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Staging neuropsychiatric disorders

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  • 1. Staging in Neuropsychiatry: A Heuristic Modelfor Understanding, Prevention and TreatmentPatrick D. McGorryReceived: 11 November 2009 / Revised: 22 March 2010 / Accepted: 22 March 2010 / Published online: 3 April 2010Ó Springer Science+Business Media, LLC 2010Abstract The main mental disorders which develop andpersist through adult life typically emerge during the crit-ical developmental phase of adolescence and early adult-hood, and are frequently associated with considerableassociated distress and functional decline. Our currentdiagnostic system lacks validity and therapeutic utility,particularly for the early stages of these mental disorders,when symptoms are still evolving and may have not yetstabilised sufficiently to fit familiar or traditional syndro-mal criteria. Furthermore, there is often difficulty in dis-tinguishing transient developmental or normative changesfrom the early symptoms of persistent and disabling mentalillness. These factors point to the need for reform of ourcurrent diagnostic systems. The clinical staging modelseeks to define the extent of progression of a disorder at aparticular point in time and aims to differentiate early,milder clinical phenomena from those that accompanyillness progression and chronicity. The staging frameworkallows clinicians to select treatments relevant to earlierstages of an illness, and to evaluate their effectiveness inpreventing progression and producing remission or returnto milder or earlier stages of disorder. For staging to be avalid approach, interventions in the early stages need toshown to be not only more effective but also safer thantreatments delivered later in the course of illness. Stagingmay also allow a more efficient integration of our rapidlyexpanding knowledge of the biological, social andpsychological vulnerability factors involved in develop-ment of mental illness into what may ultimately resemble aclinicopathological staging model.Keywords Clinical staging Á Pluripotential risksyndrome Á Psychosis Á Schizophrenia Á Bipolar disorder ÁMood disorder Á Early intervention Á Youth mental healthI feel certain that many incipient cases might bearrested before the efficient contact with reality iscompletely suspended. (Sullivan 1927)The majority of the psychiatric morbidity which mani-fests during adult life emerges for the first time before theage of 25 years, either evolving from childhood emotionaland behavioural disorder, or appearing de novo frompuberty through to the mid-twenties as a surge of newincident cases (Kessler et al. 2005). Lifetime risk formental disorder can reach as much as 50% (Kessler et al.2005). There are many biological, psychological andsociological reasons for this pattern of onset (Arnett 2004;Eckersley 2008; Paus et al. 2008).The onset of mental disorder can be difficult to distin-guish from transitory and normative changes in emotionsand behaviour, especially in young people. This is consis-tent with the high rate of initial resolution, even with min-imal or no intervention (Stice et al. 2007), which converselyunderestimates the level of underlying chronicity. There areno clear criteria at present for defining a threshold for initial‘caseness’, a status most commonly attained in emergingadulthood. How symptoms are acquired, intensify andcohere into syndromes, and how these ebb and flow, has notbeen widely considered (Eaton et al. 1995). We also lackvalid definitions for distinguishing between benign andP. D. McGorryCentre for Youth Mental Health, University of Melbourne,Melbourne, AustraliaP. D. McGorry (&)Orygen Youth Health Research Centre, Locked Bag 10,Parkville, VIC 3052, Australiae-mail: pmcgorry@unimelb.edu.auNeurotox Res (2010) 18:19–30DOI 10.1007/s12640-010-9179-xOriginally published in Neurotoxicity Research, Volume 18, Nos. 3-4
  • 2. self-limiting states and states which represent the earlystages of what will become persistent and disabling condi-tions (Kessler et al. 2005). While much distress seems,initially at least, self-limiting (Eaton et al. 1995), it isimportant not to trivialise the significance of this since sub-threshold symptoms strongly predict future disorder (Eatonet al. 1995; Harrington and Clark 1998; Yung et al. 2004a, b;Hetrick et al. 2008a, b; Seeley et al. 2009). The concepts anddefinitions we have used to date, since they are quasi-syn-dromal, polythetic and descriptive, tend to lack discriminantvalidity and therapeutic utility. Arbitrary strategies to forcediscriminant validity such as hierarchies, have merelyobscured the problem and are breaking down; however,currently popular dimensional adjuncts are just as unlikelyto solve it. There is an overdue impatience with the tradi-tional ‘purer’ categories and a welcome desire to explorelarger super-ordinate categories with a complementarydimensional crosscutting matrix (Regier et al. 2009).However, no practical research strategy has yet been for-mulated to take us beyond the current impasse. We need aheuristic strategy that aims to develop ground rules forclarifying as early as possible which people with emotionaland behavioural disturbance are at specific risk of persistentand disabling mental illness, and what the sequence ofestablished and novel therapeutic strategies is which is mostlikely to not only successfully achieve remission of currentsymptoms and psychosocial recovery, but also to reduce therisk of persistence and recurrence.We have been very patient with the traditional diag-nostic system, which, for the psychotic and mood disor-ders, is over a century old. Having struggled withProcrustean diagnostic concepts that receive little valida-tion until the illness has fully evolved, we are nowbeginning to see how a more flexible system linking thecourse, extension and pattern of illness over time might bemore strategically useful not only in clinical practice butalso in basic research. Our current diagnostic systems arecharacterised by artificial divisions based on cross-sec-tional symptom sets, propped up with course and outcomevariables. Early clinical features are not differentiated fromthose that become apparent as a disorder persists, and noconsideration is given to the definition of the onset of adisorder. The traditional diagnostic concepts in the moodand psychotic disorders have been derived from the moreprevalent subsamples of chronic patients, thereby enhanc-ing the impression of stability and validity. However, ineveryday clinical practice these operationally defineddiagnostic criteria have unfortunately done little more thancreate a spurious precision which does not extend farbeyond the research setting, and questions of validity andutility remain unresolved (Jansson and Parnas 2007). Theymay be alternately viewed as stable outcome variables,rather than useful tools for guiding early intervention ortreatment of people with less severe illness, or uncoveringunderlying pathological mechanisms.The ubiquity of comorbidity and polypharmacy providesevidence of the practical weakness of our current diag-nostic concepts. Drug therapies lack specificity for indi-vidual diagnoses as reflected in high levels of off-label useand ever-widening indications. Psychosocial treatmentsappropriately focus on broader personal and social needsand hence range freely across the diagnostic landscape.How can we reform and refine diagnosis so that treatmentscan be selected in a safer, more effective manner, prognosiscan be more accurately assessed, and the confusing array ofbiological disturbances rearranged into something resem-bling a clinicopathological framework? Clinical staging, adeceptively simple and practical tool found useful in otherareas of medicine, may provide a way forward (McGorryet al. 2006, 2007a, b). In a pre-emptive psychiatry (Insel2007) based on the clinical staging paradigm, end-stagesyndromes such as deficit schizophrenia may fade into thebackground as destinations to be avoided. This is a wel-come departure from the deterministic thinking that hasplagued psychiatry for so long, and opens the door forbetter understanding of gene–environment interactions inthe onset and course of psychiatric illness (Insel 2007).What is Clinical Staging?Clinical staging is, simply, a more refined form of diag-nosis. Its value is recognised in the treatment of malig-nancies and many other potentially serious medicalillnesses, such as diabetes and arthritis, where limiting theextension and secondary impacts of the disease, andimproving quality of life and survival, all rely on the ear-liest possible delivery of effective interventions. Clinicalstaging differs from conventional diagnostic practice inthat it not only defines the extent of progression of a dis-order at a particular point in time, but also where a personlies currently along the continuum of the course of an ill-ness. The differentiation of early and milder clinical phe-nomena, from those that accompany illness extension,progression and chronicity, lies at the heart of the concept,which therefore makes it especially useful in adolescenceand early adulthood, when most adult-type disordersemerge for the first time. A staging framework enablesclinicians to select treatments relevant to earlier stages ofan illness, and generally assumes that such interventionswill be both more effective and less harmful than treat-ments delivered later in the course.Early successful treatment may change the originalprognosis and thus prevent progression to subsequentstages, optimally resulting in remission and cure. Ourcurrent diagnostic categories are disconnected from the20 Neurotox Res (2010) 18:19–30
  • 3. underlying substrates of the disorders and impose artificialboundaries without utility. In addition to guiding treatmentselection, a staging framework, which cuts across thecurrent ‘diagnostic silos’ to encompass a broader range ofclinical phenotypes, yet which introduces subtypes along alongitudinal dimension, has the potential to organiseendophenotypic and biomarker data in a more coherent andmutually validating fashion.How do We Define the Stages of a Disorder?In other medical conditions, clinical stages are defined by theextent and progression of the illness and its biological impacton the patient, which in turn must correlate with prognosis.This approach usually depends on a capacity to definepathologically, as well as clinically, the limits or extent of thedisease process. In clinical psychiatry, this could involve notonly a cross-sectional clinical definition, but a wider bio-psychosocial definition of extent or progression. Therefore,in addition to the severity, persistence and recurrence ofsymptoms, biological changes (e.g. hippocampal volumeloss, neurocognitive deficits and dysregulation of the HPA)and the social impact of a disorder (e.g. the effect on socialrelationships and employment) could also be drawn into thedefinition. Ultimately, something approaching a clinico-pathological model could emerge.What are the Potential Benefits of Staging?On the clinical side, defining discrete stages according toprogression of disease creates a framework for the evalu-ation of interventions oriented towards prevention andcure. The aim is to prevent progression to more advancedstages, or to promote regression to an earlier stage,including full and sustained remission. In order to achievethis, an accurate understanding of the social, biological,and personal risk and protective factors that influenceprogression from one stage to the next will be essential.Furthermore, we need to know the relative potency of theserisk factors and which of them may be responsive to cur-rent interventions. While some factors may operate acrossseveral or all stage transitions, others may be stage-spe-cific; for example, substance misuse or stress may beespecially harmful in triggering the onset of the first epi-sode of an illness, yet be less toxic subsequently (or viceversa). Gene–environment interactions probably underpinand mediate these transitions and recent advances in theunderstanding of epigenetics and brain plasticity offer newpathways to study this process.A clinicopathological staging model that spans thecurrent diagnostic categories and allows the mapping of therelationships between biological markers and the stages ofdisorder will allow us to define and validate more mean-ingful boundaries for clinical entities, and distinguish corebiological processes from epiphenomena and sequelae,enabling existing knowledge to be better represented andunderstood (McGorry et al. 2006). It is likely that byfocusing earlier on what appear to be pluripotential syn-dromes, and testing broader psychosocial and more genericneuroprotective interventions, we may learn more about thesubtle pathophysiology of the onset and persistence ofdisorder and distinguish this better from vulnerability onthe one hand, and sequelae on the other.The Pluripotential Risk Syndrome Versus the SpecificProdromeThe above discussion points to several questions regardingthe specificity of the earliest stages of psychiatric disorders.First, if we define target syndromes such as deficitschizophrenia, persistent or recurrent major depression orfully developed mania, how soon can specific indicators ofprogress towards such defined syndromes or disorders berecognised? A second, related question is whether earlierstages of disorders, which tend to be phenotypically verysimilar, are in fact ‘pluripotential’ (i.e. may develop intoone of a range of disorders) or whether they contain a‘mixed bag’ of people on the way to a fixed destination,a particular target or outcome, such as schizophrenia (i.e.,a ‘predetermined’ outcome). If we follow prospectivecohorts, we may see a gradual separation and intensifica-tion over time within individual patients of symptomclusters and syndromes, often in a kaleidoscopic fashion.An apparently pluripotential prodrome may exit into psy-chotic disorders, non-psychotic mood and anxiety disor-ders, substance use disorders or comorbid combinations ofthese disorders.Can these alternative models, pluripotentiality versuspredetermination, of the evolution of psychiatric disordersbe distinguished? The question can be addressed by natu-ralistic studies to some extent, but ultimately randomisedtrials of different interventions and measurement ofpotentially predictive biomarkers and risk factors may bemore informative in revealing to what extent the clinicalpathways are fluid or fixed.Staging and Psychosis: A Framework for PreventivelyOriented CareOver the past 15 years or so, an international collaborativeendeavour has sought to modify and apply the principlesand practice of early diagnosis and staged treatment to the21Neurotox Res (2010) 18:19–30
  • 4. field of psychotic disorders (McGorry et al. 1996;McGlashan 1998; Edwards and McGorry 2002; McGorryand Yung 2003). One pillar of the early intervention par-adigm has been the relationship between prolonged illnessduration and poor outcome in the psychotic disorders(Harrigan et al. 2003). In a recent metaanalysis (Marshallet al. 2005) and systematic review (Perkins et al. 2005),longer duration of untreated psychosis (DUP) was associ-ated with poorer response to antipsychotic treatment asmeasured by severity of global psychopathology, positiveand negative symptoms, demoralisation, depression andfunctional outcomes. Neuroimaging studies have alsoindicated that prolonged untreated illness is associated withmore pronounced structural brain abnormalities, while thisis less prominent earlier in the course of the disorder(Keshavan and Amirsadri 2007). Treatment delay may bereduced by early detection and intervention, resulting inimproved short-term and longer-term outcome (Johannes-sen et al. 2001, 2005; Larsen et al. 2001, 2006). Ran-domised trials have also suggested that initiation ofatypical antipsychotic therapy at the first episode mayprevent progression of the structural changes seen in thedisorder (Lieberman et al. 2005).The Prodromal or Ultra-High Risk StageInitially, the early psychosis focus was on the timely rec-ognition and phase specific treatment of first-episode psy-chosis (FEP; see below). However, it was also recognisedthat for most patients a prolonged period of attenuatedsymptoms and impaired functioning precedes the firstpsychotic episode (Hafner et al. 1993; Yung and McGorry1996a, b). Much of the disability associated with the psy-chotic disorders, particularly schizophrenia, develops longbefore the onset of frank psychosis and is difficult toreverse even if the first psychotic episode is successfullytreated (Hafner et al. 2003). This pre-onset period of illnesshas been termed the prodromal phase (Huber et al. 1979;Yung 2003). Intervening during this phase may ameliorate,delay or even prevent onset of fully fledged disorder,thereby reducing the burden of disability, prevalence andpossibly even the incidence of psychotic disorders(McGorry et al. 2001).However, this goal presented the major challenge ofprospectively identifying the prodromal phase, a taskcomplicated by the non-specific nature of prodromalsymptoms (Yung et al. 1998). Criteria were introduced forthe prospective identification of individuals at heightenedrisk of developing FEP within a brief time period—that is,as possibly being in the prodromal phase of illness. Thesecriteria are based on a combination of known trait and staterisk factors for psychosis, including attenuated positivepsychotic symptoms, brief self-limited psychotic symp-toms and family history of psychotic disorder. They havebeen termed the ‘ultra-high risk’ (UHR) criteria (Yunget al. 2004a, b). The first published study using the UHRcriteria found a transition rate of 40% to threshold psy-chotic disorder within 1 year (Yung et al. 2003), despitethe provision of needs-based psychosocial intervention andantidepressant treatment where indicated. This finding hassubsequently been replicated by several groups interna-tionally (Miller et al. 2002; Mason et al. 2004; Riecher-Rossler et al. 2007), including the recent multi-centreNorth American Prodromal Longitudinal Study (NAPLS)(Addington et al. 2007; Cannon et al. 2008). Using acombination of studies, Ruhrmann et al. (2003) reported anaverage 1 year transition rate of 36.7% in UHR subjectswho did not receive antipsychotic treatment. These resultsindicated that the UHR criteria are valid and reliable cri-teria for predicting psychosis onset in this population.Intervention Studies in Ultra-High Risk GroupsThe successful identification of the ‘at-risk’ populationfacilitated two important advances in the early psychosisfield: (i) research into processes associated with the onsetof psychosis, including psychopathological, neurocognitiveand neurobiological variables; and (ii) the implementationof intervention trials aimed at treating existing symptom-atic and functional impairment in the UHR population anddetermining whether specific interventions are able toameliorate, delay or prevent onset of fully fledged psy-chotic disorder in this population.The intervention studies to date are summarised brieflybelow (see McGorry et al. (2009) for review). The firstsuch intervention trial, conducted by our group in Mel-bourne, Australia, compared combined cognitive behaviourtherapy (CBT) and low dose atypical antipsychotic medi-cation (risperidone) (n = 31) with usual case management(n = 28) (McGorry et al. 2002). Subjects were randomised,but neither patients nor investigators were blind to theintervention received. The rate of psychosis onset in thetreatment group was significantly lower than in the controlgroup at the end of the 6 month treatment phase (9.7 vs.35%, P = 0.026). However, after a further 6 months offollow up this finding was no longer statistically significantdue to patients who were not fully adherent to their anti-psychotic medication developing a psychotic disorder overthe second 6 month period. Those who were fully adherentto risperidone during the initial 6 month treatment phase allremained non-psychotic over the follow up period eventhough they had ceased drug treatment. This study dem-onstrated that the onset of psychosis can at least bedelayed, if not prevented, by specific intervention.22 Neurotox Res (2010) 18:19–30
  • 5. However, the active component of the treatment regimecould not be identified since medication and CBT werecombined. The results also suggested that further benefitmay be obtained with a longer treatment time, an outcomereinforced by a longer-term follow up of the sample whichfailed to show any persisting benefit over 3–4 years in theexperimental group (Phillips et al. 2007).A randomised double-blind placebo-controlled trial wasthen conducted by researchers from Yale University, USA(McGlashan et al. 2004). Low dose olanzapine (n = 31)was compared to placebo (n = 29) for 12 months followedby a 12-month monitoring period. Although there was atrend towards the olanzapine-treated group having areduced rate of transition to psychosis, this finding was notsignificant. There were also some adverse effects associ-ated with olanzapine treatment, leading to a more conser-vative interpretation of the results (McGlashan et al. 2006).The risk–benefit ratio for olanzapine thus appears to be lessfavourable than risperidone at this stage of illness.A third treatment trial in UHR patients was conducted inManchester, UK (Morrison et al. 2004). Subjects (n = 58)were randomised to receive cognitive therapy for 6 monthsor monitoring of mental state only. The group that receivedcognitive therapy had a significantly lower rate of transi-tion to full-threshold disorder (6 vs. 26%, P 0.05) and asignificantly greater reduction in psychiatric symptoms(P 0.02) at 12 months. At 3 year follow up, cognitivetherapy was associated with a significantly lower rate oftransition to psychosis when baseline cognitive factorswere controlled for and a significantly reduced likelihoodof being prescribed antipsychotic medication (Morrisonet al. 2007). Consistent with this, Bechdolf et al. (2007)reported that for patients in the early initial prodromalstate, as identified by the presence of basic symptoms, CBTwas superior to supportive counselling in reducing pro-gression to sub-threshold psychotic symptoms and to full-threshold psychosis over 24 months. The OPUS trial(Nordentoft et al. 2006) also indicated that transition ratescould be reduced in a group of patients with schizotypaldisorder by intervening with the OPUS package, whichconsisted of intensive clinical case management, familyinvolvement and a psychoeducational approach within acognitive behavioural framework.Recently, there has been interest in the possibility ofusing antidepressants to reduce risk of psychosis in high-risk samples. Cornblatt et al. reported a naturalistic study ofyoung people with prodromal symptoms treated either withantidepressants or antipsychotics (Cornblatt et al. 2007).Twelve of the 28 patients (43%) who had been prescribedantipsychotics progressed to full-threshold psychosis in thefollowing 2 years, whereas none of the 20 patients treatedwith antidepressants subsequently developed psychosis.Similar results are reported by Fusar-Poli et al. (2007) onthe basis of a file audit. However, these results need to beinterpreted with caution due to the uncontrolled nature ofthe studies: there may have been differences in baselinesymptom, functioning or other variables between treatmentgroups and non-adherence was far more prominentamongst patients prescribed antipsychotics than patientsprescribed antidepressants. Our initial trial (McGorry et al.2002) found that antidepressants, again prescribedaccording to clinical need, had no influence on the transi-tion rate.Open-label trials of aripiprazole and the amino acidglycine have also recently been conducted in the UHRpopulation. In the aripiprazole trial (Woods et al. 2007), 15UHR patients were treated with a flexible dose regime of5–30 mg/day for 8 weeks. Improvements on clinical mea-sures were evident by the first week and no participantstransitioned to psychosis. Adverse events were minimal.These findings indicate a promising efficacy and safetyprofile for aripiprazole for UHR patients. In the glycinepilot trial (Woods et al. 2006), 10 UHR patients weretreated with glycine over an 8-week period. No participantstransitioned to full-threshold psychosis and significantimprovements in different psychopathological domainswere reported, with minimal side effects.In a recent, more sophisticated double-blind placebo-controlled intervention trial, we have compared the com-binations of risperidone and CBT with placebo and CBT orplacebo and supportive therapy in a group of 115 UHRpatients (Phillips et al. 2009). The 6-month transition rateswere low in all three treatment groups, suggesting thatantipsychotics may not be necessary in UHR cases who aredetected early, or that recent UHR cohorts are derived fromless ‘enriched’ samples in terms of the true positive rate(McGorry et al. 2007a b; Yung et al. 2007a, b, c). Earlydetection and treatment may mean that more benigninterventions are sufficient at this stage of illness. Theseshould certainly be offered first; only when symptoms andimpairment persist or worsen should other options suchas drug therapies be considered. Furthermore, the highrates of psychotic-like experiences in community cohorts(Laurens et al. 2007; Yung et al. 2007a, b, c) is consistentwith the notion that a staged approach to treatment may beindicated, with antipsychotic agents not being necessary forall individuals with sub-threshold psychotic symptoms.Another recent study lends further support to this stagedapproach to intervention in the UHR group. This was a12-week placebo-controlled randomised trial of the omega-3fatty acid eicosapentanoic acid (EPA) in a group of 80UHR adolescents. At the end of the 12-week interventionphase, 8 of 38 (21.1%) individuals in the placebo group and1 of 38 (2.6%) in the EPA group had progressed to FEP, astatistically significant difference (P = 0.028). No clini-cally significant adverse effects were reported, and EPA23Neurotox Res (2010) 18:19–30
  • 6. was well accepted by this patient group. Most notably, thetreatment effect was maintained at 12 month follow up(Amminger et al. 2010).Previous treatment studies of EPA supplementation indifferent samples of psychotic patients indicate that theeffect of EPA is dependent on stage of illness. EPA hasbeen found to be partially effective in samples with recentonset psychosis (Emsley et al. 2002; Berger et al. 2007a, b)but has no effect in chronic schizophrenia (Fenton et al.2001). These findings support the clinical staging model inthat the effect of the intervention seems dependent on thestage of illness progression. There is also good evidencethat EPA has a generalised positive effect on mental healthcomplaints (Peet and Stokes 2005; Freeman et al. 2006).This generalised effect is appropriate for the UHR group,who have been found to have a wide variety of generalpsychiatric symptoms, not only attenuated psychoticsymptoms, and which are a target in their own right(Phillips et al. 2009).Applying the clinical staging model to treatment of theUHR population, the evidence reviewed above indicatesthat ‘gentler’ therapies such as EPA or psychosocialinterventions, including CBT or supportive therapy, maybe suitable as a first line treatment in UHR patients.However, the clinical staging model does not necessarilymean eschewing study of the role of antipsychotic medi-cation in this population. Broad spectrum antipsychoticsmay also have a neuroprotective effect, reduce anxiety anddepression, and may possess minimal side effects. Theymay still have a place in delaying or preventing psychosisonset and should be further studied especially in those whopresent late with UHR symptoms or fail to respond toinitial intervention with ‘gentler’ therapies. The best can-didates are those with a more favourable metabolic andneurological safety profile such as quetiapine and aripip-razole (Kahn et al. 2008).It is also possible that optimal treatment is not deter-mined solely by stage of illness factors (i.e., whether thepatient is high risk, the ‘degree’ of high risk, or whetherhe/she is suffering from a first episode or in a chronicstage of illness). In other words, symptom severity alone,as we have defined it in the definition of ‘transition’, maynot be a perfect guide for the need for antipsychoticmedication. There may be other factors, such as symptomtype and other clinical phenomena, comorbid substanceuse, triggers and stressors, genetic and other biomarkers,etc. that could determine optimal treatment for a givenpatient. Therefore, some UHR patients may in fact benefitfrom treatment with antipsychotics, while some FEPpatients, especially those with a very short DUP may notand may remit with intensive psychosocial interventions.Further intervention research is required in order to shedlight on these issues.Falling Transition Rates: What does this Mean?Another critical finding in the UHR group is that thetransition rate to full-threshold psychosis has been drop-ping in recent cohorts. At the PACE Clinic in Melbournethe transition rate has dropped from about 50% in 1995 toabout 12% in 2000, with each successive year showing atransition rate of 0.80 times that of the preceding year(Yung et al. 2007a, b, c). There has also been a shorterduration of symptoms prior to entering the clinic for morerecent cohorts. A similarly reducing transition rate has beenobserved in some other UHR clinics. The reasons for thereducing transition rate are unclear. It may be due to earlierdetection and treatment of UHR samples, allowing psy-chosocial intervention to be more effective in delaying orreducing transition, in line with the staging model. It mayalso be due to identifying more ‘false positives’ in UHRsamples (i.e., a ‘diluted’ sample with less inherent risk),due to different referral patterns. Against this notion is thefact that the functional level of the patients presenting tothe clinic remains reduced to the same level as previously.Alternatively, since patients now have a much shorterduration of prodromal symptoms, it may be an example oflead time bias where the patients need to be followed for alonger period before we can say that the transition rate andlevel of risk has truly been reduced. If the staging model isvalid then the ability to offer simpler interventions earliermay be responsible for a sustained reduction in transition.Even longer-term follow up, however, will not help todistinguish between these possibilities, since both greatereffectiveness of the same treatment delivered earlier in theUHR stage and a more dilute level of true risk in thesample would both result in a sustained reduction in tran-sition rates over time. The only way to distinguish wouldbe to compare monitoring alone with the existing psycho-social interventions Either way the lower transition ratesand consequently higher false positive rates (at least inshort-term follow up) mean that safer interventions must beoffered as the first line treatment for people who never-theless have a clear-cut need for care of some kind.Interventions for First-Episode Psychosis (FEP)We can divide first-episode psychosis (FEP) into the periodbefore psychosis is detected and the period after detection.All too commonly the undetected/untreated phase can beprolonged, even in developed countries (McGlashan 1999).Even when psychosis is detected, the initiation of effec-tive treatment may still be delayed. Post-detection, theintervention goals are engagement and the initiation ofpharmaceutical and psychosocial treatments. Intensiveinterventions aimed at maximal symptomatic and functional24 Neurotox Res (2010) 18:19–30
  • 7. recovery and the prevention of relapse are ideally deliveredduring the early weeks and months of treatment.The controversy surrounding the importance of DUPand treatment delay in first-episode psychosis seems tohave been largely resolved following the publication ofsome key systematic reviews (Marshall et al. 2005; Perkinset al. 2005) and recent influential longitudinal research.These studies have now established that longer DUP isboth a marker and independent risk factor for poor out-come. The TIPS study in Scandinavia has shown, throughan innovative study design, that reducing DUP leads toearly benefits in reducing suicide risk and severity of ill-ness at initial treatment, and sustained benefits in terms ofnegative symptoms and social functioning (Melle et al.2009). The relationship between DUP and outcome isrobust, being sustained over many years of follow up(Bottlender et al. 2002; Harris et al. 2005) and is also foundin low and middle income countries (Farooq et al. 2009).However, these studies do show that, though it is a mal-leable risk factor, DUP accounts for a relatively modestamount of outcome variance, underlining the importance oftreatment access, retention and quality during the earlyyears of illness, known as the critical period.There is an extensive literature attesting to the benefitsof comprehensive care of the first psychotic episode, whichhas been summarised in the International Clinical PracticeGuidelines for Early Psychosis published in 2005 (Inter-national Early Psychosis Writing Group 2005). Since then,the large multicentre EUFEST study has shown that in thetreatment of first-episode schizophreniform and schizo-phrenic disorders, second generation antipsychotics(SGAs) have some clear-cut advantages over first genera-tion agents (FGAs) (Kahn et al. 2008). While most patientswho were able to tolerate the particular medicationresponded well to both FGA and SGA medications, with nosignificant differences in efficacy, the all-cause discontin-uation rate and tolerability were clearly superior for theSGAs. This was true even when compared with very lowdose haloperidol. While the authors’ conclusions and rec-ommendations highlighted the equivalent efficacy of bothdrug classes (a secondary outcome measure), the EUFESTfindings contrast markedly with those of the CATIE studyin chronic schizophrenia where no dramatic advantageswere found for SGAs using similar primary outcomemeasures. The EUFEST data support the recommendationsin the International Clinical Practice Guidelines for EarlyPsychosis, which favours the use of the SGAs as first linetherapy due to their better tolerability (a crucial issue indrug-naı¨ve first-episode patients) and the reduced risk oftardive dyskinesia (International Early Psychosis WritingGroup 2005; Kahn et al. 2008). However, certain SGAs areassociated with a particularly high risk of significantweight gain and metabolic problems, and these risks needto be carefully managed and prevented wherever possible,particularly in view of the increased levels of medicalcomorbidity and premature death in people with psychoticillness (Parsons et al. 2009).Psychosocial treatments in early psychosis have beenextensively studied, with positive findings pointing to thevalue of cognitive therapies in accelerating and maximisingsymptomatic and functional recovery (Jackson et al. 2008).Increasingly, there has been attention to the fact that medi-cations, while assisting in symptomatic recovery, do notcontribute to a return to functioning. This has led to anincreased focus on the need to enhance social recovery(Fowler et al. 2009) especially educational and vocationalaspects (Fraser et al. 2006; Killackey et al. 2006; Killackeyet al. 2008) through the combination of effective psychoso-cial interventions with well-managed medication. There isalso an increasing focus on targeted cognitive remedia-tion and to limit the degree of cognitive decline that is oftenfound as illness progresses (Wykes et al. 2007; Eack et al.2009).Future Progress in FEP InterventionThe place of the new SGA long-acting injectables andclozapine needs to be clarified as well as adjunctive neu-roprotective agents such as omega-3, lithium and N-acetylcysteine (Berger et al. 2007a, b; Berk et al. 2008; Amm-inger et al. 2010). With the advent of very short DUP formany patients, there may be a subset of FEP patients forwhom intensive psychosocial intervention may be suffi-cient as a first line treatment approach without initialantipsychotic medication. We are currently conducting anintervention study to examine this possibility. CBT, familyintervention, targeting of substance abuse, suicide risk andvocational rehabilitation are the key psychosocial inter-ventions in early psychosis and need to be much moreintensively and widely deployed (McGlashan 1998; Yunget al. 2007a, b, c; McGorry et al. 2008a, b; Killackey andMcGorry 2008; Mihalopoulos et al. 2009). Assertivecommunity treatment for the subset of poorly engagedpatients is vital. Family interventions are also an essentialelement of care. They have been shown to lead to shorterperiods of hospitalisations in FEP patients, assisting par-ents in supporting their children within the community(Lenior et al. 2001). A family psychosocial module wasalso an essential component in a relapse prevention inter-vention, which was more effective than standard care atpreventing the occurrence of a second episode of psychosis(Gleeson et al. 2009). In patients with schizophrenia, theevidence indicates that the relapse rate can be reduced by20% if relatives are included in treatment (Addington andAddington 2008).25Neurotox Res (2010) 18:19–30
  • 8. The Critical Period in Early PsychosisThe initial few years beyond the first psychotic episodehave been referred to as the ‘critical period’ (Birchwood2000). Treatment goals in this phase are sustainedengagement and tenure in specialised care, continuingeffective medication management and the use of effectivepsychosocial interventions to minimise the risk of relapse,the development of disability and to maximise social andfunctional recovery. Proof of concept is now establishedfor these strategies at least in the short term (Craig et al.2004; Power et al. 2007; Bertelsen et al. 2008; Gleesonet al. 2009). However, there remains a large gap in mostcommunities between what works and what is available,even in high income countries and certainly in the low andmiddle income countries (McGorry et al. 2008a, b).Beyond the first episode, we know that the first 2–5 yearspost-diagnosis is crucial in setting the scene for longer-termrecovery and outcome. This is the period of maximum riskfor disengagement, relapse and suicide, as well as coincidingwith the major developmental challenges of forming a stableidentity, peer network, vocational training and intimaterelationships. It makes sense that a stream of care speciallyfocused on young people and on this stage of illness isrequired to maximise the chances of engagement, continuityof care, appropriate lifestyle changes, adherence to treat-ment, family support and vocational recovery and progress.Indeed, the available evidence from naturalistic and ran-domised studies strongly supports the value of specialisedearly psychosis programs in improving outcome in the shortterm. If these programs are only provided for 1–2 years,there is also evidence that some of the gains are eroded,suggesting that for a substantial subset at least, specialisedearly psychosis care needs to be provided for a longer period,probably up to 5 years in many cases (Harris et al. 2005;Bertelsen et al. 2008; Killackey and McGorry 2008). At thispoint persisting illness and disability may be present in amuch smaller percentage of people whose needs may sub-sequently be well met by more traditional mental healthservices for older adults. This may be a much better point totransfer care.Risk Syndromes, Staging and Early Interventionfor Mood DisordersWith the target for early intervention in psychotic disordersextending forward to the prepsychotic or ultra-high riskstage, a key question to now ask is: can we treat evenearlier (Egeland et al. 2000; Angst et al. 2003; Lewinsohnet al. 2003; Thompson et al. 2003; Kessing et al. 2004;Correll et al. 2007; Duffy et al. 2010)? Furthermore, theUHR criteria described above which were defined with theprediction of non-affective psychosis in mind lead to aheterogeneous range of diagnoses across the spectrum ofpsychosis, including psychotic depression and mania(Mason et al. 2004). Prior to the onset of attenuated psy-chotic features, in the early prodrome of schizophrenia,general symptoms such as irritability, anxiety and depres-sion are known to occur, which could evolve into a numberof different clinical outcomes (as well as resolve or remit)(Yung and McGorry 1996a b). Ha¨fner et al. failed to dis-tinguish the prodromal stage of schizophrenia from that ofdepression in a retrospective study (Hafner et al. 2005).Thus, the challenge here is to determine if different end-stage syndromes (such as schizophrenia, bipolar disorderand unipolar depression) have a common ‘pluripotential’early onset phase, or whether there is any early specificityof the clinical phenotype, perhaps enhanced through bio-markers. More work is required to clarify whether there is aspecific prodromal stage for mood disorders that can bereliably differentiated from the prodrome of psychotic dis-orders. This would justify specific early identification andintervention strategies for mood disorders. The alternativeapproach is to have a broader risk identification and inter-vention approach, consistent with the pluripotential model.Fava and Tossani reviewed the literature for identifying aprodrome for depressive disorders (Fava and Tossani 2007).They concluded that anxiety and irritability are commonlyobserved in the prodromal phase of depression; that sub-threshold or minor depression is implicated as a risk factorfor the development of major depression, reinforcing thenotion that depressive symptoms occur on a continuumrather than in discrete categories; and that prodromalsymptoms can persist after full-threshold episodes asresidual symptoms, which may inform efforts towardsrelapse prevention (Clarke et al. 2001). Subsyndromaldepression is significant not only as a risk factor fordepressive disorders but also because of its high prevalenceand the impact of symptoms on functioning (Hetrick et al.2008b). Eaton highlighted the greatly increased risk ofmajor depression conferred by subthreshold depressivesymptoms (Eaton et al. 1995) thus laying the foundations forintervention studies to reduce this risk (Harrington andClark 1998). Few have taken up this challenge to date.However, although including some mixed results, studies byJaycox et al. (1994), Clarke et al. (2001), Stice et al. (2008)and Garber et al. (2009) all indicate that the risk of majordepression can be reduced in adolescents with subthresholddepression, particularly in the context of a family history ofdepression. In the case of bipolar disorder, a small numberof retrospective and prospective studies have shown thatwhile there are some hints of early specificity, these areweak and it is not possible to differentiate symptomaticyoung people with emerging bipolar disorder from thosewho remit or progress to other syndromal outcomes.26 Neurotox Res (2010) 18:19–30
  • 9. In a recent presentation of the clinical staging model forintervention in depressive disorders, Hetrick et al. (2008a, b)suggest that simple and effective treatment approaches suchas psychoeducation, self-help and e-health, physical activityand exercise therapies, and related behavioural approachesmay be appropriate for the earlier stages of depressive dis-orders. Further intervention studies informed by the clinicalstaging model are required to test whether such interventionsprevent individuals progressing to later stages of depressivedisorders.ConclusionThe current diagnostic categories in psychiatry impedeprogress in understanding illness progression and identifyingthe most effective intervention strategies. Our nosology wascreatedduringthe age of steam and one suspects that even thebest attempts to tinker with it can do little more than producea better steam engine. Our current nosology is manifestlyinvalid yet we are struggling to move beyond it through lackof a more valid alternative. Clinical staging may not neces-sarily be the solution to this paralysis, however, it may beable to deliver greater utility in the targeting and evaluationof intervention strategies, and provide a framework forunderstanding illness progression, including organising theexplosion of biological research findings, thus lighting thepath to a more valid nosology.The staging model suggests the possibility of ‘lumping’at the macro level, for example merging psychoses andmood disorders at the earliest phase, and then ‘splitting’ orsub-typing at later stages. Mania, deficit schizophrenia and‘tenacious’ (persistent or chronically relapsing) depressionand may be among the more distal target syndromes thatemerge from this undifferentiated early stage of disorder.There may be a range of other outcomes, including, verycommonly, remission and recovery. The challenge remainsto map clinical and biological markers across the stages, todefine points at which diagnostic specificity and specificpredictive factors can be identified, and to refine the mosteffective intervention strategies for each stage.Acknowledgements Professor McGorry receives funding from theColonial Foundation, and from a Program Grant and a Clinical CentreResearch Excellence Grant from the National Health and MedicalResearch Council of Australia. He has also received research grantsupport from Janssen Cilag Eli Lilly, Pfizer, Novartis and AstraZeneca.ReferencesAddington D, Addington J (2008) First-episode psychosis. In: MueserKT, Jeste DV (eds) Clinical handbook of schizophrenia.Guildford Press, New York, pp 367–379Addington J, Cadenhead KS, Cannon TD, Cornblatt B, McGlashanTH, Perkins DO, Seidman LJ, Tsuang M, Walker EF, WoodsSW, Heinssen R (2007) North American Prodrome LongitudinalStudy: a collaborative multisite approach to prodromal schizo-phrenia research. 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