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Antipsychotic drugs remain the mainstay of schizophrenia treatment; however, their effectiveness has been questioned, and it is not possible to predict the response to a specific antipsychotic drug in an individual patient. Thus, it is important to compare the effectiveness of the various antipsychotics and search for possible response predictors.To investigate the effectiveness of antipsychotic drugs, we examined response trajectories and predictors for belonging to different trajectory groups.The Bergen-Stavanger-Innsbruck-Trondheim (BeSt InTro) trial compared the effectiveness of three atypical antipsychotics-amisulpride, aripiprazole, and olanzapine-in a prospective, semirandomized, rater-blind, head-to-head design. Adult participants with a schizophrenia spectrum disorder diagnosis, according to international classification of diseases, Tenth Revision (ICD-10) F20-29, were included. Participants were followed for a period of 12 mo, with assessments at baseline; after one, three and six weeks; and after three, six, nine and 12 mo. A latent class mixed model was fitted to our data. The three-trajectory model based on the Positive and Negative Syndrome Scale (PANSS) total score reduction was found to have adequate fit, and the study drugs, as well as various demographic and clinical parameters, were tested as predictors for belonging to the different trajectory groups.Overall, 144 participants were included, and 41% completed the 12-mo study period. The largest trajectory group, consisting of 74% of participants, showed a PANSS total score reduction of 59% from baseline to 12 mo (Good response group). A trajectory group comprising 13% of participants had their PANSS total score reduced by 82.5% at 12 mo (Strong response group), while the last response trajectory group comprising 13% of the participants had a PANSS total score reduction of 13.6% (Slight response group). The largest part of the total reduction for the Good and Strong response groups occurred at six weeks of treatment, amounting to 45% and 48% reductions from baseline, respectively. The use of amisulpride predicted belonging to the Strong response group, while unemployment, depression, and negative psychotic symptoms at baseline increased the chance of belonging to the Slight response group, indicating a poor response to antipsychotic drug treatment.Most of the participants (87%) had a good outcome after one year. Amisulpride users, more often than aripiprazole and olanzapine users, belonged to the response trajectory group with a strong response.

Background: Schizophrenia is a severe psychiatric disorder with periods of remission and relapse. As discontinuation of antipsychotic medication is the most important reason for relapse, long-term maintenance treatment is key. Whether intramuscular long-acting (depot) antipsychotics are more efficacious than oral medication in preventing medication discontinuation is still unresolved. We aimed to compare time to all-cause discontinuation in patients randomly allocated to long-acting injectable (LAI) versus oral medication. Methods: EULAST was a pragmatic, randomised, open-label trial conducted at 50 general hospitals and psychiatric specialty clinics in 15 European countries and Israel. Patients aged 18 years and older, with DSM-IV schizophrenia (as confirmed by the Mini International Neuropsychiatric Interview 5 plus) and having experienced their first psychotic episode from 6 months to 7 years before screening, were randomly allocated (1:1:1:1) using block randomisation to LAI paliperidone, LAI aripiprazole, or the respective oral formulations of these antipsychotics. Randomisation was stratified by country and duration of illness (6 months up to 3 years vs 4 to 7 years). Patients were followed up for up to 19 months. The primary endpoint was discontinuation, regardless of the reason, during 19 months of treatment. We used survival analysis to assess the time until all-cause discontinuation in the intention-to-treat (ITT) group, and per protocol analyses were also done. This trial is registered with ClinicalTrials.gov, NCT02146547, and is complete. Findings: Between Feb 24, 2015, and Dec 15, 2018, 533 individuals were recruited and assessed for eligibility. The ITT population included 511 participants, with 171 (33%) women and 340 (67%) men, and a mean age of 30·5 (SD 9·6) years. 410 (80%) of 511 participants were White, 35 (7%) were Black, 20 (4%) were Asian, and 46 (9%) were other ethnicity. In the combined oral antipsychotics treatment group of 247 patients, 72 (29%) patients completed the study and 175 (71%) met all-cause discontinuation criteria. In the combined LAI treatment arm of 264 patients, 95 (36%) completed the study and 169 (64%) met the all-cause discontinuation criteria. Cox regression analyses showed that treatment discontinuation for any cause did not differ between the two combined treatment groups (hazard ration [HR] 1·16, 95% CI 0·94–1·43, p=0·18). No significant difference was found in the time to all-cause discontinuation between the combined oral and combined LAI treatment groups (log rank test χ 2=1·87 [df 1]; p=0·17). During the study, 121 psychiatric hospitalisations occurred in 103 patients, and one patient from each of the LAI groups died; the death of the patient assigned to paliperidone was assessed to be unrelated to the medication, but the cause of other patient's death was not shared with the study team. 86 (25%) of 350 participants with available data met akathisia criteria and 70 (20%) met parkinsonism criteria at some point during the study. Interpretation: We found no substantial advantage for LAI antipsychotic treatment over oral treatment regarding time to discontinuation in patients with early-phase schizophrenia, indicating that there is no reason to prescribe LAIs instead of oral antipsychotics if the goal is to prevent discontinuation of antipsychotic medication in daily clinical practice. Funding: Lundbeck and Otsuka.

Background Schizophrenia is a serious illness and treatment with antipsychotic drugs remains one of the most effective types of treatment. The course of schizophrenia, however, is highly heterogeneous and currently it is not possible to predict which patient will respond adequately to which antipsychotic drug. The aim of our study was to define trajectories regarding response to antipsychotic drug treatment in patients with schizophrenia spectrum disorders. A second aim was to evaluate demographic factors and antipsychotic drugs as predictors for the different trajectories. Methods Best Intro is a randomized, rater-blind, head-to-head comparison of amisulpride, aripiprazole and olanzapine. Adult patients with a diagnosis in the schizophrenia spectrum (ICD-10 diagnoses F20-29) were included. Participants had symptoms of ongoing psychosis as determined by a score of four or more on at least one of the following PANSS (Positive and Negative Syndrome Scale) items: P1 (delusions), P3 (hallucinations), P5 (grandiosity), P6 (suspiciousness/persecution) or G9 (unusual thought content). Patients were followed over a period of 52 weeks and the assessment points were at baseline, after one week, three weeks, six weeks, three months, six months, nine months, and 12 months. Totally 359 patients were assessed for eligibility, and 144 of them were enrolled and randomized to one of the study drugs. We used the R statistical program to define trajectories of antipsychotic response. Results We identified three different trajectories regarding the reduction of PANSS total score, with Bayesian information criterion (BIC) = 6157 (BIC for two groups=6164 and for four groups=6171). A large group of patients (N=106, 74%) showed a trajectory of good improvement in PANSS total score over the first 26 weeks of follow-up and maintained it after one year with a total of 35% reduction in PANSS total score (Good response group). A second group of patients (N=19, 13%) followed a trajectory of quick response (already at one week) and a large reduction of PANSS total score (Strong response group). After one year, the reduction of PANSS total score was 58%. There was a difference in the starting point for PANSS total score in these two groups with a higher value at baseline in the Strong response group, but the ending point was quite similar. A third group of patients (N= 19, 13%) followed a trajectory of poor improvement and a 9% reduction in PANSS total score over the studied period (Slight response group). The demographic variables age, sex, civil status and living alone, or drug naivety did not predict participants grouping in the various trajectories. Furthermore, we examined the predictive value of different antipsychotic drug treatment for the different trajectories with the “Intention to treat” method. There was a statistically significant difference in favor of amisulpride treatment for belonging to the Strong response group, while olanzapine strongly predicted the belonging to the Slight response group. There was no significant difference among the antipsychotic drugs regarding the Good response group. Discussion Most patients (74%) with a schizophrenia spectrum diagnosis showed a good response during the one year follow-up and another 13% showed a remarkable strong improvement. That means that a total of 87% of patients had a satisfactory course of illness during the first year. Use of amisulpride predicts a better course compared to aripiprazole and olanzapine. This finding can be useful for clinicians when selecting antipsychotic drugs for their patients.

Background Remission in schizophrenia is difficult to achieve. Antipsychotic drugs are critical in the treatment of schizophrenia. International guidelines for the pharmacological treatment of schizophrenia recommend a 3-step algorithm with clozapine being the third-line antipsychotic agent. This study investigated the 1-year outcome and the application of the guidelines for the pharmacological treatment of nonremitted first-episode schizophrenia (FES) patients during the first year of follow-up. Methods A sample of 78 FES patients from the Norwegian TIPS (Early Treatment and Intervention in Psychosis) 2 study was assessed at the end of the first year of follow-up. The symptom remission criteria were those defined by the Remission in Schizophrenia Working Group. The adherence to the pharmacological guidelines was assessed by reading the medical files and by a digital search of the words “clozapine,” “klozapin,” and “Leponex” in the hospital electronic data system. Results The majority (n = 53, 67.9%) of the patients included were nonremitted at the 1-year follow-up. The majority of the nonremitted patients received either none (7.5%), one (56.6%), or 2 types (15.1%) of antipsychotic drugs during the first year of follow-up. Only 2 (3.8%) received treatment with clozapine, and 3 (5.7%) in total were offered it. Conclusions For our FES sample, there was a low 1-year remission rate and a poor adherence to the pharmacological guidelines. Higher adherence to treatment guidelines with a more intensified antipsychotic treatment, which in some cases will include clozapine, will enhance the quality of treatment and may enhance the rates of remission for schizophrenia. publishedVersion

Background The aim of this study is to examine the one-year outcome in a cohort of patients with a first-episode core schizophrenia diagnosis (schizophrenia, schizophreniform psychosis, schizoaffective disorder) and the use of clozapine in the non-remitted patients at one-year control. Methods The population studied is the patients who were included with a first-episode psychosis in the TIPS project in the period 01.01.2002-31.12.2010 and had a core schizophrenia diagnosis. We divided the patients into two groups according to their remission status at one-year follow up and compared their main characteristics. We then performed a digital search in the hospitaĹs journal of the non-remitted group for the words “clozapine” and “Leponex”. Results Out of the 78 patients with first-episode core schizophrenia diagnosis included in the TIPS project during the examined period, 53 were continuously psychotic at one-year follow up. The one-year remission rate for our sample was therefore 32%. All of the non-remitted patients during the first year could be eligible for clozapine, but clozapine was considered to only 3 of them (5.7 %) and only two of them were offered clozapine. The mean number of periods with antipsychotic treatment in this group was four (4). Discussion The findings in our study show firstly a surprisingly low one-year remission rate for first-episode schizophrenia (32 %). This is much lower than what corresponding studies of the last years show. Our results also prove the underutilization of clozapine in non-remitted patients with a first-episode core schizophrenia diagnosis. Therefore, the clinicians did not follow the recommended guidelines for the treatment of schizophrenia. The possible reasons for this low use of clozapine will be discussed, but it was not possible to verify them as there was not found any relevant information in the patients’ files.