Objectives: Alzheimer's disease (AD) is the most common cause of dementia and it is associated with increased mortality. The use of antipsychotics is common among the elderly, especially in those with dementia. Evidence suggests an increased risk of mortality associated with antipsychotic use. Despite the short-term benefit of antipsychotic treatment to reduce the behavioral and psychological symptoms of dementia, it increases the risk of mortality in patients with AD. Our aim is to discuss the findings from the literature about risk of mortality associated with the use of antipsychotics in AD.

Methods: We searched Internet databases indexed at MEDLINE using following MeSH terms: "Antipsychotic Agents" AND "Alzheimer Disease" OR "Dementia" AND "Mortality" and selected articles published in the last 5 years.

Results: Antipsychotics are widely used in the pharmacological treatment of agitation and aggression in elderly patients with AD, but their benefit is limited. Serious adverse events associated with antipsychotics include increased risk of death. The risk of mortality is associated with both typical and atypical antipsychotics. Antipsychotic polypharmacy is associated with a higher mortality risk than monotherapy and should be avoided. The mortality risk increases after the first few days of treatment, gradually reducing but continues to increase after two years of treatment. Haloperidol is associated with a higher mortality risk and quetiapine with a lower risk than risperidone.

Conclusions: If the use of antipsychotics is considered necessary, the lowest effective dose should be chosen and the duration should be limited because the mortality risk remains high with long-term use. The risk / benefit should be considered when choosing the antipsychotic. Further studies on the efficacy and risk of adverse events with antipsychotics are needed for a better choice of treatment and adequate monitoring with risk reduction.

In an open-label study, famotidine was added to the regular neuroleptic regimen of 11 schizophrenic patients for 4 weeks. Each patient was scored weekly with SAPS, SANS, CGI and HAM-D-17 scales. The results suggest that famotidine is indeed effective as an adjunctive drug to neuroleptics in the treatment of schizophrenia.

Studies on long-term efficacy and safety should be a main concern in the evaluation of novel antipsychotics. The present paper is a review of important issues related to the design and performance of such trials. The variability of the natural course of schizophrenia, the variability in treatment response, and the variability of actions of different neuroleptics need to be considered. Long-term studies need to address maintenance of efficacy, prevention of relapse and recurrence, health economics, quality of life and a large number of safety issues in order to get approval for new drug applications and reimbursement on expensive new medicines. Assessment instruments for efficacy, tolerability and safety, need to be supplemented with rating scales for various aspects of psychopathology (positive, negative, deficit symptoms), social and work functioning, drug induced mental side effects, quality of life and accounts of total treatment costs.

Controlled clinical trials have shown that the atypical neuroleptic clozapine is highly effective in schizophrenic patients who are unresponsive to conventional neuroleptic agents. The long-term outcome of clozapine treatment was studied in 122 patients who were treated between 1974 and 1991. The mean duration of treatment was 5.2 years. At follow-up, 74 patients (61%) were still receiving clozapine. Only 11 patients discontinued treatment because of adverse events and eight because of poor compliance. Clinical improvement was seen in 87% of patients; 40% had resumed employment after 2 years' treatment. About one-third of patients who received clozapine for 5–10 years continued to improve during this time; this was probably because of a continuing process of socialisation. Thus, clozapine offers important advantages in schizophrenic patients resistant to conventional neuroleptics in terms of long-term efficacy and lack of extrapyramidal side-effects.

Nowadays, the rehabilitation of schizophrenic patients is a major issue for psychiatry. Regarding the role of conventional neuroleptics, the following points will be considered in this paper: the role of neuroleptics in the number, length and frequency of hospitalisations; the role of neuroleptics in the number, degree and length of relapses; the clinical effects of neuroleptics focusing particularly on their disinhibitory action, the most controversial and least studied of the clinical effects of these drugs; and the side effects, which have been intensively studied and particularly criticised during these last years, leading to the development of new drugs discussed in the next article. All the published data relating to the psychosocial profile of schizophrenic patients clearly demonstrate the need for further research in order to improve the familial, social and professional rehabilitation of these patients

The aim of this review is to summarize the present state of findings on altered neurotrophic factor levels in schizophrenic psychoses, on variations in genes coding for neurotrophic factors, and on the effect of antipsychotic drugs on the expression level of neurotrophic factors. This is a conceptual paper that aims to establish the link between the neuromaldevelopment theory of schizophrenia and neurotrophic factors. An extensive literature review has been done using the Pub Med database, a service of the National Library of Medicine, which includes over 14 million citations for biomedical articles back to the 1950s. The majority of studies discussed in this review support the notion of alterations of neurotrophic factors at the protein and gene level, respectively, and support the hypothesis that these alterations could, at least partially, explain some of the morphological, cytoarchitectural and neurobiochemical abnormalities found in the brain of schizophrenic patients. However, the results are not always conclusive and the clinical significance of these alterations is not fully understood. It is, thus, important to further neurotrophic factor research in order to better understand the etiopathogenesis of schizophrenic psychoses and, thus, potentially develop new treatment strategies urgently needed for patients suffering from these devastating disorders.

The considerable debate about the justification of coercive measures in psychiatry includes medical, ethical, legal and political arguments, patients' subjective experience of involuntary injections or restraint is barely investigated. A semi-structured interview was used to evaluate retrospective attitudes in 40 (32 schizophrenic) patients, treated involuntarily with injection of neuroleptic drugs or restrained. Of these patients, 48% rated these measures as necessary or positive, 23% as negative, and 30% were indifferent. Only patients with good insight into their disease were able to accept the involuntary treatment retrospectively as positive. Reasons for treatment refusal were inadequacy of the measures (58%), negative previous experience with neuroleptic drugs (47%), eg, akathisia, and reservations against the medical system itself (28%). ‘Fear’ and ‘powerlessness’ were the predominant feelings which patients experienced when confronted with coercive measures. Restraint was more disliked than injections. The results support the notion that disease concept and the ability to acknowledge mental illness are major factors influencing a schizophrenic patient's decision to accept of refuse treatment.

A review of the literature on placebo-controlled studies in schizophrenia reveals, that the percentage of placebo responders in short-term trials amounts to 0–40%; on active treatment the response rate is 40–60%. In relapse prevention studies 18–100% of patients on placebo relapsed as compared to 0–40% on active treatment. Factors of importance for the variability between studies are discussed. Desirable designs of explanatory and pivotal studies, the importance of placebo controlled relapse prevention studies, and more rigorous assessment methods, eg video-taped and structured interviews for diagnostic and symptom rating purposes, are proposed as a means to improve the quality of the clinical documentation of new drugs.

The aim of this survey is to present an overview of research into psychopharmacology as regards the effects of different psychoactive drugs and neuroleptics (NL) on language in normal subjects and schizophrenic patients. Eighteen studies that have investigated the effects of different drugs (alcohol, amphetamines, secobarbital, L-dopa, psilocybin, ketamine, fenfluramine) and neuroleptics (conventional and atypical) on language are reviewed. There are no studies concerning the effects of neuroleptics on language in healthy subjects. The results of the effects of other molecules indicate that language production can be increased (alcohol, amphetamine, secobarbital), rendered more complex (d-amphetamine), more focused (L-dopa) or more unfocused (psilocybin) and clearly impaired (ketamine). For schizophrenic patients, most studies show that conventional neuroleptic treatments, at a therapeutic dosage and in acute or chronic mode, reduce language disorders at all levels (clinic, linguistic, psycholinguistic). In conjunction with other molecules, the classical NL, when administered at a moderate dosage and in chronic mode, modify language in schizophrenia, either by improving the verbal flow and reducing pauses and positive thought disorder (NL + amphetamine) or by inducing an impairment in the language measurements (NL + fenfluramine). Clinical, methodological and theoretical considerations of results are debated in the framework of schizophrenic language disorders.

Retrospective evaluation of patients admitted consecutively to the psychiatric units of two general hospitals in Florence, to evaluate the rate and risk factors of neuroleptic-induced dystonia (NDA). One hundred and fifty-nine patients out of 2354 reviewed charts were included. The incidence of NDA was 15.7%. Multivariate analyses revealed that both age and neuroleptization speed (NS)—a new variable—were related to the occurrence of dystonia.

Given that we are celebrating the 50th birthday of neuroleptics introduction in psychiatry, the author proposes to take a look at certain results related to therapeutic practice. After a brief chronological literature review of the clinical practices and theoretical models that have controlled drug treatment of schizophrenia, the author presents a critical review of four meta-analyses. Since Delay, Deniker and Harl’s initial report, the story of neuroleptics comprises several periods. In 1963, the hyper-dopaminergic theory of psychoses was proposed. Another period began with models mainly based on the serotonin/dopamine relative blockade receptor hypothesis. More recently, a new framework to understand the differential effect of antipsychotics is related to the appropriate modulation (e.g., fast dissociation) of the D2 receptor alone. The concept of atypicality has become a new vista for research and to market new compounds. However, after 50 years of neuroleptic drugs, are we able to answer the following simple questions: Are neuroleptics effective in treating schizophrenia? Is there a difference between atypical and conventional neuroleptics? How do the efficacy and safety of newer antipsychotic drugs compare with those of clozapine? Actually, the answers yielded by these simple questions by meta-analysis should elicit in us a good deal of humility. If we wish to base psychiatry on evidence-based medicine, we run a genuine risk in taking a closer look at what has long been considered fact. Each psychiatrist must continue to be critical, sceptical, optimistic (not overoptimistic) and to learn in order to integrate the positive aspects of our growing knowledge base.

Three cases of akathisia-induced impulsive suicide attempts are reported. In all three cases the patients admitted that the suicidal ideas occurred suddently. The suicidal attempts may be a result of neuroleptic – induced akathisia as they disappeared as soon as the akathisia was treated.

In older as well as younger people, antipsychotic medication is commonly used to treat psychoses. In clinical practice, antipsychotic medication is also used to control severe behavioral disturbances such as agitation, wandering, self-mutilation, as well as assaultiveness. Neuroleptic and non-neuroleptic drug treatments are used to control severe agitation and disruptive behavior.

Among typical neuroleptics, very low doses (e.g., 0.25 mg of haloperidol 1–4 times per day) may be effective and limit the development of severe extrapyramidal reactions.

Recent experience suggests that the atypical neuroleptics, olanzaine, risperidone, and quetiapine, are also useful for controlling severe agitation in elderly demented nursing home residents.

The benzamides are also known for the treatment of behavioral disturbances in Europe, but there is little experience in the U.S.A.

Although research studies in this area are virtually nonexistent, growing clinical experience sugests that the following may be quite useful: 1) trazodone; 2) buspirone (Buspar®); 3) anticonvulsants (e.g., valproate); and 4) β-blockers.

The cognitive effects of bromocriptine (10 mg/day) in chronic neuroleptic-treated schizophrenic patients were studied in a 4-month trial. Ten neuropsychological variables were used for the evaluations. Nine patients and seven controls completed the study. They were tested three times: before the beginning of the study, and after 2 and 4 months of treatment. The results showed that treated patients globally performed significantly better than the controls (P < 0.05), and that the digit symbol substitution test was significantly improved (P < 0.03). The WAIS performance score was also significantly improved (P < 0.02). The picture arrangement test was improved, but did not reach significance (P < 0.07). Verbal tests were not improved. It therefore appears that addition of a D2 dopamine agonist in neuroleptic-treated patients can improve some of their cognitive functions. Two explanations can be proposed: i) bromocriptine decreases neuroleptic-induced motor side effects or ii) has an effect on a putative hypodopaminergic function in schizophrenia.

Placebo controlled studies in patients suffering from exacerbation eg acute productive episode of schizophrenia and performed in the period between 1963-1993 are reviewed and analysed with respect to study designs; size of studies; improvement rate under placebo and drop-outs due to inefficacy under placebo. The aim of the analysis was to find out if the reported data permit some realistic estimates for a priori assumptions needed for proper planning of such studies, particularly in view of the numerous ethical and other difficulties which their performance encounters in the practice. Literature research revealed a rather limited number of rigorous, placebo-controlled, monotherapy studies (without intermittent or concomitant additional neuroleptics) in acute schizophrenia. Across comparison of findings from these studies was difficult due to differences in duration of treatment, assessment instruments and criteria of efficacy which illustrated a lack of methodological standards for studies in this indication. The improvement rate under placebo, if measured by Clinical Global Assessment (CGI) appeared, however, not to exceed 25%, whereas BPRS score reduction as efficacy criterion mostly provided higher response rates (up to 40%). Of interest however, is the finding that the response rate to conventional neuroleptics at the end of 4-6 weeks of treatment in some studies hardly exceeded 40%. The most sensitive measure of placebo effect seemed to be the drop-out rate due to inefficacy (up to 100%) and it is suggested to consider this measure and the survival analysis approach in designing future studies. The review demonstrated many unresolved methodological problems in testing antipsychotic drugs in acute schizophrenia and, particularly, the need of scientific evidence of validity and sensitivity of measures of antipsychotic efficacy. The findings reported up to now do not offer cues for rational estimates of the effect size differences between placebo and active drugs after short-term treatment in acute schizophrenia.

We report on a patient with schizoaffective disorder who was on combination therapy of lithium, carbamazepine, and the neuroleptic trifluperidol. He experienced a lobar pneumonia and developed an acute and persistent cerebellar deterioration which was most likely due to lithium toxicity, while the serum lithium level was within the therapeutic range. The combination of lithium, carbamazepine, and neuroleptics is common, and is generally considered to be safe. The reported case suggests that this regimen might increase the risk of intoxication with potentially disabling side-effects.