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ISSN: 2157-7099
Journal of Cytology & Histology

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Pharmacological options in the treatment of antipsychotic-induced extrapyramidal symptoms

Felix-Martin Werner1,2* and Rafael Coveñas2

1Higher Vocational School of Elderly Care and Occupational Therapy, Euro Academy Pößneck, Pößneck, Thuringia, Germany

2Laboratory of Neuroanatomy of the Peptidergic Systems (Lab. 14), Institute of Neurosciences of Castilla y León (INCYL), University of Salamanca, Salamanca, Spain

*Corresponding Author:
Felix-Martin Werner
Medical Doctor
Dr. med. Research field: neural networks in neurological and
psychiatric diseases University of Salamanca, Instituto de
Neurociencias de Castilla y León (INCYL)
Laboratorio de Neuroanatomía de los Sistemas Peptidérgicos (Lab. 14)c/
Pintor Fernando Gallego, 1 37007-Salamanca, Spain
Tel: +34/923/29 44 00; extn. 1856
Fax: +34/923/29 45 49
E-mail: [email protected]

Received Date: May 01, 2016; Accepted Date: May 09, 2016 ; Published Date: May 15, 2016

Citation: Werner F, Coveñas R (2016) Pharmacological Options in the Treatment of Antipsychotic-induced Extrapyramidal Symptoms. J Cytol Histol 7: 416. doi:10.4172/2157-7099.1000416

Copyright: © 2016 Werner FM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

Schizophrenia is treated by second-generation antipsychotic drugs, which are mostly D2 and 5-HT2A antagonists, and partly by first-generation antipsychotic drugs. Extrapyramidal symptoms, for example dyskinesia, dystonia or parkinsonism can occur as a consequence of the D2 receptor blockade. The functions of classical neurotransmitters in the mesolimbic and extrapyramidal systems are described, and neural networks are added. A D2 receptor blockade leads to a dopaminergic-cholinergic neurotransmitter imbalance in the extrapyramidal system. Pharmacologial options to treat transiently extrapyramidal symptoms are M4 antagonists, GABAA agonists and NMDA antagonists. The development of newer second-generation antipsychotic drug such as aripiprazole and cariprazine reduces the frequency and severeness of extrapyramidal symptoms, because these antipsychotic drugs have a partial agonism at the D2 receptor.

Keywords

Antipsychotic drug; Dopamine; Dynorphin; Extrapyramidal symptom; Extrapyramidal system; Gammaaminobutyric acid; Glutamate; Neural network; Schizophrenia; Second-generation antipsychotic drug; Serotonin; Substance P

Introduction

Schizophrenia is a chronic disabling mental illness, which becomes manifest as an acute psychosis with positive schizophrenic symptoms such as paranoia, illusions and hallucinations [1]. In this disease, due to susceptibility genes, dopamine hyperactivity via D2 receptors and serotonin hyperactivity via 5-HT2A receptors occurs in the hippocampus, mesolimbic system and prefrontal cortex [2]. Some susceptibility genes have been found, for example monoamine oxidase A/B, catechol-O-methyl transferase which encode a reduced activity of the enzymes that catalyze the degradation of dopamine; dysbindin-1 and neuregulin-1 which encode glutamate hypoactivity, and GAD 67 which encodes GABA (gamma-aminobutyric acid) hypoactivity [2,3]. Schizophrenia is mostly treated with second-generation antipsychotic drugs such as risperidone, olanzapine, quetiapine and aripiprazole and partly with first-generation antipsychotic drugs such as haloperidol [2,4]. Adverse effects above all of the first-generation antipsychotic drugs and partly of the second-generation antipsychotic drugs are extrapyramidal symptoms (EPS), for example dyskinesia, parkinsonism, dytonia and occulogyric crises [5]. Since secondgeneration antipsychotic drugs have an additional mechnism of action than the D2 receptor blockade, EPS occur less often in the treatment with second-generation antipsychotic drugs than in the therapy with first-generation antipsychotic drugs [5]. The question arises how to treat EPS, if they occur. In order to answer this question, neural networks will be described below in the mesolimbic and extrapyramidal systems.

Treatment of Schizophrenia and Adverse Effects of Antipsychotics

Schizophrenia is treated mostly with second-generation antipsychotic drugs and partly with first-generation antipsychotic drugs. Second-generation antipsychotic drugs such as risperidone, olanzapine, quetiapine and aripiprazole treat positive and negative schizophrenic symptoms and have fewer EPS, because they have a lower affinity for the D2 receptor [5]. Risperidone is a D2 and 5-HT2A antagonist with a high affinity for the D2 receptor which often causes EPS, whereas quetiapine which has a D2 and 5-HT2A antagonistic effect and shows a higher affinity for the 5-HT2A receptor, less often causes EPS [4]. Aripiprazole which has a partial agonist effect at the D2 receptor and a 5-HT2A antagonistic effect seldom causes EPS [4]. The reason for the occurrence of EPS will be explained in the section about neural networks. First-generation antipsychotic drugs such as haloperidol often have extrapyramidal adverse effects, because they strongly block the D2 receptor and lead to a dopaminergic-cholinergic neurotransmitter imbalance in the extrapyramidal system [6].

Classical neurotransmitters involved in schizophrenia

In schizophrenia, dopamine and serotonin hyperactivity and hypoactivity of the presynaptic inhibitory neurotransmitters GABA and glutamate have been reported in the hippocampus, mesolimbic system and prefrontal cortex [2]. Besides, in the prefrontal cortex an antagonistic interaction between D1 dopaminergic and M4 muscarinic cholinergic neurons has been described [2,7]. The neural network, above all, in the mesolimbic system will be pointed out below.

Dopamine

Dopamine hyperactivity, via D2 receptors, can be found in the hippocampus and the mesolimbic system. Dopamine dysfunction is due to the susceptibility genes monoamine oxidase A/B and COMT which encode a reduced activity of the enzymes catalyzing the degradation of dopamine. In the mesolimbic system, GABAergic neurons weakly inhibit D2 dopaminergic neurons via GABAA receptors and enhance dopamine hyperactivity [2,3]. In the prefrontal cortex, D1 dopaminergic neurons showing hyperactivity and M4 muscarinic cholinergic neurons have an antagonistic interaction [7].

Serotonin

Serotonin hyperactivity, via 5-HT2A receptors, in the mesolimbic system and hippocampus is partly encoded by the genes for the serotonin transporter [8]. NMDA (N-methyl-D-aspartate) receptor antagonists can induce schizophrenia-like behavior in animal experiments, which can only be relieved by 5-HT2A antagonists [9]. A possible neural connection could be that NMDA glutaminergic neurons weakly inhibit 5-HT2A serotonergic neurons and hence enhance serotonin hyperactivity [9].

GABA

In schizophrenia, GABA dysfunction has been reported in the mesolimbic system and hippocampus and is associated with cognitive impairments. GABA hypoactivity, via GABAA receptors, is encoded by the susceptibility gene GAD 67 [10].

Glutamate

Glutamate, a mostly excitatory postsynaptic and partly presynaptic inhibitory neurotransmitter exerts its effect on ionotropic glutaminergic receptors, for example the NMDA receptor and on metabotropic glutaminergic receptors. Glutamate hypoactivity, via NMDA receptors, is encoded by the susceptibility genes dysbindin-1 and neuregulin-1 [2]. A reduced presynaptic glutaminergic inhibition, via NMDA receptors, of the 5-HT2A serotonergic neurons located in the hippocampus and mesolimbic system can enhance serotonin hyperactivity [2,3].

Classical neurotransmitters and neuropeptides involved in the extrapyramidal system

In the EPS, a neurotransmitter imbalance occurs between D2 dopaminergic and M4 muscarinic cholinergic neurons as well between GABAA GABAergic and NMDA glutaminergic neurons. In Parkinson’s disease, a neurotransmitter imbalance has been described with dopamine and GABA deficiency and acetylcholine and glutamate surplus [11]. Besides, alterations of 5-HT2A serotonergic neurons and of the neuropeptides dynorphin and substance P occur. In another chapter, the neural networks in the EPS will be pointed out.

Dopamine

In the EPS, dopamine exerts its postsynaptic excitatory effect upon D1 and D2 receptors. D1 and D2 dopaminergic neurons located in the pars compacta of the substantia nigra activate dopaminergic neurons located in the caudate nucleus. D1 dopaminergic neurons activate dynorphin neurons in the caudate nucleus, and D2 dopaminergic neurons activate GABAergic neurons in the globus pallidus externus. A reduced dopamine production in the pars compacta of the substantia nigra or a blockade of D2 receptors by antipsychotic drugs can cause dopamine deficiency and Parkinsonian symptoms [11].

Acetylcholine

A dopaminergic-cholinergic neurotransmitter imbalance is important in the EPS. In the globus pallidus internus, GABAergic neurons inhibit via GABAA receptors muscarinic cholinergic neurons, which activate via M4 receptors glutaminergic neurons located in the putamen [11]. Extrapyramidal symptoms induced by antipsychotic drugs can be relieved by M4 antagonists, which counteract the dopaminergic-cholinergic neurotransmitter imbalance in the EPS caused by antipsychotic drugs [12].

Serotonin

It has been shown that in the putamen there is an antagonistic interaction between D2 dopaminergic and 5-HT2A serotonergic neurons through NMDA glutaminergic neurons. Consequently, the 5- HT2A antagonistic effect of antipsychotic drugs counteracts the D2 blockade, causing extrapyramidal symptoms [13].

GABA

GABAergic neurons in the globus pallidus internus inhibit, via GABAA receptors, muscarinic cholinergic neurons located in the putamen, which activate via M4 receptors glutaminergic neurons. GABAA agonists stabilize the dopaminergic-cholinergic neurotransmitter imbalance in the EPS and in addition enhance the antipsychotic effects of atypical neuroleptics by inhibiting, via GABAA receptors, the D2 dopaminergic neurons of the mesolimbic system [4,11].

Glutamate

NMDA antagonists counteract as well the dopaminergic-cholinergic neurotransmitter imbalance and can be used as anti-Parkinsonian drugs, because they strongly inhibit D2 dopaminergic neurons in the putamen. A blockade of NMDA receptors can enhance dopamine levels in the putamen through a reduced presynaptic inhibition [12].

Dynorphin

In the EPS, an inverse correlation between D1 dopaminergic neurons and dynorphin neurons exists. In the caudate nucleus, dynorphin neurons receive an activating impulse from D1 dopaminergic neurons and inhibit, via kappa receptors, substance P neurons [14].

Substance P

In the EPS, the release of dopamine and substance P are positively correlated. Substance P exerts its function mainly via NK1 receptors [15]. In the caudate nucleus, substance P neurons, which are presynaptically inhibited by dynorphin neurons via kappa receptors, activate via NK1 receptors GABAergic neurons located in the globus pallidus internus [16].

Neural networks in mesolimbic system and the extrapyramidal system

According to the literature [2,11], here the neural networks in the mesolimbic system and the EPS are described. Antipsychotic drugs mainly exert their therapeutic effects at the level of the mesolimbic system and in the EPS cause extrapyramidal symptoms by interfering with specific receptors.

The neural networks in the mesolimbic system (Figure 1) can be described as follows.

cytology-histology-mesolimbic-system

Figure 1: Neuronal pathways in the mesolimbic system in schizophrenia: 5-HT: serotonin; DA: dopamine; GABA: gammaaminobutyric acid; Glu: glutamate. 5-HT2A: 5-HT2A receptor of the serotonergic receptor; D2: D2 receptor of the dopaminergic receptor; GABAA: GABAA receptor of the GABAergic receptor; NMDA: N-methyl-D-aspartate receptor. A plus mark indicates a postsynaptic excitatory impulse; a minus mark indicated a presynaptic inhibitory impulse.

In this system (ventral tegmental area), D2 dopaminergic neurons with hyperactivity in schizophrenia (due to the susceptibility genes monoamine oxidase A/B and COMT) activate glutaminergic neurons, which weakly inhibit (due to the susceptibility genes dysbindin-1 and neuregulin-1) via NMDA receptors, 5-HT2A serotonergic neurons. The latter neurons with hyperactivity in schizophrenia activate GABAergic neurons, which weakly inhibit (due to the susceptibility gene GAD 67) via GABAA receptors, D2 dopaminergic neurons and allow dopamine hyperactivity. D2 dopaminergic neurons, in ventral tegmental area, activate other D2 dopaminergic neurons located in the A10 cell group, and 5-HT2A serotonergic neurons activate 5-HT2A serotonergic neurons located in the A10 cell group. In the A10 cell group, dopaminergic and serotonergic neurons activate each other and enhance dopamine and serotonin hyperactivity [2].

The neural networks in the EPS (Figure 2) can be described as follows: D1 and D2 dopaminergic neurons originating from the pars compacta of the substantia nigra activate other dopaminergic neurons located in the caudate nucleus.

cytology-histology-classical-neurotransmitters

Figure 2: Neuronal pathways, classical neurotransmitters and neuropeptides involved in the extrapyramidal system. 5-HT: serotonin; ACh: acetylcholine; DA: dopamine; Dyn: dynorphin; GABA: gamma-aminobutyric acid; Glu: glutamate; SP: substance P. The following subreceptors are indicated: ß2nAch: ß2nAch receptor: a subreceptor of the nicotinic cholinergic receptor; GABAA: GABAA receptor, a subreceptor of the GABA receptor; 5- HT2A: 5-HT2A receptor, a subreceptor of the serotoninergic receptor; D1: D1 receptor, a subreceptor of the dopaminergic receptor; D2: D2 receptor, a subreceptor of the dopaminergic receptor; kappa: kappa receptor: a subreceptor of the opioid receptor; M4: M4 receptor: a subreceptor of the muscarinic cholinergic receptor; NK1: NK1 receptor: a subreceptor of the substance P receptor; NMDA: NMDA (N-methyl-D-aspartate) receptor, a subreceptor of the ionotropic glutaminergic receptor. A plus mark indicates a postsynaptic excitatory impulse; a minus mark indicates a presynaptic inhibitory impulse.

D1 dopaminergic neurons activate dynorphin neurons, which inhibit via kappa receptors substance P neurons located in the caudate nucleus. The latter neurons activate, via NK1 receptors, GABAergic neurons in the internal globus pallidus. D2 dopaminergic neurons located in the caudate nucleus activate GABAergic neurons in the external globus pallidus which presynaptically inhibit, via GABAA receptors, glutaminergic neurons located in the subthalamic nucleus. The glutaminergic neurons inhibit, via NMDA receptors, D2 dopaminergic neurons in the substantia nigra and GABAergic neurons located in the internal globus pallidus. The GABAergic neurons in this nucleus inhibit, via GABAA receptors, thalamic glutaminergic neurons, which activate other cortical glutaminergic neurons via NMDA receptors. The latter neurons activate D1 and D2 dopaminergic neurons located in the caudate nucleus and subthalamic glutaminergic neurons. The GABAergic neurons located in the internal globus pallidus inhibit M4 muscarinic cholinergic and 5-HT2A serotonergic neurons located in the putamen. The latter neurons activate glutaminergic neurons which presynaptically inhibit D2 dopaminergic neurons in the putamen. D2 dopaminergic neurons are activated by ß2 nicotinic cholinergic neurons. D2 dopaminergic neurons located in the putamen are connected to other dopaminergic neurons located in the caudate nucleus.

Pharmacological Options in the Treatment of Extrapyramidal Symptoms Induced by Antipsychotics

Extrapyramidal symptoms (EPSS), dyskinesia, parkinsonism or dystonia can occur as a consequence of the treatment with firstgeneration antipsychotic drugs and to a lesser extent with secondgeneration antipsychotic drugs. Since these drugs exert a D2 antagonistic effect, a neurotransmitter imbalance in the EPS with D2 dopamine hypoactivity and M4 muscarinic cholinergic hyperactivity can be observed [17]. These adverse effects of antipsychotic drugs can be treated with M4 anticholinergics, GABAA agonists or NMDA receptor antagonists.

M4 anticholinergics

EPSS induced by antipsychotic drugs can be treated with M4 anticholinergics, for example biperiden and trihexyphenidyl. These drugs reduce M4 muscarinic cholinergic hyperactivity in the EPS and raise dopamine levels by activating the presynaptic inhibitory activity of glutaminergic neurons, so that the presynaptic inhibition of D2 dopaminergic neurons, via NMDA receptors, is reduced. Adverse effects of M4 anticholinergics are that these drugs can worsen positive schizophrenic symptoms, can impair cognitive functions and can cause tachycardia, constipation and an enlargement of the prostate gland [17,18].

GABAA agonists

GABAA agonists can be used to ameliorate antipsychotic-induced EPSS. In the EPS, GABAA agonists reduce M4 muscarinic cholinergic hyperactivity and raised dopamine levels. In the ventral tegmental area, GABAA agonists reduce dopamine hyperactivity and do not counteract the antipsychotic effects of atypical neuroleptics [12]. The adverse effects of GABAA agonists, for example benzodiazepines, are sedation, addiction, amnesia, and muscle relaxation [19].

NMDA receptor antagonists

NMDA receptor antagonists, for example amantadine, can be used for a short time treatment of antipsychotic-induced EPSS. A reduced presynaptic inhibition of D2 dopaminergic neurons, via NMDA receptors, in the EPS raises dopamine levels and improves movement disturbances [20]. However, NMDA receptor antagonists have a psychotomimetic effect, because in the mesolimbic system a blockade of NMDA receptors enhances 5-HT2A serotonin hyperactivity through a reduced presynaptic inhibition [20].

Development of Recently Admitted Second-Generation Antipsychotic Drugs

Second-generation antipsychotic drugs have a D2 and 5-HT2A antagonistic effect and cause EPSS to a lesser extent. Risperiodone with a D2 and 5-HT2A antagonistic effect and a higher affinity for the D2 receptor often causes EPSS, whereas quetiapine with an equivalent mechanism of action and a higher affinity for the 5-HT2A receptor seldom causes EPSS [21]. Some recently developed second-generation antipsychotic drugs such as aripiprazole and the recently admitted antipsychotic drug cariprazine show a different mechanism of action and seldom cause EPSS [22].

Aripiprazole

Aripiprazole is a second-generation antipsychotic drug with a partial agonistic effect at the D2 receptor, a 5-HT2A antagonistic effect and a 5-HT1A agonistic effect. It shows good antipsychotic and antidepressant effects. It causes seldom EPSS, because it has a partial agonism at the D2 receptor and a 5-HT2A antagonistic effect and hence counteracts the D2 partial agonistic effect at the D2 receptor in the EPS (Figure 2) [23].

Cariprazine

Cariprazine is a new-generation antipsychotic drug with a partial agonism at the D2 and D3 receptors with 10-fold greater affinity for the D3 receptor and also exerts a 5-HT1A agonistic effect. It was generally admitted by the FDA administration for the treatment of schizophrenia and bipolar disorder [22]. Cariprazine seldom causes EPSS, in 11% of the patients akathisia. The favorable effect on the EPS is due to the partial agonism at the D2 and D3 receptors [22,24].

Conclusion

Schizophrenic or schizoaffective patients are generally treated with second-generation antipsychotic drugs and partly with first-generation antipsychotic drugs. These antipsychotic drugs can cause EPSS as a consequence of the D2 receptor blockade. The functions of classical neurotransmitters in the mesolimbic system and the EPS are described. Dopamine and serotonin hyperactivity, which is due to the susceptibility genes, is treated by second-generation antipsychotic drugs, which are mostly D2 and 5-HT2A antagonists. EPSS, for example dyskinesia, parkinsonism, dystonia or occulogyric crises can occur as a consequence of the treatment with antipsychotic drugs. Pharmacological options to treat EPSS are M4 antagonists, which counteract the dopaminergic-cholinergic neurotransmitter imbalance in the EPS. Besides, the extrapyramidal adverse effects can be treated with GABAA agonists which reduce acetylcholine hyperactivity in the EPS and NMDA antagonists, which raise dopamine levels in the EPS through a reduced presynaptic inhibition. Recently developed secondgeneration antipsychotic drugs (e.g., aripiprazole, cariprazine) have the advantage to cause less often and to a lesser extent EPSS, because they have a partial agonism at the D2 receptor. In spite of the atypical mechanisms of action, aripiprazole and cariprazine are used to treat positive and negative schizophrenic symptoms like other secondgeneration antipsychotic drugs.

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