High-potency First-generation Antipsychotics Research Articles

Examination of Dosing of Antipsychotic Drugs for Relapse Prevention in Patients With Stable Schizophrenia

The doses of antipsychotic drugs needed for relapse prevention in schizophrenia is a debated issue. To examine dose-response findings in a meta-analysis of randomized clinical trials. Studies were identified through the Cochrane Schizophrenia Group's Study-Based Register of Trials (March 9, 2020), PubMed (January 1, 2021), and previous reviews. First authors and/or pharmaceutical companies were contacted for additional information. Two reviewers independently selected randomized clinical trials that compared fixed doses of a second-generation antipsychotic, haloperidol, or fluphenazine for relapse prevention in patients with stable schizophrenia. Using the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline, all parameters in duplicate were extracted and frequentist dose-response random-effects meta-analyses were conducted. Study-defined relapse (primary outcome), rehospitalization, Positive and Negative Syndrome Scale or Brief Psychiatric Rating Scale total score reduction from baseline, all-cause discontinuation, and dropouts due to adverse events. Evidence from 72 dose arms from 26 studies with 4776 participants was analyzed. The efficacy-related dose-response curves had a hyperbolic shape meaning that the probability to relapse decreased rapidly with doses of up to 5-mg/d risperidone equivalent (relative relapse risk, 0.43; 95% CI, 0.31-0.57; standardized mean difference for Positive and Negative Syndrome Scale total score reduction, -0.55; 95% CI, -0.68 to -0.41), but flattened thereafter. In contrast, dropouts due to adverse events continued to increase beyond this dose (relative risk at 5 mg/d, 1.38; 95% CI, 0.87-2.55; relative risk at 15 mg/d, 2.68; 95% CI, 1.49-4.62). In a subgroup analysis of patients in remission, a plateau was reached earlier, at approximately 2.5-mg/d risperidone equivalent. The findings of this meta-analysis suggest that doses higher than approximately 5-mg/d risperidone equivalent may provide limited additional benefit for relapse prevention but more adverse events. For patients in remission or who are receiving high-potency first-generation antipsychotics, doses as low as 2.5-mg/d risperidone equivalent may be sufficient. However, caution is needed at this low dose end when further decreases of dose may be accompanied by a disproportionally higher relapse risk. Moreover, the observations are averages, and factors such as slow or rapid metabolism, age, illness stage, comorbidities, and drug-drug interactions suggest that individual patients will often need higher or lower doses.

A case of aripiprazole-Induced neuroleptic malignant syndrome

Neuroleptic malignant syndrome (NMS) is a serious medical emergency with significant fatality rates if not recognized and treated early. High-potency first-generation antipsychotics are reported to have more incidence of NMS. Aripiprazole-induced NMS is very rare, and here we report the case of a 38-year-old woman with bipolar illness disorder. The disorder started after escalating the dose and resolved after stopping the medicine.

Neuroleptic malignant syndrome: evaluation of drug safety data from the AMSP program during 1993-2015.

Neuroleptic malignant syndrome (NMS) is a rare, but severe adverse drug reaction of drugs with anti-dopaminergic properties. The main symptoms are fever and rigor. In addition, other symptoms such as creatine kinase elevation, alteration of consciousness and various neurological symptoms may occur. A total of 52 NMS cases have been documented in the drug safety program 'Arzneimittelsicherheit in der Psychiatrie' from 1993 to 2015. We calculated incidences and analyzed imputed substances and additional risk factors to study the impact of changing therapy regimes. The overall incidence was 0.16‰. High-potency first-generation antipsychotics (FGAs) had the highest incidences, e.g. flupentixol with 0.61‰. Second-generation antipsychotics (SGAs) had lower incidences. Low-potency FGAs had very low incidences, comparable to SGAs, but in contrast to SGAs, had not been imputed alone in any case of NMS. Preexisting organic pathologies of the central nervous system, lithium treatment, infection/exsiccosis and the withdrawal of medication with anticholinergic properties or alcohol were found to be additional risk factors. With the increasing use of SGAs, one should always be aware of the risk of NMS. Better suited diagnostic criteria for 'atypical NMS' would lead to a better understanding and, therefore, to improved treatment possibilities.

Risk of gastrointestinal Hypomotility in schizophrenia and schizoaffective disorder treated with antipsychotics: A retrospective cohort study

ObjectiveThe risk of gastrointestinal hypomotility (GIHM) with the use of antipsychotic medications in patients with schizophrenia remains inadequately recognized. The aim of this study was to explore the incidence of GIHM and its risks in patients with schizophrenia treated with antipsychotics. MethodsWe conducted a retrospective cohort study using the National Health Insurance Research Database. We identified adult (≥ 20years of age) patients with a first-time diagnosis of schizophrenia or schizoaffective disorder in the Registry for Catastrophic Illness Patients during the period from 2001 to 2011. Each subject in the cohort was followed until their corresponding diagnosis of GIHM was made, until the time of death, or to December 31, 2012. The incidence rates of each outcome were calculated. Cox proportional hazards regression with time-dependent covariates for antipsychotics use was employed to evaluate the associations between different types of antipsychotics and the risk of GIHM. ResultsOur study found that the incidence densities of constipation, ileus, and ischemic bowel disease were 42.5, 4.4, and 0.1 per 1000 person-years. In terms of the risk of hypomotility with the use of antipsychotics, clozapine and quetiapine were significant in developing constipation, with a hazard ratio of 2.15 and 1.34, respectively. High-potency first-generation antipsychotics and clozapine were also significant in the occurrence of ileus, with a hazard ratio of 1.30 and 1.95, respectively. Similar associations were found in an anticholinergic agent subgroup analysis. ConclusionPatients receiving antipsychotics such as high-potency first-generation antipsychotics, clozapine, or quetiapine should undergo proper evaluation and intervention to minimize the disease burden and life-threatening outcomes of treatment.

Patterns of psychotropic medication use in inpatient and outpatient psychiatric settings in Saudi Arabia.

ObjectiveTo study the pattern of psychotropic medication use and compare this pattern between inpatient and outpatient psychiatric settings in Saudi Arabia.MethodThis cross-sectional observational study was conducted between July 2012 and June 2014 on patients seeking psychiatric advice at major hospitals in five main regions of Saudi Arabia. Male (n=651) and female (n=594) patients who signed the informed consent form and were currently or had been previously using psychotropic medications, irrespective of the patient’s type of psychiatric diagnosis and duration of the disease, were included. A total of 1,246 patients were found to be suitable in the inclusion criteria of whom 464 were inpatients while 782 were outpatients.ResultsSeveral studied demographic factors have shown that compared with outpatients, inpatients were more likely to be male (P=0.004), unmarried (P<0.001), have less number of children (1–3; P=0.002), unemployed (P=0.001), have a lower family income (<3,000 SR; P<0.001), live in rural communities (P<0.001), have a lower body mass index (P=0.001), and are smokers (P<0.001); however, there were no differences with regard to age or educational levels. The current frequency of use of psychotropic medications in overall patients was antipsychotics (76.6%), antidepressants (41.4%), mood stabilizers (27.9%), and antianxiety (6.2%). However, compared to outpatients, the current use of medications for inpatients was more frequent (93.8% vs 89.9%, P=0.019) with inpatients more likely to be treated with multiple medications (2.1 vs 1.8 medications). A similar trend was observed in the case of antipsychotics, high potency first-generation antipsychotics, second-generation antipsychotics, mood stabilizers, and antianxiety medicines where inpatients were more frequently treated with these medications for all psychiatric diagnoses when compared with outpatients. On the contrary, in the case of antidepressant treatment, an opposite trend was observed with more number of treated outpatients in comparison to inpatients. Among elderly patients, 75.9% received antipsychotics, mainly second-generation formulations (67.2%), whereas only 41% received antidepressants and 13.8% received mood stabilizers.ConclusionBased upon the present study data, it is concluded that among all the psychotropic medications, antipsychotics were heavily used and the frequency was found to be significantly high in the case of inpatients compared with outpatients. Such a practice may lead to multiple negative consequences among the Saudi psychiatric patient population. Further, extensive use of sodium valproate in the case of bipolar disorder, and also among females either in childbearing age or during pregnancy is also the cause of concern and warrants logical use. Overall, this study may help in assessing the burden of psychiatric illness within specific patient demographics and might be effectively used to strategically plan health resources allocation, generate new treatment hypothesis, or be used as a source of evidence that could further integrate other observational studies.

Haloperidol versus first-generation antipsychotics for the treatment of schizophrenia and other psychotic disorders.

Haloperidol is worldwide one of the most frequently used antipsychotic drugs with a very high market share. Previous narrative, unsystematic reviews found no differences in terms of efficacy between the various first-generation ("conventional", "typical") antipsychotic agents. This established the unproven psychopharmacological assumption of a comparable efficacy between the first-generation antipsychotic compounds codified in textbooks and treatment guidelines. Because this assumption contrasts with the clinical impression, a high-quality systematic review appeared highly necessary. To compare the efficacy, acceptability, and tolerability of haloperidol with other first-generation antipsychotics in schizophrenia and schizophrenia-like psychosis. In October 2011 and July 2012, we searched the Cochrane Schizophrenia Group's Trials Register, which is based on regular searches of CINAHL, BIOSIS, AMED, EMBASE, PubMed, MEDLINE, PsycINFO, and registries of clinical trials. To identify further relevant publications, we screened the references of all included studies and contacted the manufacturers of haloperidol for further relevant trials and missing information on identified studies. Furthermore, we contacted the corresponding authors of all included trials for missing data. We included all randomised controlled trials (RCTs) that compared oral haloperidol with another oral first-generation antipsychotic drug (with the exception of the low-potency antipsychotics chlorpromazine, chlorprothixene, levopromazine, mesoridazine, perazine, prochlorpromazine, and thioridazine) in schizophrenia and schizophrenia-like psychosis. Clinically important response to treatment was defined as the primary outcome. Secondary outcomes were global state, mental state, behaviour, overall acceptability (measured by the number of participants leaving the study early due to any reason), overall efficacy (attrition due to inefficacy of treatment), overall tolerability (attrition due to adverse events), and specific adverse effects. At least two review authors independently extracted data from the included trials. The methodological quality of the included studies was assessed using The Cochrane Collaboration`s 'Risk of bias' tool.We analysed dichotomous outcomes with risk ratios (RR) and continuous outcomes with mean differences (MD), both with the associated 95% confidence intervals (CI). All analyses were based on a random-effects model and we preferably used data on an intention-to-treat basis where possible. The systematic review currently includes 63 randomised trials with 3675 participants. Bromperidol (n = 9), loxapine (n = 7), and trifluoperazine (n = 6) were the most frequently administered antipsychotics comparator to haloperidol. The included studies were published between 1962 and 1993, were characterised by small sample sizes (mean: 58 participants, range from 18 to 206) and the predefined outcomes were often incompletely reported. All results for the main outcomes were based on very low or low quality data. In many trials the mechanism of randomisation, allocation, and blinding was frequently not reported. In short-term studies (up to 12 weeks), there was no clear evidence of a difference between haloperidol and the pooled group of the other first-generation antipsychotic agents in terms of the primary outcome "clinically important response to treatment" (40 RCTs, n = 2132, RR 0.93 CI 0.87 to 1.00). In the medium-term trials, haloperidol may be less effective than the other first-generation antipsychotic group but this evidence is based on only one trial (1 RCT, n = 80, RR 0.51 CI 0.37 to 0.69).Based on limited evidence, haloperidol alleviated more positive symptoms of schizophrenia than the other antipsychotic drugs. There were no statistically significant between-group differences in global state, other mental state outcomes, behaviour, leaving the study early due to any reason, due to inefficacy, as well as due to adverse effects. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The findings of the meta-analytic calculations support the statements of previous narrative, unsystematic reviews suggesting comparable efficacy of first-generation antipsychotics. In efficacy-related outcomes, there was no clear evidence of a difference between the prototypal drug haloperidol and other, mainly high-potency first-generation antipsychotics. Additionally, we demonstrated that haloperidol is characterised by a similar risk profile compared to the other first-generation antipsychotic compounds. The only statistically significant difference in specific side effects was that haloperidol produced less akathisia in the medium term. The results were limited by the low methodological quality in many of the included original studies. Data for the main results were low or very low quality. Therefore, future clinical trials with high methodological quality are required.

Temporomandibular joint dislocation due to atypical antipsychotic-induced acute dystonia: a case report.

Dystonia is a movement disorder that causes sustained muscle contractions, repetitive twisting movements, and abnormal postures of the trunk, neck, face, arms or legs [Fahn et al. 1987]. It may be focal, segmental (multifocal), or generalized and may also be primary or secondary based on their etiology. It may manifest as oculogyric crisis, deviation of eyes in all directions, protrusion of tongue, trismus, lock jaw, torticolis, laryngeal spasm, difficulty in speaking, facial grimacing, opisthotonus, lordosis or scoliosis and tortipelvic crisis. Drug-induced dystonia are secondary dystonias which occur commonly with drugs with antidopaminergic effects such as antipsychotics and metoclopramide [Ropper and Samuels, 2009; Fadare and Owolabi, 2009]. They reportedly arise from a drug-induced alteration of dopaminergic–cholinergic balance in the nigrostriatum (i.e. basal ganglia). Most drugs produce dystonic reactions by nigrostriatal dopamine D2 receptor blockade, which leads to an excess of striatal cholinergic output. High-potency D2 receptor antagonists are most likely to produce an acute dystonic reaction [Marsden and Jenner, 1980]. Agents that balance dopamine blockade with muscarinic M1 receptor blockade, such as atypical antipsychotics, are less likely to cause dystonic reactions [Marsden and Jenner, 1980; Volkow et al. 1998]. The incidence of acute dystonic reactions varies according to individual susceptibility, drug identity and dose of the drug. Increased age may carry less risk for the development of dystonia because of diminished numbers of D2 receptors. It occurs commonly to young males who are naive to antidopaminergic drugs [Volkow et al. 1998]. Oromandibular dystonia is one of the focal dystonias, which can be presented as jaw clenching, jaw opening or jaw deviation and leads to impaired speech and swallowing [Eken et al. 2009]. At times, oromandibular dystonia is so severe that it can cause temporomandibular joint (TMJ) dislocation. So far, few case reports have been published about TMJ dislocation due to antipsychotic medications [Ibrahim and Brooks, 1996]. Among antipsychotic-induced TMJ dislocation, case reports were mainly for high-potency first-generation antipsychotics such as haloperidol [Eken et al. 2009; Ibrahim and Brooks, 1996; Zakariaei et al. 2012]. It has been proposed that drugs such as risperidone and amisulpride which block specific receptors of serotonin (the S-HT2 receptors) and dopamine (the D2 receptors) are less likely to cause these effects [Owens, 1994]. Therefore, the present paper reports a case of oromandibular dystonia with TMJ dislocation with atypical antipsychotics such as risperidone and amisulpride.

Antipsychotic medication-induced dysphoria: its meaning, association with typical vs. atypical medications and impact on adherence.

Antipsychotic medication-induced dysphoria is a relatively under-recognized and understudied effect of antipsychotic medication. Although the term is encountered in clinical practice and in the literature, there is no consensus regarding its exact meaning. This article is a narrative review of the literature on antipsychotic medication and dysphoria based on a pubmed database search. We found that antipsychotic medication-induced dysphoria is a term used to describe a negative and unpleasant affective state which seems to be more often associated with high potency first-generation antipsychotics and could potentially lead to medication non-adherence. Though it is plausible to expect antipsychotic medication-induced dysphoria to be related to extrapyramidal symptoms, most especially akathisia, the nature of the association remains unspecified. Furthermore, there is some evidence that dopamine blockade maybe involved in the pathogenesis of antipsychotic medication-induced dysphoria. However, the limited methods of the currently available studies make it impossible to conclusively address the question of which class of antipsychotic (first- or second-generation) has a higher prevalence and severity of the syndrome.

Risk Factors for Ileus in Patients with Schizophrenia

Constipation is a known side effect of psychotropics that possess high affinity for muscarinic cholinergic receptors. In severe cases, constipation progresses to ileus and bowel ischemia, with multiple fatalities related to sepsis and perforation described in the literature, primarily among patients with schizophrenia. A historical prospective database study was performed using registry data from psychiatric and somatic hospitals, combined with the prescription database to examine associations between medications and ileus. Only cases with an ICD-10 diagnosis of schizophrenia (F20) and a concurrent diagnosis of ileus in the years 1996-2007 were included in the study. A total of 26,720 patients with schizophrenia were identified with 123 cases of ileus noted in the study period. Increasing age (OR: 1.03 CI: 1.01-1.04) and female sex (OR: 1.60 CI: 1.10-2.31) were associated with an increased risk of ileus. Treatment with clozapine (OR: 1.99 CI: 1.21-3.29), high-potency first-generation antipsychotics (OR: 1.81 CI: 1.01-3.23), tricyclic antidepressants (OR: 2.29 CI: 1.29-4.09), anticholinergics (OR: 1.48 CI: 1.00-2.19), and opioids (OR: 2.14 CI: 1.36-3.36) were associated with an increased risk of ileus. The onset of ileus occurred on average more than 3 years after the first prescription of the offending drug. Aripiprazole and amisulpride were not associated with ileus. Nine of the ileus cases (7.3%) had a fatal course. Treatment with clozapine (OR: 6.73 CI: 1.55-29.17) or anticholinergics (OR: 5.88 CI: 1.47-23.58) were associated with increased risk of fatal ileus. Patients receiving psychotropics associated with significant anticholinergic properties should undergo proper monitoring and interventions in order to minimize the burden of constipation and the risk of ileus.

Antipsychotics associated with pulmonary embolism in a Swedish medicolegal autopsy series

To determine the association between fatal pulmonary embolism and use of antipsychotic drugs in a Swedish medicolegal autopsy series. Persons aged 18-65 years and subjected to a medicolegal autopsy in 1992-2005 were selected. On the basis of external cause of death, determined by the forensic pathologist, unnatural deaths (including fatal intoxications) were excluded and participants in whom pulmonary embolism was the cause of death were identified. Use of antipsychotics was based on the results of the postmortem analyses and categorized as use of high-potency first-generation antipsychotics, low-potency first-generation antipsychotics, second-generation antipsychotics or no use of antipsychotics. Logistic regression analyses were performed. Use of antipsychotics was verified in 538 of the 14,439 included participants. Pulmonary embolism was recorded as the cause of death in 279 participants and 33 of these used antipsychotics. Use of low-potency first-generation antipsychotics and second-generation antipsychotics was significantly associated with fatal pulmonary embolism (adjusted odds ratio: 2.39; 95% confidence interval: 1.46-3.92 and 6.91; 95% confidence interval: 3.95-12.10, respectively). Out of 26 participants classified as high-potency first-generation antipsychotic drug users, none had pulmonary embolism as the cause of death. Pulmonary embolism was overrepresented among medicolegal autopsy cases identified as users of low-potency first-generation and second-generation antipsychotics.

Lessons to Take Home From CATIE

Lessons to Take Home From CATIE