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Amlodipine Mental Health and Mood Impact: What the Evidence Actually Shows

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At a glance

  • Drug class / Dihydropyridine calcium channel blocker; peripheral arterial vasodilator [1]
  • Psychiatric events in the label / Depression, anxiety, insomnia, nervousness, abnormal dreams, depersonalization — 0.1% to 1%, cause uncertain [1]
  • Fatigue in placebo-controlled trials / 4.5% vs 2.8% on placebo [1]
  • Somnolence / 1.4% vs 0.6% on placebo [1]
  • Stopped for side effects / About 1.5% vs about 1% on placebo, at doses up to 10 mg daily [1]
  • Boxed warning / None; the only contraindication is known sensitivity to amlodipine [1]
  • Heart rate with chronic dosing / No clinically significant change in trials [1]

What the label says about mood

The Norvasc (amlodipine besylate) label, in the version effective 15 February 2023, places a group of psychiatric events in its low-frequency band: more than 0.1% and less than 1% of patients in controlled trials or marketing experience, where a causal relationship is uncertain [1]. That band covers sexual dysfunction in men and women, insomnia, nervousness, depression, abnormal dreams, anxiety and depersonalization [1].

The reactions the label does tie to dose look quite different. Edema, dizziness, flushing and palpitation rise with dose: edema in 1.8%, 3.0% and 10.8% of patients at 2.5, 5 and 10 mg versus 0.6% on placebo; dizziness in 1.1%, 3.4% and 3.4% versus 1.5%; flushing in 0.7%, 1.4% and 2.6% versus 0.0%; palpitation in 0.7%, 1.4% and 4.5% versus 0.6% [1]. No psychiatric event appears in that table [1].

Above 1% and not clearly dose related, the label reports fatigue in 4.5% versus 2.8% on placebo, nausea in 2.9% versus 1.9%, abdominal pain in 1.6% versus 0.3% and somnolence in 1.4% versus 0.6% [1]. About 1.5% of patients stopped amlodipine for adverse reactions versus about 1% on placebo, in trials using doses up to 10 mg daily [1].

A 0.1% to 1% band labelled with uncertain causality cuts both ways. It does not show that amlodipine causes depression, and it does not clear the drug either. The label's counts of reported events are the main evidence on this question.

Sleep, energy and daytime drowsiness

Insomnia sits in that same 0.1% to 1% psychiatric group [1]. Drowsiness is the more common complaint: somnolence was reported in 1.4% of amlodipine patients versus 0.6% on placebo, and it was reported more often by women (1.6% versus 0.3% on placebo) than by men (1.3% versus 0.8%) [1]. Fatigue ran at 4.5% versus 2.8% [1]. These are counts of reported events rather than sleep-quality scores [1].

Amlodipine versus a beta-blocker

A small study measured how atenolol affected overnight excretion of a melatonin metabolite; it did not measure sleep quality or mood [2]. In a randomized, double-blind, placebo-controlled crossover study of 15 healthy volunteers given single oral doses, the beta-blocking (S)-enantiomer of atenolol 50 mg reduced overnight urinary 6-sulfatoxymelatonin by 86% (P<0.01), and (S)-propranolol 40 mg reduced it by 80% (P<0.001) [2]. Verapamil 120 mg did not reduce it (14% higher than placebo, not significant), and amlodipine was not among the drugs tested [2].

The largest head-to-head trial, ASCOT-BPLA, randomized 19,257 patients with hypertension and at least three other cardiovascular risk factors to an amlodipine-based regimen (amlodipine 5-10 mg, adding perindopril as required; 9,639 patients) or an atenolol-based regimen (atenolol 50-100 mg, adding bendroflumethiazide and potassium as required; 9,618 patients) [3]. It stopped early at a median 5.5 years: total cardiovascular events and procedures were 1,362 versus 1,602 (HR 0.84, 95% CI 0.78-0.90) and all-cause mortality 738 versus 820 (HR 0.89, 95% CI 0.81-0.99) [3]. Its reported outcomes were cardiovascular events, stroke, mortality and new diabetes [3].

Memory and thinking

The label's psychiatric list stops at sexual dysfunction, insomnia, nervousness, depression, abnormal dreams, anxiety and depersonalization [1]. Its central and peripheral nervous system list covers hypoesthesia, peripheral neuropathy, paresthesia, tremor and vertigo [1]. Postmarketing reports describe a possible association with extrapyramidal disorder, again with causality uncertain [1].

Doses and label warnings

The label gives a usual adult starting dose of 5 mg once daily with a maximum of 10 mg once daily; it says small, fragile or elderly patients, patients with hepatic insufficiency, and patients adding amlodipine to other antihypertensives may start at 2.5 mg once daily [1]. Its warnings concern the circulation rather than mood: symptomatic hypotension is possible, particularly in severe aortic stenosis, and worsening angina or myocardial infarction can occur after starting or increasing the dose in severe obstructive coronary artery disease [1].

Frequently asked questions

Can amlodipine cause depression?
The Norvasc label lists depression among events seen in more than 0.1% and less than 1% of patients, where a causal relationship is uncertain [1]. Depression is not among the reactions the label ties to dose [1].
Does amlodipine cause anxiety or panic attacks?
Anxiety and nervousness are both in that 0.1% to 1% group with causality uncertain [1]. With chronic oral dosing the label reports no clinically significant change in heart rate or plasma catecholamine levels, while palpitation was dose related at 0.7%, 1.4% and 4.5% on 2.5, 5 and 10 mg versus 0.6% on placebo [1].
Can amlodipine cause insomnia?
Insomnia is listed at 0.1% to 1% with uncertain causality, and somnolence was reported in 1.4% versus 0.6% on placebo [1]. The label's sleep entries are counts of reported events rather than sleep-quality scores [1].
Is amlodipine better for mood than atenolol?
Neither the amlodipine label nor ASCOT-BPLA gives a mood comparison. In a study of 15 healthy volunteers, a single dose of (S)-atenolol reduced overnight excretion of a melatonin metabolite by 86%; (R)-atenolol did not, and amlodipine was not tested [2]. ASCOT-BPLA compared cardiovascular events, stroke, mortality and new diabetes [3].
Does amlodipine affect memory?
The label's psychiatric list covers mood and sleep terms, and its nervous-system list covers hypoesthesia, peripheral neuropathy, paresthesia, tremor and vertigo [1]. Somnolence was reported in 1.4% versus 0.6% on placebo [1].

References

  1. U.S. National Library of Medicine, DailyMed. Norvasc amlodipine besylate tablets (Viatris Specialty) prescribing information. Norvasc amlodipine besylate tablets (Viatris Specialty) label
  2. Stoschitzky K, Sakotnik A, Lercher P, Zweiker R, Maier R, Liebmann P, et al. Influence of beta-blockers on melatonin release. Eur J Clin Pharmacol. 1999;55(2):111-5. Influence of beta-blockers on melatonin release
  3. Dahlöf B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366(9489):895-906. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial
Evidence overview for amlodipine: Amlodipine Mental Health and Mood Impact: What the Evidence Actually Shows