Akathisia is a neurological movement disorder characterized by a subjective feeling of inner restlessness or nervousness with an irresistible urge to move, resulting in repetitive movements such as crossing legs, swaying, or constantly switching from one leg to another ^[1][2][1,2]. The first description in the literature dates back to 1901 when the Czech neuropsychiatrist Ladislav Gaskovec described a phenomenon that he called “inability to sit”, which was a non-drug related akathisia [3]. The first report of drug-induced akathisia appeared only in 1960 when Kruse W. described three patients who developed “muscle restlessness” while taking phenothiazines (a group of antipsychotics (APs)) [4]. Akathisia as a symptom can be a part of both hereditary and acquired neurodegenerative diseases.

The most common form of secondary akathisia is drug-induced akathisia [5]. Drug-induced akathisia can develop while taking drugs of various pharmacological groups. However, this drug-induced neurological complication most often develops while taking APs, including first-generation APs (haloperidol and chlorpromazine) and second-generation APs (risperidone, olanzapine, sulpiride, ziprasidone, quetiapine, clozapine, aripiprazole, and amisulpiride) [5].

Therefore, antipsychotic-induced akathisia (AIA) is a movement disorder occurring while taking APs and is characterized by a subjective feeling of inner nervousness with an irresistible urge to move ^[1][2][1,2].

The prevalence of AIA among adult patients with schizophrenia (Sch) varies widely between 0.85% and 55% around the world, while the average prevalence of AIA worldwide is nearly 30% [6].

Thus, AIA is a multifactorial neurological disorder in which both a genetic predisposition and environmental factors play a role. Non-modifiable risk factors for the development of AIA include female sex (for tardive AIA); middle age; and genetic predisposition. In addition, modifiable factors pose a high risk in the development of AIA, such as long-term use of APs; vitamin B6 deficiency; ferritin deficiency; low serum iron; traumatic brain injury; alcohol abuse; autoimmune NMDAR-encephalitis; and cancer. The genetic predisposition to the development of AIA involves the carriage of single nucleotide polymorphisms (SNPs) of genes, which are under the influence of external modifying factors. Based on statistical data, the incidence of SNPs in the population is 3%, thus, when also subject to risk factor conditions, the possibility of AIA increases significantly. The role of SNPs in the mechanism of AIA development has been evaluated for more than 40 years and the number of publications revealing the significance of SNPs in the pathogenesis of AIA continues to increase ^{[7][8][9][10][11]}[7,8,9,10,11]. Thus, the study of the SNPs of other candidate genes associated with AIA in patients with Sch is relevant ^{[12][13][14][15][16]}[12,13,14,15,16].

2. Genes Encoding Key Enzymes in Metabolism of Antipsychotics

Cytochrome P450 (CYP) enzymes of the liver are involved in the metabolism of more than 85% APs ^[17][49]. Many APs undergo several sequential biotransformation reactions. Biotransformation is catalyzed by specific enzyme systems which may also catalyze the metabolism of endogenous substances such as steroid hormones. The liver is the major site of biotransformation, although specific APs may undergo biotransformation primarily or extensively in other tissues ^[18][50]. Most often, APs biotransformation reactions occur in the liver, however, individual APs undergo these reactions to a greater or lesser extent in other organs and tissues of the human body ^[17][49]. APs metabolized via phase I reactions have longer half-lives ^[17][49]. Enzymes catalyzing this phase biotransformation are mostly from the cytochrome P450 system, flavin-containing monooxygenase system, monoamine oxidase, aldehyde and alcohol dehydrogenase, deaminases, esterases, amidases, and epoxide hydratases ^[19][20][51,52]. Oxidation reactions, which occur with CYP enzymes (mixed function oxidases (MFO) or mono-oxygenases), take place in the smooth endoplasmic reticulum (ER) of the cell ^[21][53]. These reactions involve cytochrome P450 reductase, nicotinamide adenine dinucleotide phosphate (NADPH), and oxygen (O2). CYP enzymes also better metabolize APs with a high-fat solubility ^[20][52]. The CYP system is involved in numerous reactions, for example, hydroxylation; dealkylation; deamination; sulfoxidation; and oxidation ^[22][54]. The isoenzymes of the main APs metabolism pathways currently studied in the treatment of Sch are CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 ^[17][49]. Most often, CYP enzymes are in the liver, but they are also founded in other organs and tissues of the human body (for example, in the small and large intestines, testicles or ovaries, duodenum, pancreas, kidneys, spleen, lymph nodes, etc.). The enzymes of the CYP system are in the endoplasmic reticulum in cells. The four phenotypes are distinguished, depending on the metabolic activity of isoenzymes, as extensive (EM—extensive metabolizers), intermediate (IM—intermediate metabolizer), poor (PM—poor metabolizer), and ultrafast (URM—ultrarapid metabolizers) and they are characterized by a normal, intermediate, reduced, and increased ability to metabolize enzyme substrates, respectively ^[23][55]. Carrying low-functional or non-functional SNPs of the genes encoding the hepatic cytochrome of P450 isoenzymes in patients with PM phenotype can greatly affect the metabolic rate of AP in one or more metabolic pathways, or AP with narrow dose ranges, such as haloperidol ^[24][25][26][56,57,58].

3. Genes Encoding the Transport Proteins of Antipsychotics (via the Blood-Brain Barrier)

The transcellular transport of biologically active substances via the blood-brain barrier (BBB) can be carried out in the following ways ^[27][28][59,60]: simple diffusion; facilitated diffusion; endocytosis via receptor-mediated transcytosis; and efflux transport. Efflux is the active removal of a substance from a cell through a protein pump embedded in the cell membrane. Efflux transport is movement in the “brain-blood” direction ^[27][59]. In recent years, much more attention has been paid to studies of this transcellular transport pathway across the BBB ^[29][30][61,62]. The most important transport efflux mechanism is believed to be the carrier-mediated excretion of APs from the brain to blood. BBB endothelial cells contain numerous membrane transporters involved in the influx or efflux of various major substrates such as electrolytes, nucleosides, amino acids, and glucose ^[15][29][31][15,61,63]. Efflux transport is based on the so-called ATP-Binding Cassette (ABC) transport proteins associated with ATP ^[15][31][15,63]. ABC transport proteins have an affinity for a broad category of solutes, especially for large fat-soluble molecules with a number of nitrogen and oxygen atoms in their structure. These ABC transport proteins use ATP hydrolysis to pump molecules across the membrane and, hence, they can cause solute efflux against a concentration gradient ^[15][32][33][15,64,65]. P-glycoprotein (P-gp: ABCB1) and breast cancer-associated protein (BCRP: ABCG2) are the main transporters of ABC efflux in the BBB ^{[30][34][35][36][37]}[62,66,67,68,69]. Active transport proteins of APs efflux across the BBB from the ABC family are increasingly recognized as important determinants of APs’ distribution in the central nervous system (CNS) and their excretion ^[27][34][59,66]. The P-gp, as a transport protein, has shown itself to be a key element of the BBB in most people. It can actively transport a huge number of lipophilic drugs from the endothelial cells of the brain capillaries that form the BBB. In addition to P-gp, other transporter proteins, such as members of the multidrug resistance protein (MRP) family and BCRP, appear to contribute to APs’ efflux across the BBB ^[38][70]. The implications of all these transport proteins at the BBB level include the minimization or prevention of AP-induced neurotoxic adverse drug reactions (ADRs) ^[15][32][33][15,64,65], aggravation of Sch symptoms ^[24][32][56,64], or development of pseudo resistance to APs ^[33][39][65,71]. At the same time, ABC transport proteins may also limit the central distribution of the APs used to treat Sch, increasing the risk of developing therapeutic resistance ^[32][33][35][64,65,67]. Therefore, knowledge of the genetically determined changes in the functional activity and expression of the aforementioned BBB transport proteins can help form a new personalized strategy for predicting the elimination of APs from the brain and provide new therapeutic opportunities for therapeutically resistant Sch. The most studied and clinically significant transport proteins provide APs’ efflux across the BBB and the membrane of target neurons of APs’ action ^[36][40][68,72]. In the case of a genetically determined decrease in the functional activity or expression of the P-gp, BCRP, and Multidrug Resistance-Associated Protein 1 (MRP1) transport proteins at the level of the BBB endothelial cell membranes, the APs’ efflux from the brain into the blood is disturbed to varying degrees (decreases significantly, insignificantly, or moderately) ^[36][68]. This, in turn, leads to an increase in the exposure time of these APs to the brain and an increased risk of cumulation during chronic (long-term) psycho pharmacotherapy, and significantly raises the risk of developing serious AP-induced neurotoxic ADRs ^[32][64]. The accumulation of APs ultimately leads to a slowdown in their metabolism due to the enzymatic system, and therefore the phenotype of such patients with Sch is more often referred to as a PM rather than a poor transporter ^[41][73].

4. Genes Encoding Targets of Antipsychotics

4.1. Key Receptors for Antipsychotics Action

Many pharmacogenetic studies have confirmed the clinical validity and importance of some brain neurotransmitter systems in mediating treatment efficacy and the onset of ADRs. The genetic variability of dopaminergic and serotoninergic receptors plays a significant role in APs’ efficacy ^[23][55]. Based on the fact that a dopaminergic receptor blockade is the leading theory for the development of AIA, the genes of the dopaminergic system are key targets ^[42][74]. At the same time, the pathogenesis of AIA is complex and the serotonergic and glutamatergic systems should also be considered. Thus, the genes of the serotonergic and glutamatergic systems are also key targets ^[43][75].

4.2. Key Enzymes of Antipsychotics Action

Key enzymes are represented by genes encoding Heparan Sulfate Proteoglycan 2 (HSPG2), catechol-O-methyltransferase (COMT), NAD(P)H Quinone Dehydrogenase 1 (NQO1), the Regulator of G Protein Signaling 2 (RGS2), Glutathione S-Transferase Pi 1 (GSTP1), Protein Phosphatase 1 Regulatory Inhibitor Subunit 1B 9 PPP1R1B), Brain-Derived Neurotrophic Factor (BDNF), and Manganese-containing superoxide dismutase (MnSOD).

5. Evidence from a Systematic Review

5.1. The DRD2 Gene

The DRD2 gene is located on the 11q23.2 chromosome and encodes D2-type dopaminergic receptors ^[44][45][79,80]. This gene is predominantly expressed in the brain, most commonly in the basal ganglia, midbrain, cerebral cortex, and pons  ^[7][46][47][7,81,82]. The D2 receptors are members of the G protein-coupled dopamine receptor family, which also includes D1, D3, D4, and D5 receptor types ^[48][83]. They are involved in the modulation of locomotion, reward, reinforcement, memory, and learning. The D2 receptor inhibits the activity of the adenylate cyclase. Abnormalities in the structure of the DRD2 gene have been associated with affective disorders ^[49][84] and with peak dose dyskinesia in patients with Parkinson’s disease (PD) ^[50][85]. A missense mutation in this gene can presumably cause myoclonic dystonia. Other SNPs have been described in patients with Sch. Alternative splicing of the DRD2 results in two transcript variants encoding different isoforms. A third variant has been described, but it has not been determined whether this form is normal due to aberrant splicing or not ^[46][51][81,86]. Researchers found two studies of SNPs of the DRD2 gene with a risk of developing AIA. Koning et al. ^[52][76] studied the association of thirteen SNPs of nine candidate genes (DRD2, DRD3, 5HTR2A, 5HTR2C, COMT, NQO1, GSTP1, RGS2, and MnSOD) with the risk of developing AIA in 402 Northern European patients with mental disorders taking APs for at least a month. Positive statistically significant associations were found with allele C of rs1800498 (NG_008841.1:g.59414C>T) (TaqI_D) (p-value = 0.001) and allele A of rs1800497 (NG_012976.1:g.17316G>A) (p-value = 0.03). Other authors also confirmed that minor allele A of rs1800497 (NG_012976.1:g.17316G>A) (TaqIA) (p-value = 0.011) is associated with the risk of developing AIA according to the Barnes Akathisia Rating Scale (BARS) among 234 Australian patients with mental disorders on AP monotherapy for at least a month (p-value = 0.011) ^[53][77].

5.2. The HTR1B Gene

The HTR1B gene is located on the 6q14.1 chromosome and encodes a G-protein-coupled 5-hydroxytryptamine (serotonin) receptor. The gene is expressed in the brain, mainly in the thalamus and basal ganglia ^[54][87]. The protein functions as a receptor for ergot alkaloid derivatives, various anxiolytics and antidepressants, and other psychoactive substances such as lysergic acid diethylamide. It also regulates the release of 5-hydroxytryptamine, dopamine, and acetylcholine in the brain and thereby influences neural activity, nociceptive processing, pain perception, mood, and behavior. In addition, it plays a role in the vasoconstriction of cerebral arteries ^[55][88]. In the study, the authors studied the association between five SNPs (rs6313, rs3813929, rs6295, rs13212041, and rs1805054) of the candidate genes (HTR1A, HTR1B, HTR2A, HTR2C, and HTR6) with the risk of developing AIA. As a result, a positive association was noted between the carriage of the homozygous genotype TT of rs13212041 (NC_000006.12:g.77461407C>T) of the HTR1B gene with the risk of AIA in patients with Sch according to the BARS scale (p-value = 0.004) ^[43][75].