The safety of atypical antipsychotics: does QTc provide all the answers?

Drug safety of atypical antipsychotics is important due to the increasing mortality gap between patients with schizophrenia and the general population. This editorial discusses the safety evaluation of ziprasidone with a focus on the risk of the potentially fatal cardiac arrhythmia, torsades de pointes (TdP). The exact incidence of antipsychotic-induced TdP remains unknown because capturing TdP warrants continuous monitoring and tens of thousands of patient-years due to the rarity of TdP. For this reason, surrogate markers such as the QTc interval are used despite their limitations. New surrogate markers Tpeak-Tend and T-wave morphology have seen the light of day but their validity remain unknown. Large pragmatic trials have been conducted, but their contributions to drug safety evaluations are controversial. Finally, psychiatrists should have in mind that safety evaluation should include more than the risk of TdP. Some atypical antipsychotics are associated with life-shortening side effects, such as severe weight gain and type 2 diabetes, which may contribute more to the overall mortality than TdP. In addition to this, suboptimal treatment may result in life-shortening behaviors such as suicide. A shared decision including a thorough discussion of risks and benefits with the patients is essential.     

Assessing QT interval prolongation and its associated risks with antipsychotics

Several antipsychotics are associated with the ventricular tachycardia torsade de pointes (TdP), which may lead to sudden cardiac death (SCD), because of their inhibition of the cardiac delayed potassium rectifier channel. This inhibition extends the repolarization process of the ventricles of the heart, illustrated as a prolongation of the QT interval on a surface ECG. SCD in individuals receiving antipsychotics has an incidence of approximately 15 cases per 10,000 years of drug exposure but the exact association with TdP remains unknown because the diagnosis of TdP is uncertain. Most patients manifesting antipsychotic-associated TdP and subsequently SCD have well established risk factors for SCD, i.e. older age, female gender, hypokalaemia and cardiovascular disease. QT interval prolongation is the most widely used surrogate marker for assessing the risk of TdP but it is considered somewhat imprecise, partly because QT interval changes are subject to measurement error. In particular, drug-induced T-wave changes (e.g. flattening of the T-wave) may complicate the measurement of the QT interval. Furthermore, the QT interval depends on the heart rate and a corrected QT (QTc) interval is often used to compensate for this. Several correction formulas have been suggested, with Bazett's formula the most widely used. However, Bazett's formula overcorrects at a heart rate above 80 beats per minute and, therefore, Fridericia's formula is considered more appropriate to use in these cases. Several other surrogate markers for TdP have been developed but none of them is clinically implemented yet and QT interval prolongation is still considered the most valid surrogate marker. Although automated QT interval determination may offer some assistance, QT interval determination is best performed by a cardiologist skilled in its measurement. A QT interval >500?ms markedly increases the risk for TdP and SCD, and should lead to discontinuation of the offending drug and, if present, correction of underlying electrolyte disturbances, particularly serum potassium and magnesium derangements. Before prescribing antipsychotics that may increase the QTc interval, the clinician should ask about family and personal history of SCD, presyncope, syncope and cardiac arrhythmias, and recommend cardiology consultation if history is positive.     

Atypical antipsychotics for neuropsychiatric symptoms of dementia: malignant or maligned?

Recent concerns regarding the use of atypical antipsychotics when used for the treatment of neuropsychiatric symptoms in dementia have led to a flurry of studies attempting to re-evaluate their place in therapy. We critically review current evidence on the safety profiles of these agents in patients with behavioural and psychological symptoms of dementia (BPSD) and provide recommendations to guide the clinician. Potential risks with this class of medications include extrapyramidal symptoms (EPS), weight gain, diabetes mellitus, cardiac conduction abnormalities (e.g. corrected QT [QTc] interval prolongation), cerebrovascular adverse events and mortality. Compared with placebo, treatment of BPSD with atypical antipsychotics leads to little or no increase in EPS and no significant weight change. Compared with typical antipsychotics, treatment of BPSD with atypical antipsychotics leads to a reduced risk of EPS, lower incidences of tardive dyskinesias and no significant weight gain. Atypical antipsychotics have not been associated with glucose intolerance, diabetes or hyperlipidaemia in elderly dementia patients. Both typical and atypical antipsychotics have been associated with cardiac conduction abnormalities, with the magnitude of QTc prolongation being slightly smaller with atypical antipsychotics. Randomised controlled trials suggest that atypical antipsychotics are associated with an increased risk of cerebrovascular adverse events, such as stroke, and an increased mortality compared with placebo. However, it appears that typical antipsychotics have similar risks of cerebrovascular adverse events and death. An increased risk of anticholinergic adverse effects and falls must also be considered with both typical and atypical antipsychotics. In summary, atypical antipsychotics are associated with potentially serious adverse events. Before prescribing these medications in elderly dementia patients, baseline EPS, ECG abnormalities and concomitant medications should be assessed, and the presence of cardiovascular, cerebrovascular and metabolic risk factors should be taken into consideration when benefits and risks are being weighed.     

Use of antipsychotics in elderly patients with dementia: Do atypical and conventional agents have a similar safety profile?

Pharmacological treatment of dementia addresses two main clinical features of the disease: cognitive deterioration with predominantly memory loss and behavioural and psychological symptoms (BPSD). While cholinesterase inhibitors are recommended in an attempt to delay memory loss and disability, what should be considered the most appropriate pharmacological treatment for BPSD has remained questionable. Antipsychotic medications, conventional and atypical agents, have been increasingly utilized in clinical practice but only a small number of clinical studies have investigated their relative cost–benefit ratio. This review focuses on the safety of atypical and conventional antipsychotics when used in patients with BPSD. Overall, atypical and conventional antipsychotics are associated with a similarly increased risk for all-cause mortality and cerebrovascular events. Relative to atypical agents users, patients being treated with conventional antipsychotics have an increased incidence of cardiac arrhythmias and extrapyramidal symptoms. Conversely, users of atypical antipsychotics are exposed to an increased risk of venous thromboembolism and aspiration pneumonia. Also, metabolic effects (i.e. increased risk of diabetes, weight gain) have consistently been documented in clinical studies with atypical antipsychotics, although this effect tends to be attenuated with advancing age and in elderly patients with dementia. Antipsychotics, both conventional and atypical, should be used with caution only when nonpharmacologic approaches have failed to adequately control BPSD. More effective interventions are necessary to improve postmarket drug safety in vulnerable populations.     

Atypical antipsychotics for the treatment of behavioral and psychological symptoms in dementia,with a particular focus on longer term outcomes and mortality

Importance of the field: Many people with Alzheimer's disease (AD) and other dementias are prescribed atypical antipsychotics for behavioral and psychiatric symptoms such as aggression and psychosis. Recent evidence has highlighted safety concerns regarding antipsychotics in these individuals.

Areas covered in this review: We summarize the evidence pertaining to efficacy and safety from short-term randomized controlled trials (up to 12 weeks), key findings from case-register studies and more detailed discussion of longer term outcome studies, including longer term mortality risk of antipsychotics in AD.

What the reader will gain: The review aims to provide a balanced and up to date overview of the efficacy and safety concerns related to atypical antipsychotics in people with AD, in particular providing a detailed overview of mortality risk, and a personal interpretation of the implications and recommendations for the way forward.

Take home message: Atypical antipsychotics confer modest benefits for short-term (up to 12 weeks) treatment of aggression and psychosis in AD. These benefits have to be balanced against the risk of serious adverse events including 1.5 – 1.8-fold increased mortality. The benefits are less clear-cut with longer term prescribing, but the mortality risk remains significantly elevated. Pharmacogenetics may provide an opportunity to more effectively focus prescribing in the future.     

药源性尖端扭转性室速的发生机制及防治

药源性尖端扭转性室速（TdP）是主要的获得性TdP之一,临床发病率较低,但致死性高。药物阻断Ikr引起QT间期延长是药源性TdP的重要机制;女性、电解质平衡紊乱、心脏及脑损伤等基础疾病、同时应用可延长QT间期的多种药物、代谢竞争引起药物蓄积是TdP的易感因素;引起TdP的常见药物有Ⅰa类和Ⅲ类抗心律失常药物、抗精神病药物、抗组胺药、大环内酯类抗生素、氟喹诺酮类抗茵药物及西沙必利、三氧化二砷、美沙酮等药物;药源性TdP治疗措施包括停用可引起QT间期延长的药物,静脉给予硫酸镁治疗,血钾应维持在较高水平,对于血流动力学不稳定者给予非同步直流电除颤。     

QTc interval prolongation and antipsychotic drug treatments: focus on sertindole

Since the 1960s, physicians have been aware of electrocardiographic (ECG) abnormalities and cases of sudden death associated with the use of antipsychotic drugs in patients with schizophrenia. Explanations for such deaths have traditionally focused on drug-induced prolongation of the QT interval leading to the development of life-threatening ventricular arrhythmias such as torsade de pointes (TdP). It is now apparent that most conventional and atypical antipsychotics can cause dose-related prolongation of the corrected QT interval (QTc), although there are important differences in the potency of individual agents. This review discusses potential mechanisms underlying QTc prolongation and arrhythmogenesis and examines the evidence for a relationship between antipsychotic drugs and prolongation of the QTc interval. New electrophysiological and epidemiological data are presented which suggest there may not be a clear-cut cause-effect relationship between QTc prolongation and the development of ventricular tachyarrhythmias for all atypical antipsychotics. For at least one of these agents (sertindole), counterbalancing mechanisms may act to reduce the risk of proarrhythmic activity arising as a result of QTc prolongation.     

Antipsychotic-related QTc prolongation,torsade de pointes and sudden death

Sudden unexpected deaths have been reported with antipsychotic use since the early 1960s. In some cases the antipsychotic may be unrelated to death, but in others it appears to be a causal factor. Antipsychotics can cause sudden death by several mechanisms, but particular interest has centred on torsade de pointes (TdP), a polymorphic ventricular arrhythmia that can progress to ventricular fibrillation and sudden death. The QTc interval is a heart rate-corrected value that represents the time between the onset of electrical depolarisation of the ventricles and the end of repolarisation. Prolongation of the QTc interval is a surrogate marker for the ability of a drug to cause TdP. In individual patients an absolute QTc interval of >500 msec or an increase of 60 msec from baseline is regarded as indicating an increased risk of TdP. However, TdP can occur with lower QTc values or changes. Concern about a relationship between QTc prolongation, TdP and sudden death applies to a wide range of drugs and has led to the withdrawal or restricted labelling of several. Among antipsychotics available in the UK, sertindole was voluntarily suspended, droperidol was withdrawn, and restricted labelling introduced for thioridazine and pimozide. The degree of QTc prolongation is dose dependent and varies between antipsychotics reflecting their different capacity to block cardiac ion channels. Significant prolongation is not a class effect. Among currently available agents, thioridazine and ziprasidone are associated with the greatest QTc prolongation. Virtually all drugs known to cause TdP block the rapidly activating component of the delayed rectifier potassium current (I(kr)). Arrhythmias are more likely to occur if drug-induced QTc prolongation coexists with other risk factors, such as individual susceptibility, presence of congenital long QT syndromes, heart failure, bradycardia, electrolyte imbalance, overdose of a QTc prolonging drug, female sex, restraint, old age, hepatic or renal impairment, and slow metaboliser status. Pharmacodynamic and pharmacokinetic interactions can also increase the risk of arrhythmias. Further research is needed to quantify the risk of sudden death with antipsychotics. The risk should be viewed in the context of the overall risks and benefits of antipsychotic treatment. It seems prudent, where possible, to select antipsychotics that are not associated with marked QTc prolongation. If use of a QTc-prolonging drug is warranted, then measures to reduce the risk should be adopted.     

Benefit-risk assessment of atypical antipsychotics in the treatment of schizophrenia and comorbid disorders in children and adolescents.

Evidence on the efficacy and safety of atypical antipsychotics in children and adolescents with schizophrenia is limited. The purpose of this review is to assess the published data on the use of atypical antipsychotics in children and adolescents with schizophrenia alone and with comorbid disorders, and to establish benefit-risk guidelines for clinicians.Risperidone, olanzapine and clozapine were found to be effective in the treatment of aggression and mania. Risperidone, and possibly also olanzapine, may be the drugs of choice in children with comorbid tic disorders. Ziprasidone has some monoamine reuptake inhibition properties and may be administered as an augmenting agent in children and adolescents with schizophrenia and comorbid anxiety and mood disorders.Compared with the typical antipsychotics, the atypical drugs seem to be more effective, better tolerated and lead to better patient adherence. Importantly, the atypical antipsychotics have a lower propensity to induce extrapyramidal symptoms and a potential (shown so far only in adults) to improve cognitive function and inhibit suicidal behaviour (especially clozapine). Yet, the adverse effects associated with these agents, especially weight gain, which may also have long-term effects, can lead to non-compliance in the young population. In children and adolescents receiving clozapine, olanzapine and quetiapine (but not ziprasidone, which does not have a pro-appetite effect), particularly those with obesity or a family history of diabetes mellitus, fasting blood glucose and lipid levels must be monitored frequently. Weight gain might be better controlled when the children and their parents are properly informed about this adverse effect and diet is regulated. Another major disadvantage of the atypical antipsychotics, especially risperidone, is their association with hyperprolactinaemia, which can lead to hypogonadism-induced osteoporosis, galactorrhoea, gynaecomastia, irregular menstruation and sexual dysfunction, all seen also with typical antipsychotics. Other atypical antipsychotics, namely olanzapine and ziprasidone, have been reported to be prolactin sparing in adults, but may not be completely devoid of hyperprolactinaemic effects in children and adolescents. Thus, prolactin levels should be assessed routinely in young patients treated with atypical antipsychotics. Further, children and adolescents with hyperprolactinaemia-related effects should be switched to a prolactin-sparing agent, such as quetiapine. All atypical antipsychotics may induce sedation and they are not devoid of extrapyramidal symptoms (especially risperidone). The use of typical antipsychotics has been limited to patients who are resistant to atypical antipsychotics, intolerant to their adverse effects, or require injections or depot preparations.Further double-blind, placebo-controlled trials and long-term safety assessments are needed before definitive conclusions can be reached about the place of atypical antipsychotics in the therapeutic armamentarium of childhood-onset schizophrenia.     

Long-acting injectable risperidone for the treatment of schizophrenia: clinical perspectives

Schizophrenia remains a severe disorder that is associated with a poor outcome in a large subgroup of patients. Major efforts should be made to improve treatment for all patients who have this debilitating disease. Second-generation antipsychotics were a major step forward in this respect; however, important unmet needs remain, such as a better solution for frequent noncompliance problems. Depot formulations are known to have advantages in this respect. However, for a long time, only depot formulations of conventional antipsychotics were available, with their high risk of extrapyramidal adverse effects. Therefore, there has been only very restricted use of depot antipsychotics, which mainly focused on patients with chronic disease who were difficult to treat and had a high risk of noncompliance. The situation may change with the advent of a depot formulation of an atypical antipsychotic. The first depot formulation of an atypical antipsychotic to be introduced to the market is long-acting injectable risperidone. On the basis of the pharmacokinetic properties of the depot formulation, a 2-week interval between administrations is recommended. The antipsychotic efficacy of long-acting risperidone was demonstrated in two 12-week, double-blind, randomised, phase III studies, one versus placebo and the other versus oral risperidone. These two studies, together with one open-label, long-term study over 12 months, belong to the core group of trials that were relevant for the licensing of long-acting risperidone. A relapse-prevention, control group study comparing the long-acting formulation versus oral risperidone was not performed because of the known principal methodological problems of such a comparison. Instead, as much clinical data as possible was collected from observational studies that investigated questions relevant for clinical practice, such as efficacy, safety and tolerability in different subgroups, and transition from pre-treatment with different kinds of antipsychotics to long-acting risperidone. On the basis of these data, it can be stated that the efficacy of the long-term formulation of risperidone is proven, and that the safety and tolerability are more or less comparable to those of oral risperidone. The local tolerability at the injection site is good. Because it is well known that noncompliance is a frequent feature of the treatment of schizophrenia, and considering the advantages of atypical antipsychotics, consideration of whether long-acting atypical antipsychotics should have a broader indication than is the case with the depot formulations of the classical antipsychotics is warranted.     

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.     

Psychotropic drugs,cardiac arrhythmia,and sudden death

A variety of drugs targeted towards the central nervous system are associated with cardiac side effects, some of which are linked with reports of arrhythmia and sudden death. Some psychotropic drugs, particularly tricyclic antidepressants (TCAs) and antipsychotic agents, are correlated with iatrogenic prolongation of the QT interval of the electrocardiogram (ECG). In turn, this is associated with the arrhythmia (TdP). This review discusses the association between psychotropic agents, arrhythmia and sudden death and, focusing on TCAs and antipsychotics, considers their range of cellular actions on the heart; potentially pro-arrhythmic interactions between psychotropic and other medications are also considered. At the cellular level TCAs, such as imipramine and amitriptyline, and antipsychotics, such as thioridazine, are associated with inhibition of potassium channels encoded by In many cases this cellular action correlates with ECG changes and a risk of TdP. However, not all psychotropic agents that inhibit HERG at the cellular level are associated equally with QT prolongation in patients, and the potential for QT prolongation is not always equally correlated with TdP. Differences in risk between classes of psychotropic drugs, and between individual drugs within a class, may result from additional cellular effects of particular agents, which may influence the consequent effects of inhibition of repolarizing potassium current.     

Antipsychotic use in elderly patients and the risk of pneumonia

Antipsychotics are frequently and increasingly prescribed off-label for the treatment of behavioral and psychological symptoms associated with dementia, despite their modest efficacy. Instead, the safety profile of antipsychotics has been questioned repeatedly in recent years with various concerns, including death. Meta-analyses of randomized controlled trials found that one of the major causes of death associated with atypical antipsychotics use was pneumonia. Only few observational studies, however, have investigated the risk of pneumonia in elderly patients, especially among those receiving conventional antipsychotics. The aim of this editorial is to synthesize the current evidence from observational studies regarding the risk of pneumonia in elderly patients receiving either conventional or atypical antipsychotics. The studies conducted so far document that the risk of pneumonia is two- to threefold increased in a dose-dependent fashion with both classes compared to nonuse, with a possibly higher risk attributable to atypical antipsychotics. The risk seems to peak at the beginning of treatment (e.g., 7 – 30 days), and dissipates over time for both conventional and atypical antipsychotics. The risk–benefit ratio suggests that there will be 1 excess hospitalization for pneumonia for every 2 – 5 patients receiving any clinical improvement in symptoms. Considering the modest improvement in terms of efficacy, the risks associated with antipsychotics in elderly patients may outweigh their benefit.     

Pharmacological treatment of the psychosis of Alzheimer's disease: what is the best approach?

Psychosis of Alzheimer's disease (PAD) forms part of the behavioural and psychological symptoms of dementia (BPSD). PAD includes symptoms of psychosis such as hallucinations or delusions, and may be associated with agitation, negative symptoms or depression. Even though the US FDA has not approved any medication for the treatment of PAD, atypical antipsychotics have been widely used and favoured by geriatric experts in the management of the condition in view of their modest efficacy and relative safety. However, the recent FDA warnings regarding the cardiac, metabolic, cerebrovascular and mortality risks associated with the use of these drugs in elderly patients with dementia have caused serious concerns regarding their use. Nevertheless, until an effective and safe medication is approved by the regulatory agencies for PAD, clinicians do not have a better choice than atypical antipsychotics for the management of the serious symptoms of this condition.     

Mortality in elderly dementia patients treated with risperidone

Agitation, aggression, and psychosis are among the most troublesome behavioral and psychological symptoms of dementia (BPSD) and impair the lives of dementia patients and their caregivers. Atypical antipsychotics have been widely prescribed to improve these BPSD. However, in a number of trials with atypical antipsychotics, a consistent increase in overall mortality has been observed. The US Food and Drug Administration issued a warning for all atypical antipsychotics as a result of a meta-analysis of 17 placebo-controlled clinical trials using various atypical antipsychotics for the treatment of BSPD. To evaluate this mortality risk specifically for risperidone, 6 phase-2/3 double-blind trials comparing risperidone with placebo were analyzed. Data were obtained from Johnson & Johnson Pharmaceutical Research and Development. Hazard ratios with 95% confidence intervals were calculated to compare the relative mortality risk between patients treated with risperidone and those treated with placebo. In this meta-analysis, 1721 patients were included. In the pooled sample, the mortality was 4.0% with risperidone versus 3.1% with placebo (relative risk, 1.21; 95% confidence interval, 0.71-2.06) during treatment or within 30 days after treatment discontinuation. The most common adverse events associated with death were pneumonia, cardiac failure or arrest, or cerebrovascular disorder. No relationship was found between risperidone dose and mortality. In conclusion, this meta-analysis found a nonsignificant increase in mortality during treatment with risperidone in dementia patients. Larger studies would be needed to rule out a small increase in mortality in these patients. Careful assessments of potential benefits and risks should be made before prescribing risperidone for the treatment of BPSD.     

All-cause mortality associated with atypical and typical antipsychotics in demented outpatients

PURPOSE: To estimate the association between use of typical and atypical antipsychotics and all-cause mortality in a population of demented outpatients. METHODS: The study cohort comprised all demented patients older than 65 years and registered in the Integrated Primary Care Information (IPCI) database, during 1996-2004. First, mortality rates were calculated during use of atypical and typical antipsychotics. Second, we assessed the association between use of atypical and typical antipsychotics and all-cause mortality through a nested case-control study in the cohort of demented patients. Each case was matched to all eligible controls at the date of death by age and duration of dementia. Odds ratios were estimated through conditional logistic regression analyses. RESULTS: The crude mortality rate was 30.1 (95%CI: 18.2-47.1) and 25.2 (21.0-29.8) per 100 person-years (PY) during use of atypical and typical antipsychotics, respectively. No significant difference in risk of death was observed between current users of atypical and typical antipsychotics (OR = 1.3; 95%CI: 0.7-2.4). Both types of antipsychotics were associated with a significantly increased risk of death as compared to non-users (OR = 2.2, 1.2-3.9 for atypical antipsychotics; OR=1.7, 1.3-2.2 for typical antipsychotics). CONCLUSIONS: Conventional antipsychotic drug should be included in the FDA's Public Health advisory, which currently warns only of the increased risk of death with the use of atypical antipsychotics in elderly demented persons.     

Nonclinical proarrhythmia models: predicting Torsades de Pointes

Prolongation of the QT interval and the cardiac action potential have been linked to a potentially fatal but rare tachyarrhythmia known as Torsades de Pointes (TdP). Nonclinical assays, such as those investigating the effect on I(Kr) (the hERG channel current), prolongation of the action potential duration (APD) and the QT interval, in vivo, have been developed to predict the risk of QT interval prolongation and TdP in man. However, there seems to be a dissociation between the risk of QT interval prolongation and the torsadogenic risk. There is an increasing mass of evidence showing that an increase in the QT interval does not necessarily lead to TdP. Thus, it appears that while standard assays are very good, although perhaps not infallible, at predicting the risk of QT interval prolongation in man they do not predict the proarrhythmic risk. Recently there has been a plethora of publications suggesting that there are electrophysiological markers associated with drug-induced TdP other than hERG channel activity, APD and the QT interval, and these markers may be better predictors of TdP. In this review, three in vitro and, briefly, three in vivo models or methods are discussed. These proarrhythmia models use electrophysiological markers such as transmural dispersion of repolarization, action potential triangulation, instability, reverse use-dependence, and the incidence of early after-depolarizations to predict the risk of TdP. Most of the models presented have been published widely. The particular variable or set of variables used by each model to predict the torsadogenic propensity of a drug has been reported to correlate with clinical outcome. While each variable/model has been shown to discriminate between antiarrhythmic and nonarrhythmic drugs, these reports should be interpreted cautiously since none has been independently (externally) assessed. Each model is discussed along with its particular merits and shortcomings; none, as yet, having shown a predictive value that makes it clearly superior to the others. Proarrhythmia models, in particular in vitro models, challenge current perceptions of appropriate surrogates for TdP in man and question existing nonclinical strategies for assessing proarrhythmic risk. The rapid emergence of such models, compounded by the lack of a clear understanding of the key proarrhythmic mechanisms has resulted in a regulatory reluctance to embrace such models. The wider acceptance of proarrhythmia models is likely to occur when there is a clear understanding and agreement on the key proarrhythmia mechanisms. Regardless of regulatory acceptance, with further validation these models may still enhance pharmaceutical company decision-making to provide a rational basis for drug progression, particularly in areas of unmet medical need.     

Mood stabilizers and atypical antipsychotics: bimodal treatments for bipolar disorder

Treatment options for bipolar disorder have rapidly expanded over the last decade, but providing optimal management remains an elusive goal. The authors reviewed the literature on the efficacy of agents with the best clinical evidence supporting their use in bipolar disorder, including the mood stabilizers lithium, valproate, lamotrigine, and carbamazepine, as well as the atypical antipsychotics olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. Most medications appear to be more effective for symptoms of mood elevation than for symptoms of depression. The efficacy, tolerability, and safety profiles of agents must be considered when making clinical decisions. Several agents, including lithium, valproate, olanzapine, quetiapine, and risperidone, can cause problematic weight gain. In addition, the use of atypical antipsychotics has been associated with an increased risk of metabolic abnormalities such as dyslipidemia, hypergylycemia, and diabetes mellitus. In most patients, monotherapy offers inadequate efficacy. Further investigation of combinations of agents such as mood stabilizers and atypical antipsychotics may yield valuable insights into the potential of combination therapies to enhance clinical outcomes in patients with bipolar disorder.     

Sudden death in patients receiving drugs tending to prolong the QT interval

AIMS

To examine risks of sudden death in the community associated with drugs grouped by their risk of causing torsades de pointes (TdP) and to explore the risks for individual drugs.

METHODS

Case–control study comparing prior drug intakes and morbidities, using the Arizona classification of drugs causing TdP. Participants included 1010 patients dying suddenly where post-mortem examination did not identify a clear cause of death, and 3030 matched living controls from primary care.

RESULTS

Noncardiac drug risk was posed by antipsychotics and antidepressants. Significantly raised odds ratios (ORs) were found for takers of typical and atypical antipsychotics, ORs [95% confidence interval] 3.94 (2.05, 7.55) and 4.36 (2.54, 7.51), and of selective serotonin reuptake inhibitors [SSRIs] rather than tricyclic antidepressants, ORs 2.21 (1.61, 3.05) and 1.44 (0.96, 2.13). No significant risk was associated with other, noncardiac or psychiatric drugs, OR 1.09 (0.85, 1.41). Arizona classified drugs considered to raise risk of TdP were associated with raised risk of sudden death, as were those only weakly associated with TdP and not considered to pose a risk in normal use, ORs 2.08 (1.45, 3.00) and 1.74 (1.33, 2.28), respectively.

CONCLUSIONS

Atypical and typical antipsychotic drug use were both strongly associated with raised risks, as were SSRIs. Tricyclic antidepressants were not associated with raised risks. The Arizona classification of risk of TdP was a poor predictor of likelihood of noncardiac drug-associated sudden death.