Hypertension Induced by Regular Doses of Milnacipran: A Case Report

Milnacipran, a selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SSNRI), generally produces fewer adverse cardiovascular effects than venlafaxine [4]. Nevertheless, mild elevation in blood pressure (BP) has been described, and hypertension has only been associated with a high-dose of milnacipran [6]. To the best of our knowledge, there have been no previous reports of hypertension induced by therapeutic doses of milnacipran. We present the case of a patient with major depressive disorder (MDD) who developed hypertension during treatment with regular therapeutic doses of milnacipran.

A 52-year-old female with a history of severe MDD was started on milnacipran 50 mg/day. She had no previous history of hypertension or cardiovascular disease, and she was not taking contraceptives or any other medication. Her BP was 120/70 mmHg and her pulse was 82 bpm. Physical examination and initial laboratory studies were all normal, including: thyroid-stimulating hormone (2.29 uUI/ml); free thyroxine (0.97 ng/dl); serum electrolytes (sodium, 142 mEq/l; potassium, 3.8 mEq/l); glucose, 92 mg/dl; full blood count (hemoglobin, 12.3 g%; hematocrit, 39.3%; leukocytes, 6.200/mm³; platelets, 328.000/mm³); and renal function (urea, 25 mg/dl; creatinine, 0.7 mg/dl). After four weeks of antidepressant treatment, the patient's depressive symptoms had only partially improved, and her daily milnacipran dose was increased to 75 mg/day. The following month, since the patient remained symptomatic, complaining of lack of concentration and irritability, the dose was increased to 100 mg/day. Five weeks after the dose of milnacipran was increased, the patient's MDD went into complete remission; however, she complained of severe occipital headache. On physical examination, her BP was 150/110 mmHg and her pulse was 92 bpm. Antihypertensive agents (diuretic plus angiotensin converting-enzyme inhibitor) were started. The patient's subjective symptoms disappeared, but her BP was still elevated at 140/90 mmHg. In addition to milnacipran, the only other medication the patient was taking was alprazolam (0.5 mg/day at bedtime). Thinking that the milnacipran could have caused the BP elevation, we reduced her daily dose to 75 mg/day. Subsequently, her BP decreased to 130/85 mmHg. We then reduced her milnacipran by 25 mg every week; within one week of completely stopping milnacipran, the patient's BP normalized and her antihypertensive agents were stopped.

The association of hypertension and milnacipran was shown by the presence of two factors: the BP became significantly elevated when the dose of milnacipran was being increased, and the resolution of the hypertension (including the withdrawal of antihypertensive agents) when milnacipran was discontinued. These two factors provide evidence of a temporal association and a dose-dependent relationship between the hypertension and milnacipran. Unfortunately, we did not systematically measure the BP and heart rate over the weeks during which the milnacipran dose was increased, since milnacipran, unlike venlafaxine, has not been previously associated with significant cardiovascular side effects. In our patient, we excluded other possible clinical conditions that are usually associated with hypertension, such as arrhythmia, hyperthyroidism, dehydration, and the use of other medications.

There is a previously published case report of a 53-year-old man who developed hypertension in association with a high dose (150 mg/day) of milnacipran [6]; this dose was 50% higher than that usually prescribed for major depression. Venlafaxine, another SSNRI, has also been associated with a dose-dependent hypertensive effect, particularly at doses higher than 300 mg/day [5].

Milnacipran could elevate BP through mechanisms that are similar to those proposed for venlafaxine, including raising the availability of NA and 5-HT at the post-synaptic receptor. The BP elevation is likely related to 5-HT modulating the peripheral vasculature combined with local contraction caused by NA [2]. The proposed mode of action of all SSNRIs, including venlafaxine, milnacipran, and duloxetine, involves an increase in NA tone and potentiation of noradrenergic transmission [6]. The binding affinity of a drug for various transporters and/or receptors theoretically predicts both the drug's clinical efficacy and its side effect profile. These three SSNRIs block the reuptake of both 5-HT and NA with differing selectivity. Whereas milnacipran blocks 5-HT and NA reuptake with equal affinity [4], the selectivity ratios for NA/5-HT human transporter blockade were 9.4 for duloxetine and 30 for venlafaxine [1].

Our patient had a rather high diastolic blood pressure (110 mmHg). A meta-analysis of 2817 patients taking venlafaxine showed that diastolic blood pressure elevations occurred in 4.8% of patients, while the mean increase in BP was only 1.02 mm Hg [5]. The diastolic blood pressure elevation that was observed could be related to a particular SSNRI effect that is related to alpha 2-adrenergic receptor stimulation by NA in the regulation of systemic vascular capacity and venous return [3].

Given that venlafaxine is well known to be associated with BP elevation and that milnacipran caused a dose-dependent elevation in BP in our patient, this case report should contribute to the discussion of the general risk of BP increase with SSNRI antidepressant treatment, including venlafaxine, milnacipran, and, possibility, duloxetine. At present, we would suggest that patients treated with SSNRIs, even at therapeutic doses, should have their BP carefully monitored.

References

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