Abstract
Introduction
Second-generation antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are considered to have a superior cardiovascular safety profile compared to older tricyclic antidepressants. 1 This makes SSRIs the drug of choice in patients with depression and cardiovascular disease. 2 Fluvoxamine in particular has been widely studied in this regard and evidence shows that it is safe for patients with cardiovascular disease. 1 However, case reports and studies are beginning to suggest otherwise.3, 4 We present a case of chest pain in an elderly lady that was probably precipitated by fluvoxamine use.
Case presentation
A 66-year-old Indian woman with a major depressive disorder and who was taking fluvoxamine, was admitted under the cardiology team at a general hospital for a one-day history of left-sided chest pain that occurred the morning after first taking fluvoxamine at the prescribed dose of 25mg at night. Her past medical history is characterized by hypertension, hyperlipidaemia, type 2 diabetes mellitus, cervical spondylosis, chronic back pain and ischaemic heart disease. She had had coronary stenting and coronary artery bypass graft surgery for the latter 14 years ago. Apart from fluvoxamine, she was also on aspirin with omeprazole, simvastatin, fenofibrate, metformin, dapagliflozin and subcutaneous insulin.
Further history revealed constant left-sided chest pain of an atypical nature that was sharp in character with radiation to the neck. It was not triggered by exertion with no associated symptoms of dyspnoea, palpitations, dizziness, nausea or diaphoresis. The physical examination performed was unremarkable. The results of blood tests (including cardiac troponin), electrocardiography, chest x-ray and echocardiography were normal. Her hospitalization lasted six days, during which she was referred to a psychiatrist for review of her antidepressant therapy as the above investigations were negative and the cardiology team had noted a close association between her symptoms and consumption of fluvoxamine. A low (quoted 3%5, 6) risk of chest pain was noted on review of the adverse effects of fluvoxamine. Therefore, the psychiatrist advised that fluvoxamine should be suspended and the patient commence alternative antidepressant therapy with escitalopram 2.5mg every night.
Within two days of stopping fluvoxamine, there was resolution of her chest pain. Furthermore, at the two-month outpatient follow-up, the patient was well. However, at the four-month follow-up, the patient had developed insomnia and had on one occasion self-medicated with a dose of fluvoxamine in an attempt to aid her sleep. Interestingly, shortly after ingestion of fluvoxamine there was again the onset of similar left-sided chest pain, which spontaneously resolved three hours after ingestion.
Discussion
Cardiovascular side effect of fluvoxamine
Earlier studies looking at the cardiovascular effects of fluvoxamine showed that apart from a slight and clinically unimportant reduction of the heart rate, fluvoxamine appeared to have no other cardiac effects. 7 However, there have been reports of chest pain as an adverse drug reaction of SSRIs, especially in patients with coronary artery disease. 8 In particular, with regard to fluvoxamine, it is estimated that 2.21% of patients on this drug develop chest pain as a side effect with a majority (60.57%) being female. The likelihood of developing chest pain with fluvoxamine also increases with age, with 30.32% of cases occurring in patients over 60 years of age. 9
The proposed mechanism for this is that serotonin produces unopposed vasoconstriction in atherosclerotic coronary arteries. A 1991 study looked at the effect of an intracoronary infusion of serotonin on 22 patients undergoing routine cardiac catheterization. 10 They found that normal coronary vessels have a net vasodilatory response to intracoronary serotonin, whereas atherosclerotic coronary vessels instead showed a progressive vasoconstriction. The basis for this is that when serotonin binds to 5-HT1 receptors on vascular endothelium, there is a release of nitric oxide, which leads to vasodilation. Simultaneously, when serotonin binds to 5-HT2 receptors on smooth muscle cells it causes vasoconstriction. The net effect in normal coronary vessels is vasodilation. However, in atherosclerotic coronary vessels, the damaged endothelium is unable to release enough nitric oxide to counter the vasoconstriction, leading to angina (Figure 1).
The varying effects of serotonin on a normal and atherosclerotic coronary artery.
Other potential mechanisms of chest pain
Drug interaction with simvastatin
Fluvoxamine is a potent inhibitor of the cytochrome P3A3/4 isoenzyme (CYP3A3/4). 11 CYP3A3/4 is responsible for the metabolism of several cardiac medications, including statins. There have been case reports of nefazodone, which is a potent inhibitor of CYP3A4, causing myopathy and rhabdomyolysis with concurrent use of simvastatin. 12 Therefore, it is plausible that fluvoxamine, which is also an inhibitor of CYP3A4, could have caused the episode of atypical chest pain in our patient secondary to myalgia from the drug interaction with simvastatin. However, it is of note that her pain was localized to the left chest wall rather than generalized, which would be more characteristic of myalgia.
Unexplained somatic symptoms as a manifestation of depression
Depression is a common comorbidity in patients with cardiac disease. 11 However, studies have shown that cardiac patients’ reports of depressive symptoms tend to be less typical with more likely complaints being of unexplained somatic symptoms, including atypical chest pain. 13 They also tend to attribute somatic symptoms of their depression to their cardiac disease. Considering the normal investigations in our patient, it is possible that her episode of atypical chest pain was a somatic manifestation of her depression. However, we were unable to elicit a psychosocial stressor preceding the development of her chest pain. Furthermore, she did not have any other somatic complaints, making somatization unlikely in this case.
Chest pain secondary to underlying anxiety
A World Health Organization study found that depression and anxiety were the most common co-occurrence amongst psychological problems, 14 with up to 85% of patients with depression also experiencing anxiety symptoms. 15 Therefore, another consideration is that there was possibly an element of anxiety associated with our patient’s chest pain. However, on detailed history taking, her chest pain was an isolated symptom with no other associated features of panic. She denied experiencing any underlying fear or anxiety concurrent with the chest pain and, again, there was no identifiable stressful trigger related to the onset of her chest pain.
Conclusion
The clear temporal relationship between and reproducibility of the onset of chest pain following ingestion of fluvoxamine is strongly suggestive of an adverse medication effect in our patient. Chest pain as a side effect is not commonly explained to patients when psychiatrists prescribe fluvoxamine. Understandably, when experienced, chest pain can be significantly distressing for a cardiac patient, and this may, potentially, lead to future non-compliance with antidepressants. In addition, as chest pain is taken seriously in the clinical context of cardiac disease, it may lead to extensive and unnecessary investigations for patients. We suggest the need for more studies into the association of fluvoxamine with chest pain.