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Selective Serotonin Reuptake Inhibitors and Patients With Carcinoid Tumor

Received Oct. 1, 2004; revision received Nov. 13, 2004; accepted Dec. 16, 2004. From the Department of Psychiatry and Psychology, Mayo Clinic. Address correspondence and reprint requests to Dr. Williams, Mayo Clinic, 200 First St., SW, Rochester, MN 55905; williams.mark{at}mayo.edu (e-mail).

INTRODUCTION

TOP INTRODUCTION DISCUSSION REFERENCES

 
Serotonin is targeted in the treatment of depression with selective serotonin reuptake inhibitors (SSRIs). In the patient with carcinoid tumor, tumor cells manufacture serotonin. What direction does the psychiatrist take in treating a patient with both depression and carcinoid tumor? A recent review of the literature provided very little guidance. In a 1997 case report, Noyer and Schwartz¹ described a patient who developed carcinoid syndrome with pellagra and psychiatric disturbance while receiving an SSRI (sertraline). The authors recommended SSRIs as provocative agents in patients suspected of having carcinoid syndrome without overt or typical features.

We review the cases of five patients with carcinoid tumor seen at the Mayo Clinic in Rochester, Minnesota, who received SSRIs for mood disorders, with specific attention to side effects and symptoms of carcinoid syndrome elicited by the medications.

Cases
We searched electronic records for all cases of patients seen between 2000 and 2002 for which both "depression" and "carcinoid" were mentioned. Patients who had not signed releases of information for chart review were excluded. Of the remaining 38 patients, the majority were excluded because the term "carcinoid" indicated simply a suspicion and the condition was never diagnosed or because the patient was never treated with antidepressant agents.

Of the remaining five patients (Table 1), four had received a diagnosis of a mood disorder before carcinoid tumor was diagnosed. All of the patients received SSRIs, and the records of four of the five indicated improvement. Side effects other than sedation were not mentioned for any of the patients. Only one patient (patient 2) received a diagnosis of carcinoid syndrome and had a markedly elevated urinary 5-hydroxyindoleacetic acid (5-HIAA) value. The patient’s record documented that her mood improved after treatment with medication and that she had no side effects.

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TABLE 1. Case Series of Patients With Major Depression and Carcinoid Tumors Seen at the Mayo Clinic, 2000–2002

The cases of the five patients were reviewed a mean of 37.2 years after they received a diagnosis of mood disorder and a mean of 9.2 years after the diagnosis of carcinoid tumor.

DISCUSSION

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The overall incidence of carcinoid tumor in the United States is estimated to be 1–2 per 100,000 population per year.² The tumors are typically often diagnosed in the fifth or sixth decade of life, and many patients are asymptomatic at presentation. Carcinoid syndrome is characterized by flushing, diarrhea, and abdominal cramping and occasionally by wheezing, heart-valve dysfunction, and pellagra. Carcinoid syndrome is thought to result from the interaction between the 5-HIAA metabolites, kinins, and prostaglandins released by the tumor into the general circulation.³ The incidence of the syndrome is higher with metastatic disease. Intestinal carcinoid tumors are thought to be less likely to cause carcinoid syndrome, because the serotonin produced by the tumor is metabolized into 5-HIAA by the liver.

In healthy persons, as much as 99% of dietary tryptophan is metabolized into nicotinic acid, and 1% or less is made into 5-hydroxytryptamine (5-HTP).⁴ In patients with carcinoid tumor, up to 60% of the body’s tryptophan is shunted to 5-hydroxylation, resulting in large quantities of serotonin (5-HT), 5-HTP, and 5-HIAA in the body. This process may result in a reduction in nicotinic acid pools and lead to pellagra. 5-HT does not cross the blood-brain barrier, and CNS 5-HT is synthesized from tryptophan within CNS serotonergic neurons. In patients with carcinoid tumor, the shunting of tryptophan into 5-HT in the body may result in a relative deficiency of this precursor in the brain. In studies of acute tryptophan depletion, depressive symptoms were induced in 50%–60% of SSRI-treated, recovered depressed patients,⁵ and mood response to tryptophan depletion was found to be predictive of future depressive episodes.⁶

Psychiatric diseases have been reported in patients with metastatic carcinoid disease. Carcinoid syndrome has been associated with psychosis in two case reports^7,8 and with depression in two chart-review studies.^9,10 The reported frequency of depression in carcinoid patients varies widely, from 50% in the study by Major et al.¹⁰ to less than 1% among all patients in the study by Patchell and Posner⁹ or 11% among the carcinoid patients with elevated urinary 5-HIAA values in Patchell and Posner’s review. In a study by Russo et al.,¹¹ the cognitive patterns of 14 patients with metastatic carcinoid tumors more closely resembled those of tryptophan-depleted patients than of depressed patients.

The case report by Noyer and Schwartz¹ identifying sertraline as a provocative agent that can reveal carcinoid syndrome suggests the need for caution in the use of SSRIs to treat patients with carcinoid tumors. As noted earlier, the frequency of depression in carcinoid patients is difficult to estimate. The deficiency of CNS tryptophan associated with carcinoid tumors may predispose vulnerable patients to the development of depression, and an SSRI may be considered as a treatment for those patients. None of the patients in the cases we reviewed showed an increase in carcinoid syndrome symptoms while taking SSRI medications. The patient who had a diagnosis of carcinoid syndrome was also treated with somatostatin. This treatment may have helped to minimize the development of some of the symptoms seen in the case described by Noyer and Schwartz.¹ The risk of exacerbating flushing, diarrhea, and other symptoms of carcinoid syndrome or of inducing a serotonin syndrome when treating carcinoid patients with serotonergic agents remains uncertain, and it may be premature to entirely avoid a potentially helpful line of treatment for depression in carcinoid patients. Further research is needed on the biology of carcinoid syndrome and the factors that differentiate carcinoid patients who are susceptible to serotonin syndrome.

REFERENCES

TOP INTRODUCTION DISCUSSION REFERENCES

 

1. Noyer CM, Schwartz BM: Sertraline, a selective serotonin reuptake inhibitor, unmasking carcinoid syndrome. Am J Gastroenterol 1997; 92:1387–1388[Medline]
2. Modlin IM, Sandor A: An analysis of 8,305 cases of carcinoid tumors. Cancer 1997; 79:813–829[CrossRef][Medline]
3. Schnirer II, Yao JC, Ajani JA: Carcinoid: a comprehensive review. Acta Oncol 2003; 42:672–692[CrossRef][Medline]
4. Bender DA: Biochemistry of tryptophan in health and disease. Mol Aspects Med 1983; 6:101–197[CrossRef][Medline]
5. Booij L, Van der Does W, Benkelfat C, Bremner JD, Cowen PJ, Fava M, Gillin C, Leyton M, Moore P, Smith KA, Van der Kloot WA: Predictors of mood response to acute tryptophan depletion: a reanalysis. Neuropsychopharmacology 2002; 27:852–861[CrossRef][Medline]
6. Moreno FA, Heninger GR, McGahuey CA, Delgado PL: Tryptophan depletion and risk of depression relapse: a prospective study of tryptophan depletion as a potential predictor of depressive episodes. Biol Psychiatry 2000; 48:327–329[CrossRef][Medline]
7. Hanna SM: Carcinoid syndrome associated with psychosis. J Postgrad Med 1965; 41:566–567
8. Trivedi S: Psychiatric symptoms in carcinoid syndrome. J Indian Med Assoc 1984; 82:292–294[Medline]
9. Patchell R, Posner J: Neurological complications of carcinoid. Neurol 1986; 36:745–749[Abstract/Free Full Text]
10. Major LF, Brown LG, Wilson WP: Carcinoid and psychiatric symptoms. South Med J 1973; 66:787–790[Medline]
11. Russo S, Nielen MM, Boon JC, Kema IP, Willemse PH, de Vries EG, Korf J, den Boer JA: Neuropsychological investigation into the carcinoid syndrome. Psychopharmacology (Berl) 2003; 168:324–328[Medline]

Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Email this article to a Colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to My Articles & Searches Download to citation manager Citing Articles via Google Scholar Articles by Williams, M. D. Articles by Dolenc, T. J. Search for Related Content PubMed Citation Articles by Williams, M. D. Articles by Dolenc, T. J. Syndromes Secondary to General Medical Disorders Antidepressants

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