Does mirtazapine (Remeron) affect blood pressure?

Comment by InpharmD Researcher

Mirtazapine’s impact on blood pressure remains inconclusive, with some studies reporting possible orthostatic hypotension in a small percentage of patients, while others show no significant effect. Despite the cautionary note in the prescribing information for mirtazapine regarding its use in patients with known cardiovascular disease, the overall evidence indicates that mirtazapine is generally considered safe for most cardiovascular patients, at least in the short term. However, it is still recommended to be mindful of the potential for autonomic dysregulations when treating patients with mirtazapine.

Background

A 2021 literature review summarizes how antidepressant drugs may influence blood pressure, including potential effects caused by norepinephrine-serotonin modulators, such as mirtazapine. It has been reported that mirtazapine may cause orthostatic hypotension in approximately 7% of treated patients. However, conflicting findings exist in the literature, with other studies showing no significant effect on blood pressure. As a result, mirtazapine has recently been considered a safe drug for cardiovascular patients. Although prescribing information cautions starting use in patients with known cardiovascular disease, there is limited evidence on mirtazapine use contributing to an effect on blood pressure, with rare cases of orthostatic hypotension reported in connection with mirtazapine use. [1]

A 2020 qualitative narrative review examines the cardiovascular effects of 12 newer non-selective serotonin reuptake inhibitors (SSRIs) in older adults and patients with, or who have a high-risk for, cardiovascular disease (CVD). The review includes a randomized controlled trial that examined the efficacy and safety of 15 to 45 mg/day mirtazapine over 24 weeks in adult patients hospitalized with a myocardial infarction who also had depression (N= 331). The results from the trial showcased that there were no significant differences in blood pressure between patients treated with mirtazapine and the placebo group. This finding indicates that mirtazapine may not have a significant impact on blood pressure in patients with a history of CVD, and may be safe in these subjects, at least in the short-term. [2], [3]

A 2015 open-label, uncontrolled, prospective study evaluated the efficacy and tolerability of mirtazapine in patients with major depressive disorder (MDD). The study consisted of 93 patients with a diagnosis of MDD and a Hamilton Depression Rating Scale (HDRS) score of ≥ 14. The patients received mirtazapine for a six-week period and were assessed at baseline, one, two, four, and six weeks. The starting dosage of mirtazapine was 11.5 ± 6.4 mg/day and patients were titrated to a maintenance dosage of 23.1 ± 9.4 mg/day. Pertaining to blood pressure, the results showcased that there was no significant difference in systolic blood pressure during the trial period (from 119.5 ± 5 to 118.8 ± 12.0 mmHg, mean change −1.27 ± 7.7 mmHg, p= 0.222). However, diastolic blood pressure had a minor but statistically significant decrease from 77.1 ± 9.4 mmHg to 75.9 ± 8.9 mmHg (mean change −2.4 ± 8.1 mmHg, p= 0.031). Although this decrease in diastolic blood pressure had statistical significance, it was not clinically significant. [4]

A 2002 randomized, placebo-controlled study investigated the influence of acute oral administration of 15 mg mirtazapine on cortisol, corticotropin, growth hormone, and prolactin secretion in six healthy male subjects. Mean arterial blood pressure (MAP) was used to evaluate the blood pressure effects of mirtazapine. MAP was recorded at baseline and blood samples were drawn 1 hour before mirtazapine or placebo administration, at the time of administration, and every hour for 12 hours following administration. There were no significant differences found in the effects of mirtazapine 15 mg vs. placebo on MAP (p= 0.418) or heart rate (p= 0.968). The MAP area under the curve (AUC) after administering mirtazapine was 1,111.81 ± 102.02 mmHg x hour, while under placebo conditions, the MAP AUC was 1,155.05 ± 72.70 mmHg x hour. [5]

Relevant Prescribing Information

WARNINGS AND PRECAUTIONS
Serotonin Syndrome: Serotonergic antidepressants, including mirtazapine tablets, can precipitate serotonin syndrome, a potentially life-threatening condition. Serotonin syndrome signs and symptoms may include mental status changes (e.g., agitation, hallucinations, delirium, and coma), autonomic instability (e.g., tachycardia, labile blood pressure, dizziness, diaphoresis, flushing, hyperthermia), neuromuscular symptoms (e.g., tremor, rigidity, myoclonus, hyperreflexia, incoordination), seizures, and gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea). [6]

Use in Patients with Concomitant Illness: Mirtazapine tablets have not been systematically evaluated or used to any appreciable extent in patients with a recent history of myocardial infarction or other significant heart disease. Mirtazapine tablets were associated with significant orthostatic hypotension in early clinical pharmacology trials with normal volunteers. Orthostatic hypotension was infrequently observed in clinical trials with depressed patients. Mirtazapine tablets should be used with caution in patients with known cardiovascular or cerebrovascular disease that could be exacerbated by hypotension (history of myocardial infarction, angina, or ischemic stroke) and conditions that would predispose patients to hypotension (dehydration, hypovolemia, and treatment with antihypertensive medication). [6]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Does mirtazapine affect blood pressure?

Please see Tables 1-2 for your response.

Hypertensive Urgency After Administration of A Single Low Dose of Mirtazapine-A Case Report
Design	Retrospective case report
Case presentation	A 73-year-old man with a 25-year past medical history of hypertension, who takes 5 mg amlodipine for 10 years, presented to the emergency department complaining of severe headache and vertigo one hour after taking a single dose of mirtazapine 7.5 mg. Prior to admission, his blood pressure was controlled at 120–130/70–80 mmHg on amlodipine 5 mg for the previous 10 years. The patient was also taking aspirin 100 mg daily at home. There was no reported history of tuberculosis, HIV infection, diabetes mellitus, hyperlipidemia, or other major organ disease. At the time of presentation, he complained of shortness of breath, chest distress, and sweating. Physical examination was significant in a pale appearance. His blood pressure was 215/145 mmHg, heart rate 116 beats/min, respiratory rate 35 breaths/min, and tympanic temperature 36.5 °C. Sinus rhythm and infrequent premature atrial contractions were present on the electrocardiogram. Twenty minutes after treatment with 50 mg of urapidil the blood pressure decreased to 180/105 mmHg, heart rate 96 beats/min, respiratory rate 22 breaths/min. Shortness of breath, chest distress, and headache were all alleviated after treatment. After an hour the patient’s complexion appeared less pale but he was still lacking in strength. His blood pressure returned to 145/92mmHg with his heart rate decreasing to 84 beats/min. After an overnight stay, the patient was discharged with alprazolam 0.4 mg in place of the mirtazapine and instructed to monitor his blood pressure once a day. At follow-up, the patient reported a blood pressure of 132/74 mmHg and no other complaints. The relationship between the patient’s hypertensive urgency and mirtazapine was probable according to the Narajio adverse drug reaction probability scale.
Study Author Conclusions	With numerous types of research, mirtazapine shows positive features in terms of efficacy, safety, and tolerability. Although a few hypertensive events were reported, pharmacists and physicians must be aware of potential drug interactions, especially in patients with cardiovascular risk. Plasma concentrations of mirtazapine would be monitored in those patients with combination therapy of antihypertensive agents.

References:

Shi J, Wang X, Ying Y, Xu L, Zhu D. Hypertensive urgency after administration of a single low dose of mirtazapine-a case report. Iran J Public Health. 2015;44(2):282-284

Heart Rate Variability During Antidepressant Treatment With Venlafaxine and Mirtazapine
Design	Open-label, randomized study N= 72
Objective	To compare the influence of venlafaxine or mirtazapine on the autonomic regulation of the heart, using heart rate variability (HRV), blood pressure (BP), and heart rate (HR) as outcome parameters
Study Groups	Control (n= 28) Mirtazapine (n= 24) Venlafaxine (n= 20)
Inclusion Criteria	Adult inpatients with a major depressive episode diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and a score of at least 18 points on the Hamilton Depression Rating Scale (HDRS, 21 items) after a 6-day washout period; non-depressed subjects for control
Exclusion Criteria	Lifetime diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder and current substance dependence; drugs that may affect HRV, BP, or HR; cardiac pacemakers and known arrhythmia
Methods	Inpatient subjects were randomized to either venlafaxine or mirtazapine. Three patients who were given venlafaxine or mirtazapine before and were either not tolerating or responding to these drugs were assigned in an open-label design to the alternative. Additional subjects were recruited by ads to serve as healthy controls in comparison to treatment arms. A 6-day washout period was given to eliminate the potential inclusion of other psychotropic agent use. Dosages ranged from 150 to 300 mg for venlafaxine and 30 to 75 mg for mirtazapine.
Duration	Study treatment: 28 days
Outcome Measures	Time-dependent changes in the HRV frequency domain parameters total power (TP) and relative low-frequency (LF) and high-frequency (HF) power components
Baseline Characteristics		Patients (n= 44)	Control (n= 28)
	Age, years	47.1 ± 13.5	48.0 ± 13.1
	BP diastolic at rest, mmHg	72.2 ± 11.4	70.2 ± 8.6
	BP diastolic standing, mmHg	77.1 ± 11.7	76.0 ± 9.1
	BP systolic at rest, mmHg	118.1 ± 24.0	117.2 ± 13.9
	BP systolic standing, mmHg	120.0 ± 20.6	124.0 ± 15.9
	HR at rest, bpm	73.2 ± 11.3	62.4 ± 8.7
	HR standing, bpm	87.9 ± 14.4	73.6 ± 11.7
	LF/HF at rest	3.14 ± 3.11	1.27 ± 1.12
	LF/HF standing	9.34 ± 11.08	4.84 ± 4.57
	TP at rest, m/s²	578 ± 684	3,607 ± 8,512
	TP standing, m/s²	1,163 ± 2,362	2,385 ± 5,286
	bpm, beats per minute Mirtazapine and venlafaxine were reported in one cohort for baseline characteristics.
Results	Endpoint (Day 28)	Mirtazapine (n= 24)	Venlafaxine (n= 20)	p-value
	LF/HF at rest	3.30 ± 4.56	2.92 ± 2.79	0.072
	LF/HF at activation	9.17 ± 8.93	9.30 ± 11.74	NS
	TP at rest, m/s²	379 ± 698	370 ± 344	0.0006
	TP at activation, m/s²	695 ± 868	501 ± 607	0.0018
	BP diastolic at rest, mmHg	71.4 ± 12.1	73.9 ± 12.1	NS
	BP diastolic at activation, mmHg	79.7 ± 13.3	81.2 ± 12.6	NS
	BP systolic at rest, mmHg	122.1 ± 20.1	126.1 ± 19.0	0.035
	BP systolic at activation, mmHg	121.7 ± 22.9	123.0 ± 21.7	NS
	HR at rest, bpm	81.3 ± 11.5	78.8 ± 10.2	0.002
	HR at activation, bpm	94.7 ± 12.2	89.9 ± 13.0	0.063
	NS, not significant P-value is given for the difference in treatment influence in comparison to control, not between medication arms.
Adverse Events	See result
Study Author Conclusions	Both mirtazapine and venlafaxine may lead to sympathetic activation after 28 days of treatment. Clinicians are advised to consider autonomic dysregulation while treating with venlafaxine or mirtazapine.
InpharmD Researcher Critique	Although randomized, this study has a small sample size and was open-label in design. The baseline characteristics of patients in the treatment arms were not separated to determine potential causal factors, and inclusion criteria were also not clearly listed. Systolic BP at rest was the only finding to be statistically significant on day 28 of therapy.

References:

Terhardt J, Lederbogen F, Feuerhack A, et al. Heart rate variability during antidepressant treatment with venlafaxine and mirtazapine. Clin Neuropharmacol. 2013;36(6):198-202. doi:10.1097/WNF.0b013e3182a76fbb