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Importance: Antipsychotic-induced akathisia (AIA) occurs in 14% to 35% of patients treated with antipsychotics and is associated with increased suicide and decreased adherence in patients with schizophrenia. However, no comprehensive review and network meta-analysis has been conducted to compare the efficacy of treatments for AIA. Objective: To compare the efficacy associated with AIA treatments. Data Sources: Three databases (MEDLINE, Web of Science, and Google Scholar) were systematically searched by multiple researchers for double-blind randomized clinical trials (RCTs) comparing active drugs for the treatment of AIA with placebo or another treatment between May 30 and June 18, 2023. Study Selection: Selected studies were RCTs that compared adjunctive drugs for AIA vs placebo or adjunctive treatment in patients treated with antipsychotics fulfilling the criteria for akathisia, RCTs with sample size of 10 patients or more, only trials in which no additional drugs were administered during the study, and RCTs that used a validated akathisia score. Trials with missing data for the main outcome (akathisia score at the end points) were excluded. Data Extraction and Synthesis: Data extraction and synthesis were performed, estimating standardized mean differences (SMDs) through pairwise and network meta-analysis with a random-effects model. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. Main Outcomes and Measures: The primary outcome was the severity of akathisia measured by a validated scale at the last available end point. Results: Fifteen trials involving 492 participants compared 10 treatments with placebo. Mirtazapine (15 mg/d for ≥5 days; SMD, -1.20; 95% CI, -1.83 to -0.58), biperiden (6 mg/d for ≥14 days; SMD, -1.01; 95% CI, -1.69 to -0.34), vitamin B6 (600-1200 mg/d for ≥5 days; SMD, -0.92; 95% CI, -1.57 to -0.26), trazodone (50 mg/d for ≥5 days; SMD, -0.84; 95% CI, -1.54 to -0.14), mianserin (15 mg/d for ≥5 days; SMD, -0.81; 95% CI, -1.44 to -0.19), and propranolol (20 mg/d for ≥6 days; SMD, -0.78; 95% CI, -1.35 to -0.22) were associated with greater efficacy than placebo, with low to moderate heterogeneity (I2 = 34.6%; 95% CI, 0.0%-71.1%). Cyproheptadine, clonazepam, zolmitriptan, and valproate did not yield significant effects. Eight trials were rated as having low risk of bias; 2, moderate risk; and 5, high risk. Sensitivity analyses generally confirmed the results for all drugs except for cyproheptadine and propranolol. No association between effect sizes and psychotic severity was found. Conclusions and Relevance: In this systematic review and network meta-analysis, mirtazapine, biperiden, and vitamin B6 were associated with the greatest efficacy for AIA, with vitamin B6 having the best efficacy and tolerance profile. Trazodone, mianserin, and propranolol appeared as effective alternatives with slightly less favorable efficacy and tolerance profiles. These findings should assist prescribers in selecting an appropriate medication for treating AIA.

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BACKGROUND: Antidepressant-induced paradoxical anxiety is a fairly common phenomenon seen in patients who are initiated on antidepressants. However, akathisia is a very uncommon manifestation of antidepressants. Much more rarely, antidepressants are also associated with the emergence of motor and vocal tics. This case adds to the growing literature of rare adverse events induced by antidepressants and aims to stimulate future research into the mechanism and risk factors of this phenomenon. CASE PRESENTATION: In this case report, we describe a patient with panic disorder and co-morbid Crohn's disease who developed worsening anxiety, akathisia and vocal tics upon initiation of fluvoxamine. This is the first case report to describe the emergence of both akathisia and vocal tics in the same patient following antidepressant initiation. After discontinuation of fluvoxamine, the patient's symptoms resolved. CONCLUSION: Antidepressant-induced akathisia and tics are often distressing both to the patient and their loved ones, and can be very puzzling to the clinician. It is important for clinicians to recognise that, although rare, antidepressants can adverse effects. When these symptoms arise, it should prompt immediate discontinuation of the offending antidepressant.

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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.

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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.

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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.

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Repeated psychostimulant administration results in behavioral sensitization, a process that is relevant in the early phases of drug addiction. Critically, behavioral sensitization is not observed in all subjects. Evidence shows that differential neuronal activity in the dorsolateral striatum (DLS) accompanies the expression of amphetamine (AMPH) locomotor sensitization. However, whether individual differences in DLS activity previous to AMPH administration can predict the expression of locomotor sensitization has not been assessed. Here, we examined DLS neuronal activity before and after repeated AMPH administration and related it to the susceptibility of rats to sensitize. For that, single-unit recordings on DLS medium spiny neurons (MSNs) were carried out in freely moving male Sprague Dawley rats during repeated AMPH administration. We also examined differences in neurostructure that could accompany sensitization. We quantified the density of the inhibitory postsynaptic marker gephyrin (Geph) in the entopeduncular nucleus (EP) and globus pallidus (GP). A higher burst firing and a lower percentage of correlation between MSNs post-Saline firing rate vs. locomotion predicted the expression of locomotor sensitization. Moreover, during the AMPH challenge, we observed that burst firing decreased in sensitized rats, in contrast to non-sensitized rats in which burst firing was maintained. Finally, a higher Geph density on GP but not EP was observed in non-sensitized rats after AMPH challenge. These results indicate that initial differences in DLS burst firing might underlie the susceptibility to express locomotor sensitization and suggest that the potentiation of dorsal striatum indirect pathway could be considered a protective mechanism to locomotor sensitization.

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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.

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Akathisia is a movement disorder affecting the trunk and limbs, characterized by subjective and objective restlessness. Key signs include continual, repetitive rocking, leg shuffling, and fidgeting. Antipsychotic-induced akathisia is optimally managed by reducing the medication dose or switching to a second generation antipsychotic that is less prone to inducing akathisia. However, since medication changes are often not feasible, we review the available classes of rescue agents for akathisia symptoms. The fitting acronym, "B-CALM", which stands for Beta-blockers, Clonazepam, Anticholinergics, cLonidine and Mirtazapine, will assist prescribers in facile recall of evidence-based treatment options for akathisia. Pharmacological agents such as mianserin, trazodone, Vit B6, amantadine, gabapentin, and pregabalin have also been examined as treatment options for antipsychotic-induced akathisia. Although initial exploratory reports on these agents have been promising, the current evidence is insufficient. Akathisia has a good prognosis when managed early in the course of treatment. A variety of safe rescue agents are available for the management of this condition, however, current evidence best supports the use of propranolol and mirtazapine.

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OBJECTIVE: Akathisia is among the most troubling effects of psychiatric drugs as it is associated with significant distress on behalf of the patients, and it limits treatment adherence. Though it most commonly presents during treatment with antipsychotic drugs which block dopamine D2 receptors, Akathisia has also been reported during treatment with selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), stimulants, mirtazapine, tetrabenazine and other drugs. MATERIALS AND METHODS: This article was designed as a narrative review on akathisia with a focus on its clinical presentation, pathophysiology and management. A PubMed search for akathisia was conducted which returned 8481 articles. RESULTS: Akathisia is experienced as severe restlessness commonly accompanied by dysphoria and purposeless movement which relieves subjective tension. It has been attributed to an imbalance between dopaminergic and noradrenergic neurotransmission in the basal ganglia. Acute akathisia commonly resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment. Even drugs which induce no other extrapyramidal side effects (such as clozapine, quetiapine, aripiprazole and cariprazine) may induce akathisia. A high index of suspicion should be maintained in patients with motor disabilities, drug-induced parkinsonism and those under mechanical restraint. Propranolol and low-dose mirtazapine are the most thoroughly studied pharmacological interventions for akathisia, though benzodiazepines, voltage-gated calcium channel blockers (gabapentin, pregabalin) and opioids may be effective. CONCLUSIONS: Pharmacological management may pose a challenge in chronic akathisia. Rotation between different pharmacological management strategies may be optimal in resistant cases. Discontinuation of the causative drug and use of b-blockers, mirtazapine, benzodiazepines or gabapentinoids for symptomatic relief is the basis of management.

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Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6 J mice were pretreated with PG01037 (0-10 mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6-56 mg/kg), 2) locomotor sensitization following repeated morphine (56 mg/kg), 3) antinociception following acute morphine (18 mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56 mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.

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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.

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La acatisia es uno de los eventos adversos inducidos por antipsicóticos más prevalentes y puede generar severa angustia en quien lo experimente. Se caracteriza por inquietud psicomotora objetiva y subjetiva. Pertenece al gran paraguas de los "síntomas extrapiramidales", sin embargo, tiene sus particularidades clínicas lo que representa un desafío clínico, tanto en su diagnóstico como en su manejo específico. La presente revisión sintetiza la información disponible a la fecha y ofrece al clínico recomendaciones para prevenir, reconocer y manejar esta complicación frecuente de una de las familias de psicofármacos de mayor prescripción clínica en la actualidad.

Abstract. Akathisia is one of the most prevalent antipsychotic-induced adverse events and causes severe distress in those who experience it. It is characterized by objective and subjective psychomotor restlessness. Usually classified under the great umbrella of extrapyramidal symptoms; however, it has its own clinical peculiarities, which might represent a challenge for the clinician in diagnosis as well as specific management. This review synthesizes the information available to date on antipsychotic-induced akathisia and offers the clinician recommendations to prevent, recognize and treat this prevalent complication of one of the most widely prescribed psychotropic medications today.

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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.

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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.

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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.

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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.

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BACKGROUND: Toxicity from antimuscarinic agents precipitates a constellation of signs and symptoms; two of the most significant are agitation and delirium. Benzodiazepines are commonly used for treatment; physostigmine is also effective but is underutilized due to concerns for safety and short duration of action. The objective of this study was to compare lorazepam to physostigmine for the treatment of antimuscarinic delirium and agitation. METHODS: This was a blinded, randomized clinical trial in patients presenting for antimuscarinic toxidrome. Inclusion criteria were: ≥10-<18 years old, at least one central and two peripheral antimuscarinic symptoms, delirium and moderate agitation. Subjects were randomized to either (1) lorazepam bolus (0.05 mg/kg) followed by a 4-h normal saline infusion, or (2) physostigmine 0.02 mg/kg bolus followed by a 4-h physostigmine infusion (0.02 mg/kg/h). Primary outcomes were the control of delirium and agitation after bolus and during the infusion. RESULTS: Ten (53%) subjects were enrolled in the lorazepam arm, 9 (47%) in the physostigmine arm. Diphenhydramine was the most common agent ingested (16, 84%). Fewer patients receiving physostigmine had delirium after the initial bolus (44% vs 100%, p = 0.01) and at the 4th hour of infusion (22% vs 100%, p < 0.001) compared to patients who received lorazepam. There was a significant decrease in agitation scores in the physostigmine arm compared to the lorazepam arm after the initial bolus (89% vs 30%, p = 0.02), but no difference at the 4th hour of infusion (p > 0.99). There were no seizures, bradycardia, bronchorrhea, bronchospasm, intubation, or cardiac dysrhythmias. CONCLUSION: Physostigmine was superior to lorazepam in controlling antimuscarinic delirium and agitation after bolus dosing, and control of delirium after a 4-h infusion. There were no serious adverse events in either treatment arm. Physostigmine bolus and infusion should be considered in adolescent patients with significant delirium and agitation from antimuscarinic agents.

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