How long clinicians should wait before considering an antipsychotic ineffective and changing treatment in schizophrenia is an unresolved clinical question. Guidelines differ substantially in this ...regard. The authors conducted a diagnostic test meta-analysis using mostly individual patient data to assess whether lack of improvement at week 2 predicts later nonresponse.
The search included EMBASE, MEDLINE, BIOSIS, PsycINFO, Cochrane Library, CINAHL, and reference lists of relevant articles, supplemented by requests to authors of all relevant studies. The main outcome was prediction of nonresponse, defined as <50% reduction in total score on either the Positive and Negative Syndrome Scale (PANSS) or Brief Psychiatric Rating Scale (BPRS) (corresponding to at least much improved) from baseline to endpoint (4-12 weeks), by <20% PANSS or BPRS improvement (corresponding to less than minimally improved) at week 2. Secondary outcomes were absent cross-sectional symptomatic remission and <20% PANSS or BPRS reduction at endpoint. Potential moderator variables were examined by meta-regression.
In 34 studies (N=9,460) a <20% PANSS or BPRS reduction at week 2 predicted nonresponse at endpoint with a specificity of 86% and a positive predictive value (PPV) of 90%. Using data for observed cases (specificity=86%, PPV=85%) or lack of remission (specificity=77%, PPV=88%) yielded similar results. Conversely, using the definition of <20% reduction at endpoint yielded worse results (specificity=70%, PPV=55%). The test specificity was significantly moderated by a trial duration of <6 weeks, higher baseline illness severity, and shorter illness duration.
Patients not even minimally improved by week 2 of antipsychotic treatment are unlikely to respond later and may benefit from a treatment change.
Different effectiveness profiles among antipsychotics may be a key point to optimize treatment in patients suffering a first episode of psychosis to impact on long-term outcome. The aim of this study ...is to compare the clinical effectiveness of olanzapine, risperidone, haloperidol, aripiprazole, ziprasidone, and quetiapine in the treatment of first episode of psychosis at 3-year follow-up.
From February 2001 to January 2011, 2 phases of a prospective, randomized, open-label study were undertaken. A total of 376 first-episode drug-naïve patients were randomly assigned to olanzapine (n = 55), risperidone (n = 63), haloperidol (n = 56), aripiprazole (n = 78), ziprasidone (n = 62), or quetiapine (n = 62) and followed up for 3 years. The primary effectiveness measure was all cause of treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted in the analysis for clinical efficacy.
The overall dropout rate at 3 years reached 20.75%. Treatment discontinuation rates were significantly different among treatment groups (olanzapine = 69.09, risperidone = 71.43, aripiprazole = 73.08%, ziprasidone = 79.03%, haloperidol = 89.28%, and quetiapine = 95.53%) (χ2 = 79.86; P = .000). Statistically significant differences in terms of lack of efficacy, adherence, and tolerability were observed among treatment groups along the 3-year follow-up, determining significant differences in time to all-cause discontinuation (log-rank = 92.240; P = .000). Significant differences between treatments were found in the categories of sleepiness/sedation, increased sleep duration, akinesia, weight gain, ejaculatory dysfunction, extrapyramidal-symptoms, and amenorrhea.
Olanzapine, risperidone, and aripiprazole presented advantages for the first-line treatment of first episode of psychosis in terms of effectiveness. Identifying different discontinuation patterns may contribute to optimize treatment selection after first episode of psychosis.ClinicalTrials.gov Identifier: NCT02526030 https://clinicaltrials.gov/show/NCT02526030.
Aim
To explore if the entire duration of active psychosis (DAP) is related to neurocognitive performance at baseline and at 3‐year follow‐up in patients with first episode psychosis (FEP).
Methods
...DAP was estimated for 481 FEP patients. A neuropsychological battery was administered to measure neurocognitive specific domains, and a global indicator of neurocognitive impairment (global deficits score, GDS) was calculated. According to the DAP quartiles, four subgroups were formed, and these were compared. In addition, a logistic regression analysis was carried out to predict neurocognitive impairment at 3‐year follow‐up.
Results
FEP patients with the longest DAP (more than 18.36 months) presented a more severe global neurocognitive impairment evidenced in their GDS, both at baseline (F = 5.53; p˂ .01) and at 3‐year follow‐up (F = 4.16; p˂ .01). Moreover, a subgroup of participants with DAP between 7.40 and 18.36 months showed a specific attentional decline over the 3‐year follow‐up (F = 3.089; p˂ .05).The logistic regression model showed that sex (Wald = 7.29, p < .010), premorbid adjustment (Wald = 7.24, p < .010), attention (Wald = 12.10, p < .001), verbal memory (Wald = 16.29, p < .001) and visual memory (Wald = 9.41, p < .010) were significant predictors of neurocognitive impairment 3 years after the FEP. The variables composing the DAP were not significant predictors in this model.
Conclusions
DAP seems to be related to global neurocognitive impairment in FEP patients. These findings contribute in several ways to our understanding of the effects of active psychosis on the brain, and provide the basis for future research.
Selecting the first antipsychotic agent for the acute phase of a first episode of psychosis (FEP) is a critical task that may impact on the long-term outcome. Despite that, there is a lack of ...research comparing head-to-head different second-generation antipsychotics at this stage. The aim of this study was to compare the effectiveness of aripiprazole and risperidone in the treatment of the acute phase after a FEP. For that purpose, from February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode, drug-naïve patients were randomly assigned to aripiprazole (n = 136), or risperidone (n = 130) and followed-up for 6-weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy. The overall dropout rate at 6-week reached 19.5%. Effectiveness measures were similar between both treatment groups as treatment discontinuation rates (χ2 = 1.863; p = 0.172) and mean time until all-cause discontinuation (log rank = 1.421; p = 0.233) showed no statistically significant differences. In terms of clinical efficacy, risperidone proved a statistically significant better performance according to BPRS mean change between baseline and 6-week total score (t = 3.187; p = 0.002). Patients under risperidone treatment were significantly more likely to suffer sex-related adverse events. In conclusion, no differences regarding effectiveness were found between aripiprazole and risperidone for the acute-phase treatment of FEP. Despite the importance of efficacy during this phase of treatment, selecting the most effective treatment for the long-term outcome, requires addressing safety and patient´s preferences.
Antipsychotic choice for the acute phase of a first episode of psychosis (FEP) is of the utmost importance since it may influence long-term outcome. However, head-to-head comparisons between ...second-generation antipsychotics remain scarce. The aim of this study was to compare the effectiveness in the short term of aripiprazole and risperidone after FEP outbreak.
From February 2011 to October 2018, a prospective, randomized, open-label study was undertaken. Two hundred-sixty-six first-episode drug-naïve patients were randomly assigned to aripiprazole (n = 136) or risperidone (n = 130) and followed-up for 12 weeks. The primary effectiveness measure was all-cause treatment discontinuation. In addition, an analysis based on intention-to-treat principle was conducted to assess clinical efficacy.
The overall dropout rate at 12 weeks was small (6.39%). Effectiveness measures were similar between treatment arms as treatment discontinuation rates (χ 2 = 0,409; P = .522), and mean time to all-cause discontinuation (log rank χ 2 = -1.009; P = .316) showed no statistically significant differences. Despite no statistically significant differences between groups regarding clinical efficacy, aripiprazole required higher chlorpromazine equivalent dosage (χ 2 = 2.160; P = .032) and extended mean time (W = 8183.5; P = .008) to reach clinical response. Sex-related adverse events and rigidity were more frequent in the risperidone group, whereas sialorrhea was on the aripiprazole group.
No differences regarding effectiveness were found between aripiprazole and risperidone for the short-phase treatment of FEP. Despite the importance of efficacy during this phase, differences in side effect profiles and patient's preferences are essential factors that may lead clinical decisions for these patients.
NCT02532491. Effectiveness of Second-Generation Antipsychotics in First Episode Psychosis Patients: 1-year Follow-up (PAFIP3_1Y).
Higher levels of pro-inflammatory cytokines are consistently found in the serum of first episode psychosis (FEP) patients and this immune dysfunction could contribute to neural harm. On the other ...hand, lengthy periods of active psychosis during the early phases of the illness appear to be associated to worst functional outcome. We aim to explore the possible relationship between lengthy periods of active psychosis during early phases of the illness and the levels of pro-inflammatory cytokines. This is a prospective clinical study consisting of a 3-year clinical follow-up. We assessed the relation between the duration of active psychosis in patients with FEP and the serum levels of 21 cytokines at baseline and 3 months after initiating antipsychotic medication. We used the Human High Sensitivity T Cell Magnetic Bead Panel protocol from the Milliplex® Map Kit. The sample consisted of 59 patients with a FEP. The percentage of variation of the serum levels of the chemokine MIP-3α during the first 3 months of antipsychotic treatment and the score in negative psychotic symptoms 3 months after the initiation of antipsychotic medication, acted as predictors of the initial time to remission of positive psychotic symptoms. Our findings open the possibility to investigating the potential use of the variation in chemokine MIP-3α serum levels during the first months of antipsychotic treatment to identify a subtype of FEP patients that could benefit from an add-on treatment with immune modulators.
NCT02897167.
September 13, 2016.
“Study of the Activation of Proinflammatory Pathways of Toll-like Receptors in Schizophrenia Patients (PAFIP_TLR)”.
https://clinicaltrials.gov/ct2/show/NCT02897167.
•The variation in chemokine MIP-3α serum levels predicted the time to remission in patients with a first episode of psychosis.•The score in negative psychotic symptoms also predicted the time to remission in patients with a first episode of psychosis.•MIP-3α levels could identify a subtype of psychotic patients that could benefit from an add-on immune modulating treatment.
Abstract New models of interaction between genetic and environmental factors have been proposed to explain the pathogenesis of schizophrenia. The Val158Met polymorphism of the COMT ...(Catechol-O-Methyltransferase) gene, involved in dopamine regulation and related to negative symptoms, has been previously thought to interact with cannabis use in the modulation of risk of psychosis. The aim of the study was to explore the existence of an interaction between COMT genotype and cannabis use in early stages of psychosis and its effects on the age of onset in a representative group of first-episode psychosis patients. Age of onset, DUP (Duration of Untreated Psychosis) and cannabis use (regular user versus sporadic or non-user) were assessed in 169 Caucasian patients with a first-episode schizophrenia spectrum disorder. COMT polymorphism was typed using PCR of the relevant region followed by digestion with NlaIII and electrophoresis. A multivariate ANCOVA was performed with DUP and age of onset as dependent variables, cannabis and the COMT genotype as fixed factors, and gender as a covariate. The MANCOVA was significant for age of onset and DUP. Cannabis users had a significant earlier age of onset. Age of onset was later in the Met homozygote group (non-significant). The cannabis–COMT interaction showed a significant effect on both DUP and age of onset. Post hoc analyses showed that differences between genotypes were only present in the non-users' group. Based on these results, the use of cannabis could exert a modulator effect on the genotype, suppressing the delay effect for the age of onset in the case of the Met allele patients.
Longer duration of active psychosis (presence of positive psychotic symptoms) has been associated to worsening of functional and symptomatic outcome in patients with a first-episode of psychosis. ...There could be a “critical period” of increased brain vulnerability in the early phases of the illness when the effect of active psychosis would be exceptionally pernicious.
We aim to explore the impact of lengthy periods of active psychosis during early phases of illness on long-term functional outcome.
This is a prospective clinical study. We assessed the effect of the duration active psychosis in patients with a first-episode of nonaffective psychosis on long-term social functioning and functional recovery. The study consisted of a 3-year clinical follow-up and a functional evaluation performed after a 10-year period.
The sample consisted of 169 patients with a first-episode of non-affective psychosis. The duration of active psychosis after treatment (DAT) during the 3-year clinical follow-up acted as predictor of social functioning at the 10-year functional evaluation (Wald: 10.705; p = .001), but not of functional recovery. The duration of untreated psychosis (DUP) did not act as a predictor of any of the two long-term measures of functional outcome.
Active psychosis in early phases of the illness seems to be correlated to worst long-term functionality. In this study the duration of active psychosis after treatment (DAT) was a better predictor of long-term outcome than the duration of untreated psychosis (DUP). Reducing DAT should be considered an important objective for early intervention programs.
Abstract Background The severity and pattern of cognitive deficits in epidemiological cohorts of patients with first-episode schizophrenia spectrum disorders still remains unclear. We aimed to ...characterize the basic cognitive functioning of a representative sample of patients with a first-episode schizophrenia spectrum disorders. Method One hundred thirty-one patients experiencing first-episode psychosis and 28 healthy volunteers were administered a comprehensive neuropsychological evaluation. To reduce the number of cognitive test measures into meaningful cognitive dimensions, before analyzing differences between patient and healthy volunteer samples, exploratory factor analysis was carried out on data collected in patients group. The method of extraction was Principal Components Analysis with oblique rotation. Results An eight-factor model including verbal learning/memory, verbal comprehensive abilities, speed of processing/executive functioning, motor dexterity, motor speed, sustained attention, and impulsivity emerged. A significant below average performance in all cognitive dimensions, except impulsivity, was found. Patient’s performance in speed of processing/executive functioning, motor dexterity and sustained attention dimensions exceeded one standard deviation below healthy comparison subjects. Conclusions At early stages of the illness, patients display a marked impairment in several functionally relevant cognitive domains.
Abstract Background Preventing relapse during the first years of illness has a critical impact on lifelong outcomes in schizophrenia. A better understanding and improvement in factors which influence ...relapse should diminish the risk of relapse and consequently improve the outcome of the illness. Objective To identify factors associated with relapse after 3 years of a first episode in a sample of non-affective psychosis patients who are representative of clinical practice in an epidemiological catchment. Method We analyzed socio-demographic and clinical data from a cohort of patients who were treated in a specialized early intervention service and who were at risk of relapse during a 3-year follow-up. Univariate analyses, logistic regression and survival analyses were performed. The analyzed variables included gender, age at onset, duration of untreated psychosis, clinical severity at baseline, insight at baseline, premorbid functioning, substance use, family history of psychosis and adherence to medication. Results Of the 140 patients considered to be at risk for relapse, 91 (65%) individuals relapsed at least once over the three-year period. The relapse rates at 1 year and 2 years were 20.7% and 40.7%, respectively. Adherence to medication was the only significant predictor of relapse after a three-year follow-up hazard ratio (HR) 4.8, 95% confidence interval (CI) 2.9–7.7; p < 0.001. Comparison of the mean time of relapse between adherent and non-adherent patients also revealed statistically significant differences (933 and 568 days, respectively). 50% of patients will relapse despite being categorized as treatment adherents. Conclusion Non-adherence to medication is the biggest predictive factor of relapse after a first episode of psychosis.
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