A Review and Case Study of the Action of Chlorpromazine on Dopaminergic Pathways and its Associated Extrapyramidal Disturbances

Abstract

As a first-line antipsychotic, Chlorpromazine is an excellent blocking agent of the D2 receptor. Dopamine pathways are predominantly affected by the use of this medicine in schizophrenia therapy, leading to the development of drug-induced Parkinsonism (DIP). Extrapyramidal symptoms (EPS) include motor rigidity, tremors, restlessness, dystonia, stumbling, nervousness, improper posture, Tardive dyskinesia, Akathisia, and many other side effects. In seniors over 70 suffering from schizophrenia, DIP has become very common and is the second most common cause of Parkinsonism behind Parkinson\'s disease (PD). A concise review of the actual mechanism of blockade by chlorpromazine is presented in this article, with a particular focus on EPS and other adverse effects.

Introduction

I. INTRODUCTION

Schizophrenia is an intricate, chronic mental health disorder characterized by a range of different symptoms that comprise hallucinations, impaired cognitive function, delusions, and inappropriate speech or behavior.[1] The synthesis of the first neuroleptic drug Chlorpromazine (CPZ) used in its therapy was done by Paul Charpentier on 11th December 1951 in the French chemical and pharmaceutical company Rhône-Poulenc. It was later available on prescription in France in 1952.[2] Since the introduction of CPZ, it is proven to be highly effective in treating the positive and negative symptoms of schizophrenia. It falls in the class of first-line antipsychotics and these are termed “typicals.” These typicals have equivalent mechanisms of action and analogous efficacy. The two most complicated adverse effects are EPS and Tardive dyskinesia (TD). These enfeebling symptoms of EPS are familiar to occur in 75% to 90% of patients taking antipsychotics. [3] Extrapyramidal is a conventional terminology that generally cites impaired motor control, referring to dysfunction of the basal ganglia. EPS are of 2 major groups of signs and ailments: hypokinetic which is found in Parkinson’s disease after the short-term consumption of dopamine blockers and hyperkinetic which accounts for Huntington’s disease after long-term intake of dopamine antagonists. [4]

II. DOPAMINERGIC PATHWAYS IN THE TREATMENT OF SCHIZOPHRENIA BY CHLORPROMAZINE

A. Mesolimbic DA pathway

CPZ effectively reduces the positive symptoms of schizophrenia (by balancing the dopamine levels) caused by the high yield of dopamine from the Ventral Tegmental Area (VTA) to the Nucleus Accumbens (NA) in the Mesolimbic dopaminergic (DA) pathway. This pathway generally has projections from the VTA that innervate many forebrain areas (Figure 1), the most significant is the NA. [5, 6, 7] It also shows cognitive impairment, and produced EPS at therapeutic doses. The pharmacological action of CPZ includes the antagonism of dopamine D2 receptors which may require as much as 6-8 weeks to show its full potential and efficacy. [8] There is hyperactivity of the Mesolimbic circuit and also a substantial decrease in the positive symptoms if they are dosed to block a significant number of D2 receptors in the Mesolimbic pathway. [6, 9]

B. Mesocortical DA pathway

In the Mesocortical pathway, the dopamine volume is relatively on a lower yield on account of which it shows negative symptoms of schizophrenia. These low levels of dopamine are due to the less flow of the dopaminergic neurons that project from the VTA to the prefrontal cortex (Figure 2). CPZ also blocks the D2 receptors in this pathway which in turn worsens these negative symptoms even though there is a lower density of D2 receptors in the cortex. [5, 6]

C. Nigrostriatal DA Pathway

The Nigrostriatal pathway is an integral part of the extrapyramidal nervous system, these motor side effects are usually related to D2 receptor blockade in this part of the brain is what we call EPS. This pathway has 80% of the dopamine that is present in the brain and the tract projects from cell bodies in the pars compacta of the substantia nigra to terminals that innervate the striatum (Figure 3) which comprises 2 main portions

1. Caudate and
2. Putamen [5, 6]

The blockage of a substantial number of D2 receptors in this pathway by first-line antipsychotics like Chlorpromazine induces:

III. EXTRAPYRAMIDAL SYMPTOMS

These are major dose-limiting side effects that are more predominant with high potency drugs like CPZ.

Three major forms of EPS are:

A. Drug-induced Parkinsonism

Drug-induced Parkinsonism as a side effect of chlorpromazine was first reported 3 years after its introduction. [10] Typically it has manifestations like rigidity, hypokinesia, shuffling gait, tremors, and a mask-like face that usually appears between 1-4 weeks of the entire therapy and normally persists unless the dose is reduced.[11] DIP ordinarily appears quite subsequently after taking neuroleptics with 50% of cases within the first 30 days and 90% within 72 days. Patients that are commonly treated with relatively lower doses of first-line antipsychotics or maybe anti-parkinsonian drugs tend to improve over 7-8 weeks, but it has been seen that some of the parkinsonian symptoms continue in half of the patients with DIP despite the anticholinergic drug treatment. Also, some of these patients may develop PD, presumably exhibiting early subclinical dopaminergic deficiency before administration of neuroleptics.[12] Anticholinergic agents like Trihexyphenidyl, Benztropine, Levodopa, and Amantadine have been tested for their potential to treat DIP, but there is no such significant evidence of their effects in the DIP patients.[18]

B. Dystonia

Dystonia is a cluster of disorders that are usually outlined by particular types of abnormal movements. The most vital feature is the overactivity of muscles that are generally needed for movement. [15] It has been observed that nearly about 2.5% of patients have been diagnosed with acute dystonia within 48 hours of the conclusion of the therapeutic dosage of neuroleptic drugs like CPZ.[14] It is more prevalent in children below the age of 10 and mostly in girls, notably after parenteral administration; the overall incidence is 2%. Primarily it lasts for about a few hours and then gets resolved spontaneously. The most obvious symptoms of dystonia are: Unusual muscle spasms, principally comprising linguo-facial muscles- grimacing, tongue thrusting, torticollis, locked jaw; these symptoms occur within a few hours of a single dose or at the most in the first week of therapy.[11]

C. Akathisia

Akathisia in simple terms is a compelling need to unnecessarily moving rock or pace and subjective feelings of agitation or restlessness.[17] Akathisia is frequently reported after treatment with first-generation antipsychotic medications, with prevalence rates ranging between 8-76%, which makes it the most common side effect associated with them. Some potential subtypes of Akathisia are Acute and Chronic Akathisia, Withdrawal Akathisia, Tardive Akathisia, Pseudoakathisia, Bing-Sicard Akathisia (caused due to Parkinsonism).[20]

IV. CASE STUDY OF A 77-YEAR-OLD WOMAN:

1. Background: In the wake of COVID-19, many people have been affected significantly on a psychological level. When she found out that everyone in her family tested severely positive for the disease, she suffered a sudden panic attack which led to an extended phase of trauma. It ultimately resulted in her developing schizophrenia and psychosis. For almost one week, the patient was silent and depressed, and was barely conscious. 
2. Symptoms Noticed: Depression, mild hallucinations, motor rigidity, forgetfulness, loss of control of involuntary moments, temporary memory loss (due to psychosis), and constant over-thinking.
3. Treatment: The combination of Chlorpromazine (50mg) and Trihexyphenidyl (2mg) was prescribed by the psychiatrist. These two drugs worked quite well together. Medication accompanied by emotional therapy of conversing constantly with the patient on topics that she liked and which were a part of her day to day life before getting depressed managed to cure the condition of schizophrenia in a period of 4 to 5 months by shooting up the levels of the happy hormone (dopamine), but in turn led to high-grade EPS as a contraindication of CPZ. The latter drug (Trihexyphenidyl) tries to inhibit the side effect (EPS) caused by CPZ, but sometimes the adverse effects are extremely powerful.
4. Outcome: The condition of such patients is generally unbearable to look for, especially the family members. The entire body becomes highly rigid making it rock hard and difficult to move, locomotion gets laggard, hands tremble and vibrate vigorously. Slowly, these symptoms begun to fade through medications, and the physical condition began to improve, but these side effects of DIP caused by the CPZ, which Trihexyphenidyl was unable to inhibit completely, the doctor gave further instructions for consuming Levodopa (100mg) + Carbidopa (25mg) so as to hinder the parkinsonian symptoms. The patient was finally out of depression, mental trauma and the worsening side effects after 8-12 months (almost a year).

Conclusion

The condition of Schizophrenia and Psychosis is severe and should not be taken for granted as it can have several life-changing effects on the body after the complete therapeutic treatment too. It is true that the adverse fade away with time and proper medical treatment, but it depends from person to person and the post condition therapy.

References

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Copyright

Copyright © 2022 Gaurav Kumar. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.