Psychosis represents one of the most profound forms of mental illness, characterized by significant disruptions in behavior, disorganized thinking, impaired understanding, and a loss of insight. Individuals may experience positive symptoms (such as hallucinations and delusions), negative symptoms (like emotional flatness and social withdrawal), and cognitive impairments, including difficulties with working memory, slowed information processing, and challenges in understanding social cues [1].
Schizophrenia is one of the most debilitating neuropsychiatric conditions, impacting around 1% of the global population [2]. Schizophrenia is a prevalent mental health disorder marked by a complex and often severely disruptive set of symptoms that affect cognition, emotions, perception, and overall behavior [3]. Schizophrenia ranks among the top ten leading causes of long-term disability worldwide, impacting approximately 1% of the global population [4].
Antipsychotic (AP) medications—while essential for managing schizophrenia—often lead to serious and common extrapyramidal side effects (EPSE). These movement-related adverse reactions can emerge just a few days after beginning treatment. Despite this, AP drugs have remained the cornerstone of schizophrenia therapy for over fifty years [5]. Moreover, acute extrapyramidal symptoms (EPS) represent a complex clinical phenomenon, encompassing a range of syndromes such as Parkinsonism, akathisia, acute dystonia, and dyskinesia. While the advent of clozapine and other second-generation antipsychotics has led to a reduction in the frequency of these side effects, EPS remains a persistent and significant concern in the treatment of schizophrenia [6]. Historically, first-generation antipsychotics, introduced in the mid-20th century, demonstrated inconsistent efficacy in managing schizophrenia symptoms and were frequently associated with extrapyramidal side effects (EPS), including acute dystonia, akathisia, Parkinsonism, and tardive dyskinesia. Furthermore, positron emission tomography (PET) studies have indicated that effective symptom control typically requires 60–70% antagonism of dopamine D2 receptors, whereas exceeding this threshold—particularly reaching 75–80% blockade—is strongly linked to the onset of acute EPS. Currently, five major extrapyramidal syndromes are recognized: Parkinsonism, akathisia, acute dystonia, tardive dyskinesia, and the potentially life-threatening neuroleptic malignant syndrome [6, 7].
Dystonia is marked by involuntary, intermittent, or sustained muscle contractions, often resulting in abnormal postures or movements. While it can develop after prolonged use of antipsychotic medications, it may also emerge shortly after treatment initiation. Notably, over half of acute dystonia cases occur within the first 48 h of antipsychotic use, with approximately 90% arising within the first four days. This condition commonly affects cranial, pharyngeal, cervical, and axial muscles, leading to symptoms such as oculogyric crisis, jaw stiffness, tongue protrusion, torticollis, laryngeal and pharyngeal spasms, dysarthria, dysphagia, and in severe cases, respiratory difficulty, cyanosis, or opisthotonus [8].
Akathisia is a common and distressing adverse effect associated with antipsychotic medications. Individuals affected by this condition typically exhibit intense restlessness and an uncontrollable urge to move, often accompanied by a subjective sense of inner tension, anxiety, and unease. Clinically, it is characterized by increased motor activity that includes repetitive, purposeless, and stereotyped movements, which can significantly impair quality of life and treatment adherence [9]. The prevalence of akathisia among extrapyramidal side effects ranges widely from 5 to 36.8%. It affects approximately 10–20% of patients treated with second-generation (atypical) antipsychotics, which is notably lower compared to the 20–52% incidence observed with first-generation (typical) antipsychotic medications [10]. Akathisia may persist throughout the course of antipsychotic treatment but typically resolves upon discontinuation of the medication. Its prevalence among extrapyramidal side effects varies widely, ranging from 5 to 36.8%. Specifically, akathisia occurs in about 10–20% of patients treated with second-generation antipsychotics, which is substantially lower than the 20–52% incidence reported with first-generation agents [11].
Drug-induced Parkinsonism is characterized by the classic triad of symptoms: bradykinesia, muscle rigidity, and tremor, with postural tremor being more prevalent than resting tremor. Among patients receiving antipsychotic treatment, the prevalence of Parkinsonism is estimated to be around 15% [12].
Tardive dyskinesia is characterized by involuntary, choreoathetoid movements affecting the orofacial area, limbs, trunk, and respiratory muscles. This condition can develop in any patient undergoing antipsychotic treatment, typically emerging after months or even years of continuous medication use. Unlike other extrapyramidal symptoms, tardive dyskinesia may persist despite discontinuation of antipsychotics and, in some cases, can be irreversible [13]. Among adults using typical antipsychotic drugs long-term, tardive dyskinesia develops at a rate of about 5% per year, with the cumulative risk rising to 25–30% annually in elderly patients. However, the incidence of tardive dyskinesia is notably lower in those treated with atypical antipsychotics, indicating a reduced risk compared to typical agents [14]. Neuroleptic malignant syndrome is a potentially fatal condition that arises in patients who exhibit extreme sensitivity to the extrapyramidal side effects of antipsychotic medications [15].
Patients experiencing extrapyramidal side effects (EPS) suffer considerable adverse impacts on their health-related quality of life. These include poorly controlled mental illness, suboptimal treatment outcomes, impaired daily functioning, increased disability and morbidity, higher rates of hospitalization, as well as significant social and financial burdens. EPS also leads to greater utilization of medical resources, diminished overall quality of life, and negatively affects patients’ responses to antipsychotic treatment, which can result in uncontrolled illness, increased risk of complications, and higher mortality rates.
Although various studies have identified numerous predictors of EPS among patients on antipsychotic medications—such as female gender, older age, potent dopamine D2 receptor blockade, use of first-generation antipsychotics, polypharmacy, prolonged treatment duration, concurrent use of anticholinergic or antiparkinsonian drugs, previous history of EPS, poor insight, lack of family support, longer illness duration, stigma, substance use, alcohol consumption, smoking, and genetic variability—there remains a significant gap in the comprehensive assessment and management of these side effects.
Specifically, in Ethiopia, there is a notable lack of research focusing on the predictors of EPS among patients receiving antipsychotic therapy, underscoring the urgent need for studies that can provide critical insights to improve clinical care and patient outcomes.
Therefore, this study is helpful to mental health professionals for routine assessment, designing effective prevention and intervention methods for extrapyramidal side effects.
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To determine the predictor of extrapyramidal side effects among patients with taking antipsychotic medications.
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Provides baseline information for further research studies.
Extrapyramidal side effects (EPS) are serious adverse reactions that result from excessive antagonism of dopamine D2 receptors by antipsychotic medications, particularly in the substantia nigra and striatum regions of the brain. EPS significantly affect drug efficacy, treatment adherence, and the social functioning of individuals with schizophrenia. Although the use of second-generation antipsychotics (SGAs) has been associated with a lower incidence of EPS, these side effects remain a major clinical concern. EPS continue to contribute to reduced quality of life, increased stigma, poor medication compliance, and higher relapse rates among patients [16].
A study conducted in China explored the determinants of antipsychotic-induced EPS among patients with schizophrenia in real-world clinical settings. The study included 679 individuals diagnosed with schizophrenia, of who 204 developed EPS while 475 did not. The findings revealed that 126 patients (18.41%) experienced drug-induced parkinsonism, 33 patients (4.8%) developed akathisia, and 23 patients (3.3%) showed signs suggestive of tardive dyskinesia (TD) [17].
Similarly, a cross-sectional study conducted among institutionalized patients with psychotic disorders in Central Estonia reported that 31.3% of the participants experienced neuroleptic-induced akathisia, 23.2% developed neuroleptic-induced parkinsonism, and 32.3% presented with neuroleptic-induced tardive dyskinesia [5].
A study from Britain revealed that between 50% and 70% of individuals with schizophrenia experience at least one serious adverse effect related to antipsychotic therapy [18]. Among these serious adverse effects, the annual incidence of parkinsonism ranged from 37 to 44%, while akathisia and tardive dyskinesia were reported in 26–35% and 8–10% of cases, respectively [19]. Beyond extrapyramidal symptoms, individuals with schizophrenia commonly encounter additional adverse effects linked to antipsychotic use. These include weight gain, increased drowsiness, difficulty sleeping, sexual dysfunction, dry mouth, constipation, urinary issues, and episodes of dizziness [20].
Findings from a study in Germany identified several risk factors for the development of extrapyramidal symptoms (EPS). These included the selection of certain second-generation antipsychotics—clozapine posed the lowest risk, while risperidone was linked to the highest—as well as higher drug dosages, a previous history of EPS, and the presence of comorbid illnesses. Moreover, all cases of tardive dyskinesia (TD) occurred in older patients compared to the overall study group [16].
A study conducted in Nigeria reported that the prevalence of tardive dyskinesia (TD) was 14.5% among female patients and 7% among male patients. However, other research found no significant difference in TD prevalence between sexes [21].
Among the various types of extrapyramidal side effects, the prevalence of akathisia ranges from 5 to 36.8%. Akathisia is observed in about 10–20% of patients receiving newer-generation antipsychotics, which is notably lower than the 20–52% prevalence reported with typical antipsychotic medications [22]. Akathisia may continue throughout the course of antipsychotic treatment but typically resolves once the medication is discontinued [23]. The prevalence of Parkinsonism among patients receiving antipsychotic medications is estimated at around 15%. Parkinsonism is generally regarded as a reversible condition that typically resolves within four months. However, in some instances, it may persist for six to eighteen months, and approximately 15% of cases of antipsychotic-induced parkinsonism are reported to become persistent [24].
In Ethiopia, the prevalence of antipsychotic-induced movement disorders has been reported as 46.4% for neuroleptic-induced parkinsonism, 28.6% for neuroleptic-induced akathisia, and 11.9% for neuroleptic-induced tardive dyskinesia [25].
A study conducted in Jimma assessed the prevalence and associated factors of tardive dyskinesia (TD) among psychiatric patients receiving first-generation antipsychotics. The study found that TD prevalence was 14.6%, with a range between 10.76% and 18.4%. Several factors showed significant associations with the development of TD. Patients older than 45 years were more than four times as likely to develop extrapyramidal side effects compared to those younger than 30 years (AOR 4.5; 95% CI: 9.7–20.4). Current cigarette smoking—defined as having smoked at least once in the past month—was linked to a 1.4-fold higher risk of TD compared to non-smokers during that period (AOR 1.4; 95% CI: 2.6–7.8). Additionally, patients receiving chlorpromazine-equivalent doses greater than 400 mg/day were 6.5 times more likely to develop TD compared to those on doses between 50 and less than 100 mg/day (AOR 6.5; 95% CI: 2.6–26.8). All of these factors were found to have a statistically significant association with the occurrence of TD induced by first-generation antipsychotics [26].
Several factors have been significantly linked to an increased risk of extrapyramidal symptoms (EPS) in patients receiving antipsychotic medications. These include demographic characteristics such as female gender and older age; pharmacological factors like the strong D2 receptor antagonism of certain antipsychotics, the use of first-generation agents, and antipsychotic polytherapy; as well as longer duration of treatment. In addition, medical conditions such as brain atrophy, diabetes, and substance use disorders, along with genetic variations, have been associated with a higher likelihood of developing EPS [27].
Factors significantly associated with the development of tardive dyskinesia (TD) include older age, female sex, and the presence of brain damage, higher cumulative doses of neuroleptic medications, longer duration of antipsychotic exposure, and the occurrence of drug-induced Parkinsonism during the early stages of neuroleptic therapy. Additionally, a primary psychiatric diagnosis of an affective disorder and the use of substances such as alcohol have been linked to an increased risk of TD [8, 17, 28].
Extrapyramidal motor symptoms significantly affect the effectiveness of antipsychotic treatment, patient adherence to medication, and the social functioning of individuals with schizophrenia. Although the broader use of second-generation antipsychotics (SGAs) has been linked to a lower incidence of EPS, these symptoms remain a major clinical concern. EPS continue to contribute to reduced quality of life, increased stigma, poor adherence to antipsychotic therapy, and a higher risk of relapse [29].
Extrapyramidal motor symptoms have a great influence on the compliance of the patients towards the antipsychotic medications leading to failure of the treatment. Hence the extrapyramidal side effects to be properly diagnosed and appropriately treated so that there is increased compliance and efficacy of the medications [1]. Extrapyramidal side effects have negative consequences in health-related quality of life, uncontrolled mental illness, poor treatment outcome, impaired functioning in daily life, disability, morbidity, increasing hospitalization and poor attitude on antipsychotic drugs [27].
The most serious side effects of FGAs are neurological and largely restrained to the extrapyramidal motor system. FGAs remain the most commonly prescribed medications in many parts of the world especially developing countries as they are considerably less expensive than newer antipsychotics drugs [30].
Assessment and management of antipsychotic medication side-effects are considered essential to prevent negative physical health outcomes, to improve tolerability and promote medication adherence [19, 31]. However, previous work suggests that clinician knowledge and skill in the management of antipsychotic medication side-effects remain poorly developed [31]. And also, to this effect, patients taking antipsychotic medications should be monitored regularly for adverse effects and managed accordingly [32, 33], This study will aim to determine the predictor of extrapyramidal side effects among patients with taking antipsychotic medications in Tigray, Ethiopia.
Recent researches have shown that extrapyramidal side effects among patients taking antipsychotic drugs global challenge. EPS has a great impact on the drug efficacy, drug compliance and social ability of patients with schizophrenia [29]. Factors that were significantly associated with EPS among patients who took antipsychotics drugs including socio-demographic factors, clinical factors, Substance use-related factors, antipsychotics use, and Psychosocial related factors like gender (female), age (elder), high D2 receptor antagonism effect of antipsychotics, usage of first-generation antipsychotics, poly-therapy of antipsychotics, longer duration of drug treatment, Perceived stigma, Social support, insight, illness such as brain atrophy, diabetes, and substance addiction, and genetic diversity are related to higher incidence of EPS [27].
Influential studies have rightfully advocated for the study of higher-order cognitive impairments in schizophrenia, considering these impairments as a central pathway for understanding core elements of the illness’ underlying pathophysiology. The frequency of motor abnormalities among patients with schizophrenia range between 50 and 65% as compared to 5% in healthy controls. Abnormal motor functioning in patients with schizophrenia has been noted since the earliest systematic clinical characterizations of the illness. With the advent of typical antipsychotics, motor dysfunction in schizophrenia has increasingly been associated with their extrapyramidal side effects. However, in addition to the early characterization of motor dysfunction, evidence recommends that antipsychotic medications may serve to exacerbate the emergence of spontaneous motor disorders, rather than being the single underlying cause [2].
Recent research shows about the association of Akathisia with socio-demography were inconsistent. Some of them reported that there was no significant difference in age between the Akathisia and non-Akathisia groups [32, 34, 35]. The relationship between Akathisia and sex has also been inadequately investigated [36]. Some studies reported a higher prevalence of Akathisia among females and Younger age both sex [27, 31, 37].
Most epidemiological studies have not reported any sex differences in the vulnerability to Akathisia [33, 38, 39].
Recent research Patients who received antipsychotic poly-therapy were at higher risk of akathisia significant after controlling the influence of age, gender, level of education, level of psychotic symptoms, substance use comorbidities, and current administration of antidepressant, anticholinergic drugs, benzodiazepines, daily-administered antipsychotic dose. The combination of second generation antipsychotics was associated with a risk of akathisia compared to second-generation antipsychotics used in mono-therapy Another study, on the other hand, stated that “Akathisia tends to prevail in men” [40].
UK journal article concluded that there was no significant gender difference for the development of drug-induced Parkinsonism but there are reports that stated the male to female ratio was 1:2 [16, 41].
According to a study in Chinese Compared with the non-EPS group and the EPS group patients are older, and they have a longer duration since first prescribed antipsychotics. The EPS group patients have higher frequency of atypical antipsychotics poly-therapy and typical and atypical antipsychotics poly-therapy or combined treatments with mood stabilizers and those antipsychotics with high D2 receptor antagonistic effect and illness duration are the risk factors of EPS [17].
Antipsychotic drugs enhance recovery by controlling symptoms, improving quality of life, regaining basic life functioning, and preventing relapse among patients who taking antipsychotics drugs. Drug compliance in patients with schizophrenia is predicted by the patients’ attitudes towards medications. Negative attitude towards antipsychotic medication is common in clinical practice with the prevalence ranges from 7.5% to 46.7%. Up to 75% of those with a negative attitude has non-adherence to antipsychotic drugs, which results in a relapse. The prevalence of relapse due to non-adherence varies from 50 to 92% globally [42].
The overall prevalence of antipsychotic polypharmacy were 28.2% from an institution based cross-sectional study conducted on 423 study subjects done to identify associated factors of antipsychotic polypharmacy among schizophrenia outpatients. Extrapyramidal side effects repeated psychiatric hospitalization, longer duration of treatment, and medications non-adherence that were significantly associated with antipsychotic polypharmacy [43].
The risk factors associated with akathisia were poorly understood; it is noted more with high potency antipsychotics possibly due to the employment of higher doses and middle-aged women are at greatest risk [26, 44]. Akathisia accounts for 50% of extrapyramidal symptoms and it is one of the most common movement disorders caused by antipsychotics drugs [44].
Factors that were significantly associated with drug-Induced Parkinsonism were high dose, high-potency drug use; elderly, female sex, hereditary susceptibility and Concurrent with tardive dyskinesia [25, 44].
Factors that were significantly associated with the occurrence of tardive dyskinesia include elderly patients, female patients with brain damage, dementia, mood disorders, longer duration of antipsychotic therapy, and use of anticholinergic drugs, antiparkinsonian drugs and history of the previous occurrence of extrapyramidal symptoms [14].
Risk factors for the development of dystonia include primarily the duration of use antipsychotic drugs and the high dose of antipsychotics drugs, younger age, male gender, and mental retardation, positive family history of dystonia, previous dystonic reaction, recent cocaine and alcohol abuse [8].
Medication non-adherence is one of the biggest problems, increasing re-hospitalization and long-lasting psychotic symptoms, and also EPS the most challenging aspect of treatment. Medication on-adherence can cause high rates of relapse within 5 years of recovery from the first episode. Lacks of adherence to medication treatment were associated with worsening of symptoms, poor prognosis, high costs and unnecessary adjustments in the medical prescriptions [43]. Factors influencing non-adherence may be broadly categorized into factors related to the treatment, patient-related factors, health care, and socio-economic circumstances [3].
Different studies show in Ethiopia that non-adherence to antipsychotics medication was varied from 26.5 to 47.9% [37, 43, 45, 46]. Prevalence of non-adherence was 41.0% among schizophrenia patients. Living in rural areas (adjusted odds ratio [AOR] = 2.07; 95% confidence interval [CI]: 1.31, 3.28), current substance use (AOR = 1.67; 95% CI: 1.09, 2.56), long duration of treatment (AOR = 2.07; 95% CI: 1.22, 3.50) and polypharmacy (AOR = 2.13; 95% CI: 1.34, 3.40) were found to be significantly associated with non-adherence [4].
Factors that were associated with medication non-adherence among patients with schizophrenia include medication side effects, poverty, lack of family supports, durations of illness, stigma, substance use, alcohol consumption, and smoking. Thus, non-adherence remains a challenge for patients with psychiatric disorders and their health care providers, contributing to a substantial worsening of the disease, frequent relapse, increased mortality, re-hospitalization, and increased health care costs [47].
Insight in mental health is the degree of the patient’s awareness and understanding of their attributions, feelings, behavior, and disturbing symptoms; self-understanding as well as the potential causes of psychiatric presentation. Insight is viewed as a multidimensional variable of the realization of the need for treatments, the ability to re-label unusual mental events as pathological and attribute appropriate causes for mental illness [48, 49].
Unawareness of having mental illness among the patients with schizophrenia viewed as an independent phenomenon rather than the secondary manifestation of schizophrenia symptoms [49].
WHO international pilot study showed that 98% of patients with schizophrenia had a lack of insight and the systematic study revealed that between 50% and 80% of patients with schizophrenia had characterized by poor insight [49]. The consequences of lack of insight are failure to recognize the need for treatment; leading to medication non-adherence and impacts on the patients, families, communities and affects the course of illness. Insight in the patient with schizophrenia has been significantly associated with depressive symptoms, positive and negative syndromes of schizophrenia, unemployed, relapse and r-hospitalization [50].
A study done in Ethiopia found that attitude towards antipsychotic medications were Positive symptoms, negative symptoms, shorter (≤ 5 years) duration of illness, first-generation, having sedation and extra-pyramidal side effects were factors negatively associated with the attitude towards antipsychotic medication treatment. Insight to illness was a factor positively associated with the attitude towards antipsychotic medications [42].
According to study done in Ethiopia found that insight was Age at first onset of illness, duration of treatments, depressive symptoms were inversely associated with mean insight score; whereas unemployed, positive and negative syndrome, previous hospitalization, >=2 episodes were positively associated with mean insight score [50].
A study done in the Canada compound analysis revealed a small and positive effect size suggesting increased EPS in substance-abusing patients. Cocaine was associated with the largest effect size estimate. Dual diagnosis patients were more frequently males than single diagnosis patients [51].
A study done in Ethiopia found that Khat, alcohol, and history of substance use factors that were significantly associated with Extrapyramidal side effects among patients taking antipsychotic drugs [25].
Conceptual frame work
According to the report of studies conducted before, several predicting factors had been found responsible for the development of extrapyramidal side effects of patients taking antipsychotic medications including socio-demographic factors, clinical factors, substance use-related factors, antipsychotics use, and psychosocial related factors. a conceptual framework is adopted from reviewing different literatures [3, 42, 52] as illustrated in (Fig. 1).
Schematic presentation of the sampling procedure of patients with taking antipsychotic medication visiting inpatients and outpatient in Mekelle town, psychiatric clinics, Northern Ethiopia, 2023