May depressed and anxious patients with carcinoid syndrome benefit from treatment with selective serotonin reuptake inhibitors (SSRIs)?: findings from a case report

To the Editor,

Carcinoid tumors are relatively rare. Incidence rates for men and women are 2.0 and 2.4 per 100 000, respectively [1]. Carcinoid syndrome is usually seen in patients with metastatic disease and is characterized by flushing, diarrhea, bronchial constriction and heart valve dysfunction. These symptoms are often caused by various substances, such as 5-HIAA metabolites, kinins, and prostaglandins, produced by the tumor [2].

Selective serotonin reuptake inhibitors (SSRIs) are considered first line treatment for depression and anxiety disorders [3]. They are effective, well tolerated and easy to use. As a result of their benign side effect profile and low degree of interactions with other medications, SSRIs are often used in the treatment of depressive and anxiety symptoms in patients with physical illnesses [4].

However, treatment with SSRIs is often regarded contraindicated in carcinoid tumor patients as the hormone releasing carcinoid tumor already produces serotonin (5-HT) leading to a variety of symptoms including diarrhea, wheezing and flushes [2]. Indeed, some case reports have indicated that the use of SSRIs led to an exacerbation of carcinoid symptoms. However, one study thus far has suggested that SSRIs may be well tolerated in this patient population [5].

We present a case report of a 56-year-old female patient with a metastatic carcinoid tumor treated with telotristat etiprate suffering from depression with comorbid panic and general anxiety disorder (GAD), which remitted after treatment with escitalopram without important gastro-intestinal side effects.

Case report

In 2012, Ms. A., a 56-year-old teacher, was diagnosed with a neuroendocrine tumor (WHO 2010 grade 2, ki 67 index of 10%) with liver metastases and carcinoid syndrome after a period of excessive diarrhea, flushing and nausea. Chromogranin level was 4630 μg/l (normal range: 40–170 μg/l) and 5-HIAA concentration in urine was 95.7 mg/24 h (normal range: 0–9 mg/24 h). She was initially successfully treated with octreotide acetate LAR 30 mg/28 days, leading to symptom reduction and tumor control. The 5-HIAA concentration in urine decreased to 27.4 mg/24 h, although chromogranin level remained high (4560 μg/l). In May 2013, she was referred for peptide receptor radionuclide therapy (PRRT) because of increasing diarrhea and flushing not responding to more intensive treatment with octreotide acetate LAR. Chromogranin level was 7060 μg/l and 5-HIAA concentration in urine 114 mg/24 h at the time of referral. One year later, after having completed four treatments with Lu-177-octreotate up to a total of 29.6 GBq, the level of chromogranin was still 6130 μg/l and the patient still reported episodes of flushing and diarrhea. In June 2013, the patient developed the first signs of carcinoid heart disease including fatigue and shortness of breath during physical activity. High doses of octreotide acetate LAR 30 mg/14 days were combined with short acting octreotide acetate t.i.d. 0.5 mg. In January 2015, the patient was asked to participate in a trial with telotristat etiprate because of the remaining important carcinoid syndrome, only just controlled by these daily injections of short acting octreotide acetate. With the latter treatment, chromogranin level and 5-HIAA concentration in urine were reduced from 686 ng/ml (at the treatment start) to 290 ng/ml (three months later; April 2015) and from 84 mg/l to 29 mg/l, respectively, and further symptoms like diarrhea and flushing were well controlled.

In April 2015, Ms. A. was hospitalized because of hypotension and syncope. During the admission she presented with depressive and anxious symptoms despite being treated with bupropion 150 mg a day for the last eight months. She was diagnosed by a junior psychiatrist with a depressive episode, panic disorder and GAD using the MINI Psychiatric Interview [6]. Further assessment with Beck depression inventory (BDI) [7] and Spielberger State/Trait Anxiety Index (STAI) [8,9] showed moderate depression (BDI: 20/63) and high state and trait anxiety (STAI state: 58 & trait: 61).

Her psychiatric history revealed a depressive episode in 2004 after the death of her mother, which had been successfully treated with daily paroxetine 20 mg during 18 months and one episode in 2012, which had been treated with daily escitalopram 5 mg until March 2014. The latter treatment had been stopped by her cardiologist because of the fear of exacerbation of the carcinoid symptoms and possible rapid deterioration of carcinoid heart disease. However, because of the recurrence of the depressive and anxiety symptoms bupropion 150 mg was started in August 2014.

During admission bupropion was switched to escitalopram 5 mg because of its previous good control of the anxiety and depressive symptoms. One week after the start of the treatment, Ms. A. already felt less emotional, depressed and anxious. No increase in diarrhea or flushing was reported. The daily dose of escitalopram was further increased to 10 mg, but after two weeks of treatment she reported a slight increase in diarrhea. As a result the dose was reduced to escitalopram 5 mg a day. Three months later, full recovery of the depressive episode (BDI-II: 9) and panic disorder and GAD (STAI state: 40, STAI trait: 37) was obtained under treatment with daily escitalopram 5 mg without any increase in diarrhea, nausea or flushing. Ms. A’s quality of life increased remarkably.

Discussion

Depression and anxiety have been frequently reported in patients with metastatic carcinoid syndrome with prevalence rates of 50% and 35%, respectively [5,10,11]. Its causes are generally accepted to be multi-factorial. It is likely that the chronic and invalidating nature of the carcinoid tumor and its treatment may have contributed to the development of depression in our patient [12]. The history of a depressive episode, already present before the development of the carcinoid tumor, and the presence of comorbid panic disorder and GAD may also point to an underlying existing vulnerability in our patient. However, the development of the depression may also be partly explained by possible tryptophan depletion caused by the carcinoid tumor. In healthy persons, 99% or more of dietary tryptophan is metabolized into nicotine acid and 1% or less into 5-hydroxytryptamine (5-HTP) [13]. In patients with a carcinoid tumor, up to 60% of the body’s tryptophan is shunted to 5-HTP, resulting in large quantities of 5-HT, 5-HTP, and 5-HIAA in the body. Central nervous system (CNS) 5-HT is only synthesized from tryptophan within CNS serotonergic neurons as 5-HT does not cross the blood–brain barrier. In patients with a carcinoid tumor, the important shunting of tryptophan into 5-HT in the body may result in a relative deficiency of this precursor in the brain. Moreover, acute tryptophan depletion induces depressive symptoms in 50–60% of SSRI treated, recovered depressed patients [14], and mood response to tryptophan depletion was found to be predictive of future depressive episodes [15].

Although 5-HT dysfunction may underlie depression in patients with carcinoid syndrome, treatment with SSRIs is theoretically and clinically controversial and even contraindicated because of the possible interaction with the 5-HIAA metabolites, kinins, and prostaglandins produced by the tumor [16]. Several case reports suggest that SSRIs may further function as a provocative agent of carcinoid syndrome and increase symptoms like diarrhea and flushing [11,16]. However, similar to our case, Williams et al. [5] has reported five cases of SSRI treated depressive episodes in patients with metastatic carcinoid tumor without occurrence of important gastro-intestinal side effects.

Our patient did not experience major symptoms, such as diarrhea and flushing, when treated with low dose SSRI. It may be possible that the additional treatment with telotristat etiprate in our patient helped to reduce the development of some of the symptoms as described in the earlier cases of Noyer and Schwartz [16] and Simbera [11]. Telotristat etiprate is an oral, systemically available, small molecule inhibitor of peripheral 5-HT synthesis. Telotristat etiprate acts by inhibiting tryptophan hydroxylase, the rate limiting enzyme in the conversion of tryptophan to 5-HT, which is primarily found in the enterochromaffin cells. The molecule was designed not to cross the blood–brain barrier at the intended dose [17]. Although we normally do not expect a dose-response curve in SSRI treatment, our patient reported an increase in gastro-intestinal side effects when the dose of escitalopram was doubled. Further research is needed to clarify whether treatment with telotristat etiprate may reduce SSRI’s induced side effects.

Conclusion

We report a case of a depressed and anxious patient with a metastatic carcinoid tumor who was successfully treated with low dose SSRI in combination with telotristat etiprate without important gastro-intestinal side effects. Further research is needed to clarify whether the low dose of SSRI and/or the additional treatment with telotristat etiprate may have benefitted our patient.