Treatment delay in early psychosis: not a linear problem
Authors: Lena Palaniyappan, Rajeev Krishnadas
Journal: The Lancet Psychiatry (2020)

Any illness, if left untreated, can become more complicated to treat. Psychosis is no exception. This should make early intervention in psychosis a pragmatic call with no prima facie argument against it. Reduction in the duration of untreated psychosis (DUP) underpins the rationale behind early detection and intervention in psychosis. Nevertheless, this very ethos of early intervention has come under scrutiny in the past decade. For example, a meta-analysis of longitudinal observational studies found that longer DUP was not a moderator of remission or recovery rates in first-episode psychosis.1Lally J Ajnakina O Stubbs B et al.Remission and recovery from first-episode psychosis in adults: systematic review and meta-analysis of long-term outcome studies.Br J Psychiatry. 2017; 211: 350-358Crossref PubMed Scopus (131) Google Scholar More recently, Jonas and colleagues explored several explanatory models of this relationship.2Jonas KG Fochtmann LJ Perlman G et al.Lead-time bias confounds association between duration of untreated psychosis and illness course in schizophrenia.Am J Psychiatry. 2020; 177: 327-334Crossref PubMed Scopus (21) Google Scholar They concluded that the apparent relationship between long DUP and poor prognosis is probably a spurious artifact of “lead time bias”, resulting from individuals with a long DUP simply being further along the trajectory of their illness than those with shorter DUP. Where experimental manipulation is not possible, verified models are needed that can explain the link between potential modifiable factors, such as DUP, and outcomes of clinical importance, to justify allocating resources to modify these factors.3Oliver D Davies C Crossland G et al.Can we reduce the duration of untreated psychosis? A systematic review and meta-analysis of controlled interventional studies.Schizophr Bull. 2018; 44: 1362-1372Crossref PubMed Scopus (60) Google Scholar In The Lancet Psychiatry, Richard Drake and colleagues use advanced statistical techniques on a large dataset of 948 patients presenting with first-episode psychosis (NEDEN) to explore the relationship between DUP and psychotic symptomatology at baseline, at 6 months and at 1 year.4Drake RJ Husain N Marshall M et al.Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling study.Lancet Psychiatry. 2020; 7: 602-610Summary Full Text Full Text PDF Scopus (16) Google Scholar Crucially, they replicate the initial findings in an independent dataset of 332 patients (Outlook). They compare several explanatory models and draw three significant conclusions. First, they found that the relationship between DUP and symptom improvement over 1 year was curvilinear. In other words, treatment delay was associated with progressively worse treatment response, but this response worsened more slowly and eventually plateaued as DUP lengthened. Second, long DUP was not associated with symptom severity at baseline in patients assessed within 3 weeks of presentation to services but predicted poor treatment response subsequently. Drake and colleagues suggest that this was probably because greater symptom severity led to a faster presentation (“confounded presentation”), thereby obscuring the relationship between DUP and baseline symptom severity. The only exception to this was depression; longer DUP was associated with both greater baseline severity and reduced treatment responsiveness (in the NEDEN cohort). Finally, they observe generality in the relationship between DUP and treatment responsiveness: all the symptom domains of psychosis respond poorly with delayed treatment. Unlike most other symptom domains of psychosis, most guidelines for psychotic disorders recommend therapeutic abstention for depression until acute psychotic symptoms resolve with treatment.5Donde C Vignaud P Poulet E Brunelin J Haesebaert F Management of depression in patients with schizophrenia spectrum disorders: a critical review of international guidelines.Acta Psychiatr Scand. 2018; 138: 289-299Crossref PubMed Scopus (8) Google Scholar Although not an interventional study, Drake and colleagues' work indicates that depression might accumulate over the early phase of psychosis, highlighting the need to consider depression as a key treatment target for early intervention. Drake and colleagues argue that treatment delay worsens profound underlying illness processes, of which we know very little. But this work gives us a vital clue. The authors observe that longer DUP does not predict baseline illness severity in patients assessed soon after presentation, but predicts the severity at follow-up. In this context, it is possible that treatment delay affects the processes underlying treatment responsiveness, rather than symptom formation per se. This interpretation seems more credible than the conventional, but often disputed, neurotoxicity argument that can reduce to toxic symptoms beget more toxic symptoms.6McGlashan TH Is active psychosis neurotoxic?.Schizophr Bull. 2006; 32: 609-613Crossref PubMed Scopus (92) Google Scholar The novel insight from Drake and colleagues' work shifts the neurobiological focus of early intervention from distal changes that precede psychosis to changes more proximal to the psychotic episode, influencing its resolution. Mechanistically, prolonged untreated psychosis—and the associated excitatory drive—might invoke processes that deplete glutathione, an antioxidant, thereby reducing responsiveness to treatment. Low levels of glutathione have been shown to be a marker of late response to antipsychotics.7Dempster K Jeon P MacKinley M Williamson P Theberge J Palaniyappan L Early treatment response in first episode psychosis: a 7-T magnetic resonance spectroscopic study of glutathione and glutamate.Mol Psychiatry. 2020; (published online March 24.)DOI:10.1038/s41380-020-0704-xCrossref PubMed Scopus (28) Google Scholar Another candidate marker is the functional connectivity of the triple network system, in particular the default mode network. Default mode network hypoconnectivity appears to mediate the relationship between long DUP and treatment response.8Maximo JO Nelson EA Armstrong WP Kraguljac NV Lahti AC Duration of untreated psychosis correlates with brain connectivity and morphology in medication-naive patients with first-episode psychosis.Biol Psychiatry Cogn Neurosci Neuroimaging. 2020; 5: 231-238Summary Full Text Full Text PDF PubMed Scopus (14) Google Scholar Untreated psychosis might invoke large-scale synaptic reorganisation characterised by hypoconnectivity; such a hypoconnected state might be suboptimal for antipsychotic drug response.9Palaniyappan L Inefficient neural system stabilization: a theory of spontaneous resolutions and recurrent relapses in psychosis.J Psychiatry Neurosci. 2019; 44: 367-383Crossref PubMed Scopus (12) Google Scholar Drake and colleagues' findings have several implications. First, studies that use predictive modelling for individualised outcomes could benefit from including variables that capture the nuanced theoretical relationships reported by Drake and colleagues.4Drake RJ Husain N Marshall M et al.Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling study.Lancet Psychiatry. 2020; 7: 602-610Summary Full Text Full Text PDF Scopus (16) Google Scholar, 10Leighton SP Upthegrove R Krishnadas R et al.Development and validation of multivariable prediction models of remission, recovery, and quality of life outcomes in people with first episode psychosis: a machine learning approach.Lancet Digital Health. 2019; 1: e261-e270Summary Full Text Full Text PDF Scopus (13) Google Scholar Second, the curvilinear relationship between DUP and treatment success in early stages of psychosis strengthens the argument for more proactive early assessment and intervention that will shorten treatment delay. It would be best to cut the curve short, so we do not see the long tail of extreme treatment delays in future clinical samples. Equally crucial is to look for means to reduce the initial gradient of this curve, so that brisk treatment response is achieved irrespective of the DUP; this involves understanding and improving the processes underlying treatment response. A flatter slope will mean latecomers to treatment are not penalised with a refractory illness. As we have learnt over the past two decades, even punctual treatment when symptoms first arise continues to be too late when it comes to psychosis. LP reports grants and personal fees from Janssen Canada and Otsuka Canada, grants from Sunovion, and personal fees from SPMM Course UK and The Canadian Psychiatric Association, outside of the submitted work. RK declares no competing interests. Effect of delaying treatment of first-episode psychosis on symptoms and social outcomes: a longitudinal analysis and modelling studyLong DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset. Full-Text PDF Open Access