This study investigated characteristic large-scale brain changes in schizophrenia. Numerous imaging studies have demonstrated brain changes in schizophrenia, particularly aberrant intrinsic ...functional connectivity (iFC) of ongoing brain activity, measured by resting-state functional magnetic resonance imaging, and aberrant gray matter volume (GMV) of distributed brain regions, measured by structural magnetic resonance imaging. It is unclear, however, which iFC changes are specific to schizophrenia compared with those of other disorders and whether such specific iFC changes converge with GMV changes. To address this question of specific substantial dysconnectivity in schizophrenia, we performed a transdiagnostic multimodal meta-analysis of resting-state functional and structural magnetic resonance imaging studies in schizophrenia and other psychiatric disorders.
Multiple databases were searched up to June 2017 for whole-brain seed-based iFC studies and voxel-based morphometry studies in schizophrenia, major depressive disorder, bipolar disorder, addiction, and anxiety. Coordinate-based meta-analyses were performed to detect 1) schizophrenia-specific hyperconnectivity or hypoconnectivity of intrinsic brain networks (compared with hyperconnectivity or hypoconnectivity of each other disorder both separately and combined across comparisons) and 2) the overlap between dysconnectivity and GMV changes (via multimodal conjunction analysis).
For iFC meta-analysis, 173 publications comprising 4962 patients and 4575 control subjects were included, and for GMV meta-analysis, 127 publications comprising 6311 patients and 6745 control subjects were included. Disorder-specific iFC dysconnectivity in schizophrenia (consistent across comparisons with other disorders) was found for limbic, frontoparietal executive, default mode, and salience networks. Disorder-specific dysconnectivity and GMV reductions converged in insula, lateral postcentral cortex, striatum, and thalamus.
Results demonstrated specific substantial dysconnectivity in schizophrenia in insula, lateral postcentral cortex, striatum, and thalamus. Data suggest that these regions are characteristic targets of schizophrenia.
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.
Depression is one of the leading causes of the global burden of disease, and it has particularly negative consequences for elderly patients. Antidepressants are the most frequently used treatment. We ...present the first single-group meta-analysis examining: 1) the response rates of elderly patients to antidepressants, and 2) the determinants of antidepressants response in this population.
We searched multiple databases for randomized controlled trials on antidepressants in the elderly with major depressive disorder above 65 years (last search: December 2017). Response was defined as 50% improvement on validated rating scales. We extracted response rates from studies and imputed the missing ones with a validated method. Data were pooled in a single-group meta-analysis. Additionally, several potential moderators of response to antidepressants were examined by subgroup and meta-regression analyses.
We included 44 studies with a total of 6373 participants receiving antidepressants. On average, 50.7% of the patients reached a reduction of at least 50% on the Hamilton Depression Scale (HAMD). Subgroup and meta-regression analyses revealed a better response to treatment for patients in antidepressant-controlled trials compared to placebo-controlled trials. Mean age, study duration, percentage of woman, severity of illness at baseline, dose of antidepressants in fluoxetine equivalents, year of publication, setting (in- or out-patients), antidepressant groups (SSRI, TCA, SSNRI, α2-antagonist, SNRI, MAO-inhibitor), ITT (intention-to-treat) analysis vs completer analysis, sponsorship and overall risk of bias were not significant moderators of response.
Our findings suggest an improvement in symptoms can be found in about 50% of the elderly with major depressive disorder treated with antidepressants.
Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological ...interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta‐analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add‐on to antipsychotics. On average, patients were moderately ill at baseline. The network meta‐analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=−0.29; 95% CI: –0.55 to −0.03), treatment as usual (SMD=−0.30; 95% CI: –0.45 to −0.14) and supportive therapy (SMD=−0.47; 95% CI: –0.91 to −0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers’ allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.
Background It is not known whether regional brain N -acetyl aspartate (NAA) changes in the progression from prodrome to chronic schizophrenia. We used effect size meta-analysis to determine which ...brain regions show the most robust reductions in NAA first episode and chronic schizophrenia as measured by proton magnetic resonance spectroscopy and to determine whether these changes are present in individuals at high risk of developing schizophrenia. Methods We identified 131 articles, of which 97 met inclusion criteria. Data were separated by stage of illness (at risk, first episode schizophrenia, chronic schizophrenia) and by brain region. For each region, mean and SD of the NAA measure was extracted. Results Significant reductions in NAA levels were found in frontal lobe, temporal lobe, and thalamus in both patient groups (effect size > .3; p < .01). In individuals at high risk of schizophrenia (of whom approximately 20% would be expected to undergo transition to psychosis), significant NAA reductions were present in thalamus (effect size = .78; p < .05), with reductions at trend level only in temporal lobe (effect size = .32; p < .1), and no reductions in frontal lobe (effect size = .05; p = .5). Conclusions These data suggest that schizophrenia is associated with loss of neuronal integrity in frontal and temporal cortices and in the thalamus and suggest that these changes in the frontal and temporal lobe might occur in the transition between the at-risk phase and the first episode.
Little is known regarding optimal antipsychotic doses in the acute phase of schizophrenia. The aim of the present study was to employ the concept of minimum effective dose (MED) in examining efficacy ...and tolerability within this population. MED was identified for each antipsychotic through a previous systematic review. We then identified double-blind placebo-controlled randomized trials that involved fixed-dose antipsychotic monotherapy in acute schizophrenia and compared the identified MED vs higher doses of the same oral antipsychotic. Studies were selected from a recent meta-analysis examining dose-response relationship of second-generation antipsychotics and haloperidol. We extracted the data on study discontinuation, psychopathology, extrapyramidal symptoms, and treatment-emergent adverse events. For each antipsychotic, we conducted a meta-analysis to compare outcomes between MED and 2-fold MED, and MED and 3-fold MED. A total of 26 studies involving 5618 patients were included in the meta-analysis. In terms of study discontinuation, significant differences were found in study discontinuation due to lack of efficacy between MED and higher doses, in favor of 2-fold and 3-fold MEDs. Regarding psychopathology, both 2-fold and 3-fold MEDs were superior to MED for total and positive symptom scores. As for side effects, 2-fold MED proved inferior to MED for parkinsonism scores and diarrhea, whereas 3-fold MED was inferior for akathisia, somnolence, and vomiting. Findings suggest that clinicians can dose an antipsychotic at 2-fold or 3-fold MED for patients with acute schizophrenia but should closely monitor side effects.
Whether there are differences in efficacy among second-generation antipsychotics in the treatment of schizophrenia is a matter of heated debate. The authors conducted a systematic review and ...meta-analysis of blinded studies comparing second-generation antipsychotics head-to-head.
Searches of the Cochrane Schizophrenia Group's register (May 2007) and MEDLINE (September 2007) were conducted for randomized, blinded studies comparing two or more of nine second-generation antipsychotics in the treatment of schizophrenia. All data were extracted by at least three reviewers independently. The primary outcome measure was change in total score on the Positive and Negative Syndrome Scale; secondary outcome measures were positive and negative symptom subscores and rate of dropout due to inefficacy. The results were combined in a meta-analysis. Various sensitivity analyses and metaregressions were used to examine bias.
The analysis included 78 studies with 167 relevant arms and 13,558 participants. Olanzapine proved superior to aripiprazole, quetiapine, risperidone, and ziprasidone. Risperidone was more efficacious than quetiapine and ziprasidone. Clozapine proved superior to zotepine and, in doses >400 mg/day, to risperidone. These differences were due to improvement in positive symptoms rather than negative symptoms. The results were rather robust with regard to the effects of industry sponsorship, study quality, dosages, and trial duration.
The findings suggest that some second-generation antipsychotics may be somewhat more efficacious than others, but the limitations of meta-analysis must be considered. In tailoring drug treatment to the individual patient, small efficacy superiorities must be weighed against large differences in side effects and cost.
Differences in efficacy between antipsychotics and placebo in schizophrenia trials have decreased over the past decades. Previous studies have tried to identify potential explanatory factors focusing ...on response to placebo; however, it is still not clear which factors, if any, specifically moderate drug-response, as they may be different from those moderating placebo-response. Therefore, in this meta-regression analysis we explore whether there is an interaction between drug-response and placebo-response in terms of effect size. We systematically searched multiple electronic databases, ClinicalTrials.gov, and the US Food and Drug Administration website for randomized, placebo-controlled trials investigating the efficacy of antipsychotics in patients with acute schizophrenia (last update: October 2016). The main outcome was the change on the Brief Psychiatric Rating Scale or the Positive and Negative Syndrome Scale score from baseline to endpoint after at least 3 weeks of treatment. Multiple patient-, design-, and drug-related potential predictors of response were analyzed by meta-regressions, as predefined in the study protocol. Overall, 167 trials with 28,102 participants were included. Publication year, the number of participants and sites, mean dose, minimum severity threshold as an inclusion criterion, chronicity, industry sponsorship, type of rating scale, diagnostic criteria, and number of medications had a different impact on drug and placebo response. By contrast, baseline severity, duration of wash-out, study duration, and study region affected drug and placebo response in a similar way without a net effect on effect sizes. No other factors had a significant effect on either drug-response or placebo-response. In conclusion, as individual moderators may have different impact on placebo-response and drug-response, it is important to consider also the specific factors influencing drug-response in order to fully understand the difference between antipsychotics and placebo. These results shed further light on the phenomenon of decreasing effect size of antipsychotics for schizophrenia over time and should help design future randomized controlled trials in the field (Prospero registration number CRD42013003342).
In many countries of the industrialised world second generation ("atypical") antipsychotics have become the first line drug treatment for people with schizophrenia. The question as to whether, and if ...so how much, the effects of the various second generation antipsychotics differ is a matter of debate. In this review we examined how the efficacy and tolerability of olanzapine differs from that of other second generation antipsychotics.
To evaluate the effects of olanzapine compared to other atypical antipsychotics for people with schizophrenia and schizophrenia-like psychosis.
1. Electronic searching We searched the Cochrane Schizophrenia Group Trials Register (April 2007) which is based on regular searches of BIOSIS, CENTRAL, CINAHL, EMBASE, MEDLINE and PsycINFO.2. Reference searching We inspected the reference of all identified studies for more trials.3. Personal contact We contacted the first author of each included study for missing information.4. Drug companies We contacted the manufacturers of all atypical antipsychotics included for additional data.
We included all randomised trials that used at least single-blind (rater-blind) design, comparing oral olanzapine with oral forms of amisulpride, aripiprazole, clozapine, quetiapine, risperidone, sertindole, ziprasidone or zotepine in people with schizophrenia or schizophrenia-like psychosis.
We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based on a random effects model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a random effects model.
The review currently includes 50 studies and 9476 participants which provided data for six comparisons (olanzapine compared to amisulpride, aripiprazole, clozapine, quetiapine, risperidone or ziprasidone). The overall attrition from the included studies was considerable (49.2%) leaving the interpretation of results problematic.Olanzapine improved the general mental state (PANSS total score) more than aripiprazole (2 RCTs, n=794, WMD -4.96 CI -8.06 to -1.85), quetiapine (10 RCTs, n=1449, WMD -3.66 CI -5.39 to -1.93), risperidone (15 RCTs, n=2390, WMD -1.94 CI -3.31 to -0.58) and ziprasidone (4 RCTs, n=1291, WMD -8.32 CI -10.99 to -5.64), but not more than amisulpride or clozapine. This somewhat better efficacy was confirmed by fewer participants in the olanzapine groups leaving the studies early due to inefficacy of treatment compared to quetiapine (8 RCTs, n=1563, RR 0.56 CI 0.44 to 0.70, NNT 11 CI 6 to 50), risperidone (14 RCTs, n=2744, RR 0.78 CI 0.62 to 0.98, NNT 50 CI 17 to 100) and ziprasidone (5 RCTs, n=1937, RR 0.64 CI 0.51 to 0.79, NNT 17, CI 11 to 33).Fewer participants in the olanzapine group than in the quetiapine (2 RCTs, n=876, RR 0.56 CI 0.41 to 0.77, NNT 11 CI 7 to 25) and ziprasidone (2 RCTs, n=766, RR 0.65 CI 0.45 to 0.93, NNT 17 CI 9 to 100) treatment groups, but not in the clozapine group (1 RCT, n=980, RR 1.28 CI 1.02 to 1.61, NNH not estimable), had to be re-hospitalised in the trials.Except for clozapine, all comparators induced less weight gain than olanzapine (olanzapine compared to amisulpride: 3 RCTs, n=671, WMD 2.11kg CI 1.29kg to 2.94kg; aripiprazole: 1 RCT, n=90, WMD 5.60kg CI 2.15kg to 9.05kg; quetiapine: 7 RCTs, n=1173, WMD 2.68kg CI 1.10kg to 4.26kg; risperidone: 13 RCTs, n=2116, WMD 2.61kg CI 1.48kg to 3.74kg; ziprasidone: 5 RCTs, n=1659, WMD 3.82kg CI 2.96kg to 4.69kg). Associated problems such as glucose and cholesterol increase were usually also more frequent in the olanzapine group.Other differences in adverse effects were less well documented. Nevertheless, olanzapine may be associated with slightly more extrapyramidal side effects than quetiapine (use of antiparkinson medication (6 RCTs, n=1090, RR 2.05 CI 1.26 to 3.32, NNH 25 CI 14 to 100), but less than risperidone (use of antiparkinson medication 13 RCTs, n=2599, RR 0.78 CI 0.65 to 0.95, NNH 17 CI 9 to 100) and ziprasidone (use of antiparkinson medication 4 RCTs, n=1732, RR 0.70 CI 0.50 to 0.97, NNH not estimable). It may also increase prolactin somewhat more than aripiprazole, clozapine and quetiapine, but clearly less so than risperidone (6 RCTs, n=1291, WMD -22.84 CI -27.98 to -17.69).
Olanzapine may be a somewhat more efficacious drug than some other second generation antipsychotic drugs. This small superiority in efficacy needs to be weighed against a larger weight gain and associated metabolic problems than most other second generation antipsychotic drugs, except clozapine. These conclusions are tentative due to the large number of people leaving the studies early which possibly limits the validity of the findings. Further large, well-designed trials are necessary to establish the relative effects of different second generation antipsychotic drugs.
Antipsychotic polypharmacy in schizophrenia is much debated, since it is common and costly with unclear evidence for its efficacy and safety. We conducted a systematic literature search and a random ...effects meta‐analysis of randomized trials comparing augmentation with a second antipsychotic vs. continued antipsychotic monotherapy in schizophrenia. Co‐primary outcomes were total symptom reduction and study‐defined response. Antipsychotic augmentation was superior to monotherapy regarding total symptom reduction (16 studies, N=694, standardized mean difference, SMD=–0.53, 95% CI: −0.87 to −0.19, p=0.002). However, superiority was only apparent in open‐label and low‐quality trials (both p<0.001), but not in double‐blind and high‐quality ones (p=0.120 and 0.226, respectively). Study‐defined response was similar between antipsychotic augmentation and monotherapy (14 studies, N=938, risk ratio = 1.19, 95% CI: 0.99 to 1.42, p=0.061), being clearly non‐significant in double‐blind and high‐quality studies (both p=0.990). Findings were replicated in clozapine and non‐clozapine augmentation studies. No differences emerged regarding all‐cause/specific‐cause discontinuation, global clinical impression, as well as positive, general and depressive symptoms. Negative symptoms improved more with augmentation treatment (18 studies, N=931, SMD=–0.38, 95% CI: −0.63 to −0.13, p<0.003), but only in studies augmenting with aripiprazole (8 studies, N=532, SMD=–0.41, 95% CI: −0.79 to −0.03, p=0.036). Few adverse effect differences emerged: D2 antagonist augmentation was associated with less insomnia (p=0.028), but more prolactin elevation (p=0.015), while aripiprazole augmentation was associated with reduced prolactin levels (p<0.001) and body weight (p=0.030). These data suggest that the common practice of antipsychotic augmentation in schizophrenia lacks double‐blind/high‐quality evidence for efficacy, except for negative symptom reduction with aripiprazole augmentation.
PDF
