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The purpose of this study was to evaluate the long-term safety and tolerability of paliperidone extended-release (ER) in adolescents with schizophrenia.
This was a 2 year open-label, multicenter study in adolescents (12-17 years of age, inclusive) with schizophrenia. Eligible patients were initially treated with 6 mg/day paliperidone ER, and the do...
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Aims: Assessment of oral paliperidone ER therapy. Methods: A subgroup analysis of patients with schizophrenia switched from unsuccessful oral risperidone therapy in a 6-month, open-label, multicenter study investigating flexibly dosed paliperidone ER. Results: 694 patients were analyzed (59.2% male; mean age: 40.0 years). Mean change in PANSS total...
Introduction
This single-group, open-label, prospective, noncomparative, multicenter, Phase IV study explored the efficacy and tolerability of paliperidone palmitate (PP) in hospitalized patients with acute exacerbation of schizophrenia.
Methods
Asian patients of either sex, between 18 and 65 years of age, diagnosed with schizophrenia (Diagnostic...
Citations
... Study settings at the time of patient enrolment were not reported in 36% (18/50) of the included studies. Most studies reporting this information recruited participants through outpatient settings, which accounted for 58% (7/12) of the clinical trials [17,18,22,[39][40][41][42] and 65% (13/20) of the observational studies [27,29,32,34,35,[43][44][45][46][47][48][49][50]. Information on the study period of enrolment was available from 54% (27/50) of the studies included in this review. ...
... Among the clinical trials and observational studies, samples comprised mostly adults (42/50; 84%). One clinical trial [41] and two observational studies included children [28,49], and one clinical trial [51] and four observational studies enrolled both children and adults [26,34,52,53]. Most studies recruited both females and males; however, females were slightly more prevalent among patients with drug-induced HPL. ...
... The number of patients with drug-induced HPL ranged from 2 (among 35 assessed patients) [15] to 220 (among 400 assessed patients) [41] among the clinical trials, and from 5 [28] to 442 [52] among the observational studies. The clinical presentations and long-term complications were reported in patients with a variety of diagnoses, but mostly (47/50; 94%) in patients with schizophrenia spectrum and other psychotic disorders. ...
Screening for drug-induced hyperprolactinaemia, a condition characterised by higher-than-normal levels of serum prolactin induced by drug treatments, requires a comprehensive understanding of the clinical presentations and long-term complications of the condition. Using two databases, Embase and MEDLINE, we summarised the available evidence on the clinical presentations and long-term complications of drug-induced hyperprolactinaemia. Clinical and observational studies reporting on drug treatments known or suspected to induce hyperprolactinaemia were included. Database searches were limited to the English language; no date or geographic restrictions were applied. Fifty studies were identified for inclusion, comprising a variety of study designs and patient populations. Most data were reported in patients treated with antipsychotics, but symptoms were also described among patients receiving other drugs, such as prokinetic drugs and antidepressants. Notably, the diagnosis of drug-induced hyperprolactinaemia varied across studies since a standard definition of elevated prolactin levels was not consistently applied. Frequent clinical presentations of hyperprolactinaemia were menstrual cycle bleeding, breast or lactation disorders, and sexual dysfunctions, described in 80% (40/50), 74% (37/50), and 42% (21/50) of the included studies, respectively. In the few studies reporting such symptoms, the prevalence of vaginal dryness impacted up to 53% of females, and infertility in both sexes ranged from 15 to 31%. Clinicians should be aware of these symptoms related to drug-induced hyperprolactinaemia when treating patients with drugs that can alter prolactin levels. Future research should explore the long-term complications of drug-induced hyperprolactinaemia and apply accepted thresholds of elevated prolactin levels (i.e., 20 ng/mL for males and 25 ng/mL for females) to diagnose hyperprolactinaemia as a drug-induced adverse event.Trial Registration PROSPERO International Prospective Register Of Systematic Reviews (CRD42021245259).
... Three of the four studies with mortality rates of 0 were randomized controlled trials conducted in the presence of a physician, with the follow-up periods p 2 years. [32][33][34] In two studies 33,34 the sample consisted of adolescents or recently hospitalized individuals. Thus, age of onset, disease severity, better compliance, and an insufficient period of time to observe deaths might explain this situation. ...
Objective:
To gather current evidence on the impact of antipsychotics on long-term mortality in patients with schizophrenia.
Methods:
We systematically searched for articles in Embase, PubMed, and PsycINFO reporting the long-term mortality (follow-up > 1 year) of patients with schizophrenia who were using any antipsychotics. We then conducted multiple meta-analyses to determine differences in long-term mortality between different types of antipsychotics.
Results:
We identified 45 articles that provided unadjusted long-term mortality rates, including 46,171 deaths during 2,394,911 person-years. The pooled mortality rate was 9.9 (95%CI = 7.4-12.7) per 1,000 person-years. The unadjusted crude mortality rate of antipsychotic drug users was lower than that of non-users (risk ratio [RR] = 0.546, 95%CI = 0.480-0.621), first-generation antipsychotics caused higher all-cause mortality than second-generation antipsychotics (RR = 1.485, 95%CI = 1.361-1.620), and polypharmacy had better effects than monotherapy on long-term mortality (RR = 0.796, 95%CI = 0.689-0.921). As for the causes of death, heart disease and cardiovascular disease ranked highest among cause-specific mortality (5.6 per 1,000 person-years).
Conclusion:
Since antipsychotics had a beneficial effect on long-term mortality in schizophrenia, greater precaution should be taken with patients who do not take them. However, since disease severity, comorbidities, and other confounding factors cannot be fully controlled, further research and verification are needed.
... From these, we selected 31 studies, of which 15 involved short-term treatment, 58-72 10 evaluated longer-term, continuation, or maintenance treatment for schizophrenia, 2,14,50,73-79 and 6 were single-arm trials. [80][81][82][83][84][85] Included reports appeared between 1996 and 2020 (Table 1). ...
Background:
Psychotic disorders produce important morbidity and disability in children and adolescents. There have been few relevant treatment trials, encouraging assessment of research aimed at testing efficacy and safety of antipsychotics for juveniles. We aimed to compare the short- and long-term efficacy and safety of antipsychotics to treat psychotic disorders among children and adolescents.
Methods:
Four major bibliographic databases (PubMed, MEDLINE, PsycINFO, and EMBASE) were searched for clinical trials of antipsychotics in children or adolescents, from database inception to May 2021. We searched for clinical trials comparing antipsychotics with control conditions for juvenile psychosis based on blinded review by 2 independent investigators (C.S.Y. and M.L.). We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-analyses and applied the Cochrane risk-of-bias tool to appraise study quality. One reviewer (A.B.) performed data abstraction which was confirmed by 2 independent, blinded reviewers (C.S.Y. and M.L.). Primary outcomes were scores rating psychosis symptoms and dichotomized retention in treatment protocols versus dropouts because of adverse events. Effect sizes were pooled using frequentist random-effects network meta-analysis modeling to generate summary rate ratios (RRs) and Cohen d standardized mean differences.
Results:
Systematic searching generated 1330 unique records. Of these, short-term (n = 15, for 6 [3-12] weeks) and long-term (n = 10, for 12 [6-60] months) treatment trials involved 2208 (39.2% females; median age, 15.3 years), and 1366 subjects (35.0% females; median age, 15.6 years), respectively. Short-term reduction of psychosis scores ranked clozapine (d = -1.35; 95% confidence interval [CI], -1.97 to -0.73]), molindone (-1.22; 95% CI, -1.68 to -0.75), olanzapine (-1.12; 95% CI, -1.44 to -0.81), and risperidone (-0.93; 95% CI, -1.22 to -0.63) as the most effective agents. In longer-term treatment, only lurasidone was effective. Clozapine (RR, 12.8) and haloperidol (RR, 5.15) led to more all-cause and adverse event-related dropouts. There were few trials/drug (1 each for aripiprazole, asenapine, lurasidone, molindone, paliperidone, and ziprasidone, short term; aripiprazole, clozapine, haloperidol, lurasidone, and molindone, long-term). Heterogeneity and inconsistency were high, especially in long-term trials, without evidence of publication bias.
Conclusions:
Some antipsychotics were effective and tolerated short term, but longer-term evidence was very limited. The overall paucity of trials and of adequate controls indicates that more well-designed randomized controlled trials are required for adequate assessment of antipsychotic drug treatment for juveniles.
Systematic review registration:
PROSPERO CRD42021232937.
... 19 Minimal data are available from long-term studies assessing the safety, tolerability, and effectiveness of antipsychotic agents for schizophrenia in adolescent populations. 20,21 The current study is one of the only large-scale antipsychotic treatment studies we are aware of that prospectively followed adolescent patients with schizophrenia for 2 years. Lurasidone is an atypical antipsychotic agent with high binding affinity for D 2 , 5-HT 2A , and 5-HT 7 receptors (antagonist); moderate affinity for 5-HT 1A receptors (partial agonist); and no appreciable affinity for H 1 and M 1 receptors. ...
... These rates compare favorably to rates in other prospective, long-term studies of atypical antipsychotics in adolescents with schizophrenia. 20,21,53,54 Consistent with the results of long-term studies in adults with schizophrenia, the present study found 2 years of treatment with lurasidone to have minimal effects on physiologic growth-adjusted weight, lipids, and glycemic indices. 25,27,31 This finding is in contrast to previously reported effects of selected atypical antipsychotics on weight and metabolic parameters. ...
Background
Minimal long-term benefit: Risk data are available regarding antipsychotic treatments for schizophrenia in pediatric populations. This study evaluated the long-term safety, tolerability, and effectiveness of lurasidone in adolescents with schizophrenia.
Methods
Patients aged from 13 to 17 who completed 6 weeks of double-blind (DB), placebo-controlled treatment with lurasidone were enrolled in a 2-year, open-label (OL), flexible dose (20-80 mg/day) lurasidone treatment study. Safety was assessed via spontaneous reporting, rating scales, body weight measurement, metabolic, and prolactin testing. Effectiveness measures included the Positive and Negative Syndrome Scale (PANSS) total score.
Results
About 271 patients completed 6 weeks of DB treatment and entered the 2-year OL extension study. Altogether, 42.4% discontinued prematurely, 10.7% due to adverse events. During OL treatment, the most common adverse events were headache (24.0%); anxiety (12.9%), schizophrenia, and nausea (12.5%); sedation/somnolence (12.2%); and nasopharyngitis (8.9%). Minimal changes were observed on metabolic parameters and prolactin. Mean change from DB baseline in weight at week 52 and week 104 was +3.3 kg and + 4.9 kg, respectively, compared to an expected weight gain of +3.4 kg and + 5.7 kg, respectively, based on the sex- and age-matched US Center for Disease Control normative data. Continued improvement was observed in PANSS total score, with mean change from OL baseline of −15.6 at week 52 and −18.4 at week 104.
Conclusion
In adolescents with schizophrenia, long-term lurasidone treatment was associated with minimal effects on body weight, lipids, glycemic indices, and prolactin. Continued improvement in symptoms of schizophrenia was observed over 2 years of lurasidone treatment.
... After removing duplicates, the titles and abstracts of 1101 citations were screened, 25 of which were retained for full-text review (see Online Appendix 1). Results of the full-text review yielded 12 trials that met eligibility criteria [25][26][27][28][29][30][31][32][33][34][35][36]. In addition, a clinical trial report from Study D1050301 was provided by Sunovion Pharmaceuticals Inc (subsequently described by Goldman et al. [37]). ...
... The only comparison informed by both direct and indirect evidence that demonstrated inconsistency on the Bucher tests was weight change between aripiprazole and placebo. Direct evidence from Findling et al. [28] indicated that aripiprazole led to greater weight gain relative to placebo; however, the indirect evidence (involving data from Singh et al. [32], Savitz et al. [33], and Findling et al. [28]) indicated less weight gain compared to placebo. This inconsistency suggested potential issues with the comparability of the studies comparing these treatments. ...
This network meta-analysis assessed the efficacy and tolerability of lurasidone versus other oral atypical antipsychotic monotherapies in adolescent schizophrenia. A systematic literature review identified 13 randomized controlled trials of antipsychotics in adolescents with schizophrenia-spectrum disorders. A Bayesian network meta-analysis compared lurasidone to aripiprazole, asenapine, clozapine, olanzapine, paliperidone extended-release (ER), quetiapine, risperidone, and ziprasidone. Outcomes included Positive and Negative Syndrome Scale (PANSS), Clinical Global Impressions-Severity (CGI-S), weight gain, all-cause discontinuation, extrapyramidal symptoms (EPS), and akathisia. Results were reported as median differences for continuous outcomes and odds ratios (ORs) for binary outcomes, along with 95% credible intervals (95% CrI). Lurasidone was significantly more efficacious than placebo on the PANSS (− 7.95, 95% CrI − 11.76 to − 4.16) and CGI-S (− 0.44, 95% CrI − 0.67 to − 0.22) scores. Lurasidone was associated with similar weight gain to placebo and statistically significantly less weight gain versus olanzapine (− 3.62 kg, 95% CrI − 4.84 kg to − 2.41 kg), quetiapine (− 2.13 kg, 95% CrI − 3.20 kg to − 1.08 kg), risperidone (− 1.16 kg, 95% CrI − 2.14 kg to − 0.17 kg), asenapine (− 0.98 kg, 95% CrI − 1.71 kg to − 0.24 kg), and paliperidone ER (− 0.85 kg, 95% CrI − 1.57 kg to − 0.14 kg). The odds of all-cause discontinuation were significantly lower for lurasidone than aripiprazole (OR = 0.28, 95% CrI 0.10–0.76) and paliperidone ER (OR = 0.25, 95% CrI 0.08–0.81) and comparable to other antipsychotics. Rates of EPS and akathisia were similar for lurasidone and other atypical antipsychotics. In this network meta-analysis of atypical antipsychotics in adolescent schizophrenia, lurasidone was associated with similar efficacy, less weight gain, and lower risk of all-cause discontinuation compared to other oral atypical antipsychotics.
... Paliperidone extended-release (pali ER) is approved in the United States (US), European Union (EU) and many other countries for treating schizophrenia in adults, and in the US, EU, China, and many other regions for treating schizophrenia in adolescents (12-17 years; EU: 15-17 years) (Invega, product information). Several studies have demonstrated short-term and long-term efficacy and safety of paliperidone in adolescents with schizophrenia (Savitz et al., 2015a;Savitz et al., 2015b;Singh et al., 2011). Although it is known that paliperidone may lead to additional cognitive and social functional improvements in adults and elderly patients (Singh et al., 2011;Suzuki et al., 2014), little information is available on the long-term effect of pali ER on cognitive function in adolescents with schizophrenia. ...
... Although it is known that paliperidone may lead to additional cognitive and social functional improvements in adults and elderly patients (Singh et al., 2011;Suzuki et al., 2014), little information is available on the long-term effect of pali ER on cognitive function in adolescents with schizophrenia. A long-term (2 year), openlabel (OL), flexible-dose pali ER safety study (NCT00488319) (Savitz et al., 2015a) demonstrated that the safety profile of pali ER in adolescents was consistent with the known profile of pali ER in adults (Emsley et al., 2008;Marder et al., 2007;Meltzer et al., 2008) and of risperidone in adolescents (Emsley et al., 2008;Findling et al., 2010;Haas et al., 2009;Harrington and English, 2010) as well as its long-term efficacy in treating the symptoms of adolescent schizophrenia. The current exploratory analysis from this OL pali ER study was designed to evaluate the change in cognitive functioning and whether there is a relationship between cognitive deficits and functioning, and to examine correlations between functioning and cognition among patients demonstrating improvement with 6-month pali ER treatment in adolescents with schizophrenia. ...
... The primary long-term safety study with details of study design, inclusion and exclusion criteria is described elsewhere (Savitz et al., 2015a). Briefly, adolescents (12-17 years old) with schizophrenia (diagnosed as per the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition [DSM-IV] criteria) were enrolled. ...
Objective
To assess cognitive functioning in adolescents (12–17 years old) with schizophrenia during open-label treatment with paliperidone extended-release (pali ER).
Methods
In this exploratory analysis, adolescents treated with pali ER (oral, flexibly dosed, 1.5–12 mg/day) underwent cognitive assessments at baseline and month 6 using a battery of cognitive tests validated in adolescents. Correlation analysis was used to explore the relationship between cognitive assessments and clinical symptoms (Positive and Negative Syndrome Scales [PANSS] and factors) and functionality (Children Global Assessment Scale [CGAS]) at baseline and at 6 months.
Results
A total of 324 of 393 patients had evaluable neurocognitive data. Changes in cognition function tests from baseline to endpoint were generally small to modest, with improvement noted for most cognitive domains (motor speed, attention/working memory, verbal learning and memory, social cognition, speed of processing, executive functioning). No improvement was noted for visual learning and memory. At baseline, there were modest negative correlations between disorganized thoughts and most cognitive domains; these correlations persisted at 6 months. Other significant negative correlations at 6 months were between speed of processing and PANSS total score, positive symptoms, negative symptoms and uncontrolled hostility (p < 0.05). At 6 months, higher CGAS scores (improved functioning) positively correlated with speed of processing and executive functioning, especially among pali ER responders.
Conclusions
In this large sample of adolescents with schizophrenia, frank cognitive deficits across multiple domains were observed. Treatment with pali ER over 6 months did not worsen neurocognitive functioning and was possibly associated with positive improvement in certain domains.
... It was concluded that both medications provided clinically meaningful symptomatic and functional improvement in this population. Savitz et al. (2015b) also investigated the medication's longterm safety in adolescents with schizophrenia in a 2-year open-label study. Patients 12-17 years of age were flexibly dosed between 1.5 and 12 mg/day and, after completion of the study by 220 participants (184 completed the 2 years, 36 completed a 6-month study before trial extension), the results showed an improvement in schizophrenia symptoms (as measured by PANSS total score) within the first 3 months. ...
Objectives:
The use of atypical antipsychotic medications in pediatric patients has become more prevalent in recent years. The purpose of this review is to provide a clinically relevant update of recent selected key publications regarding the use of atypical antipsychotics in this population.
Methods:
Studies reviewed included randomized, double-blind, placebo-controlled medication trials conducted within the past 5 years. A PubMed search was conducted for each of the 11 second-generation antipsychotic medications currently approved by the Food and Drug Administration for use in the United States: clozapine, risperidone, olanzapine, quetiapine, aripiprazole, ziprasidone, paliperidone, asenapine, iloperidone, lurasidone, and cariprazine. Trials published in English with subjects 18 years of age and younger were included in this review. Additional studies, chosen for their significance to clinical practice, were also included at the discretion of the authors.
Results:
This review demonstrates that more empiric data are available regarding both the acute efficacy and, to a lesser extent, the longer-term efficacy and tolerability for several of the considered antipsychotic medications. The clinical conditions for which these medications have been studied include schizophrenia, bipolar disorder, Tourette's disorder, and autism spectrum disorder. They have also been used as an adjunctive treatment for disruptive behavior disorders with aggression, which have not responded to treatment with stimulants.
Conclusion:
Evidence regarding the efficacy and tolerability of antipsychotic medications for mental health disorders in children and adolescents has expanded exponentially in recent years. However, more information is needed so that evidence-based comparisons between medications can be made. In the future, data enabling the selection of medications based upon individual patient characteristics could potentially lead to greater efficacy and efficiency in treating what are frequently debilitating medical conditions. Maladaptive aggression in children, often treated with antipsychotics, is one such area in which there is a dearth of actual information available to the clinician. It is to be hoped that additional, longer-term studies of these medications will further inform evidence-based practice in clinical settings.
... However, weight gain and extrapyramidal effects were more common and severe than usually reported in adults [68,69]. In a sample of 400 adolescents with schizophrenia, there was no case of TD during a 2-year period of paliperidone treatment in doses ranging from 1.5 to 12 mg daily [70]. Although quetiapine open-label studies did not report an increased risk of TD in children [71], safety concerns regarding its use in youth have also been raised [72]. ...
Introduction: Tardive dyskinesia (TD) is a chronic and disabling movement disorder with a complex pathophysiological basis. A significant percentage of patients does not receive correct diagnosis, resulting in delayed or inaccurate treatment and poor outcome. Therefore, there is a critical need for prompt recognition, implementation of efficacious treatment regimens and long-term follow up of patients with TD.
Areas covered: The current paper provides an overview of emerging data concerning proposed pathophysiology theories, epidemiology, risk factors, and therapeutic strategies for TD.
Expert Commentary: Despite considerable research efforts, TD remains a challenge in the treatment of psychosis as the available strategies remain sub-optimal. The best scenario will always be the prophylaxis or prevention of TD, which entails limiting the use of antipsychotics.
... A limited number of prospective studies on the use of paliperidone in adolescents have shown that paliperidone is generally well-tolerated (13,14). However, these case reports indicate that despite the clinical differences, it is necessary to be alerted against allergic reactions in adolescents prescribed with oral palipelidone. ...
