1. Introduction

Beta-blockers are widely used for the treatment of cardiovascular and non-cardiovascular conditions ^[1][2][3][1,2,3]. Studies have shown that about 30% of the elderly are on beta-blocker treatment, hence the need to deepen the pharmacokinetic features [4]. The neuropsychiatric and cognitive effects of beta-blockers were proven many years ago. However, the evidence is limited by the use in trials of pharmaceutical preparations or different doses, but also by the application of different questionnaires of cognitive assessment ^[5][6][7][5,6,7]. The side effects on the central nervous system are heterogeneous, difficult to measure in clinical trials, and often require a prolonged follow-up. Both neuropsychiatric side effects and primary neurodegenerative diseases are common in patients with cardiovascular disease, making it difficult to attribute the symptoms to a concrete cause ^{[8][9][10][11]}[8,9,10,11].

The lipophilic property of some beta-blockers is the ability of the drug to diffuse through the blood–brain barrier [12]. First, the agent must cross it and attach directly to the beta-adrenergic receptors, the suppression of which it mediates. Second, the drug must also interact with non-adrenergic receptors, blocking their signals or destabilizing the cell membrane [13]. Highly lipophilic beta-blockers, such as propranolol, diffuse rapidly through the brain tissue compared to hydrophilic beta-blockers, such as atenolol, which lacks this property [3].

2. Central Nervous System Therapeutic Effects

2.1. Migraine

The migraine, characterized by recurrent episodes of moderate–severe headache lasting 4–72 h, is a common disease that affects 15% of the general population ^[14][15][75,76]. Prophylactic therapy is aimed at patients with at least two episodes lasting more than 24 h/month and side effects despite the acute treatment of the headache ^[16][77]. Data from randomized clinical trials show that beta-blockers, in particular propranolol, metoprolol, and timolol, are effective in the prevention of chronic migraine. For hypertensive, non-smoking patients under the age of 60, beta-blockers are a reasonable option as first-line prophylactic medications ^[17][78]. A recently published meta-analysis evaluating the efficacy of various therapeutic classes in the management of vestibular migraine (antiepileptics, calcium channel blockers, beta-blockers, and serotonin reuptake inhibitors) showed that beta-blockers were associated with the best improvement regarding the symptoms ^[18][79].

2.2. Tremor

The tremor is defined as the involuntary, rhythmic, and oscillating movement of a body segment ^[19][80]. Essential tremor, the most common cause of acting tremor in adults, can be partially treated symptomatically. Propranolol monotherapy has been shown to be effective. Doses of 120–240 mg/day may reduce the severity of limbs tremor associated with essential tremor ^[20][81]. According to the results of randomized clinical trials, propranolol may reduce tremor amplitude by approximately 55%, measured with the accelerometer. A clinical trial showed that the association of primidone reduced the tremor amplitude by 60%, thus providing additional benefits ^[21][82]. The dual combination of propranolol and primidone has been shown to be more effective than monotherapy in the treatment of postural and kinetic tremor ^[22][83].

2.3. Akathisia and Alcohol or Benzodiazepine Withdrawal Syndrome

Akathisia is a clinical syndrome characterized by the feeling of inner discomfort and an imperative need for movement ^[23][84]. Acute akathisia most often occurs as a side effect of drugs, such as neuroleptics, selective serotonin reuptake inhibitors, or calcium channel blockers. Symptoms with a prolonged duration over 3 months characterize chronic forms, late akathisia, or abstinence ^[24][85]. Treatment of akathisia is difficult. Prevention and proper dose adjustment for drugs with this side effect are the most important strategies. Propranolol is the first line of treatment for acute forms of akathisia ^[25][86]. Atenolol, by reducing the symptoms of autonomous hyperactivity, is only an adjuvant measure in patients with alcohol or benzodiazepine withdrawal syndrome, with no proven benefit over delirium or seizures ^[26][87].

2.4. Anxiety and Posttraumatic Stress Syndrome

Propranolol was the first anxiolytic generally studied, but the interest has declined as selective serotonin reuptake inhibitors have become the first-line pharmacological treatment across the range of anxiety disorders ^[27][88]. Propranolol selectively blocks protein synthesis, thereby prohibiting the ‘reconsolidation’ of the fear memory while sparing declarative memory ^[28][89]. A meta-analysis suggests that propranolol has potential for the treatment of anxiety disorders that are rooted in the presence of disturbing memories, particularly posttraumatic stress disorder ^[29][90]. The administration of propranolol in the first 6 h after trauma significantly reduces the risk of developing posttraumatic stress disorder ^[30][31][91,92]. Propranolol is currently considered an amnesic agent used to reduce traumatic memory rather than a general anxiolytic ^[32][93].

Treatment with atenolol in association with scopolamine (antimuscarinic agent) has been proposed as a fast-acting anxiolytic, useful in the management of acute anxiety, especially before medical procedures (dental, minimally invasive) ^[33][94]. Recent data from a retrospective study suggest that atenolol may achieve the control of the symptoms in patients with anxiety or posttraumatic stress disorder, with reported efficacy of up to 86% at doses of 100 mg/day. The main advantage is the better tolerability to propranolol, but the disadvantage is that, so far, there are no randomized clinical trials regarding this topic ^[34][95].

2.5. Aggression

Aggression is a motor and visceral social behavior that consists of directing aggressive stimuli, physical or mental, of attacking an individual or for defense. Overall, the evidence for any successful treatment of aggression with any agent, or class of agents, is limited. Beta-blockers appear to be a well-tolerated class of drugs in patients with aggression related to traumatic brain injury ^[35][96]. Furthermore, beta-blockers appear to be effective in reducing aggression among patients with a variety of neuropsychiatric conditions, such as schizophrenia, dementia, or behavioral disorders ^[36][37][38][97,98,99].

2.6. Obsessive–Compulsive Disorder

Obsessive–compulsive disorder is characterized by intrusive and inappropriate obsessions accompanied by repetitive behavioral or mental compulsions ^[39][100]. Specific treatment with selective serotonin reuptake inhibitors or tricyclic antidepressants is effective in 80% of cases, and 20% of them have a partial response ^[40][101]. Pindolol, although it has antagonistic action on presynaptic 5-hydroxytryptamine 1A receptors, may have serotonergic effects due to its sympathomimetic activity ^[41][102]. Pindolol amplifies the effect of selective serotonin reuptake inhibitors and thus has been used adjunctively to enhance the benefits of selective serotonin reuptake inhibitors in obsessive–compulsive disorder and panic disorders refractory to standard therapy ^[40][41][42][101,102,103].

3. Future Perspectives and Conclusions

Beta-blockers are a class of drugs with important benefits in cardiovascular pathology, mainly by reducing mortality. The number of patients with psychiatric disorders is increasing, and the elderly are one of the most affected categories. Thus, for the recommendation of beta-blockers in various pathologies (migraine, tremor, akathisia, anxiety, aggression, or obsessive–compulsive disorder), there are both pros and cons. Starting from these neuropsychiatric consequences (fatigue, depression, sleep disorders and nightmares, hallucinations, delirium, Parkinson’s disease, or the risk of falling), we suggest to the clinicians to apply special attention to the pharmacological characteristics of the different agents in the class. Hydrophilic beta-blockers may be an option in selecting the appropriate beta-blocker for the elderly patient, but further studies are needed to accurately identify patients at high risk of side effects on the central nervous system. However, the therapeutic effect of some lipophilic beta-blockers in the management of neuropsychiatric disorders is not negligible. At the same time, it is important to use beta-blockers in well-established and correct indications, in appropriate doses for each patient, and to monitor side effects throughout the treatment. Further studies regarding the benefits of lipophilic beta-blockers are needed. Thus, competent European and worldwide committees could take them into account and maybe include all the above in a guideline as a higher-class recommendation. Moreover, this paper is a place to start for researchers in the field, highlighting the fact that not only the type of beta-blocker matters but also the dosage, all being individualized for each patient profile.