cares about feeling better if this impairs the reason for going to all the trouble in the first place?

Let’s address the first issue, and then the second. In fact, a number of studies suggest that antidepressant pretreatment can ameliorate the development of depression, not just in response to cancer chemotherapy but to other medical interventions that are also associated with inflammation. In terms of chemotherapy, the classic study was done by Andy Miller and Dominique Musselman at Emory just before I joined the Mind-Body group there. Based on studies in animals showing that antidepressants can prevent sickness behavior, ¹ Andy and Dominique hypothesized that antidepressant pretreatment might also reduce the high rate of depression that occurs during treatment with the cytokine interferon (IFN)-alpha. IFN-alpha forms a mainstay of treatment for several neoplasms—including malignant melanoma and renal cell carcinoma—and for chronic hepatitis C virus (HCV) infection. ² It doesn’t work very well for cancer, but has high rates of success for HCV. To test their theory, 40 participants with non-metastatic malignant melanoma, without significant depressive or anxiety symptoms, were randomized to receive either paroxetine or placebo, commencing two weeks before IFN-alpha initiation and continuing throughout treatment. Consistent with prior reports, almost 50% of patients receiving IFN-alpha plus placebo developed symptomatic criteria for major depression over the first three months of treatment, compared to only 11% in the group that received paroxetine. ³ This antidepressant response had practical consequences. Thirty-five percent of the patients receiving IFN-alpha plus placebo elected to discontinue the IFN-alpha due to severe depressive symptoms, whereas only 5% discontinued for similar reasons in the paroxetine-treated group.

As far as I know this is the only randomized, double-blind study of antidepressant prophylaxis initiated prior to cancer chemotherapy. But similar results were observed in a far larger study of cancer patients conducted by Morrow and colleagues. These investigators hypothesized that selective serotonin reuptake inhibitors would improve chemotherapy-induced fatigue. To test this theory, they randomized 549 participants who had developed fatigue after an initial course of chemotherapy to either paroxetine or placebo and then followed these participants through several more rounds of chemotherapy. Paroxetine showed no benefit for fatigue, but significantly reduced chemotherapy-associated depressive symptoms. ⁴ Interestingly, when Lucile Capuron from our group went back and looked more closely at data on paroxetine pretreatment for IFN-alpha treatment of malignant melanoma, she found a similar result. The SSRI had completely blocked the development of sad mood, anxiety, and irritability, but had been no better than placebo in reducing fatigue, sleep, or appetite. ⁵ These data suggest that SSRIs are more effective in reducing the emotional symptoms of depression than they are in reducing somatic symptoms. A similar pattern has been observed in medically healthy patients with depression. ⁶ Whether other classes of antidepressants would be more effective choices for chemotherapy prophylaxis has never been rigorously examined.

Several studies have extended the work on antidepressant pretreatment prior to IFN-alpha therapy by examining patients receiving the cytokine for HCV. In general, these studies suggest that—as with malignant melanoma—SSRIs initiated prior to IFN-alpha can reduce the development of depression. ⁷ Not all studies find this. ⁸ If one looks closely at the literature, however, a consistent pattern emerges. As our group showed several years ago, people without premorbid risk factors are not likely to develop clinically relevant depressive symptoms in response to the lower doses of IFN-alpha used to treat HCV and do not benefit much from antidepressant pretreatment. ⁹ On the other hand, even mildly increased depression or anxiety prior to treatment significantly increases the risk of IFN-alpha-induced depression. And people who are even a little bit down or anxious prior to IFN-alpha therapy do much better in terms of behavioral side effects if they receive antidepressant pretreatment. ⁹

These findings remind me of a verse from the Bible: “To those who have more will be given.” This aptly describes how to think about who is at risk for developing depression in response to any depressogenic challenge, not just cytokine therapy. People with a past history of depression and/or with current subsyndromal depressive and anxiety symptoms are primed to run into trouble in the face of environmental adversity, be it immunological or psychological. Our group and others have also identified a number of physiological risks for developing depression. For example, we have shown that the more of the stress hormone cortisol the body makes in response to a first dose of IFN-alpha, the more likely a person is to be depressed after two months of IFN-alpha treatment for malignant melanoma. ¹⁰ We and others have observed that increased levels of proinflammatory cytokines prior to treatment seem to confer a similar risk for developing depression under the strain of IFN-alpha-induced chronic inflammatory activation. ¹¹

Although IFN-alpha is the best studied chemotherapeutic agent in terms of antidepressant prophylaxis, similar results have been shown in several other oncological treatment settings. For example, pretreatment with fluoxetine prior to adjuvant chemotherapy for breast cancer was found to reduce depressive symptoms, improve quality of life, and lead to higher chemotherapy completion rates over a six month period. ¹² Similarly, pretreatment with citalopram prior to chemotherapy for head and neck cancer reduced depressive symptoms and reduced deterioration in quality of life. ¹³

That is a quick summary of the literature on antidepressant pretreatment for cancer chemotherapy. Now to the second issue, which is the question of whether antidepressants might impede therapeutic response by lowering inflammation. Studies have gone back and forth on whether antidepressant use in general is a risk factor for cancer development or progression, and my take on this literature is that the answer is most likely no. In fact, recent research suggests that SSRIs might actually have tumor fighting potential, especially in gastrointestinal cancers. ¹⁴ Perhaps these complications are to be expected because a complex relationship exists between inflammation and cancer. On the one hand, inflammatory processes are an essential component in immune-based defense against oncogenesis. But on the other hand, data increasingly implicate the body’s inflammatory activity in multiple aspects of cancer development and spread. Even mild elevations in inflammatory markers have been shown in prospective studies to increase the risk for cancer development. ¹⁵ Inflammation has been repeatedly implicated in metastatic processes. ¹⁶ Finally, inflammation contributes significantly to the development of resistance to chemotherapy. ¹⁷ Not surprisingly, given all this, novel anti-inflammatory strategies are at the forefront of novel chemotherapeutic agent development. ¹⁸

How would I summarize all this? I think data support the use of antidepressant prophylaxis for vulnerable patients being exposed to any proinflammatory medical situation. Many lines of evidence suggest that most of us have more inflammation than we need to optimally fight modern wear-and-tear disorders such as cancer or cardiovascular disease, so I think it is likely that—other things being equal—antidepressants are more likely to help, or be neutral, in regard to medical outcomes than to harm patients. Data for antidepressant prophylaxis are best for IFN-alpha, but I would consider this strategy in the face of any serious or long-term medical/surgical intervention. Vulnerable individuals include those with a past history of depression and/or with anxiety or depressive symptoms prior to the immune challenge.

—Charles Raison, MD

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