Status Review Report 03 02 2011 Anthony Pike J 64886
Early on interventions to foreclose psychosis: systematic review and meta-analysis
Megan R Stafford
1National Collaborating Middle for Mental Wellness, Royal College of Psychiatrists, London, UK
Hannah Jackson
oneNational Collaborating Centre for Mental Wellness, Purple Higher of Psychiatrists, London, Britain
Evan Mayo-Wilson
iiEye for Outcomes Research and Effectiveness, Research Department of Clinical, Educational and Health Psychology, University College London, London, U.k.
Anthony P Morrison
3Schoolhouse of Psychological Sciences, University of Manchester, Manchester, UK
Tim Kendall
fourSheffield Wellness and Social Intendance NHS Foundation Trust, Sheffield S10 3TH, UK
Abstract
Objective To make up one's mind whether any psychological, pharmacological, or nutritional interventions can prevent or delay transition to psychotic disorders for people at high risk.
Blueprint Systematic review and meta-analysis.
Data sources Embase, Medline, PreMedline, PsycINFO, and CENTRAL were searched to Nov 2011 without brake to publication status.
Review methods Randomised trials comparison any psychological, pharmacological, nutritional, or combined intervention with usual services or another handling. Studies of participants with a formal diagnosis of schizophrenia or bipolar disorder were excluded. Studies were assessed for bias, and relevant limitations were considered in summarising the results.
Results eleven trials including 1246 participants and eight comparisons were included. Median sample size of included trials was 81 (range 51-288). Meta-analyses were performed for transition to psychosis, symptoms of psychosis, depression, and mania; quality of life; weight; and discontinuation of treatment. Testify of moderate quality showed an result for cognitive behavioural therapy on reducing transition to psychosis at 12 months (adventure ratio 0.54 (95% confidence interval 0.34 to 0.86); chance difference −0.07 (−0.14 to −0.01). Very low quality evidence for omega-3 fat acids and low to very low quality prove for integrated psychotherapy also indicated that these interventions were associated with reductions in transition to psychosis at 12 months.
Conclusions Although evidence of benefits for whatsoever specific intervention is not conclusive, these findings propose that it might exist possible to delay or forbid transition to psychosis. Farther research should be undertaken to establish conclusively the potential for benefit of psychological interventions in the treatment of people at high risk of psychosis.
Introduction
The incidence of likely psychosis in customs surveys in the Great britain appears to be stable, at about five per 1000 adults.[1] [2] Schizophrenia is the nigh common grade of psychosis and i of the leading causes of long term inability,[3] affecting about 25 1000000 people worldwide. Schizophrenia disrupts social and family relationships, resulting in severe educational and occupational damage, lost productivity, unemployment, physical affliction, and premature mortality.[iv] As a result, schizophrenia costs about £55 000 (€67 500; $88 000) per person per twelvemonth in the United kingdom.[5]
Schizophrenia is ordinarily preceded by a prodromal flow lasting i to 3 years.[vi] This period is characterised by a range of non-specific behavioural and psychological symptoms, functional deterioration, and past both attenuated positive symptoms and brief limited intermittent psychotic symptoms (BLIPS).[7] Amidst people at "ultra high risk" of psychosis, nigh 22% to twoscore% transition within 12 months.[8][9][ten] Interventions that filibuster or prevent transition to psychosis from this prodromal syndrome could be clinically and economically important.
Antipsychotic drugs and family therapy could reduce the likelihood of relapse for established and showtime episode schizophrenia, and cognitive behavioural therapy (CBT) might reduce symptoms and hospital admission for people with schizophrenia.[11] Combining these treatments in an integrated strategy might add together substantial clinical[12] and economic benefits[13] for people with psychosis and early schizophrenia. These interventions could prevent or delay the onset of psychosis and schizophrenia if delivered to people at high risk, and several trials have examined whether these interventions preclude transition from a loftier risk country to psychosis. A previous review of early interventions[14] found limited prove about interventions to forbid psychosis, but the searches were conducted in 2009, and several studies conducted since then have been sufficiently large to change the review's conclusions. An updated review is needed to determine whether any interventions tin can forestall or delay transition to psychotic disorders.
Methods
Eligibility criteria
We evaluated the issue of whatever intervention (pharmacological, psychological, nutritional, or combination) for participants with prodromal symptoms. Included participants were judged to be at risk of developing psychosis on the basis on a clinical assessment identifying prodromal features. Studies including participants with a formal diagnosis of schizophrenia or bipolar disorder (including first episode psychosis) were excluded. Randomised controlled trials for people at chance and for participants with schizotypal disorders were included.
Types of outcome measures
The primary upshot was transition to psychosis. Secondary outcomes were symptoms of psychosis (total, positive, and negative), low, and mania; quality of life; weight; and discontinuation. Analyses were conducted for outcomes measured inside half dozen months of randomisation, between six and 12 months of randomisation, and later on 12 months of randomisation.
Search strategy
We searched Embase, Medline, PreMedline, PsycINFO, and CENTRAL from the inception of the databases to November 2011. Searches in Embase, Medline, PreMedline and PsycINFO were combined with a highly sensitive filter for randomised controlled trials. The search was initially adult in Medline before existence translated for use in other databases. The box details the Medline search for groups at run a risk (web appendix i shows the total list of search terms used beyond databases). We also searched the reference lists of included studies, excluded studies, and previous reviews, and contacted study authors and experts.
Cess of bias
Studies were assessed independently by two authors (MRS, HJ) using the Cochrane Collaboration risk of bias tool.[xv] Disagreements were discussed with a tertiary author (EM-W) and resolved by consensus. Each report was rated for risk of bias attributable to sequence generation; allocation concealment; blinding of participants, assessors, and providers; selective outcome reporting; and incomplete data. Take a chance of bias for each domain was rated as high (seriously weakens confidence in the results), low (unlikely to seriously alter the results), or unclear.
Information management
Data extraction and adventure of bias assessments were completed using an Excel spreadsheet. Nosotros collected data for time points and measures, recruitment, inclusion and exclusion criteria, age, sex, setting, and location.
Statistical assay
For continuous outcomes, we calculated the standardised mean difference, Hedges g.[xvi] For dichotomous outcomes, an overall gamble ratio was calculated. All outcomes are reported with 95% conviction intervals. Overall furnishings were calculated using a random furnishings model. Continuous effects were weighted by the inverse of variance; dichotomous effects were weighted using the Mantel-Haenszel method.[17] [eighteen]
Missing information were noted for each result. When dropout was non reported, we contacted the authors. If both primary and secondary outcomes reported data for completers equally well equally controlled for dropouts (for case, data imputed using regression methods), we used the information controlling for dropout. Nosotros conducted sensitivity analyses for the chief outcome (transition to psychosis) when studies reported data for completers only.
Statistical heterogeneity was assessed by visual inspection of woods plots, by performing the χ2 test (assessing the P value), and past computing the I2 statistic,[19] [20] which describes the percentage of observed heterogeneity that would not be expected by risk. If the P value was less than 0.10 and Itwo exceeded 50%, we considered heterogeneity to be substantial. Meta-analyses were conducted using RevMan.[21] Conviction in the results was assessed using the Form method,[22] which is a structured assessment of the quality of evidence attention to the post-obit factors: risk of bias, inconsistency, indirectness, imprecision, and publication bias.
Results
Trial flow
Of 1913 potentially relevant citations, we retrieved 39 papers; of these, 18 were excluded equally they did not meet our eligibility criteria (spider web appendix 2). The nigh common reason for exclusion was that the written report was non a randomised controlled trial. Eleven randomised controlled trials reported in 21 published papers met all inclusion criteria (fig one ), and authors provided unpublished data for two of these.[23] [24]
Fig 1 PRISMA flowchart. *Number of records screened for eligibility for the guideline in which the current work was a part
Report characteristics
Eleven included trials assigned 1246 participants with a median sample size of 81 (range 51-288). The median of the mean ages was 21 years, and 710 (57%) randomised participants were male person. Eight studies[23][24][25][26][27][28][29][30] included participants coming together 1 or more of three operationally divers groups (attenuated psychotic symptoms, transient psychotic symptoms, trait and state risk factors). The first two groups were operationalised as scoring above a threshold on a screening instrument: the structured interview for prodromal symptoms,[ix] the positive and negative symptom scale (PANSS)[31], the brief psychiatric rating scale (BPRS),[32] or the comprehensive cess of at adventure mental states (CAARMS).[33] I study included adults who met ICD-x (international classification of diseases, 10th revision)[34] research criteria for schizotypal disorder,[35] two studies used the early on recognition inventory (ERIraos),[36] with one study identifying participants in the early initial prodromal state[37] and one study not reporting the eligibility threshold used.[38] Table 1 lists characteristics of the included studies.
Table ane
Characteristics of included studies
| Studies | Land | No | Screening instrument | Participant age (years, range) | Comparing | Duration (weeks) | Follow-upwards (weeks) |
|---|---|---|---|---|---|---|---|
| Addington 201125 | Canada | 51 | Structured interview for prodromal symptoms | xx.9 (NR) | CBT v supportive counselling | 26 | 52 and 78 |
| Amminger 2010fourteen, 26 | Republic of austria | 81 | PANSS | 16.four (NR) | Omega 3 fatty acids (1200 mg/day) v placebo | 12 | 52 |
| Bechdolf 201237, 39 | Federal republic of germany | 128 | ERIraos | 25.viii (NR) | Integrated therapies v supportive counselling | 52 | 104 |
| McGlashan 200327, 54-56 | U.s. | 60 | Structured interview for prodromal symptoms | 17.8 (12-36) | Olanzapine (8 mg/twenty-four hours) v placebo | 52 | 104 |
| McGorry 2002thirty, 57 | Australia | 59 | BPRS | 20 (14-28) | Risperidone (1.3 mg/day) and CBT v supportive counselling | 26 | 156-208 |
| Morrison 200423, 58, 59 | Not bad Britain | lx | PANSS | 22 (16-36) | CBT and supportive counselling five supportive counselling | 52 | 156 |
| Morrison 201128, 52 | Great U.k. | 288 | CAARMS | 20.7 (14-34) | CBT and supportive counselling v supportive counselling | 26 | 104 |
| Nordentoft 200635 | Denmark | 79 | ICD-10 | 24.9 (NR) | Integrated therapies five standard treatment | 104 | NA |
| Phillips 200924, 60 | Commonwealth of australia | 115 | CAARMS | 17.nine (NR) | Risperidone (2 mg/24-hour interval) and CBT v CBT and placebo five supportive counselling and placebo | 52 | 104 |
| Ruhrmann 200738 | Germany | 124 | Early Recognition Inventory (ERIraos) | 25.6 (NR) | Amisulpride (118.7 mg/day) and NBI five NBI | 12 | NA |
| Van der Gaag 201229, 61 | Netherlands | 201 | CAARMS | 22.7 (NR) | CBT v supportive counselling | 26 | 52 and 78 |
NR=non reported; NBI=needs based intervention.
The eleven included studies made 8 comparisons. Four trials compared CBT with supportive counselling and monitoring.[23] [25] [28] [29] Two trials compared risperidone and CBT with supportive counselling.[24] [30] Ane trial each compared risperidone and CBT with placebo and CBT,[24] olanzapine with placebo,[27] integrated therapies with supportive counselling,[37] integrated therapies with standard treatment,[35] omega-three fatty acids with placebo,[26] and amisulpride plus a needs based intervention with the needs based intervention lonely.[38]
Trials of CBT[23][24][25] [28][29][30] provided manualised, problem focused, fourth dimension limited treatments including normalisation, cognitive restructuring, and behavioural experiments. Supportive counselling and monitoring[23][24][25] [28] [30] [37] were designed to match interventions for non-specific effects of treatment, and included psychoeducation, referral, and crisis management. "Treatment equally usual" for participants currently seeking help for mental health issues occurred in mental health services[29] or at a customs mental health centre.[35] Integrated psychological therapies included CBT for individual patients, group skills training, cerebral remediation, and family treatments, with concomitant antipsychotic treatment[35] or without treatment.[39] In one study, the needs based intervention included usual clinical management and could include psychoeducation, crunch intervention, family counselling, and aid with education or work related difficulties.[38] Spider web appendix iii provides a detailed description of the psychological interventions used in the included trials.
Transition to psychosis was defined in several ways, including ICD-10[34] diagnosis of psychotic disorder[35]; diagnosis of schizophrenia spectrum disorders[25] using the Diagnostic and Statistical Transmission of Mental Disorders, fourth edition (DSM-IV)[40]; a measure developed by the authors[27]; PANSS[31] symptom severity[23] [26] and CAARMS[33] symptom severity[24] [28] [29]; and presence of positive psychotic symptoms.[30] I report assessed the transition from the early on initial prodromal state to either the evolution of attenuated or transient symptoms (that is, subthreshold psychosis) or a DSM-IV psychotic disorder.[37]
Gamble of bias
We rated risk of bias ratings for each trial (fig 2 ) using the Cochrane take chances of bias tool.[41] No trials were at loftier risk of bias for sequence generation (not truly random), however, the method of randomisation was unclear (non reported) in three trials.[27] [30] [38] Risk of bias owing to poor allocation darkening was unclear in 4 trials.[25] [27] [xxx] [38] Lack of blinding of assessors created a high risk of bias for some outcomes in 3 studies.[30] [35] [38] Eight studies were at loftier risk of bias because participants or staff were not blind,[23] [25] [28][29][30] [35] [37] [38] which was incommunicable for studies of psychological interventions.
There was a high risk of bias due to incomplete outcome data for all included trials, which reflected a high charge per unit of attrition in studies of this type of population rather than a methodological deficiency in the studies themselves.[vi] [23][24][25][26][27][28][29][thirty] [35] [37] [38]. In i report, some participants were not followed up for the terminal 12 months (that is, those entering in the final year of the study), and missing data could non exist calculated on basis of the number of participants randomised.[28] Simply four studies were clearly free of selective consequence reporting[23] [28] [29] [38]; three trials did non written report all outcomes,[26] [35] [37] and it was unclear whether four trials reported all outcomes.[24] [25] [27] [30]
This review included several modest studies of pharmacological and nutritional interventions. Because of minor numbers, nosotros were unable to assess publication bias formally—that is, using a trim and fill analysis[42]—merely previous reviews have shown that studies of such interventions for children take been systematically nether-reported in mental wellness, and that effects have been systematically overstated and harms systematically underestimated every bit a consequence.[43] Most of these interventions were developed before the introduction of mandatory trial registration,[44] rules with which manufacturers might fail to comply.[45] Because 1 or two modest unpublished studies would be sufficient to change our view of the relative benefits and harms of these interventions, we considered that in that location was a loftier risk of publication bias.
Quantitative data synthesis
We conducted meta-analyses for eight comparisons. I trial with three handling groups was included in 3 pairwise comparisons.[24] Nosotros analysed transition to psychosis (table 2 ); symptoms of psychosis and low; quality of life; dropout; and where possible, side effects (web appendix 4). Some evidence indicated that transition can be delayed (tabular array 2) in trials of CBT,[23][24][25] [28] [29] CBT and risperidone,[30] integrated psychotherapy,[35] [37] and omega-3 fat acids.[26] However, confidence in these estimates ranged from moderate to very low.
Tabular array two
Summary of effects for transition to psychosis
| Comparison | Time betoken (months of treatment) | No (%) of trials in analysis | No (%) of participants in analysis | Risk ratio (95% CI), random furnishings | Heterogeneity (Itwo (%), χ2 (P)) | Quality of evidence (GRADE) |
|---|---|---|---|---|---|---|
| CBT v supportive counseling23-25, 28, 29 | 0-6 | 4 (eighty) | 591 (88) | 0.62 (0.29 to 1.31) | 17, 3.6 (P=0.31) | Low*‡ |
| 6-12 | 5 (100) | 645 (71) | 0.54 (0.34 to 0.86) | 0, ii.51 (P=0.64) =0.P2) | Moderate* | |
| 12+ | 4 (eighty) | 570 (85) | 0.63 (0.40 to 0.99) | 0, 2.50(P=0.48) | Low*‡ | |
| CBT and risperidone v supportive counselling24, 30 | 0-6 | 2 (100) | 130 (100) | 0.35 (0.13 to 0.95) | 0, 0.59 (P=0.44) | Very low*ठ|
| 6-12 | 2 (100) | 130 (100) | 0.63 (0.33 to i.21) | 0, 0.25 (P=0.61) | Very low*ठ| |
| 12+ | 1 (l) | 41 (32) | 0.59 (0.34 to 1.04) | NA | Very low*ठ| |
| Integrated psychotherapy five supportive counselling37 | half dozen-12 | one (100) | 125 (100) | 0.nineteen (0.04 to 0.81) | NA | Very low*ঠ|
| 12+ | one (100) | 125 (100) | 0.32 (0.xi to 0.92) | NA | Very depression*ঠ| |
| Integrated psychotherapy v standard care35 | six-12 | 1 (100) | 67 (85) | 0.24 (0.07 to 0.81) | NA | Low*‡ |
| 12+ | 1 (100) | 65 (82) | 0.52 (0.26 to 1.02) | NA | Low*‡ | |
| CBT and risperidone v CBT and placebo24 | 0-vi | ane (100) | 87 (100) | 1.02 (0.15 to 6.94) | NA | Very low*ठ|
| 6-12 | 1 (100) | 87 (100) | 1.02 (0.39 to 2.67) | NA | Very depression*ठ| |
| Olanzapine v placebo27 | vi-12 | one (100) | 60 (100) | 0.43 (0.17 to 1.08) | NA | Very low*ठ|
| Omega 3 fatty acids v placebo26 | 0-half-dozen | 1 (100) | 76 (94) | 0.13 (0.02 to 0.95) | NA | Low*§ |
| 6-12 | 1 (100) | 81 (100) | 0.18 (0.04 to 0.75) | NA | Low*§ |
Psychological and complex psychosocial interventions
Within the kickoff half-dozen months of treatment, four studies comparing CBT with supportive counselling and monitoring[25] [28] [29] [46] reported that CBT did not reduce transition to psychosis (run a risk ratio 0.62 (95% confidence interval 0.29 to ane.31)). Merely trials included only 40 events (591 participants), and overall this evidence was of low quality. All the same, there was moderate quality show at 12 months indicating that more than completers in the supportive counselling grouping transitioned to psychosis (0.54 (0.34 to 0.86); fig 3 ), which remained pregnant in sensitivity analysis (0.64 (0.44 to 0.93)). At 18 months, there was low quality bear witness that CBT is associated with fewer transitions (0.63 (0.40 to 0.99)), and the effect did not remain pregnant in sensitivity analysis (0.55 (0.25 to 1.19)).
Fig iii Transition to psychosis for participants receiving CBT versus supportive counselling, (at half-dozen-12 months; includes completers only). Yard-H=Mantel-Haenszel
Combined furnishings for positive symptoms of psychosis (fig iv ), depression, and quality of life were not significant at whatsoever fourth dimension point, just at that place was only depression quality prove for all outcomes except for positive symptoms inside six and 12 months. One study[29] reported secondary outcomes only for participants who had not transitioned to psychosis; participants with the most astringent symptoms were omitted from these analyses. In sensitivity analyses excluding this report, there was a meaning issue for positive symptoms (standardised mean difference −0.27 (95% confidence interval −0.47 to −0.06)), just effects for other outcomes remained not-significant. In that location was depression quality bear witness for total symptoms of psychosis and negative symptoms of psychosis, and effects were not significant. Dropout rates were similar betwixt groups within the first six months (take chances ratio 1.09 (0.88 to 1.35)).
Fig iv Positive symptoms of psychosis for participants receiving CBT versus supportive counselling (at half dozen-12 months). Iv=inverse variance
There was very low quality show for the benefits and harms associated with CBT and risperidone from two studies comparison CBT and risperidone with supportive counselling.[24] [xxx] Inside the first six months of treatment, fewer people receiving CBT and risperidone transitioned to psychosis (hazard ratio 0.35 (95% conviction interval 0.13 to 0.95)), but these trials included just 17 events (130 participants). The effect was no longer significant after 12 months (0.63 (0.33 to 1.21); fig 5 ) or afterwards 36 months (0.59 (0.34 to 1.04)). At that place were no pregnant furnishings of this treatment on quality of life, symptoms of psychosis (total, positive, or negative), depression, or mania. Within vi months, there were no dropouts in i study,[thirty] and the dropout rate in the 2nd study[24] was similar betwixt groups (0.76 (0.28 to 2.03)).
Fig 5 Transition to psychosis for participants receiving CBT and risperidone versus supportive counselling (at vi-12 months; includes completers only). Yard-H=Mantel-Haenszel
There was bear witness of very depression quality for the benefits and harms associated with integrated psychotherapy from one report[39] comparing integrated psychotherapy (mean number of sessions fifteen.viii (standard deviation 6.8)) with supportive counselling (23.7 (13.i)) in participants in the early initial prodromal state.[37] This study measured transition to an ultra high risk or loftier risk mental country or a DSM-Four psychotic disorder. Inside the first 12 months, fewer people completing integrated psychotherapy transitioned to an ultra high or loftier gamble mental state or to psychosis (risk ratio 0.xix (95% confidence interval 0.04 to 0.81)), only there were only 13 events (125 participants). The consequence was maintained at 24 months (0.32 (0.11 to 0.92)). Dropout was similar between groups at 12 months (1.55 (0.68 to iii.53)) and 24 months (0.95 (0.61 to 1.49)).
At that place was low quality show from one study comparison integrated psychotherapies with standard treatment.[35] Within 12 months, fewer people receiving integrated psychotherapy transitioned to psychosis (run a risk ratio 0.24 (95% confidence interval 0.07 to 0.81)), simply in that location were only 13 events (67 participants). The upshot remained big when we assumed that dropouts transitioned (0.41 (0.20 to 0.85)), but the effect was not quite significant afterwards 24 months (0.52 (0.26 to one.02)). There was no effect for positive or negative symptoms of psychosis at either time betoken. Dropout was like between groups at 12 months (0.63 (0.22 to i.81)) and 24 months (0.66 (0.25 to 1.73)).
Pharmacological interventions
I study compared CBT and risperidone with CBT and placebo.[24] Very low quality evidence within the first six months of treatment suggested no divergence in transition to psychosis (risk ratio 1.02 (95% confidence interval 0.15 to half-dozen.94)), which remained at 12 months (1.02 (0.39 to ii.67)). Differences in symptoms of psychosis (total, positive, or negative), depression, and quality of life were non significant. Dropout was similar betwixt groups (1.09 (0.62 to 1.92)), although the bear witness was besides rated as very depression quality.
In that location was very low quality testify for the benefits and harms associated with olanzapine, from one study comparison olanzapine with placebo.[27] We saw no difference in transition to psychosis afterwards 12 months (risk ratio 0.44 (95% confidence interval 0.17 to 1.08)). Dropout was similar between groups at 12 months (i.59 (0.88 to 2.88)). For participants taking olanzapine, there was a large effect on weight during the outset 8 weeks (standardised hateful difference 0.81 (0.28 to 1.34)), which remained large at 12 months (1.xviii (0.62 to 1.73)). Effects on symptoms of psychosis (total, positive, or negative), low, and mania were not pregnant. Information at 24 months were non analysed because fewer than 50% of participants remained.
We besides constitute very low quality evidence for the benefits and harms associated with amisulpride, from one study comparison amisulpride and a needs based intervention with the needs based intervention lone.[38] Transition was not reported. Within six months, effects on total and negative symptoms of psychosis were not significant, just amisulpride was associated with a moderate reduction in positive symptoms (standardised mean divergence −0.53 (95% confidence interval −0.93 to −0.thirteen)), and low (−0.51 (−0.91 to −0.xi)). The improver of amisulpride was associated with a moderate reduction in dropout (run a risk ratio 0.59 (0.38 to 0.94)).
Nutritional supplements
We found low quality evidence for the benefits and harms associated with omega-three fatty acids, from one report comparing omega-3 fatty acids with placebo.[26] Participants received handling for 12 weeks, which was associated with a large reduction in transition to psychosis after treatment (risk ratio 0.13 (95% confidence interval 0.02 to 0.95)), but there were only nine events (76 participants). Assuming participants who dropped out transitioned to psychosis, the effect remained large at 12 weeks (0.39 (0.13 to 1.xiv)). This issue remained significant afterwards 12 months (0.18 (0.04 to 0.75)), although the number of events was only xiii (81 participants). Handling effects on total symptoms of psychosis (standardised hateful difference −1.26 (−1.74 to −0.78)), positive symptoms (−two.08 (−two.63 to −i.54)), negative symptoms (−two.22 (−2.77 to −1.66)), and symptoms of depression (−0.56 (−one.01 to −0.12)) also favoured omega-3 fatty acids subsequently 12 months. Dropouts at the cease of treatment were not reported; notwithstanding, dropout later 12 months was low and like betwixt groups (hazard ratio one.46 (0.26 to 8.xxx)).
Discussion
Comparison with other studies
This systematic review and meta-analysis of treatments for people at high risk of developing psychosis included 11 trials and 1246 participants seeking treatment. Participants received a range of psychological, pharmacological, nutritional, and complex psychosocial interventions. This review included twice the number of studies and participants equally a previous review, which did non find clear testify of benefit.[14] Recent studies have contributed to a much larger dataset, which suggests that transition to psychosis from a high risk mental country could be preventable. These findings as well suggest the future research strategies that are near likely to exist fruitful, highlighting treatments that have the well-nigh potential for reducing transition to psychosis. On the basis of this review, farther research is clearly warranted to determine the benefits of both psychological interventions—especially CBT with or without family treatment and a nutritional additive (omega-three fatty acids).
Summary of results
Overall, five trials of CBT had a moderate effect on transition to psychosis at both 12 and 18 months. In sensitivity analyses, assuming dropouts had transitioned, the effect of CBT on transition remained significant at 12 months; withal, the effect at xviii months was no longer pregnant. In that location has also been evidence that complex psychosocial interventions could reduce transition or filibuster onset of psychosis, relative to supportive counselling or treatment every bit usual. For omega-3 fatty acids, low quality evidence suggests a beneficial effect for a 12 week form of nutritional supplementation compared with placebo. However, the data emerged from a single trial with few participants, and this result has never been replicated to our knowledge. Although the accented furnishings of treatments will vary across populations with different risks of psychosis at baseline (table three ), effects for the about promising interventions are probable to be clinically meaningful for many psychiatric services.
Table 3
Absolute effects of treatments for patients at high run a risk and very high risk of developing psychosis. Data are number of participants per g who volition transition
| Population | Intervention | Control |
|---|---|---|
| CBT (gamble ratio=0.54) | ||
| Very high risk | 162 | 300 |
| High risk | 54 | 100 |
| CBT and risperidone (take chances ratio=0.63) | ||
| Very high risk | 189 | 300 |
| High risk | 63 | 100 |
| Integrated psychotherapy (risk ratio=0.nineteen) | ||
| Very high chance | 57 | 300 |
| High take a chance | 19 | 100 |
| Fish oil/omega-three fat acids (risk ratio=0.18) | ||
| Very loftier hazard | 54 | 300 |
| High risk | 18 | 100 |
Although no other treatments showed any clear or reliable effects, well-nigh of the studies included in this review had several problems. Many trials were at an unclear chance of option bias, and some trials were rated as having high risk of detection bias. We considered it unlikely that blinding of participants or providers would introduce any important bias, and nosotros did not downgrade for this reason. It is possible to bullheaded assessors in studies of psychological interventions, and we considered that whatsoever lack of assessor blinding could introduce bias and contribute to downgrading our quality cess. Only 4 studies were clearly free of selective issue reporting, with several studies not reporting all outcomes.
All identified trials were at a high hazard of bias owing to incomplete outcome data; however, this result reflected a high rate of attrition in studies of this type of population rather than a methodological deficiency in the studies themselves. In improver, the definitions of prodromal, high risk, and ultra high risk mental states varied between studies. One study[37] used the development of subthreshold psychosis (or "ultra loftier take chances" mental state, which was the entry criteria for virtually of the other studies) equally function of their primary outcome. Although broadly similar, the unlike entry criteria and operational definitions of transition to psychosis could account for the overall transition rates being lower than expected; therefore, caution should exist exercised when interpreting our results. Similarly, epidemiological problems related to sampling, temporal fluctuation in symptoms, and risk enrichment strategies used in these trials, which would pose problems for the generalisability of these findings to routine healthcare settings.
Although most of the interventions used have some bear witness for effectiveness in populations with frank psychosis, the included studies used different comparators, limiting comparisons between treatments and meta-analysis. Furthermore, control conditions that include active interventions could underestimate the effect of some interventions relative to no intervention. For example, comparisons included combinations of supportive counselling, regular and frequent monitoring of mental states, and handling as usual. Consequently, transition at 12 months ranged from 7.1%[28] to 27%.[30] Additionally, 25% of participants in one study were inpatients at baseline,[35] suggesting an already sick population, perhaps even having already transitioned to psychosis, or representing people at loftier risk of self harm. Moreover, most studies recruited people who were seeking handling, which necessarily omitted people who could benefit from help but did not seek it.
Our analyses were sensitive to assumptions well-nigh dropouts. Analyses of study completers suggest that psychological interventions (CBT with or without family intervention) accept a beneficial issue; however, some findings were not meaning when dropouts were causeless to take fabricated transition. Since transition to psychosis is probably associated with service use, and most trials traced participants lost to follow-up via health records and family doctors, completer analyses (which are similar to analyses bold that dropouts did not transition) might accurately stand for participant outcomes. Because most outcomes were reported within i year, we considered the simple dichotomous effect to be the all-time at measuring time to transition. Time to transition was measured and reported in several ways that would not facilitate a meaningful and transparent synthesis or a sensitivity analysis to examination the importance of assumptions near dropouts.
Strengths and limitations of written report
Our choice of primary upshot (dichotomous transition to psychosis) reflects the master outcomes used in the clinical trials. However, it has been argued[47] that this crossing of a threshold is arbitrary and overemphasises the importance of positive symptoms, and that other dimensions might be more informative, such every bit negative symptoms, functioning, and quality of life. Therefore, we too analysed these outcomes, but fewer trials reported these variables and our analyses are probably underpowered equally a result.
Importantly, nosotros found no bear witness to support the early promise of some antipsychotic drugs in delaying or preventing transition to psychosis. In addition, antipsychotic drugs are associated with clinically significant side effects. Although this is best described equally an absenteeism of testify rather than evidence of absence, this review identifies no reason to pursue this line of enquiry. Many people at ultra high risk will non progress to psychosis, and we expect that any prove indicating that the benefits outweigh the harms in this population would have been published. Furthermore, in a recent study of young people at take a chance of developing psychosis enrolled in a psychosocial handling program, pregnant clinical improvements were found without the apply of antipsychotic drugs.[48]
Psychological treatments are also associated with meaning side effects, with about x% of participants in such treatments deteriorating,[49] [50] only psychological therapies are unlikely to cause the harms associated with antipsychotic drugs. Psychological handling might be associated with an increment in stigma and other consequences for participants who would non develop psychosis even without treatment. Furthermore, there are ethical considerations in the delivery of all interventions for this population. Any future trials of psychological interventions should measure out and report such agin effects.
Directions for future inquiry
The findings of this review do suggest two possible directions for hereafter enquiry. Firstly, the results of the trial using omega-3 fatty acids suggest that this intervention might have a beneficial effect on transition rates. A replication study with a larger sample is needed to decide whether this intervention has any merit. The use of omega-3 fatty acids is a relatively rubber treatment with few wellness risks that could accept other potential benefits (such as for cardiovascular status).[51] Therefore, this intervention has particular appeal.
The 2nd arroyo is based on the possible benefits from CBT, with or without family intervention. Proficient evidence indicates that family unit interventions are effective in reducing relapse rates in first episode psychosis and in established schizophrenia; and at that place is evidence that individual CBT has symptomatic benefit in both these contexts.[eleven] Preliminary prove too indicates that cerebral therapy could benefit patients with showtime episode psychosis in the absence of antipsychotic drug treatment.[52] Moreover, the strongest show for prevention of recurrent psychotic episodes is for family interventions rather than individual CBT.[11] Transition from a high gamble country to a first episode of psychosis might be susceptible to a treatment strategy combining family and individual CBT.
CBT may be particularly appropriate in light of the loftier prevalence of feet and mood disorders in this population.[28] [thirty] That is, guidelines for treatment of anxiety and low recommend individual CBT, suggesting that CBT might also exist helpful to patients who present in services merely who will never transition to psychosis. Consideration of how to deliver these psychological interventions in an accessible and timely style is required. Considerable investment would probably be needed in preparation therapists in this approach, or innovative methods need to exist developed and evaluated. In the U.k., it may be possible to incorporate this approach inside the existing Increasing Access to Psychological Therapies programme, which has recently been extended to include children and young people as well as adults. To overcome some of the epidemiological issues outlined to a higher place, treatments could be embedded within a general staging model of mental healthcare. This model aims to deliver preventative, early interventions to young people in the promise of fugitive the development of more astringent disorders.[53]
Conclusions and policy implications
Schizophrenia and the psychoses are highly disabling, recurrent, and near often lifelong conditions with substantial costs to the patient, their family, and the state—arguably greater than almost all other psychiatric conditions. The possible prevention of transition to psychosis and schizophrenia for people at high gamble clearly represents an of import finding.[54] Therefore, further research should be undertaken in the form of a large, multicentre trial of combined family and individual CBT for high adventure groups, evaluating both benefits and potential harms (for example, possible increased stigma). In the concurrently, the use of these psychological treatments now represents the most advisable intervention available for helping people avert what could be a personal, social, and fiscal catastrophe.
Web Extra. Extra textile supplied by the author
Web appendices: Supplementary fabric
Notes
Contributors: All authors contributed to the development of the review questions. MS and EMW drafted the protocol. Sarah Stockton of the National Collaborating Centre for Mental Health) designed and implemented the searches. MS, HJ, and EMW assessed the eligibility of the studies for inclusion, extracted information, assessed gamble of bias, and applied the Course criteria. All authors contributed to the assay. All authors contributed to writing the manuscript, agreed on the final typhoon, had full admission to the data (including statistical results and tables), and take responsibleness for the integrity of the data and accuracy of the analysis. TK is the guarantor.
Funding: The National Collaborating Heart for Mental Health receives £i.four million per yr from the National Institute for Health and Clinical Excellence to develop guidelines for the treatment of mental health issues.
Competing interests: All authors have completed the Unified Competing Interest form at www.icmje.org/coi_disclosure.pdf (available on asking from the corresponding writer) and declare: back up from the National Found for Health and Clinical Excellence for the submitted work; TK is codirector of the National Collaborating Centre for Mental Health; this work was conducted as part of a guideline about psychosis in children and young people, and the full review protocol is available from the authors; AM was an author of two studies included in this review.
Ethical approval: None required.
Data sharing: No additional data bachelor.
Notes
Cite this every bit: BMJ 2013;346:f185
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