EDITORIAL
Early Detection and Intervention for People With Psychosis Getting to the Bottom Line Faith Dickerson, PhD, MPH
T
he development of new medications, the availability of community-based treatment, and an attitudinal shift toward recovery have improved services for people with schizophrenia and other psychotic disorders. But these disorders remain pervasive conditions, often affecting many aspects, if not the whole fabric, of a person’s life. And because the disorders are widely prevalent and typically persist for decades, their global burden of disease is high (Whiteford et al., 2015). Unfortunately, knowledge about the etiopathology of schizophrenia and other psychotic disorders has unfolded only slowly. It was widely assumed that the application of recently developed molecular techniques would result in an increased understanding of the disease process and the identification of major genes that would inform diagnosis and treatment. Instead, a recent study found that there are more than 100 genetic variants of small effect that contribute to a portion of disease risk and that none has been shown to be specific to schizophrenia (Schizophrenia Working Group, 2014). In addition, psychological theories of schizophrenia etiology have been debunked, and environmental factors have not yet led to treatments that can be put into routine clinical practice. But we cannot wait to develop new approaches and to improve the lives of persons living with schizophrenia and other psychotic disorders. There is now a consensus that if we can identify people early in the course of the illness, or even before the illness starts, there will be a better chance to improve outcomes. If we can identify people who are going to become psychotic in the future, we can offer treatment that will forestall, if not prevent, illness and disability. If we can discover etiological pathways that contribute to disease risk, we will be able to develop novel treatment approaches that complement existing medications. If we cannot cure schizophrenia, at least we can improve the quality of life and lower the rate of premature deaths. There is now an imperative to do so. The articles in this special issue bring together some recent developments in the field of early detection and intervention for people with psychosis. The issue includes 13 articles by some of the preeminent researchers in this rapidly evolving field. In the US, research on the topic has taken its cue from investigators in Australia, Canada, England, Denmark, and other countries, some of whose work is represented here. The issue includes five articles focused primarily on the prodrome or the prediction of psychosis, seven that are focused on the treatment or outcome of first-episode psychosis, and one on immunologic-based medication treatments. Among the contributions are original research reports, review articles, and personal commentaries. McGorry, a pioneer in early intervention research and practice, provides a personal account of the field's history over the past 30 years (McGorry, 2015). McGorry is critical of most current treatment for serious mental illness, noting “the soft bigotry of low expectations” and the “palliative mindset of traditional mental health care.” Motivated to improve the system, McGorry describes how his work progressed from the initiation of a specialized first-episode unit in 1984 to a worldwide movement and to his current vision for the wider application of early intervention beyond psychosis to all mental disorders. There has been much cross-fertilization between McGorry and other leading researchers, including McGlashan, who also has an article in this issue (McGlashan, 2015). Additional contributions are focused on the prodrome or prediction of psychosis. The article by Weber and colleagues presents intriguing findings from a unique data set, persons in the US military who developed schizophrenia and bipolar disorder during their military enlistment (Weber et al., 2015). What makes these data so extraordinary is the availability of archived blood samples that were obtained months or years before the onset of psychosis and the availability of a carefully matched comparison group. These samples are a unique resource toward the goal of identifying pre-onset biomarkers of serious mental illness. The investigators found that levels of pentraxin 3, a marker of innate immunity, were lower in the individuals who went on to develop schizophrenia than in the matched controls. This finding adds to the growing evidence identifying innate immunity and other Sheppard Pratt Health System, Baltimore, MD. Send reprint requests to Faith Dickerson, PhD, MPH, Sheppard Pratt Health System, 6501 N Charles St, Baltimore, MD 21285. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0022-3018/15/20305–0307 DOI: 10.1097/NMD.0000000000000294
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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307
Editorial
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015
immune pathways as contributing factors to schizophrenia etiology (Benros et al., 2012). These results do not enable us now to make clinical predictions about individual persons but represent a step toward the goal of identifying biological markers of psychosis risk that can be measured in a practical manner. If we do not yet have a reliable method to predict from biological measures who will go on to develop schizophrenia before the onset of any illness symptoms, we can certainly learn from the study of people who are identified clinically as having prodromal symptoms. The articles by Carpenter, Addington and colleagues, and Chung and Cannon provide a timely update about work on this topic (Carpenter, 2015; Addington et al., 2015; Chung and Cannon, 2015). Carpenter has championed the creation of a new disorder category, attenuated psychosis syndrome (APS), in order to better identify persons who are in distress and who have subclinical psychotic symptoms and who are thus vulnerable to develop psychosis. APS is unusual in that the disorder is conceived as a placeholder with the assumption that the affected individual, typically age 15 to 35 years old, will progress to have another diagnosable disorder, possibly but not necessarily schizophrenia, or to no disorder. Carpenter argues that the creation of this new category will enable more persons to receive treatment and also help in accumulating and organizing knowledge about the development of psychosis. Carpenter notes that his views “reflect frustration with the minimal advances in schizophrenia therapeutics over the past 60 years.” After considerable debate, APS was not included in DSM-5 as a formal diagnostic category but remains a DSM-5 disorder under study. Addington’s article (Addington et al., 2015) describes a sample of patients who meet criteria similar to the APS proposed by Carpenter. The North America Prodrome Longitudinal Study (NAPLS) represents a close collaboration among eight sites in North America who have collectively identified, assessed, and followed 764 young persons at clinical high risk for psychosis, the vast majority with attenuated psychotic symptoms. Interestingly, the cumulative prevalence rate of conversion to psychosis was only 12% at the 2-year follow-up, and the group as a whole showed improvement on all of the carefully assessed symptom dimensions. What will be the long-term outcome of these persons? The ultimate answer is currently not known, but in the short term, it appears that they are not all destined to develop psychosis. The article highlights the broad range of outcomes of persons with a purported prodromal syndrome. The article by Chung and Cannon (2015) provides a comprehensive review of brain imaging studies in prodromal patients transitioning to schizophrenia, including some findings from the NAPLS cohort. The article notes that neuroimaging studies that have been performed to date show a steeper rate of gray matter loss in high-risk cases who convert to psychosis relative to those who do not convert and also relative to matched healthy controls. Of particular interest is a recent finding that higher levels of a blood-based index of proinflammatory cytokines at baseline were predictive of steeper rates of gray matter reduction among high-risk cases who converted to psychosis. In the final article focused on studies of individuals before the onset of psychosis, Thompson et al. (2015) describe psychosocial interventions with clinically high-risk individuals such as those who have attenuated psychosis symptoms. These interventions are predicated on previous studies suggesting that the risk of psychosis may be reduced considerably by early treatment. Therapeutic strategies with this population are variable given the clinical heterogeneity of individuals in this group. The authors argue for modular-based treatments drawing on practices that have been proven effective for the treatment of schizophrenia and then modified to fit the needs of high-risk patients. The next set of articles is directed at individuals with a first episode of psychosis; McGlashan in his personal account describes his odyssey from providing psychoanalytic psychotherapy to persistently ill patients to promoting early detection and treatment (McGlashan, 2015). After performing a thorough follow-up of patients, 308
www.jonmd.com
most with schizophrenia, hospitalized for long-term psychiatric care at Chestnut Lodge Hospital in Maryland, McGlashan looked objectively at the dismal outcomes and concluded that there must be a better way. Personal note: In the mid 1980’s, McGlashan presented his Chestnut Lodge findings at Sheppard Pratt where I was involved in the creation of a new specialized hospital unit for schizophrenia. I was then, and still am, impressed by the rigor of McGlashan’s methods and his willingness to examine critically a treatment approach with which he was highly identified. In the article in this issue, McGlashan describes the landmark early intervention program that he subsequently helped develop and lead in Norway and Denmark. The intervention, examined in a controlled study, was associated with better outcomes for those with early schizophrenia whose treatment was detected in the early intervention program and initiated after a short duration of untreated psychosis (DUP) than those not identified in the early detection program who had a longer DUP. The issue also includes articles by two clinical researchers who have developed and implemented programs for patients in North America with a first episode of psychosis. As described in the article by Iyer and colleagues, Malla initiated and has led an early intervention program in Ontario, Canada, that has made concerted efforts to engage patients early in the illness course via an open referral system and rapid response protocol (Iyer et al., 2015). An evaluation of patients receiving these services shows overall favorable outcomes, which the authors attribute to the relatively short DUP of their sample. The article by Marino and colleagues reports on the evaluation of an early intervention program, the RAISE Connection program (Marino et al., 2015). The components of the services provided to patients in the RAISE Connection program are similar to those described in the Malla program (Iyer et al., 2015), including a teambased intervention sensitive to patients’ developmental needs and focused on psychosocial outcomes as well as psychiatric symptoms. The Marino article reports on mediators and moderators of outcome in the early intervention program. The article reports that greater improvement in occupational functioning was predicted by higher verbal fluency scores at baseline and that greater improvement in social functioning was predicted by family involvement in the course of the intervention, both predictors representing potentially modifiable factors. Another RAISE program, a randomized controlled trial of a similar intervention for early course patients, is currently underway and will further add to this body of knowledge (Correll et al., 2014). It is of note that initial feasibility data from the RAISE Connection study were instrumental in the passage of Congressional legislation in 2014 that calls for setting aside funds from the Community Mental Health Block Grant program to support dissemination of interventions for first-episode patients similar to those tested in RAISE (http://www.nimh.nih.gov/about/director/2014/best-of-2014.shtml). This new funding stream is unprecedented in creating dedicated resources throughout the US for the treatment of first-episode patients. In another original research report, Vohs and colleagues describe the results of a cross-sectional study in which they found significant associations between illness insight and aspects of metacognition (an awareness of one’s mental processes) in a sample of patients with a first episode of psychosis (Vohs et al., 2015). Illness insight is predictive of recovery, so modifiable factors that may increase illness insight are important. Metacognition is also of interest because of an increasing emphasis on the lived experiences of people with mental illness and on approaches that help such persons to better understand themselves and their interactions with others. Additional contributions are directed at epidemiology. The article by Revier and colleagues reports on the results of the AESOP-10 study, a 10-year follow-up of patients with a first episode of psychosis evaluated at two sites in England (Revier et al., 2015). As in the Addington study of prodromal patients (Addington et al., 2015), a marked variability in clinical outcome was found. Of interest, the © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015
authors found a high prevalence of symptom remission at follow-up but extensive social disability with the vast majority of patients unemployed. Mortality data were striking with a fourfold increase in all-cause mortality compared with that in the general population and a 20- fold increase in mortality due to suicide. Similar to results in the RAISE Connection study, family participation was predictive of better outcomes; it was found that full family involvement at first contact with services was associated with a reduced risk of unnatural death. However, neither study was a randomized controlled trial of family intervention, making cause-effect relationships difficult to define. The article by Nordentoft and colleagues continues on the topic of morbidity and mortality and provides a review of additional epidemiological studies (Nordentoft et al., 2015). The article presents compelling data about the high mortality of individuals with schizophrenia and the fact that the rate of suicide may be as high as 10% in the first year of treatment. Nordentoft and colleagues raise the intriguing point that suicide attempts may take place before the individual has the first contact with mental health services during the period of untreated psychosis, so the rate of suicide may actually be higher in this population than previously assumed. Nordentoft and colleagues also note the considerable rate of suicide during stays in the hospital, assumed to be a setting of safety, and argues for particularly close patient contact and monitoring of symptoms during and right after the hospital stay. In the final article included in this issue, Cox and colleagues review the extant literature on the immune system in schizophrenia and lay out the evidence for this system as a potential target of pharmacologic interventions (Cox et al., 2015). They note that immune modulatory agents may lower the proinflammatory status of some schizophrenia patients toward the levels of healthy controls. Initial trials of some agents, including N-acetyl cysteine, aspirin, and estrogens, show promise as adjunctive treatments although there is not yet enough of an evidence base to recommend their use in routine practice. What is the reader to conclude from this collection of articles that represent a detailed presentation of early intervention studies? Clearly, there is now urgency to improve outcomes for patients with schizophrenia starting early in the illness or even before the illness begins, to cast a wider net in identifying vulnerable individuals, and to provide specialized services for high-risk and for early-onset patients. In addition, and as demonstrated by several articles here, unraveling the etiological factors of schizophrenia and determining the full scope of patient outcomes is no easy task. It requires large collaborative efforts such as NAPLS and the use of population-based data such as those from the US military or from cohorts based on national health systems. There is a need for approaches that integrate biological and clinical markers and for long-term observational studies as well as clinical trials. The goal is the development of practical and effective methods for early detection and intervention. Such methods would have a profound effect on the health and well-being of all individuals affected by these devastating disorders. DISCLOSURE The author declares no conflict of interest.
Editorial
REFERENCES Addington J, Liu L, Buchy L, Cadenhead KS, Cannon TD, Cornblatt BA, Perkins DO, Seidman LJ, Tsuang MT, Walker EF, Woods SW, Bearden CE, Mathalon DH, McGlashan TH (2015) North American prodrome longitudinal study (NAPLS 2): The prodromal symptoms. J Nerv Ment Dis. 203:328–335. Benros ME, Mortensen PB, Eaton WW (2012) Autoimmune diseases and infections as risk factors for schizophrenia. Ann N Y Acad Sci. 1262:56–66. Carpenter WT (2015) Attenuated psychosis syndrome: A new diagnostic class? J Nerv Ment Dis. 203:325–327. Chung Y, Cannon TD (2015) Brain imaging during the transition from psychosis prodrome to schizophrenia. J Nerv Ment Dis. 203:336–341. Correll CU, Robinson DG, Schooler NR, Brunette MF, Mueser KT, Rosenheck RA, Marcy P, Addington J, Estroff SE, Robinson J, Penn DL, Azrin S, Goldstein A, Severe J, Heinssen R, Kane JM (2014) Cardiometabolic risk in patients with first-episode schizophrenia spectrum disorders: Baseline results from the RAISE-ETP study. JAMA Psychiatry. 71:1350–1363. Cox D, Chan MK, Bahn S (2015) The potential of immune biomarkers to advance personalized medicine approaches for schizophrenia. J Nerv Ment Dis. 203:393–399. Iyer S, Jordan G, MacDonald K, Joober R, Malla A (2015) Early intervention for psychosis: A Canadian perspective. J Nerv Ment Dis. 203:356–364. McGlashan TH (2015) From treating to preventing psychosis: Personal perspectives. J Nerv Ment Dis. 203:352–355. McGorry PD (2015) Early intervention in psychosis: Obvious, effective, overdue. J Nerv Ment Dis. 203:310–318. Marino L, Nossel I, Choi JC, Nuechterlein K, Wang Y, Essock S, Bennett M, McNamara K, Mendon S, Dixon L (2015) The RAISE Connection program for early psychosis: Secondary outcomes and mediators and moderators of improvement. J Nerv Ment Dis. 203:365–371. Nordentoft M, Madsen T, Fedyszyn I (2015) Suicidal behavior and mortality in firstepisode psychosis. J Nerv Ment Dis. 203:387–392. Revier CJ, Reininghaus U, Dutta R, Fearon P, Murray RM, Doody GA, Croudace T, Dazzan P, Heslin M, Onyejiaka A, Kravariti E, Lappin J, Lomas B, Kirkbride JB, Donoghue K, Morgan C, Jones PB (2015) Ten-year outcomes of first-episode psychoses in the MRC ÆSOP-10 study. J Nerv Ment Dis. 203: 379–386. Schizophrenia Working Group of the Psychiatric Genomics Consortium (2014) Biological insights from 108 schizophrenia-associated genetic loci. Nature. 511:421–427. Thompson E, Millman ZB, Okuzawa N, Mittal V, DeVylder J, Skadberg T, Buchanan RW, Reeves GM, Schiffman J (2015) Evidence-based early interventions for individuals at clinical high risk for psychosis: A review of treatment components. J Nerv Ment Dis. 203:342–351. Vohs JL, Lysaker PH, Liffick E, Francis MM, Leonhardt BL, James A, Buck KD, Hamm JA, Minor KS, Mehdiyoun N, Breier A (2015) Metacognitive capacity as a predictor of insight in first-episode psychosis. J Nerv Ment Dis. 203:372–378. Weber NS, Larsen RA, Yolken RH, Cowan DN, Boivin MR, Niebuhr DW (2015) Predictors of the onset of schizophrenia in US military personnel. J Nerv Ment Dis. 203:319–324. Whiteford HA, Ferrari AJ, Degenhardt L, Feigin V, Vos T (2015) The global burden of mental, neurological and substance use disorders: An analysis from the Global Burden of Disease Study 2010. PLoS One. 10(2):e0116820.
© 2015 Wolters Kluwer Health, Inc. All rights reserved. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Early Detection and Intervention for People With Psychosis Getting to the Bottom Line Faith Dickerson, PhD, MPH
T
he development of new medications, the availability of community-based treatment, and an attitudinal shift toward recovery have improved services for people with schizophrenia and other psychotic disorders. But these disorders remain pervasive conditions, often affecting many aspects, if not the whole fabric, of a person’s life. And because the disorders are widely prevalent and typically persist for decades, their global burden of disease is high (Whiteford et al., 2015). Unfortunately, knowledge about the etiopathology of schizophrenia and other psychotic disorders has unfolded only slowly. It was widely assumed that the application of recently developed molecular techniques would result in an increased understanding of the disease process and the identification of major genes that would inform diagnosis and treatment. Instead, a recent study found that there are more than 100 genetic variants of small effect that contribute to a portion of disease risk and that none has been shown to be specific to schizophrenia (Schizophrenia Working Group, 2014). In addition, psychological theories of schizophrenia etiology have been debunked, and environmental factors have not yet led to treatments that can be put into routine clinical practice. But we cannot wait to develop new approaches and to improve the lives of persons living with schizophrenia and other psychotic disorders. There is now a consensus that if we can identify people early in the course of the illness, or even before the illness starts, there will be a better chance to improve outcomes. If we can identify people who are going to become psychotic in the future, we can offer treatment that will forestall, if not prevent, illness and disability. If we can discover etiological pathways that contribute to disease risk, we will be able to develop novel treatment approaches that complement existing medications. If we cannot cure schizophrenia, at least we can improve the quality of life and lower the rate of premature deaths. There is now an imperative to do so. The articles in this special issue bring together some recent developments in the field of early detection and intervention for people with psychosis. The issue includes 13 articles by some of the preeminent researchers in this rapidly evolving field. In the US, research on the topic has taken its cue from investigators in Australia, Canada, England, Denmark, and other countries, some of whose work is represented here. The issue includes five articles focused primarily on the prodrome or the prediction of psychosis, seven that are focused on the treatment or outcome of first-episode psychosis, and one on immunologic-based medication treatments. Among the contributions are original research reports, review articles, and personal commentaries. McGorry, a pioneer in early intervention research and practice, provides a personal account of the field's history over the past 30 years (McGorry, 2015). McGorry is critical of most current treatment for serious mental illness, noting “the soft bigotry of low expectations” and the “palliative mindset of traditional mental health care.” Motivated to improve the system, McGorry describes how his work progressed from the initiation of a specialized first-episode unit in 1984 to a worldwide movement and to his current vision for the wider application of early intervention beyond psychosis to all mental disorders. There has been much cross-fertilization between McGorry and other leading researchers, including McGlashan, who also has an article in this issue (McGlashan, 2015). Additional contributions are focused on the prodrome or prediction of psychosis. The article by Weber and colleagues presents intriguing findings from a unique data set, persons in the US military who developed schizophrenia and bipolar disorder during their military enlistment (Weber et al., 2015). What makes these data so extraordinary is the availability of archived blood samples that were obtained months or years before the onset of psychosis and the availability of a carefully matched comparison group. These samples are a unique resource toward the goal of identifying pre-onset biomarkers of serious mental illness. The investigators found that levels of pentraxin 3, a marker of innate immunity, were lower in the individuals who went on to develop schizophrenia than in the matched controls. This finding adds to the growing evidence identifying innate immunity and other Sheppard Pratt Health System, Baltimore, MD. Send reprint requests to Faith Dickerson, PhD, MPH, Sheppard Pratt Health System, 6501 N Charles St, Baltimore, MD 21285. E-mail: [email protected]. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved. ISSN: 0022-3018/15/20305–0307 DOI: 10.1097/NMD.0000000000000294
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
www.jonmd.com
307
Editorial
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015
immune pathways as contributing factors to schizophrenia etiology (Benros et al., 2012). These results do not enable us now to make clinical predictions about individual persons but represent a step toward the goal of identifying biological markers of psychosis risk that can be measured in a practical manner. If we do not yet have a reliable method to predict from biological measures who will go on to develop schizophrenia before the onset of any illness symptoms, we can certainly learn from the study of people who are identified clinically as having prodromal symptoms. The articles by Carpenter, Addington and colleagues, and Chung and Cannon provide a timely update about work on this topic (Carpenter, 2015; Addington et al., 2015; Chung and Cannon, 2015). Carpenter has championed the creation of a new disorder category, attenuated psychosis syndrome (APS), in order to better identify persons who are in distress and who have subclinical psychotic symptoms and who are thus vulnerable to develop psychosis. APS is unusual in that the disorder is conceived as a placeholder with the assumption that the affected individual, typically age 15 to 35 years old, will progress to have another diagnosable disorder, possibly but not necessarily schizophrenia, or to no disorder. Carpenter argues that the creation of this new category will enable more persons to receive treatment and also help in accumulating and organizing knowledge about the development of psychosis. Carpenter notes that his views “reflect frustration with the minimal advances in schizophrenia therapeutics over the past 60 years.” After considerable debate, APS was not included in DSM-5 as a formal diagnostic category but remains a DSM-5 disorder under study. Addington’s article (Addington et al., 2015) describes a sample of patients who meet criteria similar to the APS proposed by Carpenter. The North America Prodrome Longitudinal Study (NAPLS) represents a close collaboration among eight sites in North America who have collectively identified, assessed, and followed 764 young persons at clinical high risk for psychosis, the vast majority with attenuated psychotic symptoms. Interestingly, the cumulative prevalence rate of conversion to psychosis was only 12% at the 2-year follow-up, and the group as a whole showed improvement on all of the carefully assessed symptom dimensions. What will be the long-term outcome of these persons? The ultimate answer is currently not known, but in the short term, it appears that they are not all destined to develop psychosis. The article highlights the broad range of outcomes of persons with a purported prodromal syndrome. The article by Chung and Cannon (2015) provides a comprehensive review of brain imaging studies in prodromal patients transitioning to schizophrenia, including some findings from the NAPLS cohort. The article notes that neuroimaging studies that have been performed to date show a steeper rate of gray matter loss in high-risk cases who convert to psychosis relative to those who do not convert and also relative to matched healthy controls. Of particular interest is a recent finding that higher levels of a blood-based index of proinflammatory cytokines at baseline were predictive of steeper rates of gray matter reduction among high-risk cases who converted to psychosis. In the final article focused on studies of individuals before the onset of psychosis, Thompson et al. (2015) describe psychosocial interventions with clinically high-risk individuals such as those who have attenuated psychosis symptoms. These interventions are predicated on previous studies suggesting that the risk of psychosis may be reduced considerably by early treatment. Therapeutic strategies with this population are variable given the clinical heterogeneity of individuals in this group. The authors argue for modular-based treatments drawing on practices that have been proven effective for the treatment of schizophrenia and then modified to fit the needs of high-risk patients. The next set of articles is directed at individuals with a first episode of psychosis; McGlashan in his personal account describes his odyssey from providing psychoanalytic psychotherapy to persistently ill patients to promoting early detection and treatment (McGlashan, 2015). After performing a thorough follow-up of patients, 308
www.jonmd.com
most with schizophrenia, hospitalized for long-term psychiatric care at Chestnut Lodge Hospital in Maryland, McGlashan looked objectively at the dismal outcomes and concluded that there must be a better way. Personal note: In the mid 1980’s, McGlashan presented his Chestnut Lodge findings at Sheppard Pratt where I was involved in the creation of a new specialized hospital unit for schizophrenia. I was then, and still am, impressed by the rigor of McGlashan’s methods and his willingness to examine critically a treatment approach with which he was highly identified. In the article in this issue, McGlashan describes the landmark early intervention program that he subsequently helped develop and lead in Norway and Denmark. The intervention, examined in a controlled study, was associated with better outcomes for those with early schizophrenia whose treatment was detected in the early intervention program and initiated after a short duration of untreated psychosis (DUP) than those not identified in the early detection program who had a longer DUP. The issue also includes articles by two clinical researchers who have developed and implemented programs for patients in North America with a first episode of psychosis. As described in the article by Iyer and colleagues, Malla initiated and has led an early intervention program in Ontario, Canada, that has made concerted efforts to engage patients early in the illness course via an open referral system and rapid response protocol (Iyer et al., 2015). An evaluation of patients receiving these services shows overall favorable outcomes, which the authors attribute to the relatively short DUP of their sample. The article by Marino and colleagues reports on the evaluation of an early intervention program, the RAISE Connection program (Marino et al., 2015). The components of the services provided to patients in the RAISE Connection program are similar to those described in the Malla program (Iyer et al., 2015), including a teambased intervention sensitive to patients’ developmental needs and focused on psychosocial outcomes as well as psychiatric symptoms. The Marino article reports on mediators and moderators of outcome in the early intervention program. The article reports that greater improvement in occupational functioning was predicted by higher verbal fluency scores at baseline and that greater improvement in social functioning was predicted by family involvement in the course of the intervention, both predictors representing potentially modifiable factors. Another RAISE program, a randomized controlled trial of a similar intervention for early course patients, is currently underway and will further add to this body of knowledge (Correll et al., 2014). It is of note that initial feasibility data from the RAISE Connection study were instrumental in the passage of Congressional legislation in 2014 that calls for setting aside funds from the Community Mental Health Block Grant program to support dissemination of interventions for first-episode patients similar to those tested in RAISE (http://www.nimh.nih.gov/about/director/2014/best-of-2014.shtml). This new funding stream is unprecedented in creating dedicated resources throughout the US for the treatment of first-episode patients. In another original research report, Vohs and colleagues describe the results of a cross-sectional study in which they found significant associations between illness insight and aspects of metacognition (an awareness of one’s mental processes) in a sample of patients with a first episode of psychosis (Vohs et al., 2015). Illness insight is predictive of recovery, so modifiable factors that may increase illness insight are important. Metacognition is also of interest because of an increasing emphasis on the lived experiences of people with mental illness and on approaches that help such persons to better understand themselves and their interactions with others. Additional contributions are directed at epidemiology. The article by Revier and colleagues reports on the results of the AESOP-10 study, a 10-year follow-up of patients with a first episode of psychosis evaluated at two sites in England (Revier et al., 2015). As in the Addington study of prodromal patients (Addington et al., 2015), a marked variability in clinical outcome was found. Of interest, the © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
The Journal of Nervous and Mental Disease • Volume 203, Number 5, May 2015
authors found a high prevalence of symptom remission at follow-up but extensive social disability with the vast majority of patients unemployed. Mortality data were striking with a fourfold increase in all-cause mortality compared with that in the general population and a 20- fold increase in mortality due to suicide. Similar to results in the RAISE Connection study, family participation was predictive of better outcomes; it was found that full family involvement at first contact with services was associated with a reduced risk of unnatural death. However, neither study was a randomized controlled trial of family intervention, making cause-effect relationships difficult to define. The article by Nordentoft and colleagues continues on the topic of morbidity and mortality and provides a review of additional epidemiological studies (Nordentoft et al., 2015). The article presents compelling data about the high mortality of individuals with schizophrenia and the fact that the rate of suicide may be as high as 10% in the first year of treatment. Nordentoft and colleagues raise the intriguing point that suicide attempts may take place before the individual has the first contact with mental health services during the period of untreated psychosis, so the rate of suicide may actually be higher in this population than previously assumed. Nordentoft and colleagues also note the considerable rate of suicide during stays in the hospital, assumed to be a setting of safety, and argues for particularly close patient contact and monitoring of symptoms during and right after the hospital stay. In the final article included in this issue, Cox and colleagues review the extant literature on the immune system in schizophrenia and lay out the evidence for this system as a potential target of pharmacologic interventions (Cox et al., 2015). They note that immune modulatory agents may lower the proinflammatory status of some schizophrenia patients toward the levels of healthy controls. Initial trials of some agents, including N-acetyl cysteine, aspirin, and estrogens, show promise as adjunctive treatments although there is not yet enough of an evidence base to recommend their use in routine practice. What is the reader to conclude from this collection of articles that represent a detailed presentation of early intervention studies? Clearly, there is now urgency to improve outcomes for patients with schizophrenia starting early in the illness or even before the illness begins, to cast a wider net in identifying vulnerable individuals, and to provide specialized services for high-risk and for early-onset patients. In addition, and as demonstrated by several articles here, unraveling the etiological factors of schizophrenia and determining the full scope of patient outcomes is no easy task. It requires large collaborative efforts such as NAPLS and the use of population-based data such as those from the US military or from cohorts based on national health systems. There is a need for approaches that integrate biological and clinical markers and for long-term observational studies as well as clinical trials. The goal is the development of practical and effective methods for early detection and intervention. Such methods would have a profound effect on the health and well-being of all individuals affected by these devastating disorders. DISCLOSURE The author declares no conflict of interest.
Editorial
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