Acetaminophen improves tardive akathisia induced by dopamine D2 receptor antagonists.

Tardive akathisia is a movement disorder characterized by internal restlessness with an uncontrollable urge to move, leading to repetitive movements. It is a common side effect of long-term treatment with dopamine D2 receptor antagonists. In the present study, we analyzed the FDA Adverse Event Reporting System and IBM MarketScan Research Database to find a drug that can be used concomitantly with dopamine D2 receptor antagonists and still reduce the risk of akathisia. Acetaminophen was determined to be the most effective akathisia-suppressing drug. In an experimental validation of the hypothesis, chronic treatment of rats with haloperidol caused akathisia symptoms, including increased stereotyped behavior and locomotor activity, and decreased immobility time. Acute treatment with acetaminophen significantly attenuated haloperidol-induced akathisia. In the ventral striata of these rats, acetaminophen prevented haloperidol-induced decrease in the number of c-Fos+ preproenkephalin+ neurons. These results suggest that acetaminophen is effective in suppressing tardive akathisia by activating indirect-pathway medium spiny neurons.

Akathisia Among Patients Undergoing Antipsychotic Therapy: Prevalence, Associated Factors, and Psychiatric Impact.

OBJECTIVES: The prevalence of akathisia is variably reported in the literature and its psychiatric impact is little studied. The aim of this study was to establish the prevalence, the associated factors, and the psychiatric impact of akathisia among patients undergoing antipsychotic treatment. METHODS: A cross-sectional descriptive study was carried out at the Department of Psychiatry A, at Razi Hospital, in Tunis. It included patients with psychosis, undergoing antipsychotic treatment, from June 2016 to February 2017. Akathisia was diagnosed according to the Barnes Akathisia Scale. RESULTS: The prevalence of akathisia was 19.5% (n = 24, schizophrenia/schizoaffective disorder, n = 20; bipolar disorder, n = 4). The delay between the diagnosis of the disease and the onset of akathisia was 7.1 ± 8.8 years. Among the sample of patients with akathisia, 20/24 were on monotherapy of which 14 on conventional antipsychotics and six on atypical antipsychotics. Patients with akathisia were on atypical (8/24), low-potency conventional (4/24), or high-potency conventional (17/24) antipsychotics. The average dose of antipsychotics in chlorpromazine equivalent was 2294.5 ± 3037.7 mg. After adjusting for confounders, the only factor significantly positively associated with the diagnosis of akathisia was the dose of antipsychotics prescribed ( P = 0.01). The following psychiatric manifestations were reported by patients with akathisia: dysphoria/irritability (16/23), anxiety (18/24), sadness (15/24), suicidal thoughts (11/24), heteroaggressivity (8/23), sleep disturbances (16/24), and suicidal attempts (9/24). CONCLUSIONS: Despite the high psychiatric and social burden of akathisia, it remains largely underdiagnosed and undertreated, because in part of its subjective component.

Reassessment of amphetamine- and phencyclidine-induced locomotor hyperactivity as a model of psychosis-like behavior in rats.

Locomotor hyperactivity induced by psychotomimetic drugs, such as amphetamine and phencyclidine, is widely used as an animal model of psychosis-like behaviour and is commonly attributed to an interaction with dopamine release and N-methyl-D-aspartate (NMDA) receptors, respectively. However, what is often not sufficiently taken into account is that the pharmacological profile of these drugs is complex and may involve other neurotransmitter/receptor systems. Therefore, this study aimed to assess the effect of three antagonists targeting different monoamine pathways on amphetamine- and phencyclidine-induced locomotor hyperactivity. A total of 32 rats were pre-treated with antagonists affecting dopaminergic, noradrenergic and serotonergic transmission: haloperidol (0.05 mg/kg), prazosin (2 mg/kg) and ritanserin (1 mg/kg), respectively. After 30 min of spontaneous activity, rats were injected with amphetamine (0.5 mg/kg) or phencyclidine (2.5 mg/kg) and distance travelled, stereotypy and rearing recorded in photocell cages over 90 min. Pre-treatment with haloperidol or prazosin both reduced amphetamine-induced hyperactivity although pre-treatment with ritanserin had only a partial effect. None of the pre-treatments significantly altered the hyperlocomotion effects of phencyclidine. These findings suggest that noradrenergic as well as dopaminergic neurotransmission is critical for amphetamine-induced locomotor hyperactivity. Hyperlocomotion effects of phencyclidine are dependent on other factors, most likely NMDA receptor antagonism. These results help to interpret psychotomimetic drug-induced locomotor hyperactivity as an experimental model of psychosis.

CYP2D6 Genotyping and Antipsychotic-Associated Extrapyramidal Adverse Effects in a Randomized Trial of Aripiprazole Versus Quetiapine Extended Release in Children and Adolescents, Aged 12-17 Years, With First Episode Psychosis.

PURPOSE/BACKGROUND: The aim of this study was to examine the association between genetically predicted CYP2D6 phenotypes and extrapyramidal symptoms (EPSs). METHODS/PROCEDURES: Data from the Tolerability and Efficacy of Antipsychotics trial of adolescents with first-episode psychosis randomized to aripiprazole versus quetiapine extended release were studied. Extrapyramidal symptom assessments included the Simpson-Angus Scale and the Barnes Akathisia Rating Scale. Patients were CYP2D6 genotyped. Plasma concentrations of antipsychotics and antidepressants were analyzed. FINDINGS/RESULTS: One hundred thirteen youths (age, 12-17 years; males, 30%; antipsychotic naive, 51%) were enrolled. Poor metabolizers had a significantly higher dose-adjusted aripiprazole plasma concentration (±SD) compared with normal metabolizers at week 4 (24.30 ± 6.40 ng/mL per milligram vs 14.85 ± 6.15 ng/mL per milligram; P = 0.019), but not at week 12 (22.15 ± 11.04 ng/mL per milligram vs 14.32 ± 4.52 ng/mL per milligram; P = 0.067). This association was not found in the quetiapine extended release group. No association between CYP2D6 genotype groups and global Barnes Akathisia Rating Scale score or Simpson-Angus Scale score was found in any of the treatment arms. IMPLICATIONS/CONCLUSIONS: Our results do not support routine use of CYP2D6 testing as a predictor of drug-induced parkinsonism or akathisia risk in clinical settings. Further studies with larger samples of CYP2D6 poor metabolizers are needed.

[Tardive akathisia after long-term metoclopramide treatment].

This case report describes a 57-year-old male with symptoms of tardive akathisia after long-term metoclopramide treatment. As metoclopramide is a dopamine receptor antagonist, it has the potential to cause drug-induced movement disorders, including akathisia, which is characterised by an inner restlessness resulting in a need for constant movement. Tardive akathisia, in contrast to acute akathisia, evolves after prolonged exposure to the triggering medication and can be a permanent condition. Treatment duration of metoclopramide should be restricted, and awareness of neurological side effects is important.

Safety and effectiveness of oral blonanserin for schizophrenia: A review of Japanese post-marketing surveillances.

Schizophrenia significantly limits social functioning with positive and negative symptoms and cognitive dysfunction. Blonanserin (LONASEN®), a novel second-generation antipsychotic approved for treating schizophrenia in Japan in 2008, reportedly shows beneficial effects on cognitive function as well as positive and negative symptoms, with potential for improving social functioning. To understand the safety and effectiveness of blonanserin in the real clinical practice, five Japanese post-marketing surveillances have been conducted and published to date. In this article, we reviewed all the Japanese post-marketing surveillances and discussed the clinical usefulness of blonanserin in patients with schizophrenia having diverse clinical characteristics. Adverse drug reactions, such as akathisia and extrapyramidal symptoms, were common in all surveillances. However, those specific to second-generation antipsychotics, such as weight gain and abnormalities in glycometabolism or lipid metabolism, were rarely observed. In addition, no adverse drug reactions apart from clinical trial results were found. Brief Psychiatric Rating Scale total scores in all surveillances significantly lowered at the last evaluation than at baseline. These results were consistent through 1-year of treatment, suggesting that effectiveness is maintained even after long-term use. In conclusion, blonanserin is considered a beneficial drug in real clinical practice for patients with schizophrenia having diverse characteristics.

Adult Emergence Agitation: A Veteran-Focused Narrative Review.

Emergence agitation (EA) is a self-limited state of psychomotor excitement during awakening from general anesthesia. EA is confined to the emergence period as consciousness is restored, which sharply distinguishes it from other postoperative delirium states. Sporadic episodes of EA may become violent with the potential for harm to both patients and caregivers, but the long-term consequences of such events are not fully understood. Current literature on EA in adults is limited to small-scale studies with inconsistent nomenclature, variable time periods that define emergence, a host of different surgical populations, and conflicting diagnostic criteria. Therefore, true incidence rates and risk factors are unknown. In adult noncardiac surgery, the incidence of EA is approximately 19%. Limited data suggest that young adults undergoing otolaryngology operations with volatile anesthetic maintenance may be at the highest risk for EA. Currently suggested EA mechanisms are theoretical but might reflect underblunted sympathetic activation in response to various internal (eg, flashbacks or anxiety) or external (eg, surgical pain) stimuli as consciousness returns. Supplemental dexmedetomidine and ketamine may be utilized for EA prevention. Compared to the civilian population, military veterans may be more vulnerable to EA due to high rates of posttraumatic stress disorder (PTSD) manifesting as violent flashbacks; however, confirmatory data are limited. Nonetheless, expert military medical providers suggest that use of patient-centered rapport tactics, PTSD trigger identification and avoidance, and grounding measures may alleviate hyperactive emergence phenomena. Future research is needed to better characterize EA in veterans and validate prophylactic measures to optimize care for these patients. This narrative review provides readers with an important framework to distinguish EA from delirium. Furthermore, we summarize current knowledge of EA risk factors, mechanisms, and adult management strategies and specifically revisit them in the context of veteran perioperative health. The anesthesiology care team is ideally positioned to further explore EA and develop effective prevention and treatment protocols.

Positive and negative side effects of androgen abuse. The HAARLEM study: A one-year prospective cohort study in 100 men.

An estimated 4-6% of fitness center visitors uses anabolic-androgenic steroids (AAS). Reliable data about adverse reactions of AAS are scarce. The HAARLEM study aimed to provide insight into the positive and negative effects of AAS use. One hundred men (≥18 years) who intended to start an AAS cycle on short notice were included for follow-up. Clinic visits took place before (T0 ), at the end (T1 ), and three months after the end of the AAS cycle (T2 ), and one year after the start of the cycle (T3 ), and comprised a medical history, physical examination, laboratory analysis, and psychological questionnaires. During the follow-up period, four subjects reported a serious adverse event, that is, congestive heart failure, acute pancreatitis, suicidal ideation, and exacerbation of ulcerative colitis. All subjects reported positive side effects during AAS use, mainly increased strength (100%), and every subject reported at least one negative health effect. Most common were fluid retention (56%) and agitation (36%) during the cycle, and decreased libido (58%) after the cycle. Acne and gynecomastia were observed in 28% and 19%. Mean alanine transaminase (ALT) and creatinine increased 18.7 U/l and 4.7 µmol/L, respectively. AAS dose and cycle duration were not associated with the type and severity of side effects. After one-year follow-up (T3 ), the prevalence of observed effects had returned to baseline. There was no significant change in total scores of questionnaires investigating wellbeing, quality of life, and depression. In conclusion, all subjects experienced positive effects during AAS use. Four subjects experienced a serious adverse event. Other side effects were mostly anticipated, mild, and transient.

Cariprazine as a therapeutic option for schizophrenia: a drug evaluation.

Introduction: Schizophrenia is a very disabling condition that may result in a significant impairment of individual, professional, and social adjustments. Antipsychotics (APs), the first-line treatment for schizophrenia, in many cases modify the course of the disease, by reducing the institutionalization risk, at the price of severe and invalidating side effects. Cariprazine is one of the latest second-generation APs (SGAs) acting as a partial agonist of type 2 and 3 dopamine receptors, which was recently approved for the treatment of adult schizophrenia.Areas covered: The authors provide a critical review and commentary on the currently available data on the effectiveness and tolerability of cariprazine in schizophrenic patients, with a particular focus on its specific target symptoms.Expert opinion: Cariprazine appears significantly effective on both acute and maintenance treatment of schizophrenia, and in improving positive, negative, and cognitive symptoms, slightly more than other SGAs. It shows a good safety and tolerability profile, with akathisia being its most common side effect. Although further independent studies are needed to clarify its precise advantages over other SGAs, cariprazine seems a promising compound not only in schizophrenia, but also in a broad range of psychiatric conditions, including perhaps bipolar and addictive disorders.

Trazodone as an Alternative Treatment for Neuroleptic-Associated Akathisia: A Placebo-Controlled, Double-Blind, Clinical Trial.

BACKGROUND: Akathisia is a distressing extrapyramidal complication that follows the use of antipsychotic medications. Early treatment of neuroleptic-associated akathisia (NAA) is of great importance because it may lead to poor therapeutic response and ultimately treatment noncompliance. Considering the lack of adequate response of some patients to conventional treatments and the assumption that serotonin might be involved in the pathophysiology of the disease in addition to dopaminergic mechanisms, we aimed to evaluate the effectiveness of trazodone as an antidepressant agent with strong antagonistic effects on serotonin receptors in the treatment of akathisia. METHODS: In a double-blind clinical trial, 52 patients receiving antipsychotic medications who were diagnosed to have mild to severe NAA using Barnes Akathisia Rating Scale were treated with trazodone 50 mg daily for 5 days and compared with the placebo control group. RESULTS: Patients receiving trazodone did not show a significant difference compared with the control group in terms of the severity of akathisia symptoms until the third day of the study. In contrast, at the end of the fifth day, there was a significant improvement in objective (P = 0.01) and subjective (P = 0.001) symptoms of akathisia and the global clinical assessment of akathisia scale (P = 0.001). Moreover, there was no clear difference between trazodone and placebo group in terms of adverse effects. CONCLUSIONS: Considering the antagonistic effect of trazodone on postsynaptic 5-hydroxytryptamine2A receptors as a possible mechanism of efficacy of this agent in the treatment of NAA, this study suggests that trazodone might be an effective and relatively safe drug.

Movement disorders induced by psychiatric drugs that do not block dopamine receptors.

Most movement disorders in psychiatric patients are induced by neuroleptic antipsychotic medications, all of which are dopamine D2 receptor blocking drugs. These include: acute onset disorders: dystonic reactions, akathisia and the neuroleptic malignant syndrome (NMS); non-acute onset parkinsonism; and the tardive syndromes. However, many other medications, when used at recommended doses, also induce movement disorders, with tremor being the most common. With the exception of serotonin syndrome, they are rarely as severe or disabling as the neuroleptic extrapyramidal syndromes may be. The serotonin reuptake inhibiting (SSRI) drugs are associated with the serotonin syndrome, a life-threatening disorder, but may also cause tremor and akathisia. While SSRI's have been thought to occasionally cause a tardive dyskinesia-like syndrome, this almost never occurs without prior or concurrent neuroleptic exposure as well. There also are few reliable data to support an association between antidepressants and parkinsonism. Valproic acid has been shown to cause parkinsonism, and lithium may as well, in addition to both having the well-known side effect of tremors. Myoclonus and asterixis are usually induced by toxic levels of medications but may appear with therapeutic levels, particularly with anticonvulsant mood stabilizers, and clozapine. Ataxia rarely occurs with non-toxic levels of drug, particularly anticonvulsants, benzodiazepines and lithium.

Intravenous Migraine Treatment in Children and Adolescents.

PURPOSE OF REVIEW: Pediatric migraine is a common, chronic, and disabling neurological disorder in children and adolescents. Outpatient management is not always effective, and intravenous migraine management may be necessary for headache treatment in the pediatric emergency department. Most current treatment is based on retrospective evidence and there is a lack of well-designed randomized double-blinded controlled pediatric studies. Intravenous drug treatment agents including intravenous fluids, prochlorperazine, diphenhydramine, metoclopramide, dexamethasone, magnesium, valproate and propofol, and dihydroergotamine are reviewed in this paper. RECENT FINDINGS: Nineteen studies were reviewed including one prospective randomized double-blind; one single-blinded randomized; one prospective; and one open-label, randomized clinical trial. Most studies were retrospective and the quality of the studies was limited. No definite conclusions can be drawn from the studies, but appropriate prospective trials between major pediatric headache institutions will move pediatric intravenous migraine management forward.

Akathisia and Newer Second-Generation Antipsychotic Drugs: A Review of Current Evidence.

Akathisia continues to present a significant challenge in clinical practice. As a class, so-called atypical, or second-generation, antipsychotics (SGAs) are the mainstay of treatment for schizophrenia and are commonly used to treat mood disorders. These medications have traditionally been distinguished from first-generation antipsychotics by their lowered risk of extrapyramidal side effects (EPS) such as dystonia, dyskinesia, akathisia, and pseudoparkinsonism. However, the occurrence of EPS, particularly akathisia, has been demonstrated to some degree in all commercially available SGAs. This review examines the incidence of akathisia in nine newer SGAs in patients with schizophrenia, bipolar disorder, and major depressive disorder (MDD). We performed a search of PubMed, ClinicalTrials.gov, Cochrane Central Register, and Google Scholar, as well as manufacturer websites and product labeling for published and unpublished clinical trials, meta-analyses, and systematic reviews. Studies evaluating adult patients with schizophrenia, bipolar disorder, or MDD were eligible for inclusion. Data on treatment-emergent akathisia rates were gathered from each study, and potential dose-response relationships were explored. A total of 177 studies were included in this review, comprising 58,069 patients across 414 treatment arms. Compared with placebo with a composite 3.7% incidence of akathisia, individual SGAs produced akathisia at total composite rates ranging from 2.9-13.0% across the included studies. High doses of an SGA were generally associated with an increased risk of akathisia. Clinicians should consider the risk of akathisia when choosing a treatment option and monitor for akathisia in patients beginning therapy with an SGA or following a dose increase of the SGA.

Pregabalin induced visual hallucinations - a rare adverse reaction.

BACKGROUND: Pregabalin is an anticonvulsive, analgesic and anxiolytic medication. The typical side effects include dizziness, somnolence and weight gain. Few studies or case reports have demonstrated psychiatric side effects resulting from its use. CASE PRESENTATION: We present a patient who suffered visual hallucinations and agitation associated with an increase in pregabalin dose, resolving completely after pregabalin discontinuation. CONCLUSIONS: Acute visual hallucinations should be considered in the clinical spectrum of very rare side effects of pregabalin use, especially at higher doses. Tapered discontinuation of the medication can improve and resolve symptoms.