Anticholinergics in the era of atypical antipsychotics: short-term or long-term treatment?

Anticholinergic agents are usually prescribed to prevent or treat antipsychotic-induced extrapyramidal symptoms. Their long-term benefits are questionable and they carry diverse adverse effects, including cognitive impairment and worsening of tardive dyskinesia. This literature review explores the impact of anticholinergic medication discontinuation on movement disorders, cognition and psychopathology in patients receiving antipsychotics. Medline, Embase and PsycInfo were searched from 1950 to July 2011 using "cessation /withdrawal /discontinuation /stopping" with "anticholinergic*" or "antiparkinson*" and "neuroleptic*" or "antipsychotic*". Additional articles were obtained by searching the bibliographies of relevant references. Earlier studies of anticholinergic agent discontinuation in patients receiving first-generation antipsychotics reported relapse rates of extrapyramidal symptoms between 4% and 80%, reflecting the heterogeneity of the studies. Two recent studies of patients prescribed second-generation antipsychotics obtained relapse rates of 4% and 33%. Some studies suggest improvement in tardive dyskinesia with cessation of anticholinergics. Four studies examined the effects of anticholinergic agent discontinuation on cognition and all observed an improvement post-discontinuation. Changes in symptoms of schizophrenia with anticholinergic discontinuation are conflicting, with more recent studies suggesting an improvement. Given their questionable benefit with continued use, clinicians should consider a gradual withdrawal of anticholinergic agents in stable patients receiving antipsychotics.     

Tardive oculogyric crisis during treatment with clozapine: report of three cases

Tardive oculogyric crisis (OGC) is a dystonic syndrome that starts after long-term use of dopamine receptor antagonists. Atypical antipsychotics have reduced liability for inducing tardive dystonia and show antidystonic properties in patients with pre-existing tardive dystonia. Clozapine is an atypical antipsychotic drug, and there have been case reports that clozapine may be an effective treatment for tardive dystonia. Surprisingly, we found that three patients appeared to develop tardive OGC while taking clozapine. The relationship between tardive OGC and clozapine is still unknown. However, it is possible that the previous antipsychotic exposure could have created a sensitising or priming effect on the striatum. Also, there are some suggestions of an underlying susceptibility and possibly a genetic predisposition, at least in some patients.     

Extrapyramidal symptoms with atypical antipsychotics : incidence, prevention and management.

The treatment of schizophrenia changed drastically with the discovery of antipsychotic medications in the 1950s, the release of clozapine in the US in 1989 and the subsequent development of the atypical or novel antipsychotics. These newer medications differ from their conventional counterparts, primarily based on their reduced risk of extrapyramidal symptoms (EPS). EPS can be categorised as acute (dystonia, akathisia and parkinsonism) and tardive (tardive dyskinesia and tardive dystonia) syndromes. They are thought to have a significant impact on subjective tolerability and adherence with antipsychotic therapy in addition to impacting function. Unlike conventional antipsychotic medications, atypical antipsychotics have a significantly diminished risk of inducing acute EPS at recommended dose ranges. These drugs may also have a reduced risk of causing tardive dyskinesia and in some cases may have the ability to suppress pre-existing tardive dyskinesia. This paper reviews the available evidence regarding the incidence of acute EPS and tardive syndromes with atypical antipsychotic therapy. Estimates of incidence are subject to several confounds, including differing methods for detection and diagnosis of EPS, pretreatment effects and issues surrounding the administration of antipsychotic medications. The treatment of acute EPS and tardive dyskinesia now includes atypical antipsychotic therapy itself, although other adjunctive strategies such as antioxidants have also shown promise in preliminary trials. The use of atypical antipsychotics as first line therapy for the treatment of schizophrenia is based largely on their reduced risk of EPS compared with conventional antipsychotics. Nevertheless, EPS with these drugs can occur, particularly when prescribed at high doses. The EPS advantages offered by the atypical antipsychotics must be balanced against other important adverse effects, such as weight gain and diabetes mellitus, now known to be associated with these drugs.     

Switching to amisulpride

The introduction of atypical antipsychotics represents an important advance in the treatment of schizophrenia. As their therapeutic efficacy, tolerability and safety profiles are clearly superior to classical neuroleptics, atypical antipsychotic agents are considered to be the treatment of choice in first episode patients. In addition, an increasing number of patients are being switched from classical to atypical antipsychotic agents. Switching is especially relevant in patients with a poor therapeutic response to classical neuroleptics and persistent symptoms (positive symptoms, negative symptoms, depressive syndromes, cognitive deficit); in patients with a psychotic relapse despite compliance; in patients with important side-effects (not only acute and tardive extrapyramidal symptoms [EPS] and general side-effects, but also dysphoria or neuroleptic-induced deficit syndrome [NIDS]); and in patients who are non-compliant due to side-effects. Switching to atypical antipsychotics should be performed with extreme care in stabilised patients; or in patients who present a danger to themselves or others at relapse; or in patients who are on depot neuroleptics who were non-compliant to previous oral treatment. Switching requires careful planning to reduce the risk of withdrawal effects (neuroleptic withdrawal syndrome, cholinergic rebound, exacerbation of symptoms or relapse, rebound of parkinsonism, dystonia, akathisia, dyskinesia), which may mask the beneficial effects and lead to early discontinuation of the new treatment. Patients, family and carers should be actively involved at all stages, and educated about the possible benefits and problems associated with switching therapy. Cross-tapering old and new treatment is the preferred method for switching and this involves tapering off the previous antipsychotic agent and any adjunctive treatment (sedatives, anticholinergic medication), while gradually titrating the new atypical antipsychotic agent to the established therapeutic dose. Switching patients to amisulpride treatment offers effective antipsychotic therapy, with a positive effect on negative and depressive symptoms. Amisulpride treatment also results in improved quality of life and social functioning in addition to fewer relapses and days of hospitalisation during long-term follow-up.     

Managing antipsychotic-induced tardive dyskinesia.

Antipsychotic-induced tardive dyskinesia is a common and clinically significant hazard of long term antipsychotic therapy. The arrival of atypical antipsychotics has markedly improved the outlook: atypical antipsychotics are emerging as effective treatments and may also reduce the prevalence and incidence of tardive dyskinesia. In mild cases, careful monitoring of tardive dyskinesia by serial Abnormal Involuntary Movements Scale (AIMS) assessments may be the appropriate course. More severe tardive dyskinesia calls for intervention in order to treat the dyskinesia. Atypical antipsychotics and tocopherol (vitamin E) are effective and generally well tolerated treatment options for tardive dyskinesia. Tardive dyskinesia variants such as tardive dystonia and tardive akathisia tend to be more severe and difficult to treat compared with typical tardive dyskinesia. Prevention of tardive dyskinesia is possible through careful selection of patients for antipsychotic therapy, use of the lowest effective antipsychotic dosages, use of atypical rather than traditional antipsychotics and concurrent tocopherol administration. The clinician can now undertake the management of tardive dyskinesia with growing confidence.     

Insomnia related to biperiden withdrawal in two schizophrenic patients

It is not uncommon for patients who are receiving antipsychotic medication to be given anticholinergic agents, such as biperiden, despite the relative absence of neurological side-effects. Two cases of schizophrenia are reported in which insomnia developed after biperiden withdrawal or reduction. The insomnia continued until biperiden treatment was reinstated, despite the fact that the patients did not exhibit signs or report symptoms indicative of antipsychotic drug-induced neurological side-effects. The occurrence of insomnia following the withdrawal of biperiden or reduction in the dose has not been previously reported. One potential explanation for the insomnia is cholinergic rebound following the withdrawal of biperiden.     

Extrapyramidal symptoms during treatment of first schizophrenia episode: Results from EUFEST

The European First Episode Schizophrenia Trial (EUFEST) included first-episode schizophrenia patients, assessing the efficacy of five antipsychotic drugs (haloperidol, amisulpride, olanzapine, quetiapine and ziprasidone) over one year. Baseline frequency of extrapyramidal symptoms (EPS) in this group of patients (n=490) was as follows: parkinsonism 10.8%, akathisia 10.0%, dystonia 1.8%, and dyskinesia 0.6%. The frequency of parkinsonism at baseline was greater in patients with a brief prior exposure to antipsychotics (≤2 weeks) compared with antipsychotic-naïve ones, and was positively correlated with the intensity of negative symptoms and negatively with depressive symptoms. After one month of treatment, the increase of parkinsonism was highest in patients receiving haloperidol (+13%), that of akathisia in patients treated with ziprasidone (+14%), and 10.1% of the patients were taking anticholinergic drugs, most frequently in the haloperidol group (24%). In 291 patients remaining on treatment after one year, both parkinsonism and akathisia had decreased: the frequency of parkinsonism was 3%, highest in the haloperidol group (9.1%), that of akathisia was 3%, highest in the quetiapine group (7.5%), and 4% of patients were taking anticholinergic drugs, most frequently those receiving haloperidol (10.5%). The results obtained suggest that in first-episode schizophrenia patients during the first year of antipsychotic treatment (in this case amisulpride, haloperidol in low doses, olanzapine, quetiapine and ziprasidone), EPS were present as manageable clinical problems.     

Persistence with polypharmacy and excessive dosing in patients with schizophrenia treated in four European countries

The purpose of this study was to calculate the proportion of patients with schizophrenia receiving persistent antipsychotic polypharmacy and excessive dosing in four European countries; to test the hypothesis that excessive dosing and/or antipsychotic polypharmacy is associated with higher levels of psychopathology; and to establish whether use of second-generation antipsychotics is a protective or a risk factor for polypharmacy and excessive dosing. Participants with schizophrenia were recruited from patients under the care of psychiatric services serving geographical catchment areas in Croydon (UK), Verona (Italy), Amsterdam (Netherlands), and Leipzig (Germany). We defined patients persistently receiving high antipsychotic dose (i.e. excessive dosing) as those with a prescribed daily dose/defined daily dose ratio of >1.5 both at initial assessment and after 1 year of follow-up. Similarly, we defined patients persistently receiving polypharmacy as those being prescribed two or more antipsychotic drugs both at baseline and at follow-up. A sample of 375 participants with schizophrenia was analyzed. A proportion of 28% of patients persistently received high-dose antipsychotic drugs, and a proportion of 13% of patients persistently received antipsychotic polypharmacy. In the multivariate analysis, psychopathology was not a predictor of persistent polypharmacy and excessive dosing; similarly, use of second-generation antipsychotics was not associated with polypharmacy and excessive dosing; however, persistence with high antipsychotic doses was predicted by baseline use of first-generation antipsychotics and second-generation antipsychotics concurrently. Antipsychotic drug use for patients with schizophrenia is only sometimes satisfactory and offers the opportunity of improvement. Clinicians should consider that dose reduction strategies have been shown to be a feasible intervention in patients with schizophrenia.     

Pharmacokinetic-pharmacodynamic analysis of antipsychotics-induced extrapyramidal symptoms based on receptor occupancy theory incorporating endogenous dopamine release

We aimed to analyze the risks of extrapyramidal symptoms (EPS) induced by typical and atypical antipsychotic drugs using a common pharmacokinetic-pharmacodynamic (PK-PD) model based on the receptor occupancy. We collected the data for EPS induced by atypical antipsychotics, risperidone, olanzapine and quetiapine, and a typical antipsychotic, haloperidol from literature and analyzed the following five indices of EPS, the ratio of patients obliged to take anticholinergic medication, the occurrence rates of plural extrapyramidal symptoms (more than one of tremor, dystonia, hypokinesia, akathisia, extrapyramidal syndrome, etc.), parkinsonism, akathisia, and extrapyramidal syndrome. We tested two models, i.e., a model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition and a model not considering the endogenous dopamine release, and used them to examine the relationship between the D2 receptor occupancy of endogenous dopamine and the extent of drug-induced EPS. The model incorporating endogenous dopamine release better described the relationship between the mean D2 receptor occupancy of endogenous dopamine and the extent of EPS than the other model, as assessed by the final sum of squares of residuals (final SS) and Akaike's Information Criteria (AIC). Furthermore, the former model could appropriately predict the risks of EPS induced by two other atypical antipsychotics, clozapine and ziprasidone, which were not incorporated into the model development. The developed model incorporating endogenous dopamine release owing to 5-HT2A receptor inhibition may be useful for the prediction of antipsychotics-induced EPS.     

Managing antipsychotic-induced acute and chronic akathisia.

Akathisia is a frequent and common adverse effect of treatment with antipsychotic (neuroleptic) drugs. This syndrome consists of subjective (feeling of inner restlessness and the urge to move) as well as objective components (rocking while standing or sitting, lifting feet as if marching on the spot and crossing and uncrossing the legs while sitting). Antipsychotic-induced akathisia can be classified according to the time of onset in the course of antipsychotic treatment (acute, tardive, withdrawal and chronic akathisia). Reported prevalence rates vary widely between 5 and 36.8%. Numerous risk factors for acute akathisia have been described and the exact pathophysiology of akathisia is still unknown. Since akathisia is a drug-induced adverse effect, optimal management involves its prevention rather than treatment. Standardised titration and the use of novel antipsychotics are successful measures of prevention. This paper reviews different forms of therapeutic approaches for the treatment of akathisia. Based on the available literature, propranolol or other lipophilic beta-blockers seem to be the most consistently effective treatment for acute akathisia. There is nothing in the literature to guide a clinician when treatment with beta-blockers fails. Addition of benzodiazepines would appear to be a sensible next choice, especially if subjective distress persists. If all of these drugs are unsuccessful, amantadine or clonidine can be tried. Other agents that have been investigated include ritanserin, piracetam, valproic acid (sodium valproate) and tricyclic antidepressants. Evidence on the treatment of tardive akathisia is unsatisfactory.     

Olanzapine induced tardive dystonia

Advent of atypical antipsychotics was thought to be a major advancement in the psychopharmacology for schizophrenia. It was thought that these drugs would have low propensity to induce extrapyramidal symptoms including tardive movements. Olanzapine is a thienobenzodiazepine derivative, second generation (atypical) antipsychotic agent. Compared to typical antipsychotics, it has a greater affinity for serotonin 5-HT2A than dopamine D2 receptors, with preferential action at mesolimbic than nigrostriatal dopaminergic pathways. However, only few reports of olanzapine induced tardive dystonia (TD) are available in the literature. We wish to report another case of TD, in a male patient with schizophrenia, which developed after 15 months of treatment with olanzapine.     

Antipsychotic-Induced movement disorders in the elderly: epidemiology and treatment recommendations

We reviewed the epidemiological aspects of antipsychotic-induced movement disorders as they pertain to older patients. The incidence and prevalence of drug-induced parkinsonism and tardive dyskinesia (TD) are significantly greater in the older patient than in the younger patient whereas akathisia seems to occur evenly across the age spectrum and dystonia is uncommon among older patients. The literature on risk factors associated with treatment-emergent movement disorders is highly variable. Treatment practices vary across the age range and the interaction between age and antipsychotic dosage confounds our understanding of the relative importance of treatment-related risk factors. However, there is general agreement that pre-existing extrapyramidal signs (EPS) increase the vulnerability of the patient to developing significant drug-induced movement disorders. Elderly patients with dementia are at greater risk than patients without dementia for persistent drug-induced EPS. Management of drug-induced movement disorders in the older patient requires careful consideration of the contraindications imposed by such agents as anticholinergics and beta-blockers. At present, well-controlled double-blind studies of second-generation antipsychotics such as clozapine, risperidone. olanzapine or quetiapine for reducing the risk of treatment-emergent movement disorders in the elderly have not been published. However, open-label studies of atypical antipsychotics demonstrate a markedly lower incidence of both EPS and TD compared with conventional antipsychotic treatment in the elderly. There is emerging literature in support of atypical antipsychotics for the treatment of existing drug-induced movement disorders. More controversial is the use of adjunctive antioxidants in newly treated patients who are vulnerable to drug-induced movement disorders. While the evidence is mixed in support of antioxidants for the treatment of TD, the possibility remains that prophylactic use of antioxidants may help reduce the incidence of TD. The development of a drug-induced movement disorder often reduces the quality of life in an elderly patient. Effective pharmacological management requires cooperation from the patient and family, which can be fostered early in the patient's care through proper informed consent. The risks and benefits of antipsychotic treatment in the elderly patient need to be communicated to the patient and family. At the present time, there is no consistently effective treatment for patients with TD once it develops. Therefore, attention should focus on its prevention and close monitoring.     

Recent progress in akathisia]

Neuroleptic-induced akathisia should be definitely diagnosed as acute, tardive, withdrawal, and chronic. The diagnostic assessment must be identified from the subjective report and objective features. Various assessments of measuring akathisia can be clinically used by instrumental methods and rating scales. The pharmacological basis of neuroleptic-induced akathisia is the inhibition of the dopamine receptors in the brain. The pathogenesis of neuroleptic-induced akathisia may involve GABAergic hypoactivity, noradrenergic hyperactivity, and serotonergic dysfunction in CNS. Iron deficiency and hyperglycemia may be risk factors of neuroleptic induced akathisia in relation to the dopamine function in the brain. Neurological disorders may be associated with the development of a syndrome resembling drug-induced akathisia. The lesion of the thalamic nuclei would originally produce the syndrome. The difference between acute and tardive akathisia on the strategy of the drug treatment should be sufficiently comprehended. In particular, the long-term use of anticholinergic drugs and benzodiazepines should not be prevailed.     

Antipsychotic-induced rabbit syndrome: epidemiology, management and pathophysiology

Rabbit syndrome is an antipsychotic-induced rhythmic motion of the mouth/lips, resembling the chewing movements of a rabbit. The movement consists of a vertical-only motion, at about 5Hz, with no involvement of the tongue. Usually, the involuntary movements associated with rabbit syndrome appear after a long period (in most cases months or years) of antipsychotic treatment; however, a few patients with the syndrome have had treatment histories with no antipsychotic involvement. The reported prevalence of rabbit syndrome ranges from 2.3 to 4.4% of patients treated with typical antipsychotics. There have been isolated reports of rabbit syndrome in patients treated with the atypical agents risperidone and clozapine.Patients with rabbit syndrome are most often misdiagnosed as having oral tardive dyskinesia. In such cases the key for correct diagnosis is the involvement of tardive tongue movements, which does not occur in rabbit syndrome.The treatment of rabbit syndrome is empirical, reflecting poor understanding of its neuropathology. The first step is to reduce the amount of antipsychotic treatment as much as possible. However, since, in most cases, full withdrawal of antipsychotic treatment is impossible, the syndrome cannot be completely abolished without additional measures. The next stage of treatment involves specific drugs that aim to control the syndrome. Anticholinergic drugs are the best known treatment. Rabbit syndrome does not respond to treatment with levodopa or dopamine agonists.The most striking aspect of this syndrome is its specificity. Rabbit syndrome affects only the buccal region, and within this area it involves a highly stereotyped involuntary movement. This immediately focuses attention on the basal ganglia, in particular the substantia nigra pars reticulata, which is also implicated in oral dyskinesia. Continuing neurophysiological and pharmacological research of the basal ganglia holds the key to better understanding and treatment of this syndrome in the coming years.     

药物引起的兔唇综合征

兔唇综合征（ RS）是一种长期应用药物特别是抗精神病药物引起的迟发性锥体外系不良反应。抗精神病药物所致RS的发生率为1.5%-4.4%。RS以口和咀嚼肌的快速、节律性不自主运动为临床特征，发病机制可能与基底神经节的胆碱能神经递质及多巴胺能神经递质功能失衡有关。RS须与迟发性运动障碍进行鉴别诊断。RS的治疗首选抗胆碱药物，部分患者可换用抗胆碱效应强的非典型抗精神病药物。     

Effect of anticholinergics in preventing acute deterioration in patients undergoing abrupt clozapine withdrawal

BACKGROUND: The most serious adverse effect of clozapine, agranulocytosis, was described for the first time in Finland in 1975. It caused the immediate withdrawal of clozapine from the market and immediate discontinuation of this medication in all patients. It is now known that abrupt withdrawal of clozapine may cause a rapid deterioration in psychotic symptoms. OBJECTIVE: The aim of this retrospective study was to investigate the effect of abrupt clozapine withdrawal on psychiatric patients, and to examine whether anticholinergic drugs are effective in preventing acute deterioration. MATERIALS AND METHODS: We reviewed the hospital case records from Pitk?niemi Psychiatric Hospital, Tampere, Finland, of the 28 patients with schizophrenia who had been receiving clozapine and from whom it was abruptly withdrawn due to the withdrawal of the drug from the market in the summer of 1975. We assessed the incidence of deterioration and whether or not patients in whom this occurred were receiving anticholinergic drugs. RESULTS: We found a rapid deterioration after clozapine withdrawal in almost half (46.4%; n = 13) of the patients. Patients receiving anticholinergic drugs (such as antiparkinsonians, tricyclic antidepressants and antipsychotics with anticholinergic properties) were significantly less likely to deteriorate than those not receiving these drugs (21.4% vs 71.4%, p = 0.008). The condition of the patients who deteriorated was poor for up to 1 month after discontinuation, but had improved slightly by the end of 1975. CONCLUSION: Anticholinergic medication should be considered for preventing possible symptom deterioration when clozapine is abruptly discontinued.     

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects

Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D₁ antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT₂ serotonergic/DA D₁ and D₂ antagonist) and DOD 647 (DA D₁ and D₂ antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses. Received: 31 October 1997/Final version: 9 November 1998