Pathophysiology and management of Akathisia 70 years after the introduction of the chlorpromazine, the first antipsychotic.

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resolves upon treatment discontinuation but tardive and chronic akathisia may persist after the causative agent is withdrawn and prove resistant to pharmacological treatment.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.

Acatisia inducida por antipsicóticos: recomendaciones para la práctica clínica / Antipsychotic-induced akathisia: recommendations for clinical practice

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.

Ertapenem-induced encephalopathy.

Neurotoxicity is an unusual side effect of carbapenems, and it has been reported most commonly presenting as seizures, encephalopathy and hallucinations. Ertapenem neurotoxicity most classically presents as seizures in patients with end-stage renal disease (estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2). We present a patient with a baseline eGFR of 30-59 mL/min/1.73 m2 with acute kidney injury who developed non-seizure neurotoxicity after ertapenem exposure. This patient is a middle-aged Caucasian man who received intravenous ertapenem for treatment of empyema. Although the empyema improved, he developed delirium beginning on day 7 of ertapenem. The delirium progressed to constant agitation and visual hallucinations requiring transfer to the intensive care unit with eventual intubation for airway protection. No improvement in mental status was observed with cessation of other medications. Ertapenem was discontinued and within 24 hours, he was extubated, and his mental status returned to baseline. He was discharged from the hospital the following day. The timely resolution after ertapenem discontinuation makes ertapenem-induced encephalopathy the most likely explanation for this patient's course.

Remission of treatment-resistant depression with tardive akathisia with electroconvulsive therapy.

This report presents a case of drug-induced severe tardive akathisia developing after the combination of a selective serotonin reuptake inhibitor and an antipsychotic, in a woman with severe major depression. The trial and combination of multiple medications is common practice in treatment-resistant patients with depression. With the increase in the prevalence of treatment-resistant depression, adverse effects of medication such as tardive akathisia are becoming more common. Tardive akathisia persists even after the withdrawal of the causative agent and is very challenging to treat. The patient did not respond to any standard medications indicated for drug-induced akathisia. As a result, the patient became suicidal and extremely distressed with all treatment options exhausted. Guidelines on the management of drug-induced tardive akathisia are non-existent. This reflects the importance of this case study, which reveals the complete remission of both tardive akathisia and all the patient's depressive symptoms after electroconvulsive therapy . This report provides evidence of an established treatment intervention used in a new situation.

Current Evidence-Based Practice for Pediatric Emergence Agitation.

This article provides a systematic review of pediatric emergence agitation, also known as emergence delirium. Major topics of this review include the incidence, risk factors, and impact of the phenomenon, in addition to current evidence-based strategies for prevention of pediatric emergence agitation. Emergence agitation causes tremendous psychological distress for the patient, family, and healthcare providers, as well as concerns for physical safety. Risk factors for pediatric emergence agitation are the child's age, genetic profile, length and type of surgical procedure, and use of inhalational anesthesia. In an attempt to prevent this problem, anesthesia providers should consider these factors and possible interventions when implementing an anesthetic plan. Evidence-based interventions that may decrease the incidence of pediatric emergence agitation include technology, familial involvement, pharmacologic adjuncts, and alternative methods of general anesthesia.

Deep brain stimulation for tardive syndromes: Systematic review and meta-analysis.

Among the broad entity of tardive syndromes, tardive dystonia and classical tardive dyskinesia sometimes require advanced treatments like deep brain stimulation of the globus pallidus internum (Gpi-DBS) or the subthalamic nucleus (STN-DBS). This systematic review has analyzed the currently available literature reporting cases with either tardive dystonia or dyskinesia treated with DBS. The key words for the literature search included all tardive syndromes and "deep brain stimulation." Thirty-four level VI studies and one level II study with 117 patients were included. Level I studies were not identified. Only four of the patients had tardive dyskinesia. All the others had tardive dystonia. The majority had Gpi-DBS (n = 109). Patients had a mean age of 47.4 (± SD 14.7) years. The duration of follow-up was 25.6 months ±â€¯26.2. The Abnormal Involuntary Movement Scale was reported in 51 patients with an improvement of 62 ±â€¯15% and the Burke-Fahn-Marsden scale was reported in 67 cases with an improvement of 76 ±â€¯21%. Reported adverse events were surgery-related in 7 patients, stimulation-induced in 12, and psychiatric in 3 patients. These reports thus suggest favorable effects of DBS and it seems to be relatively safe. DBS can be considered for patients with severe, medication-resistant symptoms. Controlled and randomized studies with blinded outcomes are needed.

The nosology of tardive syndromes.

Since the original description of side effects of neuroleptics, different terminologies and definitions for tardive dyskinesia (TD) and tardive syndrome (TS) have been used by different authors, and often these two terms have been used interchangeably. This paper proposes a nosology designed to define and clarify various terms and phenomenologies within the TS spectrum. We propose to use the term tardive dyskinesia to refer to the original description of repetitive and complex oral-buccal-lingual (OBL) movements, as well as to the analogous repetitive movements that can appear in the limbs, trunk, or pelvis. The repetitive, relatively rhythmic nature of the movements is the common denominator of this phenomenologic category. The term tardive syndrome refers to the spectrum of all persistent hyperkinetic, hypokinetic and sensory phenomenologies resulting from chronic dopamine receptor blocking agents (DRBA) exposure. Thus, TS is an umbrella term. When dystonia is the main feature of TS it is considered to be tardive dystonia (TDyst). Retrocollis appears to be the predominant form of cervical dystonia in this condition. Cranial dystonias, particularly oromandibular dystonia, are also common forms of TDyst. Tardive akathisia refers to the inability to remain still with an urge to move, giving the appearance of restlessness. It is a sensory phenomenon and a common and disabling form of TS. Unlike acute akathisia, tardive akathisia tends to occur late and persists after the drug is withdrawn. In tardive tourettism, the patient exhibits the features of Tourette syndrome with complex motor and phonic tics associated with premonitory urge and relief of tension after performing the tic behavior. Tardive tremor differs from the resting tremor seen in drug-induced parkinsonism in that it is mainly a postural and kinetic greater than resting tremor. Tardive pain has been reported in association with chronic use of DRBA's. The pain involved the mouth, tongue and the genital region. The patients tended to obsess over the pain and usually had some other form of motor tardive syndrome, either tardive dyskinesia, tardive akathisia or tardive dystonia. The term tardive parkinsonism has been proposed for those drug induced parkinsonism patients who have persistent symptoms following discontinuation of the DRBA. However, there is a strong possibility that the DRBA may have simply unmasked subclinical parkinsonism or that there is coincident Parkinson disease developing during the period the patient is taking the DRBA.

Updating the recommendations for treatment of tardive syndromes: A systematic review of new evidence and practical treatment algorithm.

BACKGROUND: Management of tardive syndromes (TS) is challenging, with only a few evidence-based therapeutic algorithms reported in the American Academy of Neurology (AAN) guideline in 2013. OBJECTIVE: To update the evidence-based recommendations and provide a practical treatment algorithm for management of TS by addressing 5 questions: 1) Is withdrawal of dopamine receptor blocking agents (DRBAs) an effective TS treatment? 2) Does switching from typical to atypical DRBAs reduce TS symptoms? 3) What is the efficacy of pharmacologic agents in treating TS? 4) Do patients with TS benefit from chemodenervation with botulinum toxin? 5) Do patients with TS benefit from surgical therapy? METHODS: Systematic reviews were conducted by searching PsycINFO, Ovid MEDLINE, PubMed, EMBASE, Web of Science and Cochrane for articles published between 2012 and 2017 to identify new evidence published after the 2013 AAN guidelines. Articles were classified according to an AAN 4-tiered evidence-rating scheme. To the extent possible, for each study we attempted to categorize results based on the description of the population enrolled (tardive dyskinesia [TD], tardive dystonia, tardive tremor, etc.). Recommendations were based on the evidence. RESULTS AND RECOMMENDATIONS: New evidence was combined with the existing guideline evidence to inform our recommendations. Deutetrabenazine and valbenazine are established as effective treatments of TD (Level A) and must be recommended as treatment. Clonazepam and Ginkgo biloba probably improve TD (Level B) and should be considered as treatment. Amantadine and tetrabenazine might be considered as TD treatment (Level C). Pallidal deep brain stimulation possibly improves TD and might be considered as a treatment for intractable TD (Level C). There is insufficient evidence to support or refute TS treatment by withdrawing causative agents or switching from typical to atypical DRBA (Level U).

Suspected Synthetic Cannabinomimetic Intoxication: Case Series and Review.

PURPOSE: The purpose of this work was to retrospectively review patient cases presenting to the University of Kentucky Chandler Medical Center (UKCMC) emergency department (ED) with symptoms of suspected synthetic cannabinomimetic (SC) intoxication. These drugs, currently undetected by standard urine drug screen tests, comprise a structurally diverse group of compounds designed to mimic the psychoactive effects of Δ9-tetrahydrocannabinol (Δ9-THC), the primary psychoactive cannabinoid in marijuana. SUMMARY: Fourteen cases of suspected SC intoxication were identified between July 1, 2015, through September 30, 2015. The median patient age was 25.5 years (range: 13-45 years), and most (64%) patients were males. The most common psychoactive symptom was agitation (n = 6, 42.9%), while the most common physical symptoms were altered level of consciousness (n = 9, 64.3%) and mydriasis (n = 3, 21.4%). Most cases resolved without complication in 24 hours; 2 patients required hospitalization. CONCLUSION: Recent legislation has failed to curb the public health concerns emanating from SC misuse. Education about the risks of SC use along with additional regulation may be required to remove the false sense of safety that some individuals, especially adolescents and young adults, may associate with these compounds, which are often misconstrued as "herbal marijuana." Clinicians need to be prepared to identify and treat symptoms of SC intoxication as incidents of toxicity continue to rise.

Correspondence between negative symptoms and potential sources of secondary negative symptoms over time.

There has been a debate in the literature about the distinction between primary and secondary negative symptoms of schizophrenia. Our aim was to study the associations between negative symptoms and potential sources of secondary negative symptoms over time. A sample of 275 participants with at least mid-moderate negative symptoms was randomized into body psychotherapy or Pilates class in a previous study. No significant differences were found between groups over time and changes in the symptom domains were modest. The present investigation considers the longitudinal correlation between variables of interest at baseline, 3 and 9 months follow-up. Measures were the Clinical Assessment Interview for Negative Symptoms (CAINS), the Positive and Negative Symptom Scale (PANSS), the Calgary Depression Scale (CDSS) and the Simpson-Angus Extrapyramidal side-effects Scale (SAS). Mixed models were computed to test the longitudinal association between these variables. In a sensitivity analysis, the dosages of antipsychotic, illness duration and allocated intervention were taken into account. Overall, the course of extrapyramidal side-effects, depressive and positive symptoms was significantly related to the course of negative symptoms. Only extrapyramidal effects were longitudinally correlated to expressive negative symptoms. The sensitivity analyses showed unaltered results for positive symptoms and depression but a lack of association between extrapyramidal effects and the CAINS outcomes. In conclusion, the unambiguous interpretation between primary and secondary negative symptoms may lead to refined treatment approaches for schizophrenia and to increased effects of the interventions.

The Incidence of Akathisia in the Treatment of Schizophrenia with Aripiprazole, Asenapine and Lurasidone: A Meta-Analysis.

Akathisia is a troubling side effect that leads to non-adherence with antipsychotic regimens. Second generation antipsychotics (SGAs) tend to cause less akathisia than older agents but the risk still exists and rates vary between agents. Little is known about the incidence of akathisia among the newer SGAs. The purpose of this study was to conduct a meta-analysis of akathisia incidence rates for three of the newer SGAs: aripiprazole, asenapine, and lurasidone. Data were drawn from published and unpublished clinical trials comparing the drug of interest to either placebo or another SGA in adults with schizophrenia. Twenty-four studies (11 aripiprazole, 5 asenapine, and 8 lurasidone) provided incidence rates for akathisia and related nervous system events. Data showed that the relative risk (RR) of akathisia was double that of controls, with lurasidone having the highest individual RR at 2.7 [CI: 2-3.6]. Sensitivity analysis changed the RR of akathisia to less than 10%. The RR of akathisia was still elevated (1.75 [1.4-2.1]) when these drugs were compared only to actives (older SGAs). Agitation and anxiety RRs were also higher with the newer SGAs as compared to the older SGAs. Previous theory suggests antagonism of serotonin (5-HT)2A receptors may decrease akathisia risk. Expectations were that aripiprazole, asenapine and lurasidone would have a low incidence of akathisia, as all display strong antagonism at 5-HT2A. However, in this study all three had a significantly higher risk of akathisia compared to placebo or other SGAs. This suggests the pathophysiology of akathisia involves other receptors and is multifactorial.

Selective serotonin reuptake inhibitor-induced akathisia.

OBJECTIVE: To review available information in the literature about akathisia (inner restlessness) caused by the selective serotonin reuptake inhibitors (SSRIs). DATA SOURCES: Databases searched included Medline, PsychInfo, the International Pharmaceutical Abstracts, and Google Scholar. Search terms included drug-induced akathisia, psychomotor agitation, drug-induced side effect, movement disorders, and extrapyramidal symptoms. These search terms were cross-referenced with selective serotonin reuptake inhibitors and each of the currently marketed SSRIs: fluoxetine, fluvoxamine, sertraline, paroxetine, citalopram, and escitalopram. STUDY SELECTION: Relevant articles were chosen if they specifically mentioned the word akathisia. Case reports were chosen based on a clear view that an SSRI was a contributing or causative agent of akathisia. DATA SYNTHESIS: Recognizing akathisia is important because it can be very bothersome and may cause suicidal ideations. Akathisia can be recognized by examining symptoms, looking at predisposing factors, and using the Barnes Akathisia Rating Scale (BARS). Predisposing factors include use of multiple akathisia-inducing drugs, recent increases in SSRI dose, previous development of akathisia, baseline psychiatric disorders, and brain trauma. Treatment options include the addition of a centrally acting beta-blocker, a benzodiazepine, or an anticholinergic agent. CONCLUSION: Pharmacists can play an active role in recognizing akathisia by being aware of its characteristics, conducting a thorough medication history to identify causative agents, and using BARS to evaluate patients. These efforts may preclude unnecessary discomfort for the patient and reduce the potential for nonadherence induced by akathisia.

[Akathisia--diagnosis, pathophysiology and therapy]. / Akatyzja--diagnoza, patofizjologia i terapia.

Akathisia is an atypical disorder (or the symptom) of the motor system standing on the border of neurology and psychiatry. In neurology, akathisia is a disorder resulting mainly from disturbed dopaminergic transmission; in the field of psychiatry it is recognized as one of the extrapiramidal side effects during the treatment with neuroleptics. The paper describes the historical context of disorder defined as akathisia, its clinical course, pathophysiology, as well as therapy.

Drug-induced movement disorders in children.

This article reviews the current state of knowledge of drug-induced movement disorders (DIMDs) in children. The objective is to aid clinicians who treat children with medications that may induce DIMDs, as well as specialists consulted on DIMDs. As with adults, the most common agents are dopaminergic and dopamine-blocking medications, and prescriptions for these agents have increased markedly in children. Unfortunately, most evidence-based reviews, including those from the Cochrane Collaboration cited here, have few systematic data to analyze. Many publications are small case series. This report attempts to provide useful information, with appropriate caution and discussion of the limitations of what we know.

Akathisia and an unusual symptomatic treatment: a case report.

We present a case of medication-induced akathisia in a 47-year-old woman with metastatic carcinoma of the ovary. Severe pacing and restlessness started after commencing a subcutaneous infusion with cyclizine 150 mg, haloperidol 2.5 mg and oxycodone 20 mg. She was also taking levomepromazine and fluoxetine orally at the time. By making changes to her medication, her symptoms resolved gradually. During the time of convalescence, she gained great symptomatic relief from using exercise pedals and it allowed her to go about usual everyday activities, such as eating and reading, while continuously treading the pedals.