Antihypertensive drugs and brain function: mechanisms underlying therapeutically beneficial and harmful neuropsychiatric effects

Abstract

A bidirectional relationship exists between hypertension and psychiatric disorders, including unipolar and bipolar depression, anxiety, post-traumatic stress disorder (PTSD), psychosis, schizophrenia, mania, and dementia/cognitive decline. Repurposing of antihypertensive drugs to treat mental disorders is thus being explored. A systematic knowledge of the mechanisms of action and clinical consequences of the use of antihypertensive agents on neuropsychiatric functions has not been achieved yet. In this article, we review the putative role of antihypertensive agents in psychiatric disorders, discuss the targets and mechanisms of action, and examine how and to what extent specific drug classes/molecules may trigger, worsen, or mitigate psychiatric symptoms. In addition, we review pharmacokinetics (brain penetration of drugs) and pharmacogenetics data that add important information to assess risks and benefits of antihypertensive drugs in neuropsychiatric settings. The scientific literature shows robust evidence of a positive effect of α1 blockers on PTSD symptoms, nightmares and sleep quality, α2 agonists on core symptoms, executive function and quality of life in Attention-Deficit/Hyperactivity Disorder, PTSD, Tourette’s syndrome, and β blockers on anxiety, aggression, working memory, and social communication. Renin-angiotensin system modulators exert protective effects on cognition, depression, and anxiety, and the loop diuretic bumetanide reduced the core symptoms of autism in a subset of patients. There is no evidence of clear benefits of calcium channel blockers in mood disorders in the scientific literature. These findings are mainly from preclinical studies; clinical data are still insufficient or of anecdotal nature, and seldom systematic. The information herewith provided can support a better therapeutic approach to hypertension, tailored to patients with, or with high susceptibility to, psychiatric illness. It may prompt clinical studies exploring the potential benefit of antihypertensive drugs in selected patients with neuropsychiatric comorbidities that include outcomes of neuropsychiatric interest and specifically assess undesirable effects or interactions.

Cardiogenic control of affective behavioural state

“…We show that the optically induced tachycardia was not intrinsically aversive, but rather elicited anxiety-like behaviours and apprehension in potentially risky environments. Although diverse mechanisms may contribute to this effect, we consider that anxiogenic effects of evoked tachycardia are not likely to be mediated through a reduction in blood pressure 51 , as drugs that reduce systolic blood pressure tend to be anxiolytic (for example, propranolol and clonidine) or neutral (for example, Ca 2+ -channel blockers). Our observation of anxiogenesis in response to increased heart rates (900 bpm or 15 Hz) is in line with clinical observations that accelerated heart rates-but not other forms of altered haemodynamics (for example, increased heart rate variability)are associated with panic and other anxiety-related disorders 52,53 .…”

Edible mushrooms as potential functional foods in amelioration of hypertension

“…Hypercalcemia, excess fluid loss, heart palpitations, dizziness, fatigue, and swelling are common side effects of antihypertensives. These drugs potentially cross blood–brain barrier and blood cerebrospinal fluid barrier, thereby exerting psychotropic effects (Carnovale et al, 2022; Hollis et al, 2019). There are rising incidences of pregnancy‐related hypertension called, gestational hypertension and preeclampsia (Ford et al, 2022).…”

Angiotensin‐converting enzymes as druggable features of psychiatric and neurodegenerative disorders

“… Note : References: AbdAlla et al (2013); Ahmad (1996); Anderson (2010); Andrade (2020); Barnes et al (1992); Boal et al (2016); Borsook and Sava (2009); Carnovale et al, 2022; Chrissobolis et al (2020); Currie et al (1990); Diniz et al (2018); Hu and Lin (2021); Ivanova and Tchekalarova (2019); Jo et al (2022); Khoury et al (2012); Min et al (2014); Nocito et al (2020); Saavedra (2012); Saavedra (2021); Thakur et al (2015); Thomas et al (2021); Torika et al (2016); Urmila et al (2021); Vasconcelos et al (2021); Wang et al (2016). …”

“…Interestingly, some studies reported that certain antihypertensive drugs, such as the ACEi captopril or the ARB losartan, could increase the risk of SCZ and psychotic episodes (Ahmad, 1996; Bridenbaugh & Lafft, 1977; Doane & Stults, 2013), while RAS modulators, especially ARBs, demonstrated potential as adjunctive therapy to the currently available antipsychotic medications for SCZ treatment (Anderson, 2010; Benicky et al, 2011; Carnovale et al, 2022; Fan et al, 2017; Thakur et al, 2015; Wincewicz & Braszko, 2014). Interestingly, the influence of sex on inflammatory and oxidative changes was evaluated in a two‐hit model for SCZ involving the perinatal immune activation followed by peripubertal unpredictable stress, showing that the ARB candesartan was effective in both males and females, opening new avenues to possibly prevent and control this devasting mental illness (Vasconcelos et al, 2021).…”