Schizophrenia affects over 23 million people worldwide (Vos et al, 2013). Current treatments offer relief from symptoms for many, but medication has no direct or lasting influence on the course of the illness and underlying pathophysiology.
Treatment of symptoms in schizophrenia does not affect the causes, and some patients respond poorly to current medication (Millan et al, 2016).
The recent review paper in World Psychiatry by Paolo Fusar‐Poli, Pat McGorry and John Kane provides an overview of interventions for first episode psychosis (Fusar-Poli et al, 2017) by reviewing the current evidence on available treatments and their efficacy in relation to different stages of psychotic illness; from the premorbid to the treatment-resistant stage, based on the model of clinical stages of psychiatric disorders (McGorry et al, 2006). The authors discuss the interventions in the context of two distinct services, one for individuals at Clinical High Risk of Psychosis (CHR-P), and the other the Early Intervention in Psychosis teams.
Four stages of psychotic illness (and the relevant interventions) are presented:
- Stage 0: Asymptomatic genetic risk that is present in the premorbid stage;
- Stage 1: Negative and cognitive symptoms, Attenuated psychotic symptoms and Short-lived remitting psychotic episodes in individuals with high risk of psychosis;
- Stage 2: Full-threshold First Episode Psychosis (FEP) present in people who experience early and full recovery;
- Stage 3: Single relapse of psychotic disorder, Multiple relapses, and Incomplete recovery from first episode in groups that experience late and/or incomplete recovery from symptoms; and finally, severe, persistent, or unremitting illness in individuals who present with chronic symptoms.
The authors present a list of 9 trials, aimed at primary prevention of psychosis. The asymptomatic risk stage poses challenges in research terms, as no pathophysiological mechanisms have been validated in the development of psychosis and therefore existing trials are based on a number of hypotheses.
The authors outline the environmental and social risks that may increase the risk of psychosis in asymptomatic individuals, amongst others: heavy cannabis use, traumatic experiences, being a first or second-generation migrant, and complications in pregnancy. However they also state that there are currently no recognised interventions that would reduce the risk of developing psychosis in this group and advocate a universal improvement in mental health literacy for this at-risk population.
In terms of efficacy, Clinical High Risk of Psychosis (CHR-P) services appear to improve engagement, trust, and satisfaction with services. Individuals within CHR-P services also have a shorter Duration of Untreated Psychosis (DUP) as compared to the population that present to services when already experiencing a first episode. The preventative effect of the intervention is not sustained after 24 months of follow up.
The authors outline a number of studies, detailing some results in favour of Early Intervention Teams, which showed a greater treatment response after 24 months, as compared to treatment as usual, and also in favour of family interventions in reducing family burden and severity of symptoms. The authors present a table with 12 studies (duration 9 – 144 months) and provide meta-analytical results of relapse prevention in service users under the care of Early Intervention services. A review of this evidence suggests that there is no statistically significant difference in terms of relapse ratio between service users under the Early Intervention Services compared to standard care. Fusar-Poli et al (2017) suggest that more research is needed into preventing the risk of relapse following first episode of psychosis, as the subsequent relapses may impact significantly on social functioning and other long- term outcomes (Penn et al, 2005).
The use of Long Acting Injections (LAIs) versus oral treatment in preventing relapse is inconclusive, with 7 meta analyses showing no evidence for use of LAIs in preventing relapse, and 1 meta-analysis that shows contrary results.
The length of the provision of Early Intervention Services also seems to correlate with outcomes. Chang et al (2015), comparing 2 year with 3 year provision, found that the additional year resulted in improvements in severity of positive and negative symptoms.
Conflicting evidence exists regarding discontinuation of treatment with antipsychotic medication following remission of symptoms. A recent meta- analysis found that the risk of relapse was 84% at 36 months following discontinuation (Alvarez-Jimenez et al 2016). On the other hand, two other studies showed that the relapse rate at 7 years was comparable between service users that continued or reduced/stopped treatment, with higher recovery and functional remission in the latter group (Wunderlink et al, 2013; Mayoral‐van Son et al, 2016).
The authors suggest that approximately 30% of service users with first episode psychosis show minimal response to antipsychotic treatment, and therefore argue that recognising treatment resistance early may result in earlier treatment with clozapine. In addition, Fusar-Poli et al (2017) argue that there is limited evidence to support disease progression to Stage 3 (chronic presentation), but at the same time suggest that times to recovery from subsequent episodes are longer, and doses of antipsychotic medication are higher.
The reviewers say:
In conclusion, we show that to improve outcomes of a complex, heterogeneous syndrome such as psychosis, it is necessary to globally adopt complex models integrating a clinical staging framework and coordinated specialty care programmes that offer preemptive interventions to high-risk groups identified across the early stages of the disorder.
Strengths and limitations
- Lack of a systematic methodology and limited information about the quality of the studies included in this overview makes it difficult for the reader to evaluate the quality of the evidence. The authors do not provide an overview of search strategies adapted to select and screen papers, nor the reasons for selecting the clinical staging model (McGorry et al 2006), nor whether other evidence-based frameworks were considered.
- In addition, McGorry (2006) also co-authored this paper. Poli-Fusar et al (2017) also advocated the use of a semi structured interview of their own design (Fusar-Poli and Schultze-Lutter 2016), with no other tools for identification of individuals at risk being discussed or evaluated. This raises the possible risk of bias in terms of selection of papers, and hence may affect the reliability of the conclusions.
- The issue of stigma and how it may affect access to services is not discussed in this paper.
- The authors of the review did not include cultural perspectives and their impact on access to mental health services, even though cultural background has been recognised as influencing individual decisions in accepting help and engaging with services (Memon et al, 2016).
Implications for practice
Fusar-Poli et al (2017) advocate the use of a tool (PDF) to identify individuals at risk of developing psychosis, semi structured interviews designed by Fusar-Poli and Schultze-Lutter (2016) and Fusar-Poli et al (2015). The authors quantify the effectiveness of the tool stating that compared with matched controls, up to 20% of individuals that were identified as having high risk ended up developing psychosis at 2 years.
The challenges involved in effective identification of the population at high risk of developing psychosis have resource implications. The authors state that 35% of the baseline group identified with the semi structured interview (Fusar-Poli and Schultze-Lutter 2016) as being at high risk of psychosis, who did not develop such illness after 2 years, go on to remission of their non-psychotic/behavioural symptoms. In addition, the high level of comorbidity (in 73% of individuals) means that mental health services may retain clients within secondary care due to other complex problems rather than psychosis (Fusar-Poli and Schultze-Lutter 2016), resulting in services being stretched and resources diverted away from specialist, psychosis-focused work. The authors also conclude that one third of service users that are referred to the specialist CHR-P services have already developed psychosis at the time of initial contact. This suggests that access or perhaps identification of individuals at high risk of psychosis is problematic and that for many service users it may be too late to fully benefit from preventative interventions. Given the limited resources available, it may therefore be worth considering the need for further research to develop more sensitive tools for the identification of individuals at high risk of psychosis.
Access to the CHR-P services is complicated by the fact that that 91% of clients that enter first episode services present initially to the generic secondary mental health services. This suggests that the profile of the Early Intervention in Psychosis and CHR-P services is not embedded within the wider health services, and the reasons for the low direct access levels to these specialist services needs to be examined. The authors argue that generic screening of individuals to detect risk of psychosis is not effective, and suggest the use of electronic technologies, and social media, in identifying non-help seeking individuals at risk of psychosis. The authors however are unable to provide evidence on how these non-help seeking individuals, once identified, can gain an understanding of psychosis and accept professional help at the time of need.
Fusar-Poli et al (2017) suggest that the transfer of Early Intervention clients at the end of the intervention period back to GPs or Community Teams may result in loss of any possible previous gains, as the latter teams often work with service users who have very entrenched and chronic problems, and therefore further research is needed to evaluate the efficacy of longer term Early Intervention Services, that would cover the full 5-year critical period.
The authors advocate the use of a diagnostic test (PDF) to predict non-response to treatment, based on response rate and reduction in BPRS or PANNS score following 2 weeks of initial treatment with antipsychotic medication (Samara et al, 2015). They argue that worse outcomes are seen in clients where there is delayed initiation of Clozapine, with mean delay in treatment being approximately 4 years following recognition of treatment resistance (Howes et al, 2012). Fusar-Poli et al (2017) argue that as times to remission increase with each episode, and the doses needed for effective treatment become higher as the illness progresses, it seems crucial to identify treatment resistance as early as possible.
- This review of reviews by Fusar-Poli et al (2017) suggests that short term follow up studies provide evidence in favour of Early Intervention in Psychosis services in terms of severity of symptoms, which appear to be lost at longer term follow up.
- The authors advocate further research in prevention of relapse following first episode and evaluation of effectiveness of longer term Early Intervention Programmes (5 years).
- The authors conclude that no evidence exists in favour of long acting injections, or discontinuation of medication following psychotic episode, and advocate for identification of treatment resistance at the earliest possible stage.
Conflicts of interest
Fusar-Poli P, McGorry PD, Kane JM. (2017) Improving outcomes of first-episode psychosis: an overview. World Psychiatry. 2017 Oct;16(3):251-265. doi: 10.1002/wps.20446.
Alvarez‐Jimenez M, O’Donoghue B, Thompson A et al. Beyond clinical remission in first episode psychosis: thoughts on antipsychotic maintenance vs. guided discontinuation in the functional recovery era. CNS Drugs 2016;30:357‐68
Chang WC, Chan GH, Jim OT et al. Optimal duration of an early intervention programme for first-episode psychosis: randomised controlled trial. Br J Psychiatry 2015;206:492-500.
Connor, C., Birchwood, M., Freemantle, N., Palmer, C., Channa, S., Barker, C., Patterson, P., Singh, S. (2016). Don’t turn your back on the symptoms of psychosis: the results of a proof-of-principle, quasi-experimental intervention to reduce duration of untreated psychosis. BMC Psychiatry, 16, 127. http://doi.org/10.1186/s12888-016-0816-7
Fusar‐Poli P, Schultze‐Lutter F. Predicting the onset of psychosis in patients at clinical high risk: practical guide to probabilistic prognostic reasoning (PDF). Evidence‐Based Mental Health 2016;19:10‐5.
Fusar‐Poli P, Cappucciati M, Rutigliano G et al. (2015) At risk or not at risk? Meta‐analysis of the prognostic accuracy of psychometric interviews for psychosis prediction. World Psychiatry 2015;14:322‐32
Howes OD, Vergunst F, Gee S et al. Adherence to treatment guidelines in clinical practice: study of antipsychotic treatment prior to clozapine initiation. Br J Psychiatry 2012;201:481‐5
Mayoral‐van Son J, de la Foz VO, Martinez‐Garcia O et al. Clinical outcome after antipsychotic treatment discontinuation in functionally recovered first‐episode nonaffective psychosis individuals: a 3‐year naturalistic follow‐up study. J Clin Psychiatry 2016;77:492‐500
McGorry PD, Hickie IB, Yung AR et al (2006) . Clinical staging of psychiatric disorders: a heuristic framework for choosing earlier, safer and more effective interventions. Aust N Z J Psychiatry 2006;40:616‐22.
Memon A, Taylor K, Mohebati LM, et al (2016) Perceived barriers to accessing mental health services among black and minority ethnic (BME) communities: a qualitative study in Southeast England BMJ Open 2016;6:e012337. doi: 10.1136/bmjopen-2016-012337
Millan, MJ, Andrieux, A, Bartzokis, G, Cadenhead, K, Dazzan, P, Fusar-Poli, P, Gallinat, J, Giedd, J, Grayson, DR, Heinrichs, M, Kahn, R, Krebs, MO, Leboyer, M, Lewis, D, Marin, O, Marin, P, Meyer-Lindenberg, A, McGorry, P, McGuire, P, Owen, MJ, Patterson, P, Sawa, A, Spedding, M, Uhlhaas, P, Vaccarino, F, Wahlestedt, C & Weinberger, D (2016) Altering the course of schizophrenia: progress and perspectives. Nature Reviews Drug Discovery. DOI: 10.1038/nrd.2016.28
Penn, D. L., Waldheter, E. J.; Perkins, D. O.; Mueser, K. T.; Lieberman, J. A. (2005) American Journal of Psychiatry 2005 162:12, 2220-2220
Samara MT, Leucht C, Leeflang MM et al. (2015) Early improvement as a predictor of later response to antipsychotics in schizophrenia: a diagnostic test review (PDF). Am J Psychiatry 2015;172:617‐29.
Vos, T., Barber, R. M., Bell, B., Bertozzi-Villa, A., Biryukov, S., Bolliger, I., Charlson, F., Davis, A., Degenhardt, L., Dicker, D., Duan, L., Erskine, H., Feigin, V. L., Ferrari, A. J., et al (2013) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study. The Lancet , Volume 386 , Issue 9995 , 743 – 800 http://dx.doi.org/10.1016/S0140-6736(15)60692-4
Wunderink L, Nieboer RM, Wiersma D et al. (2013) Recovery in remitted first‐episode psychosis at 7 years of follow‐up of an early dose reduction/discontinuation or maintenance treatment strategy: long‐term follow‐up of a 2‐year randomized clinical trial. JAMA Psychiatry 2013;70:913‐20