Neurocognition

Neurocognitive impairments are a feature of severe mental illness, but it is unclear whether these impairments support a clinical staging model. In schizophrenia, cognitive impairment is large and documented across a range of cognitive domains, most notably verbal learning and memory, performance and full-scale IQ scores, sustained attention and cognitive flexibility. ^{Reference Heinrichs and Zakzanis3} Similarly, moderate impairments in a number of domains are documented in bipolar affective disorder, the largest occurring in verbal learning and memory and in executive function; ^{Reference Quraishi and Frangou4–Reference Bora, Yucel and Pantelis7} these are evident during euthymia and amplified when symptoms are experienced. ^{Reference Bearden, Hoffman and Cannon8,Reference Kurtz and Gerraty9} Individuals with major depressive disorder also show neurocognitive impairment, although the affected domains are unclear; impairments have most consistently been demonstrated in verbal learning and memory, attention and executive function, ^{Reference Zakzanis, Leach and Kaplan10–Reference McClintock, Husain, Greer and Cullum12} although to a lesser extent than in schizophrenia and bipolar disorder.

If neurocognition is to be a reliable indicator of clinical stage, then variability in performance should indicate illness severity, chronicity and progression. In schizophrenia the relationship between chronicity and impairment is not straightforward. The magnitude of neurocognitive impairment in the first psychotic episode ^{Reference Mesholam-Gately, Giuliano, Goff, Faraone and Seidman13} is equivalent to that of samples with established illness, ^{Reference Heinrichs and Zakzanis3} suggesting that there is no further decline in neurocognitive ability after the onset of frank psychotic symptoms. This is supported by a lack of longitudinal evidence of progressive deterioration over illness course. ^{Reference Szöke, Trandafir, Dupont, Méary, Schürhoff and Leboyer14} A subgroup of these individuals who develop ‘deficit’ schizophrenia, ^{Reference Carpenter, Heinrichs and Wagman15} characterised by a chronic illness course, prominent negative symptoms, poor functional outcome and significantly reduced cognitive performance, ^{Reference Fenton and McGlashan16,Reference Cohen, Saperstein, Gold, Kirkpatrick, Carpenter and Buchanan17} might show progressive impairment. However, it seems more likely that deficits are longstanding rather than associated with transition between clinical stages; cognitive deficit early in the illness course is predictive of poor functional outcome and negative symptoms many years later. ^{Reference Milev, Ho, Arndt and Andreasen18,Reference Lin, Wood, Nelson, Brewer, Spiliotacopoulos and Bruxner19} In contrast, data from samples of people with bipolar disorder show evidence of a relationship between multiple episodes (both manic and depressive) and poorer neurocognitive performance, particularly for verbal learning and memory and for executive function. ^{Reference Quraishi and Frangou4,Reference Savitz, Solms and Ramesar5} In these individuals longer illness duration is also associated with greater impairment, although not as robustly as number of affective episodes. ^{Reference Bora, Yucel and Pantelis7,Reference Bearden, Hoffman and Cannon8} Similarly, meta-analytic evidence from individuals with major depression suggests that symptom severity is significantly associated with neurocognitive impairment in episodic memory, executive function and processing speed, but these associations explain less than 10% of the variance in performance. ^{Reference McDermott and Ebmeier20} Other cross-sectional evidence for a relationship between other indices of severity (duration of illness, number of episodes and length of episodes) and cognitive deficits is variable and conclusions are difficult to draw. ^{Reference McClintock, Husain, Greer and Cullum12}

Evidence regarding the longitudinal course of neurocognitive impairment in affective disorders is limited by the lack of longitudinal studies. ^{Reference Douglas and Porter11,Reference Lewandowski, Cohen and Ongur21} The longest follow-up of individuals with bipolar disorder showed that cognitive impairment persisted but did not deteriorate over a 3-year period. ^{Reference Balanza-Martinez, Tabares-Seisdedos, Selva-Vera, Martinez-Aran, Torrent and Salazar-Fraile22} Longitudinal studies of neurocognition in major depression are rarely longer than 6 months, ^{Reference Douglas and Porter11} making it impossible to ascertain how impairment progresses over the illness. Our understanding of the course of neurocognitive impairment in affective disorders is further complicated by the fact that state-related reductions in cognitive performance may persist over the short term, leading to the misclassification of such impairment as trait-related. ^{Reference Savitz, Solms and Ramesar5,Reference Douglas and Porter11}

Another problem in interpreting the neurocognitive performance of individuals with affective disorders is the effect of confounding factors, which are often not controlled for in analyses. ^{Reference Douglas and Porter11,Reference Lewandowski, Cohen and Ongur21} These include the impact of medication, illness subtype, age, comorbid disorders and substance use, all of which may influence cognitive performance at the time of testing. In particular, a history of psychosis is rarely reported or controlled for, yet almost all of the published research has shown that current or past psychotic symptoms are associated with greater and more broad cognitive impairments in bipolar disorder and major depression. ^{Reference Martinez-Aran, Vieta, Reinares, Colom, Torrent and Sanchez-Moreno23–Reference Hill, Keshavan and Thase27} Individuals with affective disorders without psychotic features have been shown to perform at a level equivalent to healthy controls or show only minimal impairment. ^{Reference Albus, Hubmann, Wahlheim, Sobizack, Franz and Mohr28–Reference Rund, Sundet, Asbjornsen, Egeland, Landro and Lund30} The profile of individuals with non-psychotic depression is more consistent with frontostriatal dysfunction (i.e. reduced performance was most evident in attention and executive function), as opposed to the frontotemporal dysfunction associated with schizophrenia. ^{Reference Hill, Keshavan and Thase27} In line with this, meta-analytic evidence demonstrates that the largest decrements in samples with affective psychosis are in psychomotor speed, sustained attention, verbal learning and memory and semantic fluency, similar to those observed in schizophrenia. ^{Reference Heinrichs and Zakzanis3,Reference Bora, Yucel and Pantelis31} Altogether, this suggests that psychotic rather than affective pathology is driving impairments; teasing out the effects of psychosis and other confounds is vital to our understanding of the pattern of neurocognitive impairment in affective disorder in regard to clinical staging.

The utility of neurocognition in clinical staging is enhanced if alterations in cognitive performance are evident early in the illness. Research has shown that individuals who later develop schizophrenia demonstrate poor academic performance and intellectual ability in childhood and adolescence. ^{Reference Cannon, Caspi, Moffitt, Harrington, Taylor and Murray32–Reference Reichenberg, Weiser, Rabinowitz, Caspi, Schmeidler and Mark37} Furthermore, it is now accepted that individuals at ultra-high risk of psychosis also perform worse than healthy controls across a range of neurocognitive domains. Within this group, those who make the transition to frank psychosis show greater impairment than those who do not develop psychosis, primarily in the verbal domain. The most often cited reductions include lower general vocabulary or verbal IQ score, ^{Reference Eastvold, Heaton and Cadenhead38–Reference Woodberry, Seidman, Giuliano, Verdi, Cook and McFarlane41} verbal learning and memory, ^{Reference Eastvold, Heaton and Cadenhead38,Reference Pukrop, Ruhrmann, Schultze-Lutter, Bechdolf, Brockhaus-Dumke and Klosterkötter39,Reference Brewer, Francey, Wood, Jackson, Pantelis and Phillips42–Reference Lencz, Smith, McLaughlin, Auther, Nakayama and Hovey44} verbal fluency ^{Reference Pukrop, Ruhrmann, Schultze-Lutter, Bechdolf, Brockhaus-Dumke and Klosterkötter39,Reference Kim, Shin, Jang, Kim, Shim and Park43,Reference Becker, Nieman, Dingemans, van de Fliert, De Haan and Linszen45} and slower processing speed. ^{Reference Pukrop, Ruhrmann, Schultze-Lutter, Bechdolf, Brockhaus-Dumke and Klosterkötter39,Reference Seidman, Giuliano, Meyer, Addington, Cadenhead and Cannon40,Reference Riecher-Rossler, Pflueger, Aston, Borgwardt, Brewer and Gschwandtner46} It remains unclear whether a decrement in cognition occurs from the prodromal stage to the first-episode stage of illness. Some cross-sectional studies have demonstrated that the magnitude of impairment in the ultra-high risk group who later develop psychosis is comparable to first-episode populations, at least in overall ability, ^{Reference Eastvold, Heaton and Cadenhead38,Reference Lencz, Smith, McLaughlin, Auther, Nakayama and Hovey44} verbal IQ score ^{Reference Woodberry, Seidman, Giuliano, Verdi, Cook and McFarlane41} and verbal memory. ^{Reference Eastvold, Heaton and Cadenhead38,Reference Woodberry, Seidman, Giuliano, Verdi, Cook and McFarlane41} Only a few studies have followed ultra-high risk samples over the period of transition to psychosis, and these found little or no progressive impairment in neurocognitive ability. ^{Reference Wood, Brewer, Koutsouradis, Phillips, Francey and Proffitt47–Reference Becker, Nieman, Wiltink, Dingemans, van de Fliert and Velthorst49} (Further information available from the authors.)

Potential early neurocognitive impairment in bipolar disorder is less well understood. There is evidence of lowered performance in unaffected relatives of patients, particularly in verbal learning and memory and some executive functions, ^{Reference Bora, Yucel and Pantelis7,Reference Balanza-Martínez, Rubio, Selva-Vera, Martinez-Aran, Sanchez-Moreno and Salazar-Fraile50} suggesting that cognitive reductions may be trait-related. However, findings to date show neurocognition to be an unreliable indicator of future bipolar disorder. Some studies have identified intellectual and language delays and lowered visual spatial reasoning and set-shifting in young people who later developed the illness, ^{Reference Meyer, Carlson, Wiggs, Martinez, Ronsaville and Klimes-Dougan51–Reference Tiihonen, Haukka, Henriksson, Cannon, Kieseppa and Laaksonen53} but others found no reduction relative to healthy controls. ^{Reference Cannon, Caspi, Moffitt, Harrington, Taylor and Murray32,Reference Cannon, Moffitt, Caspi, Murray, Harrington and Poulton33,Reference Reichenberg, Weiser, Rabinowitz, Caspi, Schmeidler and Mark37,Reference Zammit, Allebeck, David, Dalman, Hemmingsson and Lundberg54} Once again, conclusions from these studies are limited by confounding psychotic symptoms; most studies did not differentiate the outcomes of bipolar disorder with and without psychosis.

High-risk clinics do not exist for bipolar disorder in the same way that they do for schizophrenia, making it difficult to characterise neurocognitive ability immediately prior to illness onset. Only one study has assessed cognitive performance in the prodromal period of bipolar disorder by investigating the onset of this disorder in patients at ultra-high risk of psychosis. ^{Reference Olvet, Stearns, McLaughlin, Auther, Correll and Cornblatt55} The authors found no difference in premorbid IQ, current IQ or global ability between individuals who developed bipolar disorder and those who did not develop either bipolar disorder or schizophrenia. It is similarly unclear which impairments might be present immediately after the onset of bipolar disorder, especially since a first episode of mania could have been preceded by a period of depression. Albus et al found that individuals with a first episode of mania without psychosis demonstrated cognitive performance that was equivalent to healthy controls. ^{Reference Albus, Hubmann, Wahlheim, Sobizack, Franz and Mohr28} Two other studies of first-episode mania have shown impairment in verbal fluency, perceptual–motor ability, set-shifting and psychomotor speed/attention; ^{Reference Nehra, Chakrabarti and Pradhan56,Reference Gruber, Rosso and Yurgelun-Todd57} however, neither study reported the prevalence of psychotic symptoms in the samples.

The evidence also suggests that early neurocognition is not useful as an indicator of later major depression. Studies of offspring of women with depression have identified a specific reduction in verbal ability ^{Reference Seidman, Giuliano, Smith, Stone, Glatt and Meyer58} or no decrement at all, ^{Reference Klimes-Dougan, Ronsaville, Wiggs and Martinez59,Reference Micco, Henin, Biederman, Rosenbaum, Petty and Rindlaub60} relative to healthy controls. Interestingly, in offspring of women with depression there was an association between current depressive symptoms and performance on some indices of executive function and processing speed, ^{Reference Micco, Henin, Biederman, Rosenbaum, Petty and Rindlaub60} suggesting that reductions in these domains might be related to current symptoms or occur as part of the disease process rather than being markers of vulnerability. On the other hand, evidence from a large population study demonstrated that children who later developed major depression showed poorer performance on tasks of psychomotor speed and attention at age 13 years but no reduction in other domains, ^{Reference Cannon, Moffitt, Caspi, Murray, Harrington and Poulton33} nor deviations in motor or language development. ^{Reference Cannon, Caspi, Moffitt, Harrington, Taylor and Murray32} Considering the evidence to date it is unclear whether cognition is impaired before the diagnosis of depressive disorder.

It is important to note that not all individuals with these severe mental illnesses show cognitive impairment. A quarter to a third of individuals with schizophrenia demonstrate ‘normal’ neurocognitive performance within the average range. ^{Reference Rund, Sundet, Asbjornsen, Egeland, Landro and Lund30,Reference Palmer, Heaton, Paulsen, Kuck, Braff and Harris61} Furthermore, it has been estimated that only 28% of people with major depression, ^{Reference Rund, Sundet, Asbjornsen, Egeland, Landro and Lund30,Reference Iverson, Brooks, Langenecker and Young62} and 38–41% of those with bipolar disorder, ^{Reference Iverson, Brooks, Langenecker and Young62,Reference Martino, Strejilevich, Scapola, Igoa, Marengo and Ais63} have neurocognitive impairment. It is possible that people with psychotic and affective disorders who present with neurocognitive impairments represent a different underlying disease process. Support for the concept of different disease processes comes from demographic and clinical differences between those with impaired and intact neurocognitive performance in schizophrenia and bipolar disorder. ^{Reference Palmer, Heaton, Paulsen, Kuck, Braff and Harris61,Reference Martino, Strejilevich, Scapola, Igoa, Marengo and Ais63} Clinical staging offers the potential to overcome artificial diagnostic boundaries by incorporating cognitive performance into stage definitions, although its usefulness is dependent on how well it can be used to predict illness progression and treatment response.

In summary, although there is some evidence that neurocognitive impairment might fit within a clinical staging framework, there are too many confounds at present for it to be incorporated into the model. Critically, these conclusions are limited by the large variability of clinical populations with affective disorders, particularly where data from individuals with and without psychotic symptoms are combined. Further, the lack of longitudinal data examining progression over time in affective disorders and comparing individuals with earlyv. late-stage disorder reduces our ability to draw strong inferences.

Neuroimaging

In addition to neurocognitive functioning, a model of clinical staging should differentiate the neurobiological correlates of the disorder's distinct stages. Neurobiological changes associated with mental disorders do not necessarily develop in parallel with behavioural symptoms or correlate with behaviour, ^{Reference Fornito, Yoon, Zalesky, Bullmore and Carter64} highlighting the importance of investigating both. We recently reviewed the imaging literature for psychotic disorders and showed that whereas some neurobiological changes are already present before the illness onset, others arise as it progresses and tend to be more pronounced with severity of illness. ^{Reference Wood, Yung, McGorry and Pantelis2,Reference Oertel-Knochel, Bittner, Knochel, Prvulovic and Hampel65} Similar differential patterns of biomarkers have been suggested for early v. late stages of major depression and bipolar disorder, ^{Reference Hetrick, Parker, Hickie, Purcell, Yung and McGorry66–Reference Fernandes, Gama, Maria Cereser, Yatham, Fries and Colpo69} suggesting it might also be possible to find neuroimaging markers of specific illness stages in affective disorders.

Enhanced vulnerability to psychosis is associated with grey-matter volume reductions in prefrontal, limbic and temporo-parietal regions of the brain, ^{Reference Fusar-Poli, Borgwardt, Crescini, Deste, Kempton and Lawrie70} whereas those who later develop first-episode psychosis have more specific reductions in the inferior frontal, superior temporal and parietal regions. ^{Reference Fusar-Poli, Borgwardt, Crescini, Deste, Kempton and Lawrie70,Reference Dazzan, Soulsby, Mechelli, Wood, Velakoulis and Phillips71} Not surprisingly, therefore, individuals with schizophrenia commonly present with reductions in grey matter in the frontotemporal regions. ^{Reference Fornito, Yucel, Patti, Wood and Pantelis72,Reference Ellison-Wright, Glahn, Laird, Thelen and Bullmore73} Consistent with the predictions of clinical staging, these changes become more extensive through first-episode and chronic illness. ^{Reference Chan, Di, McAlonan and Gong74–Reference Velakoulis, Wood, Wong, McGorry, Yung and Phillips77} A similar staging pattern has been observed for cortical thickness, ^{Reference Jung, Kim, Jang, Choi, Jung and Park78} and for structural abnormalities affecting white matter. ^{Reference Olabi, Ellison-Wright, McIntosh, Wood, Bullmore and Lawrie79}

Progressive brain changes and increased pathological signs related to severity of illness have also been observed in affective disorders. In major depression reduced thickness of the posterior cingulate cortex has been observed in people with non-remitted disorder compared with those in remission, and decreased perfusion in frontal regions and the anterior cingulate cortex has been shown in the non-remission group compared with healthy controls. ^{Reference Jarnum, Eskildsen, Steffensen, Lundbye-Christensen, Simonsen and Thomsen80} There are cautious suggestions that reductions in cerebral and cerebellar grey matter volume, ^{Reference Pillay, Yurgelun-Todd, Bonello, Lafer, Fava and Renshaw81} as well as basal ganglia volume, ^{Reference Pillay, Renshaw, Bonello, Lafer, Fava and Yurgelun-Todd82} are related to severity of illness. Furthermore, basal ganglia volume reductions have been linked to illness duration and the number of prior depressive episodes. ^{Reference Lacerda, Nicoletti, Brambilla, Sassi, Mallinger and Frank83} With increased duration of illness, individuals with major depression have shown reduced glutamate and increased choline concentrations in ventromedial prefrontal regions, ^{Reference Portella, de Diego-Adelino, Gomez-Anson, Morgan-Ferrando, Vives and Puigdemont84} and (more inconsistently) a reduction in hippocampal volume. ^{Reference Sheline, Wang, Gado, Csernansky and Vannier85–Reference Kempton, Salvador, Munafo, Geddes, Simmons and Frangou88} In bipolar disorder the number of episodes of illness has been related to enlargement of the lateral ventricles, ^{Reference Strakowski, DelBello, Zimmerman, Getz, Mills and Ret89,Reference Brambilla, Harenski, Nicoletti, Mallinger, Frank and Kupfer90} and decreased cerebellar vermal volume. ^{Reference DelBello, Strakowski, Zimmerman, Hawkins and Sax91} Compared with healthy individuals, grey matter density of the hippocampus, fusiform gyrus and cerebellum of individuals with bipolar disorder has been shown to reduce at an accelerated rate. ^{Reference Moorhead, McKirdy, Sussmann, Hall, Lawrie and Johnstone92}

Many structural abnormalities such as ventricular enlargement have been repeatedly associated with both schizophrenia and affective disorders, albeit with greater enlargements in schizophrenia. ^{Reference Savitz, Solms and Ramesar5,Reference Bearden, Hoffman and Cannon8,Reference Kempton, Salvador, Munafo, Geddes, Simmons and Frangou88,Reference Arnone, Cavanagh, Gerber, Lawrie, Ebmeier and McIntosh93,Reference Elkis, Friedman and Wise94} Such non-specific changes perhaps reflect the presence of psychotic symptoms in the affective disorder group, ^{Reference Bearden, Hoffman and Cannon8} and/or similarities relating to clinical stage. Diagnostic differences do exist, however. Smaller hippocampal and amygdala volumes have been observed in individuals with schizophrenia compared with bipolar disorder. ^{Reference Altshuler, Bartzokis, Grieder, Curran, Jimenez and Leight95} Further distinctions on the basis of grey matter deficits have been made, ^{Reference McDonald, Bullmore, Sham, Chitnis, Suckling and MacCabe96} and functional differences in medial frontal and visual cortex, as well as differential disruptions in white matter tracts associated with the occipital and frontal lobes, ^{Reference Sui, Pearlson, Caprihan, Adali, Kiehl and Liu97} have been shown. Whereas volumetric reductions in brain tissue, in particular temporal lobe grey matter, are more consistently found in schizophrenia than in bipolar disorder, white matter hyperintensities are more common in affective disorders. ^{Reference Bearden, Hoffman and Cannon8} Individuals with bipolar disorder additionally show enlargement of basal ganglia and amygdala, whereas those with major depressive disorder are characterised by volume reduction in these regions as well as in the hippocampus. ^{Reference Kempton, Salvador, Munafo, Geddes, Simmons and Frangou88,Reference Strakowski, Adler and DelBello98,Reference Videbech and Ravnkilde99} Affective disorders are furthermore distinguished by increased corpus callosum cross-sectional area in major depression compared with bipolar disorder. ^{Reference Kempton, Salvador, Munafo, Geddes, Simmons and Frangou88} These neurobiological differences may provide useful diagnostic markers in relation to the different stages of the individual disorders.

The reports of white matter pathology indicate that severe mental illness may not simply be a result of structural lesions to the brain, ^{Reference Savitz, Solms and Ramesar5} but rather of abnormal connectivity between regions. ^{Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100} As early as 1998 Friston suggested that schizophrenia was caused by dysfunctional interaction in the dynamics of associated brain regions rather than by dysfunctional specialisation within a region. ^{Reference Friston101} Certainly in psychotic disorders, stage of illness affects structural and functional networks differently. ^{Reference Wood, Yung, McGorry and Pantelis2} Consistent across stages of illness are findings of reduced (or in some cases increased) connectivity in frontal lobe and frontotemporal interactions, but as illness progresses these patterns become more widespread across the brain and are observed with higher frequencies. ^{Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100} Progression between stages could represent weakened strength of connections or even a total loss of connections in a network with a consequential imbalance between local and global connections. Indeed, connection patterns could show alterations, resulting in a loss of function such as working memory impairment, ^{Reference Kang, Sponheim, Chafee and Macdonald102} or phenomena such as positive symptoms. ^{Reference Rotarska-Jagiela, van de Ven, Oertel-Knochel, Uhlhaas, Vogeley and Linden103} Evidence for dysconnectivity in grey and white matter across all stages of this disorder, and even before onset of illness, is building. ^{Reference Fornito, Yoon, Zalesky, Bullmore and Carter64,Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100,Reference Patel, Mahon, Wellington, Zhang, Chaplin and Szeszko104–Reference Woodward, Rogers and Heckers106} Suggestions of dysconnectivity in affective disorders are also rapidly emerging, ^{Reference Savitz, Solms and Ramesar5,Reference Hasler and Northoff107–Reference Zhang, Wang, Wu, Kuang, Huang and He109} with distinct patterns for schizophrenia and bipolar disorder being identified. ^{Reference Ongur, Lundy, Greenhouse, Shinn, Menon and Cohen110} Factors such as genetics, insults during brain development and neurotransmitter imbalance are thought to influence the process of dysconnectivity. ^{Reference Cole, Anticevic, Repovs and Barch111}

For neurobiological changes to consolidate their position in a model of clinical staging, changes caused by the illness need to be distinguished from epiphenomena. Factors such as life stress and substance use have been related to progression in severity of illness, ^{Reference Wood, Yung, McGorry and Pantelis2,Reference Kapczinski, Dias, Kauer-Sant'Anna, Frey, Grassi-Oliveira and Colom112–Reference Foti, Kotov, Guey and Bromet114} and individual differences in dysconnectivity have been shown to relate to individual differences in symptom presentation. ^{Reference Cole, Anticevic, Repovs and Barch111} Antidepressant medication has been found to decrease resting-state functional connectivity, ^{Reference McCabe and Mishor115} and the effects of medication on brain structure, volume and functioning also require further investigation. ^{Reference Wood, Yung, McGorry and Pantelis2,Reference Fusar-Poli, Borgwardt, Crescini, Deste, Kempton and Lawrie70,Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100,Reference Savitz and Drevets113,Reference Ho, Andreasen, Ziebell, Pierson and Magnotta116,Reference Phillips, Travis, Fagiolini and Kupfer117} In addition, the influence of adolescent development, ^{Reference Wood, Yung, McGorry and Pantelis2,Reference Brambilla, Harenski, Nicoletti, Mallinger, Frank and Kupfer90,Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100,Reference Savitz and Drevets113,Reference Yatham, Kapczinski, Andreazza, Trevor Young, Lam and Kauer-Sant'anna118,Reference Chakos, Lieberman, Bilder, Borenstein, Lerner and Bogerts119} gender, ^{Reference Pettersson-Yeo, Allen, Benetti, McGuire and Mechelli100} and comorbidity, ^{Reference Wood, Yung, McGorry and Pantelis2,Reference Sheline86,Reference Owen, O'Donovan, Thapar and Craddock120,Reference Altamura, Serati, Albano, Paoli, Glick and Dell'Osso121} should be considered. Accounting for these factors provides important challenges for the immediate future.

Current models of clinical staging do not make explicit whether an individual can move down a stage, i.e. whether a remission of symptoms is equivalent to moving from stage 2 to stage 1. However, certain functions can (at least partially) be recovered. ^{Reference Payne and Lomber122,Reference Castren and Rantamaki123} Furthermore, brain volume abnormalities seem to be potentially reversible (in first-episode psychosis), ^{Reference Schaufelberger, Lappin, Duran, Rosa, Uchida and Santos124} or at least to lessen with continued development in childhood-onset schizophrenia. ^{Reference Gogtay125} This suggests regression in severity of illness to some extent, which should be reflected in the staging model.

Neurobiological evidence for staging in severe mental illness is still limited. Different methods adopted by the various studies make it difficult to compare findings and stress the need for future research to adopt a transdiagnostic perspective. Studies investigating disorders with overlapping features will not only be able to highlight shared neurobiological features but may provide evidence for distinct neurobiological markers important for treatment and prognosis. As adolescence is the critical period for onset of severe mental illness, studies should focus on brain networks that develop during this period. Furthermore, multimodal longitudinal studies will be crucial in monitoring transition between stages and associated neurobiological changes. ^{Reference Wood, Yung, McGorry and Pantelis2}

Future research

Clinical staging is a promising model for improving our understanding of the way in which severe mental illnesses develop and helping clinicians choose the most appropriate treatment. Both neurocognition and neuroimaging evidence provide tentative support for the application of a staging model to schizophrenia and affective disorders. The paradox here is that we are using the current diagnostic categories to investigate the validity of a model that explicitly attempts to negate the current categorical system. Future work needs to take a transdiagnostic and longitudinal view, covering both neurocognition and neuroimaging in order to overcome current issues.