APOS Clinical E-Mail Update #4
12 December 2003

In this Update:

Are antidepressants carcinogenic?

Sternbach H. Are antidepressants carcinogenic? A review of preclinical and clinical studies. J Clin P sychiatry 2003; 64;1153-1162.


Patients treated for cancer take an array of medications to prevent tumor growth and to treat the side effects of treatment. Antidepressants are added to that mix when the target is the treatment of depression or pain. Patients would be concerned if they thought that antidepressant medication itself might cause tumors or promote tumors. Sternbach has reviewed recent preclinical and clinical studies that bear on the questions, offering an up-to-date review of the literature.

He reviews animal models of carcinogenesis that used predominantly tricyclic antidepressants, finding 13 studies. Of these, three studies found an increase; four studies a trend to increase; and six studies no increase in risk for cancer in specific animal models. He discusses models that suggest an anti-tumor benefit of antidepressants as well as the Brandes’s and colleagues’ argument that standard tests of carcinogenicity or mutagenicity do not show whether a specific drug can promote cancer if the right initiator is already present. He notes that all agents that have been carcinogenic in humans have also produced cancer in animals; however, it is not true that all agents that are carcinogenic in animals have produced tumors in humans. So merely an animal model does not convey the risk to humans.

The review includes 3 prospective and 10 retrospective epidemiological studies. Methodological concerns are raised about the pre-clinical and epidemiological studies. He concludes that there is no present basis for recommending a change in antidepressant prescribing patterns based on risk of tumor initiation or promotion. The link remains unsubstantiated.

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A rare report of rhabdomyolysis with SSRI and irinotecan—a CYP 3A4 interaction?

Richards S, Umbreit JN, Fanucchi MP, Giblin J, Khuri F. Selective serotonin reuptake inhibitor-induced rhabdomyolysis associated with irinotecan. South Med J 2003;96:1031-1033.

This is a case report of a 74 year old white man with metastatic adenocarcinoma from the upper gastrointestinal tract who was given irinotecan as an anti-cancer agent. He had generalized weakness and creatine kinase (CK) levels of 7400 U/L (49-397) on admission, three days after chemotherapy. All medications were stopped including citalopram, alprazolam, and simvastatin. He had taken citalopram for 2 months for depression. The level of myoglobin and creatine kinase decreased in the hospital but worsened dramatically on a later day when citalopram was reintroduced briefly.

The authors discuss the possibility that irinotecan and its metabolite may have suppressed the CYP 3A4 activity necessary to metabolize citalopram. A similar effect might be seen with fluoxetine and its metabolite norfluoxetine but has not been reported.

Citalopram overdoses had been associated with neuroloeptic malignant syndrome in 6 overdoses, and delayed elevation of CK was noted in two cases with venlafaxine. However, myopathy and rhabdomyolysis are still a very unusual side effect of serotonin reuptake inhibitors.

It is interesting to note that the patient was also on simvastatin (Zocor), a medication that is a substrate of CYP3A4.1 Like other HMG-CoA reductase inhibitors, simvastatin causes myopathy and sometimes rhabdomyolysis with elevated CK in 5% of cases. The risk of myopathy/rhabdomyolysis is dose-related and related to increased levels of HMG-CoA reductase inhibitor activity in plasma. How this may have played into the rhabdomyolyis of this case is unclear.

1. Zocor (Merck) simvastatin Physician’s Desk Reference entry 2003

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Is there an association between pancreatic cancer and depression?

Carney CP, Jones LBS, Woolson RF, Noyes R, Doebbeling BN. Relationship between depression and pancreatic cancer in the general population. 2003;65:884-888.

While depression has historically been associated with cancer, it has not been clear that that the tendency to depression is associated with a higher rate of any particular cancer. The firmest link has been the association between pancreatic cancer and depression. Once a patient develops the early signs of pancreatic cancer it is difficult to decide whether the signs of depression for this patient represent the first signs of the illness or a recall bias about mood.

These authors looked at longitudinal population-based data in a retrospective cohort study of Wellmark Blue Cross/Blue Shield insurance claims in Iowa and South Dakota. They found that men with mental disorder were more likely to develop pancreatic cancer than those who had no psychiatric claims. They also found that depression more commonly preceded pancreatic cancer than other gastrointestinal malignancies or all other cancers. They looked at more than 700,000 claims over 5 years and found that about 2% who developed malignancies had first had claims for a mental condition. Of these, 9 men and 5 women, 1% of all who developed cancer after a mental condition, were diagnosed with pancreatic cancer. Men with mental disorder were more likely to develop pancreatic cancer than those without mental disorders. In 10 of 14 cases, the mental condition was depression. Of the 14 cases, only 3 had the mental disorder diagnosed within the 6 months of the cancer diagnosis. Thus, they found that depression and pancreatic cancer are associated in the general population and this fact remains intriguing. They suggest that this unique relationship invites further investigation.

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What are earliest symptoms of pancreatic cancer?

Gullo L, Tomassetti P, Migliori M, Casadei R, Marrano D. do early symptoms of pancreatic cancer exist that can allow an earlier diagnosis? Pancreas 2001;22:210-213.

Given the association of depression and pancreatic cancer, it is interesting to note a recent study that tried to identify the early symptoms that came before pain and jaundice. Of about 300 pancreatic cancer patients, about half had prior disturbances within the 6 months before jaundice and pain developed, and another 14% had symptoms more than 6 months before. The earliest symptoms were anorexia, early satiety and/or asthenia, diabetes, and acute pancreatitis. The patients with pancreatic cancer were compared to other hospitalized patients with benign conditions matched for demographic factors. Pruritis, mild diarrhea or change in bowel habits, and mood change were less common and occurred within 6 months of diagnosis. Only 10, 3.3% reported depression. Mood changes were found in the control group at a similar rate (4.3%), but mood change was usually of longer duration. Sudden disgust for coffee, for smoking, for meat, and for wine were noted as an unexpected clue to diagnosis.

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What is the benefit of methylphenidate for fatigue in ambulatory cancer patients?

Bruera E, Driver L, Barnes EA, Willey J, Shen L, Palmer JL, Escalante C. Patient-controlled methylphenidate for the management of fatigue in patients with advanced cancer: a preliminary report. J Clin Oncol 2003; 21: 4439-4443.

This is a preliminary report prospective open study of 31 fatigued patients with advanced cancer from the MD Anderson outpatient Palliative Care or Pain Clinic who were treated with methylphenidate 5 mg by mouth every two hours as needed for 7 days, with a maximum 20 mg per day. This patient-controlled format led to significant improvement in fatigue as well as improvement in anxiety, appetite, pain, nausea, depression, and drowsiness. Most patients chose to continue for up to 4 weeks. In this uncontrolled study, they also noted that patients took afternoon and evening doses. Methylphenidate has reduced fatigue in ambulatory HIV patients, patients taking interferon, and patients sedated by narcotics. The authors suggest that further controlled studies are in order.

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A review of cancer-related fatigue

Ahlberg K, Ekman T, Gaston-Johansson F, Mock V. Assessment and management of cancer-related fatigue in adults. Lancet 2003;362:640-650.

This is a review of the literature, particularly from 1997 to 2002, on cancer-related fatigue. It highlights the National Cancer Center Network 2002 guidelines and the state of recent research.

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What is the role of other symptoms in cancer-related fatigue?

Hwang SS, Chang VT, Rue M, Kasimis. Multidimensional independent predictors of cancer-related fatigue. J Pain Symptom Manage 2003; 26: 604-614.

These researchers asked 180 male cancer patients at a veteran’s hospital to fill out the Brief Fatigue Inventory, Functional Assessment of Cancer Therapy-Fatigue scale, Memorial Symptom Assessment Scale Short Form, and the Zung Self-Rating Depression Scale. Predictors of fatigue included analgesics, hemoglobin, serum sodium, the physical symptoms of drowsiness, dyspnea, pain, lack of appetite, and the psychological symptoms of feeling sad or irritable. In the multi-dimensional model, the subjective physical and psychological symptoms predicted fatigue, and laboratory measures were superseded. The authors conclude that a symptom-oriented approach to evaluation and treatment of fatigue is appropriate.

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How does cancer-related fatigue compare to fatigue in depression and the general populace?

Anderson KO, Getto CJ, Mendoza TR, Palmer SN, Wang XS, Reyes-Gibby CC, Cleeland CS. Fatigue and sleep disturbance in patients with cancer, patients with clinical depression, and community-dwelling adults. J Pain Symptom Manage 2003;25:307-318.

In order to validate the Brief Fatigue Inventory, these researchers compared the severity of fatigue in 354 patients with cancer at University of Texas, M.D. Anderson Cancer Center, 72 depressed psychiatric ambulatory patients in Madison, Wisconsin; and adult volunteers recruited at meetings of various service organizations in the Houston metropolitan area. Fatigue was more severe and more apt to interfere with daily life in psychiatric patients. Scores were not as high for cancer patients, but cancer patients had more severe fatigue and more interference with life than volunteers. The Profile of Mood States vigor and fatigue scales did not distinguish between patients with cancer and patients with a depressive disorder. Moderate sleep disturbance was reported in 62% of cancer patients.

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Are tired survivors of testicular cancer younger and more anxious?

Fossa SD, Dahl AA, Loge JH. Fatigue, anxiety, and depression in long-term survivors of testicular cancer. J Clin Oncol 2003;1249-1254.

Chronic fatigue in testicular cancer survivors (patients 18- 75 at Norwegian Radium Hospital) was compared to male survivors of Hodgkin’s disease and males from the general population using the fatigue questionnaire and the Hospital Anxiety and Depression Scale (HADS). They found chronic fatigue in 16% of survivors. Those younger than 30 had more chronic fatigue than the general population. Besides age, anxiety, depression, and co-morbidity were independent predictors of chronic fatigue. The rate of chronic fatigue was less in testicular cancer survivors than in Hodgkin’s Disease survivors. Anxiety as well as depression was associated with fatigue.

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In ovarian cancer survivors, fatigue is a clue to social support and psychological well-being

Holzner B, Kemmler G, Meraner V, Maislinger A, Kopp M, Bodner T, et al. Fatigue in ovarian carcinoma patients. A neglected issue? Cancer 2003; 97:1564-1572.

Ovarian cancer survivors who had not been treated in 6 months, on average 5 years from diagnosis were evaluated for fatigue with the Multidimensional Fatigue Inventory as well as quality of life instruments. Those reporting significant fatigue included 32 of 98. These were patients with lower quality of life, higher scores of anxiety and depression, and a perception that they had less social support. Mental adjustment, social support, anxiety, and depression as well as fatigue were predictors of quality of life in a multiple regression model.

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Donna B. Greenberg, MD, Associate Professor of Psychiatry at Harvard Medical School and Psychiatric Consultant in the Massachusetts General Hospital Cancer Center, Dana Farber Partners Cancer Care