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.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

A review of atypical antipsychotic drugs versus conventional medication in schizophrenia

Atypical antipsychotics are replacing conventional antipsychotics for the treatment of schizophrenia. They are considered to be at least as effective as conventional agents, with most producing fewer extrapyramidal symptoms. This review presents the evidence from published meta-analyses and describes differences in clinical effectiveness and tolerability between conventional and atypical antipsychotic agents. In addition, it discusses some of the more significant adverse effects including tardive dyskinesia, weight gain, diabetes and sudden death. Results from meta-analyses are conflicting, with some finding no significant advantages on measures of efficacy or tolerability for atypical antipsychotics over moderate daily doses of conventional drugs. Other results have shown that some atypical drugs have at least minor efficacy advantages over conventional comparators. Atypical antipsychotics exhibit a much reduced risk for tardive dyskinesia compared with conventional drugs. However, weight gain is more common with some atypical drugs (especially clozapine and olanzapine). Both conventional and atypical antipsychotics have been associated with diabetes, with most reports implicating both clozapine and olanzapine. Finally, atypical antipsychotics (unlike conventional drugs) have little or no effect on QT and are not associated with sudden death.     

Aripiprazole: the evidence of its therapeutic impact in schizophrenia

INTRODUCTION: An ideal antipsychotic would rapidly stabilize acute psychotic symptoms and maintain the patient, without relapse, for prolonged periods in the absence of extrapyramidal, endocrine, diabetic, or cardiovascular side effects, and without weight gain. The dopamine partial agonist aripiprazole is compared with this ideal and with conventional antipsychotics, such as haloperidol, and with atypical antipsychotics. AIMS: To review the evidence for the clinical impact of aripiprazole in the treatment of patients with schizophrenia. EVIDENCE REVIEW: There is clear evidence that aripiprazole is as effective as haloperidol in reducing the positive and negative symptoms of schizophrenia and schizoaffective disorder. In patients with schizophrenia, aripiprazole has been shown to stabilize acute psychotic symptoms, prevent relapse in stabilized patients, and maintain patients with schizophrenia following acute relapse. Furthermore, in common with other atypical antipsychotics, aripiprazole appears to be associated with a lower incidence of side effects than typical antipsychotics and may reduce discontinuation of drug therapy. Evidence also suggests that aripiprazole may be associated with a lower incidence of extrapyramidal symptoms than conventional antipsychotics, but further long-term studies concerning tardive dyskinesia are required. Studies on the cost effectiveness of aripiprazole, as well as the quality of life and general functioning of patients taking the drug are still required, although there is some evidence of improved quality of life. Further evidence comparing aripiprazole with other atypical antipsychotics would be welcome. CLINICAL VALUE: In conclusion, aripiprazole is an atypical antipsychotic suitable for first-line use in patients with schizophrenia. Its clinical value in relation to other atypical antipsychotics remains to be elucidated.     

Oxidative mechanisms and tardive dyskinesia

Tardive dyskinesia has been and continues to be a significant problem associated with long-term antipsychotic use, but its pathophysiology remains unclear. In the last 10 years, preclinical studies of the administration of antipsychotics to animals, as well as clinical studies of oxidative processes in patients given antipsychotic medications, with and without tardive dyskinesia, have continued to support the possibility that neurotoxic free radical production may be an important consequence of antipsychotic treatment, and that such production may relate to the development of dyskinetic phenomena. In line with this hypothesis, evidence has accumulated for the efficacy of antioxidants, primarily vitamin E (alpha-tocopherol), in the treatment and prevention of tardive dyskinesia. Early studies suggested a modest effect of vitamin E treatment on existing tardive dyskinesia, but later studies did not demonstrate a significant effect. Because evidence has continued to accumulate for increased oxidative damage from antipsychotic medications, but less so for the effectiveness of vitamin E, especially in cases of long-standing tardive dyskinesia, alternative antioxidant approaches to the condition may be warranted. These approaches may include the use of antioxidants as a preventive measure for tardive dyskinesia or the use of other antioxidants or neuroprotective drugs, such as melatonin, for established tardive dyskinesia.     

Drug-induced Pisa syndrome (pleurothotonus): epidemiology and management

Long-term administration of antipsychotics occasionally produces persistent dystonia of the trunk, a disorder known as Pisa syndrome (or pleurothotonus). The development of Pisa syndrome is most commonly associated with prolonged treatment with antipsychotics; however, it has also been reported, although less frequently, in patients who are receiving other medications (such as cholinesterase inhibitors and antiemetics), in those not receiving medication (idiopathic Pisa syndrome) and in those with neurodegenerative disorders. Drug-induced Pisa syndrome predominantly develops in females and in older patients with organic brain changes. It sometimes occurs after the addition of another antipsychotic to an established regimen of antipsychotics or insidiously arises in antipsychotic-treated patients for no apparent reason. The condition generally disappears after antipsychotic drugs are discontinued. Although a pharmacological therapy for drug-induced Pisa syndrome has not been established, we have reported that anticholinergic drugs are effective in about 40% of patients who have episodes of Pisa syndrome with the remaining patients responding to the withdrawal or reduction of daily doses of antipsychotic drugs. The characteristics of its development and prognosis indicate that drug-induced Pisa syndrome consists of two types of dystonia. Some patients develop clinical features of acute dystonia, whereas others develop symptoms similar to tardive dystonia. Like that of tardive dystonia, Pisa syndrome responds better than tardive dyskinesia to a relatively high daily dose of an anticholinergic. However, the significant improvement caused by the withdrawal of antipsychotic drugs in Pisa syndrome differentiates it from tardive dystonia. Thus, Pisa syndrome including these features is considered to be an atypical type of tardive dystonia. These clinical characteristics suggest that the underlying pathophysiology of drug-induced Pisa syndrome is complex. A dopaminergic-cholinergic imbalance, or serotonergic or noradrenergic dysfunction, may be implicated. Asymmetric brain functions or neural transmission may also be considered as underlying mechanisms of the development of Pisa syndrome that is resistant to anticholinergic drugs. Idiopathic Pisa syndrome is characterised by an adult-onset, segmental truncal dystonia in patients with no previous exposure to antipsychotics. It occurs rarely but shows a complete resolution with high doses of anticholinergic 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.     

Association of diabetes with dyskinesia in older psychosis patients

Rationale Older patients treated with antipsychotics are more likely to develop tardive dyskinesia (TD) than younger individuals. Advanced age is also an important risk factor for diabetes, which may be associated with TD. These observations suggest that older diabetic patients may be particularly vulnerable to developing TD.Objective To examine whether older psychosis patients with diabetes exhibit more severe dyskinesia than well-matched patients without diabetes and to test whether there are differences in dyskinesia severity between diabetic patients treated with conventional versus atypical antipsychotics versus those not taking antipsychotic medications.Method Sixty-one psychosis patients with diabetes and 122 case-matched non-diabetic comparison patients were studied. Observer-based and quantitative instrumental measures were administered to assess prevalence and severity of dyskinesia. Raters were unaware of patients diabetes status.Results Diabetic patients exhibited significantly more severe TD than non-diabetic comparison patients. Groups did not differ in terms of severity of parkinsonism. Significantly more diabetic (27.9%) than non-diabetic (14.6%) patients met research diagnostic criteria for TD. Diabetic patients treated with atypical antipsychotics at the time of assessment had significantly more severe TD than all other patient subgroups, including patients treated with conventional antipsychotics. Results from the instrumental measures of force steadiness were consistent with observer-based severity ratings.Conclusion The deleterious effect of diabetes on TD in the absence of any effect of parkinsonism supports preclinical studies of glucose-related dopamine hyperfunction and has implications for the pharmacologic management of psychosis in patients with pre-existing diabetes.     

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。     

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20 – 50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines – chlorpromazine, fluphenazine and haloperidol – belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualise therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library – one that enlists the ‘essential biomarkers’ required for optimal pharmacotherapy – may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.     

Pharmacogenetics for off-patent antipsychotics: reframing the risk for tardive dyskinesia and access to essential medicines

First-generation antipsychotics (FGAs) induce tardive dyskinesia, a debilitating involuntary hyperkinetic movement disorder, in 20-50% of individuals with a psychotic illness during chronic treatment. There is presently no curative treatment or definitive predictive test for tardive dyskinesia. The authors note that the three antipsychotic drugs enlisted in the most recent (14th) World Health Organization Model List of Essential Medicines--chlorpromazine, fluphenazine and haloperidol--belong to the FGA therapeutic class. In this regard, the need to choose between the competing objectives of ensuring global access to affordable and efficacious medicines, such as FGAs, and the formidable long-term risk for tardive dyskinesia, may create an ethical conundrum. Pharmacogenetics has thus far been conceptually framed as a tool to individualize therapy with new drugs under patent protection. However, the authors suggest that pharmacogenetics may also improve access to pharmacotherapy through the reintroduction of affordable second-line generic drugs or FGAs with suboptimal safety, as first-line therapy, in targeted subpopulations in whom they present a lower risk for tardive dyskinesia. To impact positively on global public health and distributive justice, a directory complementary to the essential medicines library--one that enlists the 'essential biomarkers' required for optimal pharmacotherapy--may benefit patients who do not have adequate access to new antipsychotic medications. This review discusses pharmacogenetic associations of tardive dyskinesia that are in part supported by meta-analyses and the oxidative stress-neuronal degeneration hypothesis.     

Atypical antipsychotic agents: a critical review.

The pharmacology, efficacy, and adverse effects of atypical antipsychotic agents when used to treat schizophrenia and other disorders are reviewed. Atypical antipsychotic agents were developed in response to problems with typical agents, including lack of efficacy in some patients, lack of improvement in negative symptoms, and troublesome adverse effects, especially extrapyramidal symptoms (EPSs) and tardive dyskinesia CTD). Atypical antipsychotics differ from typical psychotics in their "limbic-specific" dopamine type 2 (D2)-receptor binding and high ratio of serotonin type 2 (5-HT2)-receptor binding to D2 binding. In clinical trials in patients with non-treatment-resistant schizophrenia, risperidone and olanzapine were superior to placebo for positive and negative symptoms. Risperidone and olanzapine were superior to haloperidol on some measures. Quetiapine was better than placebo but was not better than typical antipsychotics. Head-to-head comparisons of atypical antipsychotics in non-treatment-resistant schizophrenia have been inconclusive. Clozapine remains the standard agent for treatment-resistant schizophrenia. Atypical agents are substantially more expensive than their typical antipsychotic counterparts. To fully determine the overall efficiency of these drugs, other potential benefits, such as improved quality of life, need to be factored in. Atypical antipsychotics are associated with a decreased capacity to cause EPSs, TD, neuroleptic malignant syndrome, and hyperprolactinemia. Clozapine carries a risk of agranulocytosis; the white blood cell count must be monitored. Atypical antipsychotics are increasingly being used for indications other than schizophrenia, such as the management of aggression, mania, and depression. Atypical antipsychotics are often considered first-line agents for treating schizophrenia and are promising treatment alternatives for other psychiatric and neurologic conditions.     

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.     

Efficacy of antiparkinson agents in preventing antipsychotic-induced extrapyramidal symptoms.

The types of extrapyramidal syndrome (EPS) reactions produced by antipsychotic agents and the prophylactic use of antiparkinson agents in preventing EPS are reviewed. EPS are classified as akathisias, dystonias, parkinson-like symptoms and tardive dyskinesia, and have a varied incidence reported to range from 10.6 to 100%. Incidence may vary with age, gender, drug and dosage. The prophylactic use of antiparkinson agents to prevent EPS is controversial. Many psychiatrists believe the effect of EPS on patients is more harmful than the side effects of anticholinergics, whereas others believe that because of side effects, increased cost, greater risk to tardive dyskinesia and improper use, the use of antiparkinson agents cannot be justified. Most studies of prophylactic use of antiparkinson agents have lacked adequate control groups, adequate blinding procedures for investigators rating EPS, uniform definitions of EPS, random sampling and careful reporting of group characteristics such as dosage and drugs received. There is a lack of definitive studies of the value of antiparkinson agents in preventing the occurrence of EPS in patients receiving antipsychotics. A large, multicenter study should be undertaken to resolve the issue.     

Tolerability of atypical antipsychotics.

Atypical antipsychotics are expected to be better tolerated than older antipsychotics because of their lower propensity to cause certain adverse effects. All atypical drugs have been shown to cause fewer acute extrapyramidal symptoms (EPS) than a standard typical agent (usually haloperidol) and some (clozapine, sertindole and quetiapine) appear to cause these effects no more often than placebo. In the longer term, clozapine, olanzapine and (less robustly) other atypical antipsychotics are thought to cause less tardive dyskinesia than typical antipsychotics. Problems caused by hyperprolactinaemia occur less often with some atypical antipsychotics than with typical drugs although risperidone and amisulpride appear to have no advantages in this respect. Other adverse effects may occur as frequently with some atypical antipsychotics as with some typical drugs. Clozapine, risperidone and quetiapine are known to cause postural hypotension; clozapine, olanzapine and quetiapine are clearly sedative; and anticholinergic effects are commonly seen with clozapine, and, much less frequently, with olanzapine. Some adverse effects are more frequent with atypical drugs. Idiosyncratic effects seem particularly troublesome with clozapine and, to a lesser extent, sertindole, olanzapine and zotepine. Bodyweight gain is probably more problematic with atypical antipsychotics than with typical drugs. Overall tolerability, as judged by withdrawals from therapy, is not clearly proven to be better with atypical drugs, although some individual trials do indicate an advantage with atypical agents. Differences in tolerability between individual atypical antipsychotics have not been clearly shown. The tolerability profile of atypical drugs certainly benefits from a lower incidence of acute EPS effects, along with less certain or less uniform benefits in symptomatic hyperprolactinaemia or tardive dyskinesia. Other, perhaps more trivial, adverse effects militate against their good tolerability, and effects such as bodyweight gain may severely reduce tolerability. Without clear advantages in tolerability in patient groups used in trials, drug choice in regard to adverse effects should continue to be on a patient to patient basis.     

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.     

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.     

The influence of psychotropic drugs on cerebral cell death: female neurovulnerability to antipsychotics

Tissue transglutaminase (tTG) is a marker for apoptosis, and its protein level is known to be increased in post-mortem Alzheimer's and Huntington's disease brains. tTG is increased in the cerebrospinal fluid of patients with Alzheimer's disease. However, the influence of psychotropic medication on acute cell death has not been studied so far in vivo, although some experiments performed in vitro suggest that antipsychotic drugs are neurotoxic. The protein level of tTG was examined in the cerebrospinal fluid obtained from 29 patients under neuroleptic medication in the last 24 h before lumbar puncture (eight patients diagnosed with Alzheimer's disease and 21 patients with other neurological diseases), and compared with those from 55 patients without antipsychotic medication (25 Alzheimer's patients and 30 others). In addition, the influence of several other psychotropic drugs on apoptosis was analysed. A significant influence (P<0.01) of antipsychotic drugs for both the Alzheimer's and the non-Alzheimer's group was found with respect to tTG protein levels in cerebrospinal fluid. By contrast to the male subgroups, the female groups showed a strong influence of neuroleptics on cerebral cell death. Surprisingly, atypical antipsychotics did not differ from typical neuroleptics in neurotoxicity. By contrast, no influence of antidepressants, cholinesterase-inhibitors, nootropics, tranquilizers and tramadol on cerebral cell death was found. The results suggest that typical and atypical antipsychotic drugs may induce cerebral cell death, especially in female patients. Subjects with Alzheimer's disease might be even more vulnerable to any antipsychotic. Therefore, subsequent research should aim to identify atypical neuroleptics without neurotoxicity. A limit on the use of first- and second-generation antipsychotics in elderly patients is proposed. Finally, the possible connection between the observed increased cerebral cell death and tardive dyskinesia, the most threatening side-effect in antipsychotic therapy, is discussed.     

Quetiapine-induced improvement of tardive dyskinesia in three patients with schizophrenia

There are very rare cases indicating the effectiveness of the atypical antipsychotics in the treatment of tardive dyskinesia except clozapine. We report three patients with schizophrenia who demonstrated improvement of tardive dyskinesia following treatment with quetiapine; two of them were unable to use clozapine because of intolerable side-effects.     

Significant changes in antipsychotic drug use during pregnancy

Atypical antipsychotics are less likely to cause hyperprolactinemia-related side effects, such as infertility; hence it is predicted that more women taking antipsychotic medications will be able to become pregnant as the use of atypical antipsychotics increases. To compare the use of conventional and atypical antipsychotics, we conducted a retrospective review of the Motherisk Program clinic schedule from 1989 to 2001 comparing the proportion of appointments made for conventional and atypical antipsychotics. In 1989, 2.7% of all appointments were about the use of antipsychotic medication. In 2001, 7.4% of appointments were regarding antipsychotic drug use. This 170% increase was due to an increase in appointments for atypical antipsychotics as the number of appointments for conventional antipsychotics remained relatively constant over the 12-y period. Since the introduction of atypical antipsychotics, more women requiring antipsychotic drug therapy have been planning or becoming pregnant. This increase may have substantial public health implications.