Youth Depression Alleviation with Anti-inflammatory Agents (YoDA-A): a randomised clinical trial of rosuvastatin and aspirin.

BACKGROUND: Inflammation contributes to the pathophysiology of major depressive disorder (MDD), and anti-inflammatory strategies might therefore have therapeutic potential. This trial aimed to determine whether adjunctive aspirin or rosuvastatin, compared with placebo, reduced depressive symptoms in young people (15-25 years). METHODS: YoDA-A, Youth Depression Alleviation with Anti-inflammatory Agents, was a 12-week triple-blind, randomised, controlled trial. Participants were young people (aged 15-25 years) with moderate to severe MDD (MADRS mean at baseline 32.5 ± 6.0; N = 130; age 20.2 ± 2.6; 60% female), recruited between June 2013 and June 2017 across six sites in Victoria, Australia. In addition to treatment as usual, participants were randomised to receive aspirin (n = 40), rosuvastatin (n = 48), or placebo (n = 42), with assessments at baseline and weeks 4, 8, 12, and 26. The primary outcome was change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: At the a priori primary endpoint of MADRS differential change from baseline at week 12, there was no significant difference between aspirin and placebo (1.9, 95% CI (- 2.8, 6.6), p = 0.433), or rosuvastatin and placebo (- 4.2, 95% CI (- 9.1, 0.6), p = 0.089). For rosuvastatin, secondary outcomes on self-rated depression and global impression, quality of life, functioning, and mania were not significantly different from placebo. Aspirin was inferior to placebo on the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q-SF) at week 12. Statins were superior to aspirin on the MADRS, the Clinical Global Impressions Severity Scale (CGI-S), and the Negative Problem Orientation Questionnaire scale (NPOQ) at week 12. CONCLUSIONS: The addition of either aspirin or rosuvastatin did not to confer any beneficial effect over and above routine treatment for depression in young people. Exploratory comparisons of secondary outcomes provide limited support for a potential therapeutic role for adjunctive rosuvastatin, but not for aspirin, in youth depression. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12613000112763. Registered on 30/01/2013.

Youth Depression Alleviation-Augmentation with an anti-inflammatory agent (YoDA-A): protocol and rationale for a placebo-controlled randomized trial of rosuvastatin and aspirin.

AIM: There is growing support for the role of inflammation and oxidative stress in the pathophysiology of major depressive disorder (MDD). This has led to the development of novel strategies targeting inflammation in the treatment of depression. Rosuvastatin and aspirin have well-documented, anti-inflammatory and antioxidant properties. The aim of the Youth Depression Alleviation: Augmentation with an anti-inflammatory agent (YoDA-A) study is to determine whether individuals receiving adjunctive anti-inflammatory agents, aspirin and rosuvastatin experience a reduction in the severity of MDD compared with individuals receiving placebo. METHODS: YoDA-A is a 12-week triple-blind, randomized controlled trial funded by the National Health and Medical Research Council, Australia. Participants aged 15-25, with moderate-to-severe MDD, are allocated to receive either 10 mg/day rosuvastatin, 100 mg/day aspirin, or placebo, in addition to treatment as usual. Participants are assessed at baseline and at weeks 4, 8, 12 and 26. The primary outcome is change in the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to week 12. RESULTS: The study is planned to be completed in 2017. At date of publication, 85 participants have been recruited. CONCLUSION: Timely and targeted intervention for youth MDD is crucial. Given the paucity of new agents to treat youth MDD, adjunctive trials are not only pragmatic and 'real-world', but additionally aim to target shortfalls in conventional medications. This study has the potential to first provide two new adjunctive treatment options for youth MDD; aspirin and rosuvastatin. Second, this study will serve as proof of principle of the role of inflammation in MDD.

Antibodies to infectious agents in individuals at ultra-high risk for psychosis.

BACKGROUND: While there is evidence that some cases of schizophrenia may be associated with microbial infections, the role of microbial agents has not been investigated in people with emerging psychosis. METHODS: Participants were 105 help seeking ultra-high risk individuals. Psychiatric measures included the Brief Psychiatric Rating Scale and the Scale for the Assessment of Negative Symptoms. Serum IgG antibodies against human herpesviruses and Toxoplasma gondii were determined using immunoassay methods. Multiple linear regression with adjustment for age and sex was applied to test associations between serum antibodies and psychiatric measures. RESULTS: Higher levels of serum IgG antibodies against Toxoplasma gondii in Toxoplasma-positive individuals were significantly associated with more severe positive psychotic symptoms. No significant association was observed between antibody levels and psychiatric measures in individuals positive for human herpesviruses. CONCLUSIONS: In some individuals infection with Toxoplasma gondii may be an environmental factor contributing to the manifestation of positive psychotic symptoms.

The relationship between duration of untreated psychosis and outcome: an eight-year prospective study.

Longer duration of untreated psychosis (DUP) prior to the initiation of treatment has been found to predict poorer short-term clinical and functional outcomes in patients with first-episode psychosis (FEP). The extent to which the relationship between DUP and outcome is maintained in the medium-to-long term however remains unclear. We examined the influence of DUP on clinical and functional outcomes in a prospective, naturalistic study of 318 FEP patients followed up 8 years after initial treatment at a specialist early psychosis service. Quality of life, social and occupational functioning, positive and negative symptoms at 8 years were assessed using standardized instruments. Multiple linear regression analyses indicated that, after controlling for the effects of other factors, shorter DUP correlated moderately with decreased severity of positive symptoms, and enhanced social and occupational functioning and quality of life. There was no uniform point associated with medium-to-long term impairment, with some domains of outcome more sensitive to treatment delay than others. However a consistent finding was that outcomes for these domains were significantly worse when DUP exceeded 3 months. Among those with a schizophrenia-spectrum diagnosis, DUP exceeding 1 year was associated with poorer outcome. No association was found between DUP and negative symptoms in either diagnostic group. As with short-term prognosis, DUP appears to be an independent predictor of prognosis in the medium-to-long term. Results support the need for assertive early detection strategies to facilitate the timely delivery of effective intervention programs to those with emerging psychotic illness in order to reduce the risk of long term deleterious outcomes.

Long-term follow-up of all-cause and unnatural death in young people with first-episode psychosis.

OBJECTIVE: To determine mortality-related estimates and causes of death in young people with first-episode psychosis (FEP), and to identify baseline predictors of mortality. METHOD: Mortality outcomes in 723 young people presenting to an early psychosis service were prospectively ascertained up to 20 years. Predictors of all-cause and unnatural death were investigated using survival techniques. RESULTS: Forty-nine participants died by study end. Most deaths (n=41) occurred within 10 years of service entry. All-cause mortality was 5.5% at 10 years, rising to 8.0% after 20 years. Unnatural death rates at 10 and 20 years were 5.0% and 5.9%, respectively. Three risk factors consistently predicted all-cause mortality and unnatural deaths. CONCLUSION: A substantial proportion of excess mortality was due to non-suicide unnatural death, and, later, natural deaths. This suggests that mental health services should expand their current focus on suicide to incorporate strategies to prevent accidental death and promote healthier lifestyles.

Outcome in early-onset schizophrenia revisited: findings from the Early Psychosis Prevention and Intervention Centre long-term follow-up study.

OBJECTIVE: To compare the long-term outcome in individuals with early-onset (before age 18) and adult-onset schizophrenia spectrum disorder who were initially diagnosed and treated in the same clinical center. METHOD: A prospective follow-up study of 723 consecutive first-episode psychosis patients (age range 14 to 30 years) on average 7.4 years after initial presentation to an early psychosis service, the Early Psychosis Prevention and Intervention Centre in Melbourne, Australia. The outcome measures included the Brief Psychiatric Rating Scale, the Schedule for the Assessment of Negative Symptoms, the Beck Depression Inventory, the Global Assessment of Functioning Scale, the Social and Occupational Functioning Assessment Scale, and the Quality of Life Scale. RESULTS: Follow-up interviews were conducted on 66.9% (484/723) individuals, of whom 75.6% (366/484) received a schizophrenia spectrum disorder diagnosis at baseline. Early-onset schizophrenia spectrum disorder was observed in 11.2% (41/366). At follow-up, individuals with early-onset reported significantly fewer positive symptoms and were characterised by significantly superior functioning on measures assessing global functioning, social-occupational functioning, and community functioning than individuals with adult-onset. The early-onset group also achieved significantly better vocational outcomes and had a more favourable course of illness with fewer psychotic episodes over the last two years prior to follow-up. Finally, when investigated as a continuous variable, younger age at onset significantly correlated with better symptomatic and functional outcomes. CONCLUSIONS: These results question the assumption that early-onset schizophrenia typically has a poor outcome. Early detection and specialised treatment for the first psychotic episode appear to be more effective at improving long-term functional outcomes in people with early-onset schizophrenia as in those with adult-onset schizophrenia. This possibility and the reasons for it need further investigation.

The EPPIC follow-up study of first-episode psychosis: longer-term clinical and functional outcome 7 years after index admission.

OBJECTIVE: To describe the longer-term clinical and functional outcome of a large, epidemiologic representative cohort of individuals experiencing a first episode of psychosis. METHOD: A naturalistic, prospective follow-up of an epidemiologic sample of 723 consecutive first-episode psychosis patients, followed between January 1998 and April 2005, at a median of 7.4 years after initial presentation to the Early Psychosis Prevention and Intervention Centre (EPPIC) in Melbourne, Australia. EPPIC is a frontline public mental health early psychosis program, servicing a geographically defined catchment area with a population of about 800,000 people. The main outcome measures included the Brief Psychiatric Rating Scale, the Schedule for the Assessment of Negative Symptoms, the Beck Depression Inventory, the Global Assessment of Functioning Scale, the Social and Occupational Functioning Assessment Scale, the Quality of Life Scale, and the remission criteria developed by the Remission in Schizophrenia Working Group. RESULTS: Follow-up information was collected on up to 90.0% (n = 651) of the baseline cohort of 723 participants, with 66.9% (n = 484) interviewed. In the last 2 years, 57% of individuals with schizophrenia/schizophreniform, 54% with schizoaffective disorder, 62% with affective psychosis, and 68% with other psychotic disorders reported some paid employment. Depending upon the criteria applied, symptomatic remission at follow-up was observed in 37%-59% of the cohort. Social/vocational recovery was observed in 31% of the cohort. Approximately a quarter achieved both symptomatic remission and social/vocational recovery. CONCLUSION: The relatively positive outcomes are consistent with a beneficial effect of specialized early intervention programs; however it is premature to draw firm conclusions. There was no control group and there are many differences between the relevant comparison studies and the present one. Although difficult to conduct, large scale controlled health services research trials are required to definitively determine the impact and optimal duration of specialized early psychosis programs.

Early Psychosis Prevention and Intervention Centre long-term follow-up study of first-episode psychosis: methodology and baseline characteristics.

AIM: This paper reports the rationale, methodology and baseline characteristics of a large long-term follow-up study of first-episode psychosis from a geographically defined catchment area. METHOD: A total of 723 first-episode psychosis patients were recruited from a specialized early psychosis service between 1989 and 2001 and prospectively followed up at a median of 7.4 years after initial presentation. Participants' baseline demographic, clinical and functional characteristics are described. Sampling bias at study recruitment was assessed by comparison with a more complete sample of Early Psychosis Prevention and Intervention Centre (EPPIC) cases rated directly from the medical records. RESULTS: At baseline, 57% of the sample were diagnosed with schizophrenia or schizophreniform disorder, whereas the full range of psychotic disorders was represented. Statistical analysis confirmed that the sample recruited was representative of total EPPIC-treated incident cases. CONCLUSIONS: The EPPIC long-term follow-up study is a large and epidemiologically representative first-episode psychosis cohort that has been subsequently prospectively followed up over a long period. Such a sample provides a rare opportunity to study the course and outcome of psychotic disorders.

Recognition of depression and psychosis by young Australians and their beliefs about treatment.

OBJECTIVES: To assess young people's ability to recognise clinically defined depression and psychosis, the types of help they thought appropriate for these problems, their knowledge of appropriate treatments, and their perceptions regarding prognosis. DESIGN: A cross-sectional telephone survey using structured interviews. Vignettes of a person with either depression or psychosis were presented, followed by questions related to recognition of the disorder, best forms of treatment and the prognosis. PARTICIPANTS: A randomly selected sample of 1207 young people aged 12-25 years. SETTING: Melbourne, Victoria, and surrounding regional and rural areas. OUTCOME MEASURES: Responses to a mental health literacy questionnaire. RESULTS: Almost half the respondents were able to identify depression correctly, whereas only a quarter identified psychosis correctly. Counsellors and family or friends were the most commonly cited forms of best help, with family or friends preferred by the younger age group for depression. General practitioners were considered more helpful for depression, and psychiatrists and psychologists more helpful for psychosis. Most respondents considered counselling and psychotherapy to be helpful. However, more than half the respondents expressed negative or equivocal views regarding the helpfulness of recommended pharmacological treatments. CONCLUSIONS: The limitations we identified in youth mental health literacy may contribute to the low rates of treatment and the long duration of untreated illness reported in other studies. There is a need for initiatives to enhance mental health literacy among young people, and those close to them, if benefits of early treatment are to be realised.

Early intervention in first-episode psychosis--the impact of a community development campaign.

OBJECTIVE: Substantial delays in providing access to treatment in first-episode psychosis have been well documented. The present study examines the impact of strategies aimed at improving access and reducing delays. METHOD: A pilot community education campaign was conducted with the aim of reducing the duration of untreated psychosis (DUP) in a geographically defined intervention sector located in the northwestern region of Melbourne, Australia. Utilising a quasi-experimental design, a comparison sector with similar demographics was selected from another part of the north-western region. A mobile early detection team and the same treatment system served both sectors. RESULTS: While there was no significant difference between the mean DUP for intervention and comparison sectors, the distributional features of DUP between the two regions were significantly different. In the intervention sector, disproportionately more cases with very long DUP were detected. When a small number of outliers were removed, the mean and median DUP in the intervention sector was reduced. CONCLUSION: These findings highlight the complexity of treatment access and delay and suggest that efforts to reduce DUP may have two effects, not one. Firstly, a different sample of cases is treated through the detection of hidden "long DUP" cases that otherwise may have remained untreated. Secondly, the DUP for the remainder may indeed be reduced. More research with larger samples and more potent campaign strategies is clearly required. It may also be worth considering whether there is a safe and ethical way to undertake a RCT of early versus delayed antipsychotic treatment to perhaps settle the DUP debate once and for all.