Cognitive-behavioural Case Management Research Articles

A Sequential Adaptive Intervention Strategy Targeting Remission and Functional Recovery in Young People at Ultrahigh Risk of Psychosis

Clinical trials have not established the optimal type, sequence, and duration of interventions for people at ultrahigh risk of psychosis. To determine the effectiveness of a sequential and adaptive intervention strategy for individuals at ultrahigh risk of psychosis. The Staged Treatment in Early Psychosis (STEP) sequential multiple assignment randomized trial took place within the clinical program at Orygen, Melbourne, Australia. Individuals aged 12 to 25 years who were seeking treatment and met criteria for ultrahigh risk of psychosis according to the Comprehensive Assessment of At-Risk Mental States were recruited between April 2016 and January 2019. Of 1343 individuals considered, 342 were recruited. Step 1: 6 weeks of support and problem solving (SPS); step 2: 20 weeks of cognitive-behavioral case management (CBCM) vs SPS; and step 3: 26 weeks of CBCM with fluoxetine vs CBCM with placebo with an embedded fast-fail option of ω-3 fatty acids or low-dose antipsychotic medication. Individuals who did not remit progressed through these steps; those who remitted received SPS or monitoring for up to 12 months. Global Functioning: Social and Role scales (primary outcome), Brief Psychiatric Rating Scale, Scale for the Assessment of Negative Symptoms, Montgomery-Åsberg Depression Rating Scale, quality of life, transition to psychosis, and remission and relapse rates. The sample comprised 342 participants (198 female; mean [SD] age, 17.7 [3.1] years). Remission rates, reflecting sustained symptomatic and functional improvement, were 8.5%, 10.3%, and 11.4% at steps 1, 2, and 3, respectively. A total of 27.2% met remission criteria at any step. Relapse rates among those who remitted did not significantly differ between SPS and monitoring (step 1: 65.1% vs 58.3%; step 2: 37.7% vs 47.5%). There was no significant difference in functioning, symptoms, and transition rates between SPS and CBCM and between CBCM with fluoxetine and CBCM with placebo. Twelve-month transition rates to psychosis were 13.5% (entire sample), 3.3% (those who ever remitted), and 17.4% (those with no remission). In this sequential multiple assignment randomized trial, transition rates to psychosis were moderate, and remission rates were lower than expected, partly reflecting the ambitious criteria set and challenges with real-world treatment fidelity and adherence. While all groups showed mild to moderate functional and symptomatic improvement, this was typically short of remission. While further adaptive trials that address these challenges are needed, findings confirm substantial and sustained morbidity and reveal relatively poor responsiveness to existing treatments. ClinicalTrials.gov Identifier: NCT02751632.

The Addition of Fish Oil to Cognitive Behavioral Case Management for Youth Depression: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Clinical Trial

BackgroundClinical trials suggest that long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) (fish oil) may reduce depressive symptoms in adults with major depressive disorder. Therefore, n-3 PUFAs may be a potential treatment for depression in youth. MethodsParticipants were 15- to-25 year-old individuals with major depressive disorder who sought care in one of three government-funded mental health services for young people in metropolitan Melbourne, Perth, or Sydney, Australia. Participants were randomly assigned in a double-blind, parallel-arm design to receive either fish oil (840 mg of eicosapentaenoic acid and 560 mg of docosahexaenoic acid) or placebo capsules as adjunct to cognitive behavioral case management. All participants were offered 50-minute cognitive behavioral case management sessions every 2 weeks delivered by qualified therapists (treatment as usual) at the study sites during the intervention period. The primary outcome was change in the interviewer-rated Quick Inventory of Depressive Symptomatology, Adolescent Version, score at 12 weeks. Erythrocyte n-3 PUFA levels were assessed pre-post intervention. ResultsA total of 233 young people were randomized to the treatment arms: 115 participants to the n-3 PUFA group and 118 to the placebo group. Mean change from baseline in the Quick Inventory of Depressive Symptomatology score was −5.8 in the n-3 PUFA group and −5.6 in the placebo group (mean difference, 0.2; 95% CI, −1.1 to 1.5; p = .75). Erythrocyte PUFA levels were not associated with depression severity at any time point. The incidence and severity of adverse events were similar in the two groups. ConclusionsThis placebo-controlled trial and biomarker analysis found no evidence to support the use of fish oil for treatment in young people with major depressive disorder.

Baseline data of a sequential multiple assignment randomized trial (STEP study).

Research has shown that preventative intervention in individuals at ultra-high risk of psychosis (UHR) improves symptomatic and functional outcomes. The staged treatment in early psychosis (STEP) trial aims to determine the most effective type, timing and sequence of interventions in the UHR population by sequentially studying the effectiveness of (1) support and problem solving, (2) cognitive-behavioural case management and (3) antidepressant medication with an embedded fast-fail option of (4) omega-3 fatty acids or low-dose antipsychotic medication. This paper presents the recruitment flow and baseline clinical characteristics of the sample. STEP is a sequential multiple assignment randomized trial. We present the baseline demographics, clinical characteristics and acceptability and feasibility of this treatment approach as indicated by the flow of participants from first contact up until enrolment into the trial. Recruitment took place between April 2016 and January 2019. Of 1343, help-seeking young people who were considered for participation, 402 participants were not eligible and 599 declined/disengaged, resulting in a total of 342 participants enrolled in the study. The most common reason for exclusion was an active prescription of antidepressant medication. Eighty-five percent of the enrolled sample had a non-psychotic DSM-5 diagnosis and symptomatic/functional measures showed a moderate level of clinical severity and functional impairment. The present study demonstrates the acceptability and participant's general positive appraisal of sequential treatment. It also shows, in line with other trials in UHR individuals, a significant level of psychiatric morbidity and impairment, demonstrating the clear need for care in this group and that treatment is appropriate.

M21. THE STEP TRIAL: A SEQUENTIAL MULTIPLE ASSIGNMENT RANDOMISED TRIAL (SMART) OF INTERVENTIONS FOR PATIENTS AT ULTRA-HIGH RISK OF PSYCHOSIS - STUDY RATIONALE, DESIGN AND BASELINE DATA

BackgroundAlthough approximately twenty randomised controlled trials have now been conducted with young people identified as being at high clinical risk of psychotic disorder, it remains unclear what the optimal type and sequence of treatments are for this clinical population. There has also been increased focus on clinical outcomes other than transition to psychotic disorder, such as psychosocial functioning, persistent attenuated psychotic symptoms and non-psychotic disorders. At Orygen, we are currently conducting a trial of a sequence of interventions consisting of two psychosocial therapies (support and problem solving [SPS] and cognitive-behavioural case management [CBCM]) and antidepressant medication. The primary outcome of the study is functional outcome after 6 months. This presentation will outline the background, rationale, design, recruitment and retention data and preliminary baseline results.MethodsSTEP is a sequential multiple assignment randomised trial (SMART) of treatments for young people (12–25 year olds) who meet ultra high risk for psychosis (UHR) criteria. Participants were recruited from primary (headspace) and secondary/tertiary (Orygen Youth Health) mental health services in Melbourne, Australia. The trial consists of three steps: Step 1: SPS (1.5 months); Step 2: SPS vs Cognitive Behavioural Case Management (4.5 months); Step 3: Cognitive Behavioural Case Management + Antidepressant Medication vs Cognitive Behavioural Case Management + Placebo (6 months). Patients who do not respond by the end of each step graduate to the next step in treatment. Responders are randomised to SPS or monitoring. Treatment response is based a combination of reduced attenuated psychotic symptoms, rated using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functional improvement (Social and Occupational Functioning Assessment Scale [SOFAS]) at the end of the treatment step. A ‘fast fail’ option is built into Step 3, whereby patients who deteriorate or have not responded 3 months into Step 3 are offered a choice of continuing existing treatment or commencing omega-3 fatty acids or low-dose antipsychotic medication. The intervention is for 12 months, with follow up at 18 and 24 months. A pilot study using the same design is currently being conducted at The University of California Davis.ResultsRecruitment has recently completed, with 342 patients recruited over a 2.4 year period, representing the largest UHR treatment study conducted to date. Preliminary results indicate an 8% response rate to Step 1 and a 23% response rate to Step 2. Discontinuation rates are 15% (step 1), 43% (step 2), 32% (step 3), primarily due to participants being lost to follow up or not wanting to start medication. The current transition to psychosis rate is 10.2%. Baseline clinical data are currently being analysed and will be presented at the conference.DiscussionPreliminary results indicate high non-response rates following SPS and moderate non-response rates following extended SPS or CBCM, possibly partly due to the stringent definition of response, which required substantial and persistent improvement in both attenuated psychotic symptoms and functioning. Discontinuation rates are low to moderate, reflecting the complexity and severity of this clinical population. The recruitment and retention data show that it is possible to conduct large-scale and complex stepped care trials with this high risk population in a primary mental health care setting (headspace services). Outcomes will inform the most effective type and sequence of treatments for improving psychosocial functioning, symptoms and reducing risk of developing psychotic disorder in this group, as well as identify predictors of treatment response.

Distress Related to Attenuated Psychotic Symptoms: Static and Dynamic Association With Transition to Psychosis, Nonremission, and Transdiagnostic Symptomatology in Clinical High-Risk Patients in an International Intervention Trial

This study examined whether distress in relation to attenuated psychotic symptoms (DAPS) is associated with clinical outcomes in an ultra-high-risk (UHR) for psychosis sample. We also investigated whether DAPS is associated with cognitive style (attributional style and cognitive biases) and whether amount of psychosocial treatment provided is associated with reduction in DAPS. The study was a secondary analysis of the 'Neurapro' clinical trial of omega-3 fatty acids. 304 UHR patients were recruited across ten early intervention services. Data from baseline assessment, regular assessments over 12 months and medium term follow up (mean=3.4 years) were used for analysis. Findings indicated: a positive association between DAPS assessed over time and transition to psychosis; a significant positive association between baseline and longitudinal DAPS and transdiagnostic clinical and functional outcomes; a significant positive association between baseline and longitudinal DAPS and non-remission of UHR status. There was no relationship between severity of DAPS and cognitive style. A greater amount of psychosocial treatment (cognitive-behavioural case management) was associated with an increase in DAPS scores. The study indicates that UHR patients who are more distressed by their attenuated psychotic symptoms are more likely to have a poorer clinical trajectory transdiagnostically. Assessment of DAPS may therefore function as a useful marker of risk for a range of poor outcomes. The findings underline the value of repeated assessment of variables and incorporation of dynamic change into predictive modelling. More research is required into mechanisms driving distress associated with symptoms and the possible bidirectional relationship between symptom severity and associated distress.

Psychosocial Intervention With or Without Antipsychotic Medication for First-Episode Psychosis: A Randomized Noninferiority Clinical Trial

Abstract This triple-blind (participants, clinicians, and researchers) randomized controlled noninferiority trial examined whether intensive psychosocial intervention (cognitive-behavioral case management, CBCM) for first-episode psychosis (FEP) in 15–25 year-olds managed in a specialized early intervention for psychosis service was noninferior to usual treatment of antipsychotic medication plus CBCM delivered during the first 6 months of treatment. To maximize safety, participants were required to have low levels of suicidality and aggression, a duration of untreated psychosis (DUP) of less than 6 months, and be living in stable accommodation with social support. The primary outcome was level of functioning as assessed by the Social and Occupational Functioning Scale (SOFAS) at 6 months. Ninety young people were randomized by computer, 46 to placebo, and 44 antipsychotic medication and 33% of those who commenced trial medication completed the entire 6-month trial period. On the SOFAS, both groups improved, and group differences were small and clinically trivial, indicating that treatment with placebo medication was no less effective than conventional antipsychotic treatment (mean difference = −0.2, 2-sided 95% confidence interval = −7.5 to 7.0, t = 0.060, P = .95). Within the context of a specialized early intervention service, and with a short DUP, the immediate introduction of antipsychotic medication may not be required for all cases of FEP in order to see functional improvement. However, this finding can only be generalized to a very small proportion of FEP cases at this stage, and a larger trial is required to clarify whether antipsychotic-free treatment can be recommended for specific subgroups of those with FEP. Trial Registration: ACTRN12607000608460 (www.anzctr.org.au).

Trajectories of symptom severity and functioning over a three-year period in a psychosis high-risk sample: A secondary analysis of the Neurapro trial

The Ultra-High Risk (UHR) for psychosis group is known to be heterogeneous with diverse outcomes. This study aimed to: 1. Identify subclasses of UHR individuals based on trajectories of symptomatic and functional change over time, 2. Identify predictors of these trajectories.A sample of 304 UHR individuals participating in the Neurapro trial were followed over an average of 40 months. All participants received cognitive-behavioural case management (CBCM). Symptomatic and functional profiles were investigated using latent class growth analysis. Multinomial regression was employed to investigate predictors of classes.Identified trajectories showed mostly parallel slopes (i.e. improving symptoms/functioning over time), which were primarily distinct regarding the severity of symptomatology/level of functioning at baseline (i.e. the intercept). Higher symptomatic/lower functioning classes were predicted by higher substance use, older age, female gender, and lower cognitive functioning.No divergent trajectories were identified as all classes improved over time. This may reflect effective treatment through CBCM, natural illness course, or effective engagement with mental health services. Nonetheless, classes highest in symptoms/lowest in functioning still showed considerable impairment during follow-up, highlighting the need for targeted intervention in these subgroups. The study emphasizes the need for more clinical attention directed towards UHR patients being female or using substances.

The NEURAPRO Biomarker Analysis: Long-Chain Omega-3 Fatty Acids Improve 6-Month and 12-Month Outcomes in Youth at Ultra-High Risk for Psychosis

Background: NEURAPRO was a multicenter, double-blind, randomised, placebo-controlled trial RCT of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFA) ('fish oil') therapy provided for 6 months in individuals at ultra-high risk (UHR) for psychotic disorders, followed by an additional 6-month follow-up period. The study was conducted in 10 specialized early psychosis treatment services in Australia, Asia, and Europe, in 304 participants who received either n-3 PUFA together with cognitive behavioral case management (CBCM) or placebo with CBCM. In the intention to treat analysis, NEURAPRO failed to replicate findings of a previous single-center study. Although the RCT design is placed at the top of the evidence hierarchy, this methodology has limitations in fish oil RCTs, since the test agent is not only present in the intervention group but n-3 PUFA are present in the diet and in the body tissue of all participants, potentially influencing outcomes. Methods: We conducted a biomarker analysis in NEURAPRO participants to determine if n-3 PUFA (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; n-3 index; EPA+DHA) levels measured in erythrocyte membranes at baseline and at month 6 (end-of supplementation) predicted clinical outcomes 6 and 12 months after study entry in the participants irrespective of their original treatment group allocation in the trial. Findings: Of the 304 participants, 285 (94%) had biomarker data at baseline and 218 (72%) participants had biomarker data at baseline and a subsequent time point (209 at month 6; 9 at transition to psychosis). Increases of the n-3 index, EPA and DHA consistently predicted less severe psychopathology and better functioning at both follow-up time points. Higher baseline levels and increases of the n-3 index also predicted overall clinical improvement at month 6 (n-3 index baseline: adjusted odds ratio (95%CI)=1.79 (1.30-2.48); n-3 PUFA increase: adjusted odds ratio (95%CI)=1.43 (1.16-1.76) and at month 12 (n-3 index baseline: adjusted odds ratio (95%CI)=2.60 (1.71-3.97); n-3 PUFA increase: adjusted odds ratio (95%CI)=1.36 (1.06-1.74). The transition to psychosis rate was lower than expected in this study (5.0% at month 6; 10.1% at month 12). No association was observed between n-3 PUFA measures and transition to psychosis. Interpretation: These data suggest that n-3 PUFA can exert protective and therapeutic effects in UHR individuals. This finding may have implications for early intervention and clinical treatment guidelines since n-3 PUFA supplementation can easily and safely be used in a wide variety of settings, from primary care to specialist services. Trial Registration: The trial was registered at the Australia and New Zealand Clinical Trials Registry (ID 12608000475347). Funding Statement: This work was supported by grant 07TGF-1102 from the Stanley Medical Research Institute, grant 566529 from the NHMRC Australia Program (Drs McGorry, Hickie, and Yung, and Amminger), and a grant from the Colonial Foundation. Drs Amminger and Yung were supported by NHMRC Senior Research Fellowships 1080963 and 566593, respectively; and Dr Nelson was supported by NHMRC Career Development Fellowship 1027532. Dr McGorry was supported by Senior Principal Research Fellowship 1060996 from the National Health and Medical Research Council of Australia (NHMRC). Declaration of Interests: Drs Amminger, Hickie, Yung, and Nelson have received National Health and Medical Research Council (NHMRC) funding. Dr McGorry reported receiving grant funding from National Alliance for Research on Schizophrenia and Depression and unrestricted research funding from AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, and Novartis, as well as honoraria for educational activities with AstraZeneca, Eli Lilly, Janssen-Cilag, Pfizer, Bristol-Myers Squibb, Roche, and the Lundbeck Institute. No other conflicts were reported. Ethics Approval Statement: The National Health and Medical Research Council of Australia (NHMRC) National Statement on Human Research was adhered to and appropriate ethical approval was obtained by each site (Melbourne, Australia: Melbourne Health Research Ethics Committee; Sydney, Australia: Sydney South West Area Health Service Ethics Review Committee; Basel, Switzerland: Ethics Commission for Basel; Zurich, Switzerland: Cantonal Ethics Commission Zurich; Jena, Germany: University Clinic Jena Ethics Commission; Copenhagen, Denmark: Capital Region Research Ethics Committee; Hong Kong: Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster; Vienna, Austria: Medical University of Vienna Ethics Commission; Singapore: National Healthcare Group Domain Specific Review Board; and Amsterdam, the Netherlands: Academic Medical Centre Medical Ethics Committee). Written informed consent was obtained for those younger than 17 years, parental or guardian consent was sought. Participants received financial compensation.

Neurocognition as a predictor of transition to psychotic disorder and functional outcomes in ultra-high risk participants: Findings from the NEURAPRO randomized clinical trial

BackgroundNeurocognitive impairments experienced by individuals at ultra-high risk (UHR) for psychosis are potential predictors of outcome within this population, however there is inconsistency regarding the specific neurocognitive domains implicated. This study aimed to examine whether baseline neurocognition predicted transition to psychosis, or functional outcomes, at medium-term (mean = 3.4 years) follow-up, while controlling for other clinical/treatment variables associated with transition to psychosis. MethodAnalysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive-behavioural case management (NEURAPRO) for UHR individuals was conducted on the 294 participants (134 males, 160 females) who completed neurocognitive assessment (Brief Assessment of Cognition for Schizophrenia) at baseline. Transition to psychosis was determined using the Comprehensive Assessment of At-Risk Mental States (CAARMS), and functioning was measured with the Global Functioning: Social and Role Scales. ResultsMean baseline z-scores indicated that UHR participants performed a quarter to half a standard deviation below normative means in all domains (range mean z = −0.24 to −0.47), except for executive functioning (mean z = 0.16). After adjusting for covariates, poorer Executive (p = .010) and Motor (p = .030) functions were predictive of transition to psychosis. Processing Speed and Verbal Fluency were significant predictors of role functioning at 12 months (p = .004), and social functioning at medium-term follow-up (p = .015), respectively. ConclusionsNeurocognitive abilities are independent predictors of both transition to psychosis and functional outcomes within the UHR population. Further research is needed to determine the best combination of risk variables in UHR individuals for prediction of psychosis transition, functioning and other psychopathology outcomes.

NEURAPRO: a multi-centre RCT of omega-3 polyunsaturated fatty acids versus placebo in young people at ultra-high risk of psychotic disorders\u2014medium-term follow-up and clinical course

This study reports a medium-term follow-up of a randomised, double-blind, placebo-controlled trial of omega-3 polyunsaturated fatty acids (PUFA) in ultra-high risk for psychosis (UHR) patients. Primary outcomes of interest were transition to psychosis and symptomatic and functional outcome. A secondary aim was to investigate clinical predictors of medium-term outcome. Three hundred four UHR participants were recruited across 10 specialised early psychosis services in Australia, Asia, and Europe. The intervention consisted of 1.4 g/daily of omega-3 PUFA or placebo, plus up to 20 sessions of cognitive-behavioural case management (CBCM), over the 6-month study period, with participants receiving further CBCM sessions on basis of need between months 6–12. Mean time to follow-up was 3.4 (median = 3.3; SD = 0.9) years. There was a modest increase in transitions between 12-month and medium-term follow-up (11–13%) and substantial improvement in symptoms and functioning between baseline and follow-up, with no differences between the treatment groups. Most improvement had been achieved by end of the intervention. 55% of the sample received mental health treatment between end of intervention and follow-up. Omega-3 PUFA did not provide additional benefits to good quality psychosocial intervention over the medium term. Although most improvement had been achieved by end of intervention the substantial rates of post-intervention mental health service use indicate longer-term clinical need in UHR patients. The post-intervention phase treatment or the longer-term effect of CBCM, or a combination of the two, may have contributed to maintaining the gains achieved during the intervention phase and prevented significant deterioration after this time.

O8.8. NEUROCOGNITION IN ULTRA-HIGHRISK INDIVIDUALS AND RELATIONSHIP TO TRANSITION TO PSYCHOSIS, DEPRESSIVE DISORDER, AND FUNCTIONING: FINDINGS FROM THE NEURAPRO TRIAL

BackgroundNeurocognitive impairments are a core feature of psychosis and major depressive disorder (MDD) and are associated with poorer functioning outcomes in these illnesses. Individuals at ultra-high risk (UHR) for psychosis have been shown to experience mild but significant cognitive impairments relative to healthy controls. Evidence suggests neurocognitive deficits are useful predictors of transition to psychotic disorder, although there is inconsistency regarding the specific domains implicated. Furthermore, depression is common in the UHR population, but the relationship between neurocognitive impairment and depression in UHR has not been investigated. The aim of this study was to examine neurocognitive functioning in UHR participants at baseline and whether neurocognitive performance is associated with i) transition to psychosis; ii) depressive disorder; and iii) functioning at medium-term follow-up (median 24 months).MethodsSecondary analysis of data collected as part of a multi-centre RCT of omega-3 fatty acids and cognitive behavioural case management (NEURAPRO) for individuals at UHR for psychosis was conducted. Baseline, 6, 12 and 24-month (median) assessments relevant to the current study included the Comprehensive Assessment of the At-Risk Mental State (CAARMS), Structured Clinical Interview for DSM-IV (SCID), Brief Assessment of Cognition for Schizophrenia (BACS), Montgomery–Åsberg Depression Rating Scale (MADRS) and Social and Occupational Functioning Assessment Scale (SOFAS). The analysis was conducted on the 287 UHR participants (129 males, 158 females) who completed these measures. Hierarchical Cox proportional hazards regression was used to examine neurocognitive predictors of transition to psychosis, while hierarchical logistic and linear regressions were used to identify neurocognitive predictors of MDD and functioning, respectively.ResultsMean z-scores at baseline indicated that the UHR participants performed on average a quarter to half a standard deviation below healthy people in most domains (range mean z=-0.24 to -0.47), except for executive functioning (mean z=0.16, SD=1.21). One hundred and nineteen (41.5%) participants met criteria for MDD at baseline. Thirty-eight (13.2%) participants transitioned to psychosis over 24 months. Results showed that poorer Executive (p=.01) and Motor (p=.03) functions were predictive of transition to psychosis over 24 months, after controlling for other clinical and treatment variables. Forty-eight (16.7%) participants met criteria for MDD at 24 months. Faster Processing Speed significantly predicted MDD at 24 months (p=.01), but failed to retain significance after controlling for other factors, with baseline and past MDD history emerging as the strongest predictors of MDD at medium-term follow-up (both p<.001). After adjustment for IQ and baseline functioning, functional outcomes at 6, 12 and 24 months were predicted by baseline Processing Speed.DiscussionThese findings suggest that neurocognitive abilities are important predictors of transition to psychosis and functional outcomes within the UHR population, but hold minimal value in predicting MDD after controlling for history of MDD. Further research is needed that examines trajectory of neurocognition over time in UHR and in relation to psychopathology and functioning outcomes.

F25. NEURAPRO REVISITED: INCREASES IN LONG-CHAIN OMEGA-3 FATTY ACIDS IMPROVE FUNCTIONAL AND SYMPTOMATIC OUTCOMES IN ULTRAHIGH RISK PATIENTS

BackgroundThe NEURAPRO multicentre randomised controlled trial (RCT) of long-chain polyunsaturated omega-3 fatty acids (ω-3 PUFAs) (‘fish oil’) in combination with high-quality psychosocial intervention (cognitive behavioural case management [CBCM]) vs. placebo in combination with CBCM in young people at ultrahigh risk (UHR) of psychosis showed that the group allocated to fish oil had no clinical benefits over the placebo group. However, a limitation of the trial was that adherence with the study medication was relatively low. Furthermore, although RCTs are placed at the top of the evidence hierarchy, this methodology has limitations in fish oil RCTs, since the test agent is not only present in the intervention group, but ω-3 fats are present in the diet and in the tissues of all participants. A biomarker analysis of ω-3 changes during the trial can ultimately determine the efficacy of ω-3 supplementation in this trial.MethodsThe NEURAPRO study was conducted from March 2010 to September 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. In this study of 304 young people at UHR for psychotic disorders, 153 (50.3%) were allocated to ω-3 PUFAs and 151 (49.7%) to placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The primary outcome was transition to psychosis assessed with the Comprehensive Assessment of the At-Risk Mental State. Secondary outcomes were levels of psychopathology and functioning assessed by the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Montgomery Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Social and Occupational Functioning Assessment Scale (SOFAS), and the Global Functioning: Social and Role scales). Levels of ω-3 PUFAs in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (amongst other fatty acids) were measured as percentage of total fatty acids in erythrocytes at baseline and at month 6 (end-of-intervention). We examined changes in cell membrane levels of EPA and DHA, as measures of ω-3 intake independent of source. Data were analysed as a single cohort. Cox proportional hazards models and linear regression analyses were used to examine relationships between the ω-3 index (EPA+DHA) with clinical outcomes at month 6 and 12.ResultsWhen analysed as a single cohort, no association was observed between the ω-3 index and transition to psychosis at any follow-up time point but increase of the ω-3 index was found significantly related with most of the functional and symptomatic measures at month 6 and 12, in linear regression models adjusting for relevant baseline factors (i.e., functioning, psychopathology, ω-3 index and smoking). The models revealed consistent results, with low functioning or high psychopathology at baseline, low levels of ω-3s at baseline and increase of the ω-3 index independently predicting clinical improvements at in this sample.DiscussionIn contrast to our RCT analysis, this study using biomarkers shows that increase in erythrocyte ω-3 PUFAs may improve clinical outcomes of UHR patients. The results also imply that people with low DHA and EPA levels may benefit more from supplementation with fish oil. The analysis also highlights shortcomings of the RCT design in situations when the tested intervention is available outside the study.

T49. THE NEURAPRO STUDY: ADHERENCE TO STUDY MEDICATION

BackgroundAdherence to a medication is generally defined as the extent to which patients take medications as prescribed by their health care providers. Poor adherence to study medication is not uncommon posing a major challenge to treatment trails. However, poor adherence may not be randomly distributed but rather be associated with demographic or illness factors. The aim of the present study was to identify factors associated with adherence to study medication in young people at ultrahigh risk of psychosis who participated in the NEURAPRO study.MethodsSecondary analysis of data collected in a multi-centre, double-blind, placebo-controlled, randomized clinical trial to prevent or delay the onset of psychosis in participants at ultrahigh risk of psychosis testing omega-3 polyunsaturated fatty acids (omega-3 PUFAs) vs. placebo, in combination with cognitive behavioural case management (NEURAPRO) were included in this analysis. Measures included the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), the Montgomery Asberg Depression Rating Scale (MADRS), the Young Mania Rating Scale (YMRS), the Social and Occupational Functioning Assessment Scale (SOFAS), and the Global Functioning: Social and Role scales. Adherence to the study medication was assessed monthly for each participant based on capsule count. The mean adherence rating over the 6-month intervention period was then computed and categorized as either adherent (≤25% of capsules returned) or non-adherent (>25% of capsules returned). Transition to psychosis was defined on the basis of operationalized criteria and assessed with the Comprehensive Assessment of the At-Risk Mental State. Levels of ω-3 PUFAs in fish oil, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (amongst other fatty acids) were measured as percentage of total fatty acids in erythrocytes at baseline and at month 6 (end-of-intervention).ResultsOf 304 randomised participants, 57.9% (N = 176) were non-adherent (>25% of capsules returned) and 128 (42.1%) were adherent (≤25% capsules returned) to the study medication.No sex differences were observed for adherence rates. At baseline the omega-3 index (EPA+DHA) was significantly lower in the non-adherent group (P = 0.018). The non-adherent group had significant lower scores on the SOFAS (P = 0.001) and the Global Functioning: Social and Role Scale at baseline assessment (P < 0.001 and P = 0.020, respectively) compared to the adherent group. No statistically significant differences were observed on symptom measures at baseline (BPRS, SANS, MADRS, YMRS). The cumulative transition to psychosis rate at month 12 was significantly higher in the non-adherent group compared to the adherent group (14.8% vs. 4.7%; Log rank test: P < 0.001).DiscussionAdherence to study medication was relatively low in NEURAPRO. Poor functioning and lower levels of ω-3 PUFAs at baseline were associated with non-adherence. Young people who were non-adherent had a significantly higher risk of progressing to first episode psychosis. Knowledge about factors associated with adherence could help to improve the delivery of interventions in young people at risk of psychosis.

Opening the Black Box of Cognitive-Behavioural Case Management in Clients with Ultra-High Risk for Psychosis

Background: Cognitive-behavioural therapy (CBT) is the first-choice treatment in clients with ultra-high risk (UHR) for psychosis. However, CBT is an umbrella term for a plethora of different strategies, and little is known about the association between the intensity and content of CBT and the severity of symptomatic outcome. Methods: A sample of 268 UHR participants received 6 months of CBT with case management (CBCM) in the context of the multi-centre NEURAPRO trial with monthly assessments of attenuated psychotic symptoms (APS). Using multilevel regressions and controlling for the initial severity of APS, the associations between (1) number of CBCM sessions received and severity of APS and (2) specific CBCM components and severity of APS were investigated. Results: In month 1, a higher number of sessions and more assessment of symptoms predicted an increase in APS, while in month 3, a higher number of sessions and more monitoring predicted a decrease in the level of APS. More therapeutic focus on APS predicted an overall increase in APS. Conclusions: Our findings indicate that the association between intensity/content of CBCM and severity of APS in a sample of UHR participants depends on the length of time in treatment. CBCM may positively impact the severity of APS later in the course of treatment. Therefore, it would seem important to keep UHR young people engaged in treatment beyond this initial period. Regarding the specific content of CBCM, a therapeutic focus on APS may not necessarily be beneficial in reducing the severity of APS, a possibility in need of further investigation.

Development and feasibility of smartphone application for cognitive-behavioural case management of individuals with early psychosis.

This article describes the development of the smartphone application for cognitive-behavioural case management of young individuals with early psychosis and examines the acceptance and potential clinical benefits of this application through a pilot survey. Gwangju Bukgu-Community Mental Health Center developed and launched a smartphone application (Heal Your Mind [HYM]) for cognitive-behavioural case management and symptom monitoring. The HYM application for clients includes 6 main modules including thought record, symptom record, daily life record, official notices, communication and scales. The key module is the "thought record" for self-directed cognitive-behavioural treatment. When the client writes and sends the self-cognitive-behavioural therapy sheet to the case manager, the latter receives a notification and can provide feedback in real time. We conducted a survey to investigate the acceptance and feasibility of this approach among young clients with early psychosis. A total of 24 clients with early psychosis participated in this survey. More than 80% of participants reported that it was easy to learn to use this application, and no one described this application as very complicated or reported that they needed a long time to learn how to use it. About 80% of participants were satisfied with this application, and 70% reported that they received help as a result of using this application. This study suggests that this smartphone application is useful for young individuals with early psychosis and that it may contribute to the development of both young customer- and case manager-friendly systems for this clinical population.

Journal Digest

Journal Digest

Effect of ω-3 Polyunsaturated Fatty Acids in Young People at Ultrahigh Risk for Psychotic Disorders

A promising treatment to prevent onset and improve outcomes in patients at ultrahigh risk for psychosis is dietary supplementation with long-chain ω-3 polyunsaturated fatty acids (PUFAs). To determine whether treatment with ω-3 PUFAs in combination with a high-quality psychosocial intervention (cognitive behavioral case management [CBCM]) is more effective than placebo plus CBCM. NEURAPRO, a double-blind, placebo-controlled, randomized clinical trial, was conducted from March 1, 2010, to September 30, 2014, in 10 specialized early psychosis treatment services in Australia, Asia, and Europe. The primary analysis used the intention-to-treat approach. A daily dose of 1.4 g of ω-3 PUFAs or placebo (paraffin oil), plus 20 or fewer sessions of CBCM over the 6-month study period. The primary outcome was transition to psychosis status at 6 months. The secondary outcomes were general levels of psychopathology and functioning, as assessed by the Brief Psychiatric Rating Scale (BPRS) (range, 24-168), Scale for the Assessment of Negative Symptoms (SANS) (range, 0-125), Montgomery-Åsberg Depression Rating Scale (MADRS) (range, 0-60), Young Mania Rating Scale (YMRS) (range, 0-44), Social and Occupational Functioning Assessment Scale (SOFAS) (range, 0-100), and the Global Functioning: Social and Role scale (range, 0-10). For SOFAS and Global Functioning: Social and Role scale, higher scores were better; for other measures, lower scores were better. In this study of 304 adults at ultrahigh risk for psychotic disorders, 153 (50.3%) received ω-3 PUFAs and 151 (49.7%) received placebo. In all, 139 (45.7%) were male; mean (SD) age was 19.1 (4.6) years. The Kaplan-Meier-estimated 6-month transition rates were 5.1% (95% CI, 1.3%-8.7%) in the control group and 6.7% (95% CI, 2.3%-10.8%) in the ω-3 PUFA group. At 12 months, the rates were 11.2% (95% CI, 5.5%-16.7%) in the control group and 11.5% (95% CI, 5.8%-16.9%) in the ω-3 PUFA group. No significant difference was observed between the transition rates of both groups (hazard ratio, 1.1; 95% CI, 0.55-2.23; P = .76, stratified log-rank test). This trial clearly failed to replicate the findings of the original single-center trial. The most likely explanation is that ω-3 PUFAs lack efficacy under these conditions. However, the lower-than-expected transition rate may have prevented a test of the main hypothesis. Given the substantial symptomatic and functional improvement in both groups, the other treatments received (ie, CBCM and antidepressants) likely produced a ceiling effect beyond which ω-3 PUFAs, even if effective, could not be shown to confer additional benefits. Nevertheless, the main conclusion is that ω-3 PUFAs are not effective under conditions where good quality, evidence-based psychosocial treatment is available. anzctr.org.au Identifier: 12608000475347.

Intensive Cognitive Behavioral Case Management for Functional Recovery of Young Patients with Schizophrenia

Intensive Cognitive Behavioral Case Management for Functional Recovery of Young Patients with Schizophrenia

NEURAPRO-E study protocol: a multicentre randomized controlled trial of omega-3 fatty acids and cognitive-behavioural case management for patients at ultra high risk of schizophrenia and other psychotic disorders.

Recent research has indicated that preventative intervention is likely to benefit patients 'at-risk' for psychosis, both in terms of symptom reduction and delay or prevention of onset of threshold psychotic disorder. The strong preliminary results for the effectiveness of omega-3 polyunsaturated fatty acids (PUFAs), coupled with the falling transition rate in ultra high-risk (UHR) samples, mean that further study of such benign, potentially neuroprotective interventions is clinically and ethically required. Employing a multicentre approach, enabling a large sample size, this study will provide important information with regard to the use of omega-3 PUFAs in the UHR group. This trial is a 6-month, double-blind, randomized placebo-controlled trial of 1.4 g day-1 omega-3 PUFAs in UHR patients aged between 13 and 40 years. The primary hypothesis is that UHR patients receiving omega-3 PUFAs plus cognitive-behavioural case management (CBCM) will be less likely to transition to psychosis over a 6-month period compared to treatment with placebo plus CBCM. Secondary outcomes will examine symptomatic and functional changes, as well as examine if candidate risk factors predict response to omega-3 PUFA treatment in the UHR group. This is the protocol of the NeuraproE study. Utilizing a large sample, results from this study will be important in informing indicated prevention strategies for schizophrenia and other psychotic disorders, which may be the strongest avenue for reducing the burden, stigmatization, disability and economic consequences of these disorders.

Youth depression alleviation: the Fish Oil Youth Depression Study (YoDA‐F): A randomized, double‐blind, placebo‐controlled treatment trial

US authorities have recommended 'black-box' warnings for antidepressants because of the increased risk of suicidality for individuals up to age 25. There is thus a clinical and ethical imperative to provide effective treatment for youth depression with an acceptable risk-benefit balance. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) play an important role in a range of physiological processes in living organisms. Supplementation with omega-3 PUFAs has been shown to have a range of beneficial effects on both physical and mental health, and results of previous trials suggest that omega-3 PUFAs may be a safe and effective treatment for depression. However, conclusions from these trials have been limited by their relatively small sample sizes. This trial will test the effectiveness of a 12-week parallel group, double-blind, randomized, placebo-controlled trial of 1.4 g day(-1) omega-3 PUFAs in help seeking 15- to 25-year-olds (N = 400) presenting with major depressive disorder. The primary hypothesis is that young people will show greater improvement of depressive symptoms after 12 weeks of treatment with omega-3 PUFAs plus cognitive behavioural case management compared with treatment with placebo plus cognitive behavioural case management. Because of using a large sample, results from this study will provide the strongest evidence to date to inform the use of omega-3 PUFAs as first-line therapy in young people presenting with major depressive disorder. The study also heralds an important step towards indicated prevention of persistent depression, which may reduce the burden, stigmatization, disability and economic consequences of this disorder.