Extrapyramidal adverse events and anticholinergics use after the long-term treatment of patients with schizophrenia with the new long-acting antipsychotic Risperidone ISM®: results from matching-adjusted indirect comparisons versus once-monthly formulations of Paliperidone palmitate and Aripiprazole monohydrate in 52-week studies.

BACKGROUND: Risperidone ISM® is a newly developed long-acting injectable (LAI) treatment for schizophrenia in adults. In the absence of head-to-head comparisons with other similar antipsychotics, the objective of this study was to generate indirect evidence of some aspects of the safety and tolerability of Risperidone ISM compared to other LAI antipsychotics for treatment of patients with schizophrenia in the maintenance treatment setting. METHODS: A literature review was conducted systematically to identify maintenance treatment studies reporting safety and tolerability outcomes for LAI antipsychotic therapies. Following an assessment of between-trial heterogeneity, a matching-adjusted indirect comparison (MAIC) was performed to account for between-trial imbalances in patient characteristics and to generate comparative evidence for safety and tolerability endpoints. RESULTS: The analysis showed that incidence of extrapyramidal symptoms (EPS) was found to be numerically, but not statistically significantly, lower in patients receiving Risperidone ISM than in those receiving Paliperidone palmitate (PP) (OR [95% CI] 0.63 [0.29, 1.38], p = 0.253) and statistically significantly lower than with Aripiprazole monohydrate once-monthly (AOM) (OR [95% CI] 0.25 [0.12, 0.53], p < 0.001). Use of anticholinergic agents for the alleviation of EPS was also shown to be significantly lower in Risperidone ISM patients than in those receiving PP (OR [95% CI] 0.29 [0.10, 0.83], p = 0.021) or AOM (OR [95% CI] 0.01 [0.003, 0.06], p < 0.001), suggesting a superior tolerability profile for clinically relevant EPS. Results from the sensitivity analyses comparing stabilized and stable patients receiving Risperidone ISM to those receiving AOM yielded similarly favorable conclusions in line with the base case analyses. CONCLUSIONS: This MAIC is consistent with the safety and tolerability results obtained during the PRISMA-3 clinical trial in the long-term treatment of schizophrenia and suggests a favorable safety and tolerability profile in terms of EPS incidence and anticholinergic agent use, relative to other antipsychotic therapies used for treatment of patients with schizophrenia in the maintenance setting.

Assessment of Extrapyramidal Symptoms Associated with Psychotropics Pharmacological Treatments, and Associated Risk Factors.

BACKGROUND: Extrapyramidal Symptoms (EPS) are unwanted symptoms commonly originating from the use of certain medications. The symptoms can range from minimal discomfort to permanent involuntary muscular movements. The aims of the study were to examine the incidence of drug-induced extrapyramidal symptoms (di-EPS), associated risk factors, and clinical characteristics. METHODS: This is a retrospective, observational study of di-EPS conducted in outpatient clinics of Jordan using the longitudinal health database (Hakeem®) for data collection. Patients who received drugs with the risk of EPS during the period 2010-2020 were included and followed. Patients with any of the known underlying conditions that may cause EPS or were currently taking drugs that may mask the symptoms were excluded. Gender and age-matched control subjects were included in the study. The Statistical Package for Social Science (SPSS®) version 26 was used for data analysis. RESULTS: The final dataset included 34898 exposed patients and 69796 matched controls. The incidence of di-EPS ranged from 9.8% [Amitriptyline 25mg] to 28.9% (Imipramine 25mg). Baseline factors associated with a significantly higher risk of developing di-EPS were age {HR: 1.1 [95%CI: 0.8-1.2, p=0.003], smoking {HR: 1.7 (95%CI: 1.3-2.2), p=0.02}, tremor history {HR: 7.4 (95%CI: 5.9-8.3), p=.002} and history of taking antipsychotics {HR: 3.9, (95% CI: 2.5-4.6), p=0.001}. Patients taking paroxetine {HR: 8.6 [95%CI: 7.4-9.8], p=.0002},imipramine {HR: 8.3, [7.1-10.5], p=0.01}, or fluoxetine {HR: 8.2 (95%CI: 6.8-9.3), p=.006} had a significantly higher risk of developing di-EPS compared to patients taking citalopram. Myoclonus, blepharospasm, symptoms of the basal ganglia dysfunction, and organic writers' cramp were reported among participants. CONCLUSION: Patients treated with paroxetine, imipramine, fluoxetine, or clomipramine had a higher risk of developing di-EPS than patients treated with citalopram. The difference in gender was not significantly related to di-EPS development. Whereas age, smoking, and history of taking antipsychotics were significantly associated with di-EPS development. KEY FINDINGS: • High incidence of drug-induced extrapyramidal symptoms (di-EPS) was reported• Age, smoking, tremor history, and history of taking antipsychotics were risk factors of drug-induced extrapyramidal symptoms.• Patients taking paroxetine, imipramine or fluoxetine had a significantly higher risk of developing di-EPS compared to patients taking citalopram.

Long-acting formulation leading to severe long-term adverse effects: a case report of fluphenazine and persistent extrapyramidal symptoms.

WHAT IS KNOWN AND OBJECTIVE: Long-acting formulations are an important therapeutic option for non-adherent patients with schizophrenia. There is a commonly held view that management of long-acting formulation-induced side effects is difficult. CASE DESCRIPTION: We present a patient with schizophrenia who developed acute and persistent extrapyramidal symptoms requiring tracheostomy and long-term rehabilitation after long-acting injections of fluphenazine decanoate. Extrapyramidal symptoms improved with declining fluphenazine concentration and antiparkinsonian drug therapy with bromocriptine. WHAT IS NEW AND CONCLUSION: Long-acting formulations may lead to severe persistent adverse effects. For preventing fluphenazine-induced side effects, a possible option might be the antiparkinsonian drug therapy with bromocriptine.

Extrapyramidal symptoms after exposure to calcium channel blocker-flunarizine or cinnarizine.

PURPOSE: Flunarizine (fz) and cinnarizine (cz) have well-known extrapyramidal side effects (EPSEs). The aim of this study was to evaluate the incidence and occurrence time of cz- and fz-related EPSEs. METHOD: Patients who took fz or cz for more than 1 month were identified from the longitudinal health insurance database 2005 and 2010. Excluded were patients with any of the underlying diseases that may cause parkinsonism. Drug-induced EPSEs were defined as the new diagnosis of parkinsonism, dyskinesia, or secondary dystonia during drug use or within 3 months after discontinuing the medication. Age- and sex-matched controls were included in this study. RESULTS: Recruited for analysis were individuals who took fz (n = 26,133) and cz (n = 7186). The incidence rates of fz- and cz-induced EPSEs were 21.03 and 10.3 per 10,000 person-months, respectively. The hazard ratios (HRs) of EPSEs among fz and cz subjects were 8.03 (95% CI 6.55-9.84) and 3.41 (95% CI 2.50-4.63) when compared with the control individuals. Both fz and cz patients had a higher cumulative incidence of EPSEs than their control individuals (p < 0.001). Among subjects who took fz, the incidence of EPSEs was higher in the second than first year of drug exposure (45.59 vs 21.03 per 10,000 person-months). CONCLUSIONS: Fz and cz significantly increased the risk of parkinsonism, dyskinesia, and dystonia. Potential benefits and risks should be weighed when considering long-term use of these drugs especially fz.

Pisa Syndrome Secondary to Drugs: A Scope Review.

BACKGROUND: Pisa syndrome, also known as pleurothotonus, is a neurological condition characterized by more than ten degrees of constant lateral curvature of the spine when upright. In this way, the present manuscript aims to systematically review Pisa syndrome secondary to drugs. METHODS: Two reviewers identified and assessed relevant reports in six databases without language restriction between January 1990 and June 2024. RESULTS: The prevalence of Pisa syndrome varied from 0.037 to 9.3%. We found 109 articles containing 191 cases of drug-induced Pisa syndrome reported in the literature. The mean and median ages were 59.70 (SD = 19.02) and 67 (range = 12-98 years). The most prevalent sex was female, 56.91% (107/188). The most frequent medications associated with Pisa syndrome were acetylcholinesterase inhibitors in 87 individuals. Of 112 individuals in which the onset time from the medication to the movement disorder occurrence was reported, 59 took place within a month. In this way, a return to baseline was observed in 45.50% of the cases, and partial recovery was observed in 14.28%. CONCLUSION: We proposed new diagnostic criteria for Pisa syndrome based on previous findings in the literature. Moreover, multiple mechanisms are probably involved in balance control and the development of lateral trunk flexions.

Efficacy and safety of prophylactic use of benzhexol after risperidone treatment.

To test the effect of prophylactic use of benzhexol in schizophrenia patients after risperidone treatment. Sixty-nine drug naïve schizophrenia patients were recruited. All patients were administered risperidone. Patients in the benzhexol group were given a benzhexol tablet of 2 mg bid daily. The controls received a placebo tablet of 2 mg bid daily. The primary outcome measured using the Extrapyramidal Symptoms Rating Scale (ESRS). The Positive and Negative Syndrome Scale (PANSS) and the Brief Psychiatric Rating Scale (BPRS) measured secondary outcome. There were significant time and group effects on the ESRS scores of the two groups. The post hoc analysis yielded significant differences at 1, 2, 4, and 8 weeks between the two groups. There was a significant time effect on the PANSS scores of the two groups. No significant group and interaction effects on the PANSS scores of the two groups. There was a significant time effect on the BPRS scores of the two groups. No serious adverse events were found in this study. Prophylactic use of benzhexol reduced extrapyramidal symptom in schizophrenia patients after risperidone treatment and did not affect the antipsychotic action of risperidone.

Syndrome of Inappropriate Antidiuretic Hormone Secretion as a Presentation of Untreated Parkinson's Disease.

Syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common electrolyte disorder associated with neurological conditions. Parkinson's disease (PD) has not been known to be causative of SIADH. We present the case of a 71-year-old male patient with diabetes type II (T2DM) and hypothyroidism admitted with progressive confusion, slow speech, and severe fatigue for one week, accompanied by sluggish body movements for a few months. A neurological exam revealed mild arm rigidity, bradykinesia, resting tremors, and stiff gait. The exam was otherwise normal. Initial blood work showed hypo-osmolar hyponatremia (Na 122 mEq/L, serum osmolarity (Osm) 275 mOsm/kg, and urine Osm 672 mOsm/Kg). CT chest showed localized infiltrate. The initial diagnosis was SIADH secondary to pulmonary process, most probably pneumonia. After starting him on a fluid restriction of 1.5 L/day and urea 15 mg BID, sodium improved gradually to 133 mEq/L on discharge. Urine osmolality continued to be elevated ranging between 700 and 800 mOsm/Kg. An active pulmonary process was ruled out by a pulmonologist. Parkinsonism was diagnosed four weeks after discharge by Neurology who started carbidopa/levodopa. As extrapyramidal symptoms improved, urine osmolality improved as well to 400 mOsm/Kg. Sodium level was maintained between 135 and 137 while urea treatment was stopped and fluid restrictions removed. New-onset SIADH was thought to be secondary to Parkinson's disease. Parkinson's disease treatment (carbidopa/levodopa) is known to cause SIADH. In this case, the treatment itself and a dose increase led to improvement in sodium levels and urine osmolality concomitantly with the improvement of the patient's extrapyramidal symptoms.

Tardive Dyskinesia in a Postoperative Gynecological Patient After Single Dose Administration of Metoclopramide.

Metoclopramide is a dopamine D2-receptor blocking agent commonly used to treat nausea, vomiting, and gastroparesis. Due to their mechanism of action, these drugs can lead to extrapyramidal side effects such as tardive dyskinesia. In this article, we report a case of a nulliparous gynecology patient who developed dyskinetic movements after intraoperative administration of metoclopramide. During further workup after stabilization, she was found to have several risk factors for tardive dyskinesia. As the occurrence of this phenomenon is somewhat rare, this case report aims to discuss the condition, associated risk factors, and differentiation from other diagnoses.

Abdominal Wall Dyskinesia: Case Report.

The clinical presentation of repetitive choreiform involuntary movements of the anterior abdominal wall was first introduced as "belly dancer's dyskinesia." Etiologies of this rare condition include idiopathic causes, medication inducement, or post-abdominal surgery. We report a case of orobuccal stereotypic movements and abdominal wall dyskinesia secondary to prochlorperazine intake. The movements began 2 weeks after cessation of prochlorperazine. The patient took this dopamine receptor-blocking medication for 6 months to treat nausea due to chemotherapy. To our knowledge, abdominal wall dyskinesia as a tardive syndrome of prochlorperazine has not been previously reported.

Dopamine-receptor blocking agent-associated akathisia: a summary of current understanding and proposal for a rational approach to treatment.

Dopamine-receptor blocking agent-associated akathisia (DRBA-A) is an adverse effect that can significantly limit the use of these important medications for the treatment of a variety of psychiatric diseases, yet there is no unifying theory regarding its pathophysiology. This knowledge gap limits clinicians' ability to effectively manage DRBA-A and mitigate negative outcomes in an already vulnerable patient population. Based on a review of the current literature on the subject, it is hypothesized that dopaminergic and noradrenergic signaling is perturbed in DRBA-A. Accordingly, it is proposed that the optimal agent to manage this extrapyramidal symptom should increase dopamine signaling in the affected areas of the brain and counteract compensatory noradrenergic signaling via antagonism of adrenergic or serotonergic receptors.

Antipsychotics for patients with pain.

Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D2 receptor bindings with strong binding to the 5-HT2A receptor, while typical antipsychotics block long-lasting, tight D2 receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.

Antipsychotics for patients with pain

Going back to basics prior to mentioning the use of antipsychotics in patients with pain, the International Association for the Study of Pain (IASP) definition of pain can be summarized as an unpleasant experience, composed of sensory experience caused by actual tissue damage and/or emotional experience caused by potential tissue damage. Less used than antidepressants, antipsychotics have also been used for treating this unpleasant experience as adjuvant analgesics without sufficient evidence from research. Because recently developed atypical antipsychotics reduce the adverse reactions of extrapyramidal symptoms, such as acute dystonia, pseudo-parkinsonism, akathisia, and tardive dyskinesia caused by typical antipsychotics, they are expected to be used more frequently in various painful conditions, while increasing the risk of metabolic syndromes (weight gain, diabetes, and dyslipidemia). Various antipsychotics have different neurotransmitter receptor affinities for dopamine (D), 5-hydroxytryptamine (5-HT), adrenergic (α), histamine (H), and muscarinic (M) receptors. Atypical antipsychotics antagonize transient, weak D₂ receptor bindings with strong binding to the 5-HT(2A) receptor, while typical antipsychotics block long-lasting, tight D₂ receptor binding. On the contrary, antidepressants in the field of pain management also block the reuptake of similar receptors, mainly on the 5-HT and, next, on the norepinephrine, but rarely on the D receptors. Antipsychotics have been used for treating positive symptoms, such as delusion, hallucination, disorganized thought and behavior, perception disturbance, and inappropriate emotion, rather than the negative, cognitive, and affective symptoms of psychosis. Therefore, an antipsychotic may be prescribed in pain patients with positive symptoms of psychosis during or after controlling all sensory components.

Factors Influencing the Subjective Sexual Function in Patients with Schizophrenia Switched to Olanzapine / 대한정신약물학회지

OBJECTIVE: Sexual dysfunction is highly prevalent in both untreated and treated patients with schizophrenia. Sexual dysfunction is a major cause of poor quality of life, negative attitude to therapy and treatment non-compliance. We thereby conducted this study to better understand the predictors of subjective sexual dysfunction. METHODS: The subjects consisted of 83 patients (46 men; 37 women) who participated in an open label study on switching antipsychotics to olanzapine. All subjects met the Tenth Revision of International Classification of Diseases diagnostic criteria for schizophrenia. To better understand the predictors of subjective sexual dysfunction, we used the Liverpool University Neuroleptic Side-effect Rating scale (LUNSERS), a comprehensive self-rating instrument for assessing and quantifying the subjective adverse events during antipsychotic treatment. All patients were taking antipsychotics at the initiation of the study and were assessed using LUNSERS, the Simpson-Angus Scale (SAS), the Barnes Akathisia Rating scale (BARS), Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression (CGI), and the Positive and Negative Syndrome Scale (PANSS). They were also checked for their serum prolactin levels and vital signs before and after a 6-week treatment with olanzapine. In order to identify the cross-sectional and longitudinal predictors of LUNSERS hormonal side effect, we carried out multiple regression analyses. RESULTS: Prolactin levels, LUNSERS hormonal side effect, CGI, PANSS, SAS, AIMS, and BARS decreased after a 6-week treatment with olanzapine. At initial evaluation, cross-sectional predictors of LUNSERS hormonal side effect were red herring and allergic reaction subscale, but after the 6-week treatment with olanzapine, none of the variables were found to significantly predict LUNSERS hormonal side effect. Longitudinal predictors of LUNSERS hormonal side effect were LUNSERS extrapyramidal system side effect and prolactin levels. CONCLUSION: These findings suggested relationships among prolactin, extrapyramidal symptom, motor function and sexual dysfunction. After switching to olanzapine, sexual function of the patients improved subjectively. More studies are warranted as these results have significant implications for quality of life and treatment adherence.

A case of myclonus, resembling epileptic seizure, induced by short-term sulpiride treatment.

An 86-year-old woman with delusional disorder was treated with oral sulpiride at a dose of 200 mg/day. On the seventh day of treatment, she suddenly developed abrupt brief rhythmical contractions every 5 s in her neck muscles, orofacial muscles, muscles of upper limbs and lower legs bilaterally. Although there was no impairment of consciousness, her speech was interrupted by the myoclonic episodes. We suspected that the epileptic seizure-like myoclonus might be a drug-induced acute extrapyramidal symptom. We therefore injected 5 mg of biperiden (i.m.), and the myoclonus ceased shortly thereafter. This myoclonus, resembling an epileptic seizure, did not recur subsequently after sulpiride treatment was discontinued. The present case shows that myoclonus can occur after even brief sulpiride treatment in certain elderly patients. (Int J Psych Clin Pract 2002; 6: 215-216 ).

Concomitant Use of Anticholinergic Agents with Atypical Antipsychotics in Schizophrenic Patients: A Preliminary Report / 대한정신약물학회지

OBJECTIVE: It is well known that antipsychotic drugs induce extrapyramidal symptoms such as dystonia, akathisia and parkinsonian symptoms even early in the treatment. With the advent of atypical antipsychotic drugs, the incidence of extrapyramidal symptoms has decreased, but danger still exists. Hence, anticholinergic agents are often indicated in treatment of schizophrenia with antipsychotics. METHODS: In this observational retrospective study, we examined the use of anticholinergic agents among schizophrenic patients who were initiated on risperidone, olanzapine, or quetiapine, the three most widely prescribed atypical antipsychotics. We reviewed medical records of schizophrenic patients who were initiated on risperidone, olanzapine or quetiapine from January 2004 through December 2004 and continuously treated with the antipsychotics for 6 months. The data were analysed using one way ANOVA, Mann-Whitney U test, chi-square test or Fisher's exact tests. RESULTS: The study yields two major findings. Firstly, compared with risperidone initiators, there were significantly fewer olanzapine initiators who used anticholinergic agent concomitantly. Secondly, there were significantly fewer olanzapine or quetiapine initiators than risperidone initiators who prescribed anticholinergic agent on the same day when antipsychotics was initiated. CONCLUSION: As the use of anticholinergic agent is a proxy for the presence of extrapyramidal symptom, these findings suggest that risperidone may be more associated with extrapyramidal symptoms than olanzapine or quetiapine. Controlled studies comparing them to one another should be of particular interest.

There Cases of Extrapyramidal Symptoms Following Fluoxetine / 신경정신의학

The selective serotonin reuptake inhibitor fluoxetine is one of the most frequently prescribed drugs for the treatment of depression and other psychiatric disorders. In the few years, there have been several reports of adverse effects encountered during coadministration of fluoxetine with or without other psychotropic drugs. We experienced three cases of extrapyamidal symptoms were developed when administered fluoxetine alone and with neuroleptics. We conclude that there is a probable or possible causal relationship between fluoxetine and extrapyramidal side effects. The pathogenesis of such adverse reactions, which may be hetero-geneous, is unknown, but it has been suggested that they might be caused by serotonergically mediated inhibition of dopaminergic transmission. From reports in those cases, it appears that fluoxetine alone may be associated with extrapyramidal side reactions. Furthermore the potential for increased levels of concomitant psychotropic medicines and increased side effects, should be borne in mind.

Two Cases of Sporadic Encephalitis Lethargica

We present two patients with clinical features suggestive of a hyperkinetic form of encephalitis lethargica described by von Economo. While undergoing treatment for viral meningoencephalitis, they both developed comatose mentality, oromandibular dyskinesia, chorea, myoclonic jerk, oculogyric crisis, opistotonus, respiratory failure, and autonomic dysfunction. One patient died of autonomic failure while the other improved several months later. In both patients, cerebrospinal fluid exmamination revealed only pleocytosis. A brain MRI and EEG showed no specific findings. In order to control severe hyperkinetism and autonomic failure, medical treatments including L-dopa, clonazepam, and steroid pulse therapy were administereed in both cases while electroconvulsive therapy was tried in one of the cases. However, they all failed. These cases and previous reports informed us of the presence of sporadic form of encephalis.

Hereditary Spastic Paraplegia

Hereditary spastic paraplegia is a familial disorder which is inherited by autosomal dominant, autosomal recessive or sex linked pattern. We experienced a family who has hereditary spastic paraplegia with mental retardation and extrapyramidal symptom that is thought inherited by autosomal dominant inheritance pattern. A review of literatures was made briefly.

Hereditary Spastic Paraplegia

Hereditary spastic paraplegia is a familial disorder which is inherited by autosomal dominant, autosomal recessive or sex linked pattern. We experienced a family who has hereditary spastic paraplegia with mental retardation and extrapyramidal symptom that is thought inherited by autosomal dominant inheritance pattern. A review of literatures was made briefly.