Tardive Dyskinesia with Antipsychotic Medication in Children and Adolescents: A Systematic Literature Review.

BACKGROUND: Tardive dyskinesia (TD) is a persisting, and potentially irreversible, movement disorder associated with treatment with dopamine receptor antagonists. Few data are available on the risk of TD in children and adolescents treated with antipsychotic medication. OBJECTIVE: To review the literature on incidence, risk factors, and treatment options for antipsychotic-associated TD in children and adolescents (aged < 18 years). METHODS: Relevant articles were identified through a systematic search of Embase and Medline performed in January 2024. Methodological quality was assessed using the Newcastle-Ottawa Scale and Joanna Briggs Institute Critical Appraisal tools. RESULTS: Thirteen studies were identified. The reported TD point prevalence was 5-20%, with higher rates in studies involving typical antipsychotics. Lower estimates (around 1%) emerged from analyses of clinical database data suggesting underdiagnosis in clinical practice. Risk factors included treatment with typical antipsychotics, higher doses, longer duration of exposure, older age, female gender, higher baseline Abnormal Involuntary Movements Scale (AIMS) scores, intellectual impairment, and perinatal complications. CONCLUSION: Although relatively few cases have been reported in children and adolescents, TD remains a risk in this population. Individuals receiving antipsychotics should be monitored carefully for the emergence of abnormal movements. Other than dose reduction, discontinuation, or switch to a lower-risk antipsychotic, few interventions have demonstrated efficacy. The strongest evidence for pharmacological treatment is for VMAT-2 inhibitors (valbenazine and deutetrabenazine), but these drugs are not licensed for use in children. To reduce risk, antipsychotics should be prescribed only if necessary, at the minimum effective dose and for the minimum necessary duration.

Evaluating fenfluramine hydrochloride as an oral solution for the treatment of seizures associated with Lennox-Gastaut syndrome.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset developmental and epileptic encephalopathy characterized by treatment-refractory seizures, including tonic/atonic 'drop' seizures, and intellectual impairment and slow spike-wave discharges on the electroencephalogram. Fenfluramine, previously prescribed as a weight-loss drug but then withdrawn, has recently been approved in the US, EU, and UK for the adjunct treatment of seizures associated with LGS. AREAS COVERED: The authors review the efficacy and safety findings from clinical trials of fenfluramine in LGS. The authors then discuss the evidence for adverse effects that may be of particular concern to fenfluramine, namely cardiac abnormalities, and weight loss, in the context of the use of fenfluramine for the treatment of the refractory seizures in LGS. EXPERT OPINION: Fenfluramine has demonstrated efficacy in reducing the frequency of seizures in LGS, notably drop seizures, in short-term and long-term clinical trials. Valvular heart disease and pulmonary hypertension have not been reported at the low doses (≤26 mg/day) used in these studies, however, data are limited. Due to its novel mechanism of action, fenfluramine may be of benefit in LGS which has not responded adequately to other antiseizure medications. However, none of these medications, including fenfluramine, achieves the ultimate goal of seizure freedom in most cases.

Drug-drug interactions between antiseizure medications and antipsychotic medications: a narrative review and expert opinion.

INTRODUCTION: Antiseizure medications (ASMs) and antipsychotic drugs are frequently coadministered with the potential for drug-drug interactions. Interactions may either be pharmacokinetic or pharmacodynamic, resulting in a decrease or increase in efficacy and/or an increase or decrease in adverse effects. AREAS COVERED: The clinical evidence for pharmacokinetic and pharmacodynamic interactions between ASMs and antipsychotics is reviewed based on the results of a literature search in MEDLINE conducted in April 2023. EXPERT OPINION: There is now extensive published evidence for the clinical importance of interactions between ASMs and antipsychotics. Enzyme-inducing ASMs can decrease blood concentrations of many of the antipsychotics. There is also evidence that enzyme-inhibiting ASMs can increase antipsychotic blood concentrations. Similarly, there is limited evidence showing that antipsychotic drugs may affect the blood concentrations of ASMs through pharmacokinetic interactions. There is less available evidence for pharmacodynamic interactions, but these can also be important, as can displacement from protein binding. The lack of published evidence for an interaction should not be interpreted as meaning that the given interaction does not occur; the evidence is building continually. There is no substitute for careful patient monitoring and sound clinical judgment.

Gabapentinoid consumption in 65 countries and regions from 2008 to 2018: a longitudinal trend study.

Recent studies raised concerns about the increasing use of gabapentinoids in different countries. With their potential for misuse and addiction, understanding the global consumption of gabapentinoids will offer us a platform to examine the need for any interventional policies. This longitudinal trend study utilised pharmaceutical sales data from 65 countries and regions across the world to evaluate the global trends in gabapentinoid consumption between 2008-2018. The multinational average annual percentage change of gabapentinoid consumption was +17.20%, increased from 4.17 defined daily dose per ten thousand inhabitants per day (DDD/TID) in 2008 to 18.26 DDD/TID in 2018. High-income countries had the highest pooled gabapentinoid consumption rate (39.92 DDD/TID) in 2018, which was more than six times higher than the lower-middle income countries (6.11 DDD/TID). The study shows that despite differences in healthcare system and culture, a consistent increase in gabapentinoid consumption is observed worldwide, with high-income countries remaining the largest consumers.

Current and emerging pharmacotherapy for the treatment of Lennox-Gastaut syndrome.

INTRODUCTION: Lennox-Gastaut syndrome (LGS) is a severe childhood-onset epileptic encephalopathy, characterized by multiple seizure types, generalized slow spike-and-wave complexes in the EEG, and cognitive impairment. Seizures in LGS are typically resistant to treatment with antiseizure medications (ASMs). Tonic/atonic ('drop') seizures are of particular concern, due to their liability to cause physical injury. AREAS COVERED: We summarize evidence for current and emerging ASMs for the treatment of seizures in LGS. The review focuses on findings from randomized, double-blind, placebo-controlled trials (RDBCTs). For ASMs for which no double-blind trials were identified, lower quality evidence was considered. Novel pharmacological agents currently undergoing investigation for the treatment of LGS are also briefly discussed. EXPERT OPINION: Evidence from RDBCTs supports the use of cannabidiol, clobazam, felbamate, fenfluramine, lamotrigine, rufinamide, and topiramate as adjunct treatments for drop seizures. Percentage decreases in drop seizure frequency ranged from 68.3% with high-dose clobazam to 14.8% with topiramate. Valproate continues to be considered the first-line treatment, despite the absence of RDBCTs specifically in LGS. Most individuals with LGS will require treatment with multiple ASMs. Treatment decisions should be individualized and take into account adverse effects, comorbidities, general quality of life, and drug interactions, as well as individual efficacy.

Current evidence for adjunct pyridoxine (vitamin B6) for the treatment of behavioral adverse effects associated with levetiracetam: A systematic review.

BACKGROUND: Levetiracetam (LVT), while an effective treatment for multiple seizure types, is associated with a high incidence of neuropsychiatric adverse events (NPAEs). In predominantly retrospective studies, supplementation with pyridoxine/vitamin B6 (PN) was associated with improvement in NPAEs in some people. A previous review highlighted a lack of double-blind, controlled trials of PN for the treatment of NPAEs in individuals treated with LVT. The current paper updates the findings from the previous review to include evidence from studies published since June 2019. METHODS: An updated systematic review of the published literature was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed, Embase, the Cochrane Library, and Google Scholar were searched to identify studies published between June 2019 and 2nd November 2022 in which supplementary PN was initiated for the treatment of LVT-associated NPAEs. All study types were eligible. The risk of bias in randomized trials was assessed using the Cochrane risk-of-bias tool. RESULTS: Seven additional studies were identified: two double-blind, randomized controlled trials (RCTs), four retrospective studies, and one retrospective case series. One RCT reported significant improvements from baseline in behavioral adverse events (BAEs) in both the intervention (PN) group and the low-dose control group (both p < 0.05), with a significantly greater improvement in the intervention group (p < 0.001). In the second RCT, differences in BAE severity between PN and placebo groups at the endpoint were not statistically significant. In one retrospective study, subjective irritability was reported to have improved from baseline in 9/20 individuals (45%) treated with supplementary PN. Data for systematic assessments (PHQ-9 and GAD-7) were available for 10 individuals. Assessment by PHQ-9 showed that six individuals improved, two worsened and two had no change. Based on the GAD-7, three people improved, two worsened and five had no change. In the second retrospective study, 18/41 individuals (44%) who commenced PN following the emergence of BAEs showed "significant" improvement. In a separate group of individuals with pre-existing behavioral problems in whom PN treatment was initiated at the same time as commencing LVT, 3/18 (16.7%) developed BAEs. This compared with 79/458 people (17.2%) who were initially treated only with LVT. The third retrospective study compared treatment-related irritability in individuals who had been treated with both LVT and perampanel, either sequentially or concomitantly. Two people who developed irritability while receiving LVT monotherapy were able to continue treatment with the addition of PN. The fourth study reported a significantly lower LVT discontinuation rate in individuals taking PN and a higher rate of improved behavior in those who were able to continue LVT. The case series reported improvements in behavioral symptoms in six people within two to three weeks of commencing supplementary PN. CONCLUSION: Data published within the last three years add to earlier evidence suggesting that PN might be effective in the treatment of NPAEs associated with LVT. However, the quality of evidence remains poor and only a few prospective trials have been published. Data from placebo-controlled trials are still largely lacking. Currently, there is insufficient evidence to justify any firm recommendation for PN supplementation to treat NPAEs associated with LVT. Further well-designed, prospective trials are warranted.

Should Antidepressants be Avoided in Pregnancy?

Many (> 40%) women discontinue antidepressants during pregnancy because of concerns about effects on the foetus, based on information from inadequately-controlled studies. The sibling-control study design provides the best control for confounding factors, notably maternal depression. The purpose of this review was to investigate the evidence from sibling-control analyses for adverse outcomes in offspring associated with antidepressant exposure during pregnancy. Fourteen sibling-control studies were identified through searches of PubMed and Embase. Outcomes included preterm birth, small for gestational age, neonatal size, birth defects, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), behavioural problems, neurodevelopmental deficits, and scholastic attainment. For the majority of these outcomes, no statistically significant associations were found when comparing exposed and unexposed siblings. Single studies reported associations with preterm birth, reduced gestational age, ADHD, anxiety at 36 months, and lower mathematics test scores, which persisted in the sibling-control analyses. However, differences were small and possibly not clinically significant. Moreover, effects of residual confounding could not be excluded. These findings provide evidence that many of the previously reported associations between prenatal antidepressant exposure and adverse outcomes in offspring are no longer statistically significant when exposed offspring are compared with unexposed siblings. The few statistically significant differences in sibling-control analyses were generally small with doubtful clinical significance. Decisions on antidepressant treatment during pregnancy should be made individually, based on evidence from properly controlled studies, not on misleading information based on studies that have not controlled adequately for confounding factors.

Adverse events in long-term studies of exogenous melatonin.

INTRODUCTION: Exogenous melatonin is regulated as a drug in the UK and EU but is available as an over-the-counter dietary supplement in the US and Canada. In the last 15 years, melatonin use has increased rapidly in many countries, in particular, in children and adolescents who frequently have many years of continuous exposure. Despite this, the potential risks associated with extended use continue to be unclear, and there remains a lack of systematically assessed safety data from long-term prospective trials. AREAS COVERED: This review focuses on adverse event data reported in long-term (≥6 months) prospective trials of melatonin. METHODS: The Embase and Medline electronic databases were searched from inception to 12 September 2022 for long-term studies of melatonin, in which adverse events were systematically monitored and reported. EXPERT OPINION: Although the reported frequency of possible adverse events associated with long-term melatonin use is low and few clinically significant adverse events have been reported, the scarcity of data from double-blind randomized placebo-controlled trials should caution against complacency. Ideally, analysis of data from large well-established research databases should be conducted to provide good quality evidence on which to base a more rigorous evaluation of the safety profile.

Antipsychotic Medication and Risk of Incident Seizure in People with Autism Spectrum Disorder: Analyses with Cohort and Within Individual Study Designs.

There are many case reports of seizures apparently associated with the prescription of antipsychotics. This study aimed to examine whether there is an association between the prescription of antipsychotics and incident seizures in individuals with autism spectrum disorder using retrospective data based on patients' chart review. A cohort study was conducted to compare the rate of incident seizure between 3923 users of antipsychotics with 10,086 users of other psychotropics. This was followed by a self-controlled case series (SCCS) analysis of 149 patients to eliminate the effect of time-invariant confounders. The results showed no evidence of increased risk of seizure after exposure to antipsychotic agents (Hazard Ratio 1.28, 95% CI 0.74-2.19) compared to other psychotropics.

Efficacy and safety of lamotrigine in the treatment of bipolar disorder across the lifespan: a systematic review.

BACKGROUND: Bipolar disorder (BD) is a cyclic mood disorder characterised by alternating episodes of mania/hypomania and depression interspersed with euthymic periods. Lamotrigine (LTG) demonstrated some mood improvement in patients treated for epilepsy, leading to clinical studies in patients with BD and its eventual introduction as maintenance therapy for the prevention of depressive relapse in euthymic patients. Most current clinical guidelines include LTG as a recommended treatment option for the maintenance phase in adult BD, consistent with its global licencing status. AIMS: To review the evidence for the efficacy and safety of LTG in the treatment of all phases of BD. METHODS: PubMed was searched for double-blind, randomised, placebo-controlled trials using the keywords: LTG, Lamictal, 'bipolar disorder', 'bipolar affective disorder', 'bipolar I', 'bipolar II', cyclothymia, mania, manic, depression, depressive, 'randomised controlled trial', 'randomised trial', RCT and 'placebo-controlled' and corresponding MeSH terms. Eligible articles published in English were reviewed. RESULTS: Thirteen studies were identified. The strongest evidence supports utility in the prevention of recurrence and relapse, particularly depressive relapse, in stabilised patients. Some evidence suggests efficacy in acute bipolar depression, but findings are inconsistent. There is little or no strong evidence in support of efficacy in acute mania, unipolar depression, or rapid-cycling BD. Few controlled trials have evaluated LTG in bipolar II or in paediatric patients. Indications for safety, tolerability and patient acceptability are relatively favourable, provided there is slow dose escalation to reduce the probability of skin rash. CONCLUSION: On the balance of efficacy and tolerability, LTG might be considered a first-line drug for BD, except for acute manic episodes or where rapid symptom control is required. In terms of efficacy alone, however, the evidence favours other medications.

Neurocognitive Effects of Antiseizure Medications in Children and Adolescents with Epilepsy.

Impairments in cognition are common in epilepsy and may be caused or exacerbated by antiseizure medications (ASMs). Positive effects on cognition may also be seen with some ASMs. Cognitive outcomes are of particular concern in children who may be at an increased risk of cognitive adverse effects of treatment. A comprehensive literature search was conducted in PubMed in order to evaluate the evidence for cognitive changes associated with treatment with ASMs in paediatric epilepsy patients. The ASMs considered were those in the current edition of the British National Formulary (BNF). For most ASMs, remarkably few studies providing robust data on cognitive effects in paediatric patients were identified. The available evidence suggests cognitive impairments may be associated with treatment with phenobarbital. Topiramate and phenytoin are also associated with negative effects on cognition, in particular word-finding difficulties and other language deficits with topiramate, but there are few data available specifically on children. Lamotrigine, levetiracetam and fenfluramine are associated with improvements in some cognitive domains, although it is unclear whether these effects are directly attributable to the medications or are a result of improvements in seizures. Neutral effects on cognition (no substantial evidence of worsening) were suggested for carbamazepine, everolimus, lacosamide, oxcarbazepine, perampanel and valproate. There is limited data for cannabidiol, clobazam, eslicarbazepine acetate, ethosuximide, rufinamide, vigabatrin and zonisamide, although the available evidence suggests these drugs are not associated with severe cognitive impairment. There was too little information to reach conclusions about the effects of brivaracetam, felbamate, gabapentin, pregabalin, retigabine, stiripentol or tiagabine.

Is Adjunct Aripiprazole Effective in Treating Hyperprolactinemia Induced by Psychotropic Medication? A Narrative Review.

Psychotropic medication treatment can cause elevated serum prolactin levels and hyperprolactinaemia (HPRL). Reports have suggested that aripiprazole may decrease elevated prolactin. The aim of this review was to assess evidence for the efficacy of adjunct aripiprazole in the treatment of psychotropic-induced HPRL. PubMed and Google Scholar were searched to identify randomised placebo-controlled trials (RCTs) of adjunct aripiprazole in patients with HPRL attributed to primary psychotropic medications. Data for individual patients from case studies, chart reviews and open-label studies were also identified and assessed. Six RCTs, with a total of 609 patients, met inclusion criteria. Primary psychotropics included risperidone, haloperidol, paliperidone, fluphenazine and loxapine. Reductions in prolactin from baseline, before the introduction of aripiprazole, were significantly greater for adjunct aripiprazole than for adjunct placebo in all the studies (p = 0.04 to p < 0.0001). Normalisation of serum prolactin levels was significantly more likely with adjunct aripiprazole than adjunct placebo (p = 0.028 to p < 0.001, data from three studies). Improvement or resolution of HPRL-related symptoms (galactorrhoea, oligomenorrhoea, amenorrhoea and sexual dysfunction) were reported in three studies. Prolactin levels decreased in all case reports and in both of two open-label studies; they normalised in 30/41 patients (73.2%) in case studies and 12/29 (41.4%) in the open-label studies. Adjunct aripiprazole was statistically significantly effective in treating elevated serum prolactin levels in six RCTs. Evidence from case reports and open-label studies suggests a degree of effectiveness in most patients.

Seizures and Epilepsy in Autism Spectrum Disorder.

Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.

Antipsychotics and Risk of Neuroleptic Malignant Syndrome: A Population-Based Cohort and Case-Crossover Study.

BACKGROUND: Neuroleptic malignant syndrome (NMS) is a rare and acute adverse drug reaction associated with antipsychotic therapy. However, few data on the risk and epidemiology of NMS are available. OBJECTIVES: The aim of this study was to ascertain the incidence risk and all-cause mortality of NMS associated with antipsychotic use, and to assess the association of recent antipsychotic exposure and NMS. METHODS: We did a population-based study using data from the Hong Kong Hospital Authority's Clinical Data Analysis and Reporting System database. Cases had a first diagnosis of NMS between 1 January 2004 and 30 November 2017. A case-crossover analysis was used to compare antipsychotic exposure 30 days before the diagnosis of NMS (index date) and a reference period 91-120 days before the index date. To adjust for potential time trends in antipsychotic exposure, we sampled from cases to match current cases and future cases, and further adjusted for select medications and acute medical conditions. RESULTS: 297,647 patients were prescribed antipsychotics, and the incidence risk of NMS was 0.11%. Of the 336 cases included in the case-crossover analysis, 20 (6%) died within 30 days after the index date; only one case had NMS recorded as the primary cause of death. When compared with the reference period, cases were more frequently prescribed multiple antipsychotics (15.8% vs 26.8%; standardized mean difference [SMD] 0.27) and short-acting injectable antipsychotics (3.6% vs 13.7%; SMD 0.37) during the 30 days prior to the diagnosis of NMS. Odds ratios for antipsychotic exposure in the case-crossover, case-crossover adjusted for time trend, and case-crossover adjusted for time trend and potential confounders analysis were 8.00 (95% confidence interval 3.42-18.69), 5.88 (2.46-14.04), and 4.77 (1.95-11.66). CONCLUSIONS: Our results suggest that recent use of antipsychotics is associated with NMS. Although a case-only design inherently controls for confounding by time-invariant factors, residual confounding by acute medical conditions with similar presentations to NMS cannot be fully excluded.

Association between methylphenidate treatment and risk of seizure: a population-based, self-controlled case-series study.

BACKGROUND: Individuals with attention-deficit hyperactivity disorder (ADHD) are at increased risk of seizures. Stimulant medications such as methylphenidate are the most commonly prescribed treatment for ADHD, but the association between their therapeutic use and the risk of seizures is unclear. We aimed to investigate the association between methylphenidate treatment and the risk of seizure. METHODS: For this population-based observational study, we used the electronic medical record database of the Hong Kong Clinical Data Analysis And Reporting System to identify individuals aged 6-25 years who received at least one methylphenidate prescription during the study period. Individuals with records of seizure or epilepsy before the study period were excluded. Individuals treated with methylphenidate who had seizures during the study period were included in the subsequent analyses, and a self-controlled case-series design was used to control for time-invariant individual characteristics. We did additional analyses using skin infection as a negative control outcome. We compared relative incidence of seizure during periods when individuals were exposed to methylphenidate with that during non-exposed periods. FINDINGS: Of 29 604 individuals prescribed methylphenidate between Jan 1, 2001, and Dec 31, 2017, 269 (199 males and 70 females) had incident seizures. The mean age at baseline was 6·66 years (SD 2·01) and the median age at the incident seizure was 9·69 years (IQR 7·62-12·99). The overall incidence of seizure during methylphenidate treatment was 4·4 per 10 000 patient-years. We detected an increased risk of seizure during the first 30 days of methylphenidate treatment compared with that during non-exposed periods, with an incidence rate ratio of 4·01 (95% CI 2·09-7·68). No increase in risk was identified during the following 31-180 days of treatment (1·13, 0·56-2·25) or during subsequent treatment (1·38, 0·92-2·07). We did not identify an increased risk in any risk window for the negative control outcome analysis. No individuals died because of a seizure during the study period. INTERPRETATION: The incidence of seizures was higher in the period immediately after the start of methylphenidate treatment than in the non-exposed period. No increased risk was observed during continuation of methylphenidate treatment. The association between methylphenidate treatment and seizures immediately after initiation of medication can be seen as a potential safety signal. Monitoring of neurological outcomes in individuals with ADHD is recommended when they first start methylphenidate treatment. FUNDING: Hong Kong Research Grants Council.

Seizures and Epilepsy in Autism Spectrum Disorder.

Epilepsy and autism frequently co-occur. Epilepsy confers an increased risk of autism and autism confers an increased risk of epilepsy. Specific epilepsy syndromes, intellectual disability, and female gender present a particular risk of autism in individuals with epilepsy. Epilepsy and autism are likely to share common etiologies, which predispose individuals to either or both conditions. Genetic factors, metabolic disorders, mitochondrial disorders, and immune dysfunction all can be implicated.

Mortality Risk Associated with Haloperidol Use Compared with Other Antipsychotics: An 11-Year Population-Based Propensity-Score-Matched Cohort Study.

BACKGROUND: Haloperidol remains a frequently prescribed first-generation antipsychotic. However, haloperidol-associated mortality risk by all causes, cardiovascular disease (CVD), and pneumonia compared with other antipsychotics is unknown. OBJECTIVE: This study investigated the mortality risk associated with long-term haloperidol treatment versus that with other antipsychotics. METHODS: We identified incident antipsychotic users from 2004 to 2014 in the Clinical Data Analysis and Reporting System (CDARS), a population-based clinical database managed by the Hong Kong Hospital Authority. We included patients who were aged ≥ 18 and received antipsychotics for any indication apart from terminal illnesses or management of acute behavioural disturbance. Patients on haloperidol and other antipsychotic agents (risperidone, quetiapine, olanzapine, chlorpromazine, aripiprazole, sulpiride, amisulpride, or trifluoperazine) were matched by propensity score. Hazard ratios (HRs) for all-cause mortality and death due to CVD and pneumonia were estimated with 95% confidence intervals (CIs) using a Cox proportional hazards model. RESULTS: In total, 136,593 users of antipsychotics were included. During a mean follow-up of 3.2 years, the incidence of all-cause mortality ranged from 186.8/1000 person-years for haloperidol to 10.4/1000 person-years for trifluoperazine. The risk of all-cause mortality was lower with non-haloperidol antipsychotics than with haloperidol, with HRs ranging from 0.68 (95% CI 0.64-0.72 [chlorpromazine]) to 0.43 (95% CI 0.36-0.53 [trifluoperazine]). Risperidone, quetiapine, sulpiride, chlorpromazine, aripiprazole, and trifluoperazine were associated with a significantly lower risk of pneumonia-related mortality. A significantly lower risk of CVD mortality was observed for risperidone, sulpiride, chlorpromazine, and quetiapine. CONCLUSION: Haloperidol was associated with increased overall mortality when compared with other antipsychotics in long-term follow-up. Treatment with haloperidol should be carefully considered, especially in older patients and patients at risk of CVD or pneumonia, since the risk of death appears to be lower with non-haloperidol agents.