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

What the lisinopril label says about mood

The lisinopril prescribing information has a psychiatric line. Under post-marketing experience, it lists, for nervous system and psychiatric disorders: mood alterations (including depressive symptoms), mental confusion and hallucinations [1]. That same section states these reactions are reported voluntarily from a population of uncertain size, so their frequency cannot be reliably estimated and a causal relationship to the drug cannot always be established [1].

A voluntary report is not a measured rate. The rates come from the controlled trials, and there the reactions that beat placebo by at least 2 percentage points were headache (3.8% more), dizziness (3.5% more) and cough (2.5% more) [1]. Mood was not among them. In the hypertension trials, 5.7% of patients stopped lisinopril because of adverse reactions [1].

What the large lisinopril trials measured

ALLHAT randomized 33,357 adults aged 55 or older with hypertension and at least one other coronary risk factor to chlorthalidone 12.5 to 25 mg, amlodipine 2.5 to 10 mg, or lisinopril 10 to 40 mg (n=9,054), with a mean follow-up of 4.9 years. The primary outcome was fatal coronary heart disease or nonfatal myocardial infarction, and secondary outcomes included all-cause mortality, stroke and heart failure [2].

GISSI-3 randomized 19,394 patients within 24 hours of an acute myocardial infarction to lisinopril (5 mg then 10 mg daily) or open control, in a factorial design with nitrates. Overall six-week mortality was 6.7%, and lisinopril reduced mortality (odds ratio 0.88, 95% CI 0.79 to 0.99) [3].

ATLAS randomized 3,164 patients with heart failure and an ejection fraction of 30% or less to low-dose (2.5 to 5 mg) or high-dose (32.5 to 35 mg) lisinopril for 39 to 58 months. Dizziness and renal insufficiency were seen more often on the high dose [5].

The outcomes in all three were cardiovascular: death, heart attack, stroke, hospitalization, ventricular function.

Comparing drug classes in a 2016 hospital database

Boal and colleagues, in Hypertension in 2016, used a hospital database of 525,046 patients to ask whether antihypertensive monotherapy was followed by hospital admission for a mood disorder. Of these, 144,066 patients aged 40 to 80 who took a single antihypertensive for more than 90 days were eligible; there were 299 admissions over 641,685 person-years of follow-up, with a median time to admission of 847 days [4].

Patients on ACE inhibitors or angiotensin receptor blockers had the lowest risk. Compared with that group, beta-blockers carried a hazard ratio of 2.11 (95% CI 1.12 to 3.98; P=0.02) and calcium channel blockers 2.28 (1.13 to 4.58; P=0.02). Thiazide diuretics (1.56; 0.65 to 3.73) and no antihypertensive at all (1.63; 0.94 to 2.82) were not significantly different [4]. The authors described the findings as exploratory.

Two limits matter. The ACE inhibitor group was pooled with ARBs, so nothing in this study is specific to lisinopril. And the outcome was a hospital admission for a mood disorder, a severe endpoint, not day-to-day mood scores.

Fatigue and dizziness

The label lists fatigue, asthenia and orthostatic effects among other clinical adverse reactions occurring in 1% or more of patients with hypertension or heart failure in controlled trials, without giving a separate percentage for them [1]. Dizziness does have numbers: 3.5% more than placebo in the hypertension trials [1], and in ATLAS 19% on high dose versus 12% on low dose, with hypotension 11% versus 7%, creatinine increase 10% versus 7%, hyperkalemia 6% versus 4% and syncope 7% versus 5% [1][5].

Cognition and dementia: class data, not lisinopril data

The dementia trial discussed here tested a different ACE inhibitor. PROGRESS randomized 6,105 people with prior stroke or transient ischemic attack to perindopril for all participants, plus indapamide where there was no contraindication, or placebo, for a mean of 3.9 years. Dementia occurred in 6.3% of the active group and 7.1% of placebo (relative risk reduction 12%, 95% CI -8% to 28%; P=0.2). Cognitive decline, defined as a drop of 3 or more points on the Mini-Mental State Examination, occurred in 9.1% versus 11.0% (risk reduction 19%, 95% CI 4% to 32%; P=0.01) [6]. Cognitive decline was significantly less common with active treatment, while the reduction in dementia was not statistically significant. The clearest effects were seen in outcomes that included recurrent stroke, with no clear effect on dementia or cognitive decline in the absence of recurrent stroke [6].

Because PROGRESS used perindopril plus indapamide, it cannot establish a cognitive effect of lisinopril either way. A review describes possible links between the brain renin-angiotensin system and Alzheimer disease but also notes large gaps in understanding [7].

Depression and the renin-angiotensin system

Murck and colleagues compared 7 medication-free patients with depression to 7 age-matched controls, sampling hormones every 20 minutes overnight alongside a sleep EEG. ACTH and renin did not differ between groups. Cortisol showed a trend toward an increase in the first half of the night (P<0.06), and aldosterone was higher in both halves (P<0.05 and P<0.01). The authors suggested hyperaldosteronism could be a marker for depression [8]. No one in that small study was taking lisinopril, so it says nothing directly about the drug's effect on mood.

Lithium: the psychiatric interaction in the label

The psychiatric-drug interaction the lisinopril label addresses is lithium. Lithium toxicity has been reported in patients taking lithium with drugs that cause sodium elimination, including ACE inhibitors, and was usually reversible when lithium and the ACE inhibitor were stopped. The label says to monitor serum lithium levels during concurrent use [1]. The label's other listed interactions are diuretics, antidiabetic medicines, NSAIDs including COX-2 inhibitors, dual renin-angiotensin blockade, injectable gold, mTOR inhibitors and neprilysin inhibitors such as sacubitril, which is contraindicated with lisinopril [1].

Bottom line

The label lists mood alterations, including depressive symptoms, plus mental confusion and hallucinations as post-marketing psychiatric reports, without a rate or an established cause [1]. The one comparison of drug classes is observational and pooled, and it places ACE inhibitors and ARBs at lower risk of hospital admission for mood disorders than beta-blockers or calcium channel blockers [4]. The measured lisinopril effects with numbers are dizziness and hypotension, and the one psychiatric-drug interaction the label calls out is lithium [1][5].