• Save
A century of schizophrenia
Upcoming SlideShare
Loading in...5
×
 

Like this? Share it with your network

Share

A century of schizophrenia

on

  • 1,728 views

 

Statistics

Views

Total Views
1,728
Views on SlideShare
1,708
Embed Views
20

Actions

Likes
3
Downloads
0
Comments
0

1 Embed 20

http://thepsychguru.com 20

Accessibility

Categories

Upload Details

Uploaded via as Microsoft Word

Usage Rights

© All Rights Reserved

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Processing…
Post Comment
Edit your comment

A century of schizophrenia Document Transcript

  • 1. A CENTURY OF SCHIZOPHRENIAWhere we came from, where we are now and where we are goingAdonis Sfera, MD, Stephen Stahl MD, PHDAbstract: As early as 1801, French psychiatrist PhillipePinel asked the question: “Does insanity dependupon organic lesion of the brain?”(1). Pinel proceeded to perform numerous autopsies and eventuallyconcluded: “no facts, yet clearly established, relative to the influence of the size and configuration of thecranium upon the faculties of the mind”(1).This view prevailed for almost two centuries, and not without a reason. There are minimal grossanatomical findings in mental diseases when compared to the degenerative neurological disorders suchas Alzheimer’s disease, Parkinson’s disease or amyotrophic lateral sclerosis. Additionally, mentaldisorders differ from progressive neurological disorders in as much as they may remit or becompensated for. Consequently, mental diseases were seen by many as “functional” as opposed to“organic” and treatment options were developed accordingly(2). Functional conditions were treatedpsychologically during the time of the analytical paradigm. It was only in the past two decades, whenadvanced functional brain mapping technologies have become widely available, that the so called“organic lesions” that Pinel failed to locate in the brains of mentally ill have been finally delineated sothat we can now state with some certainty that psychiatric illness is caused by neural damage that wecan characterize by the neuropathology involved(3). This novel data is slowly finding its way into theclinical work, but the time lag between research and clinical applications is unacceptable for this day andage(4).Where we came fromAbout 100 years ago Bleuler published his work “Dementia Praecox or the Group of Schizophrenias”(5).This is when psychiatrists first heard the term schizophrenia. The plural form used implies multipleconditions grouped under this generic name.At that time there were two schools of thought in European psychiatry- the German and the French.French psychiatry was led by Jean-Martin Charcot, and Pierre Janet while German psychiatry byWilhelm Wundt and Emil Kraepelin(6 ).Although both schools were biological in orientation, they had disagreements. French psychiatriststhought that, what we call schizophrenia today, could be reversed. Their German colleagues, primarilyKraepelin thought that it was irreversible and that it inevitably led to dementia(2)Bleuler attempted to find a middle ground for this dilemma by coining an alternative term,schizophrenia, which gradually became accepted throughout the Western world, however anotherdivision was on the horizon(5).
  • 2. At that time Freud embraced the new “functional” view of schizophrenia, while Bleuler continued towork within the “organic” paradigm. Bleuler’s young assistant Carl Jung, adopted Freud’s ideas and thetwo schools of thought (functional and organic) parted way for almost half a century(7).In 1913 Bleuler published his work Criticism of Freud’s Theories in which he denounced analytic ideasand warned about their proponents marginalizing biological psychiatry(8). Bleuler was probably one ofthe last voices in favor of organic etiology of schizophrenia In the first half of the 20th centurypsychiatry was governed by the analytic paradigm in which the emphasis was placed on the functional,thus psychological aspect of schizophrenia rather than on the neural pathology of the disease itself(9).The second half of the twentieth century ushered in the neurochemical paradigm which shifted thefocus from the psychological aspect of this condition to the chemical one. The neurochemical approachyielded biological treatments that transformed the approach to psychosis and allowed for thedeinstitutionalization of a large number of patients with schizophrenia (9). Typical and atypicalantipsychotics were discovered, but the emphasis was placed on the neurotransmitters and drugs ratherthan the neuropathology of the disease itself. Schizophrenia was considered a “dopamine disease”which was an extreme oversimplification and despite the growing number of psychotropic drugs thatwere marketed a, the mechanisms of action were predominantly the same as the original prototypesdeveloped in the 1950s (10). Even though efficacious in the treatment of delusions and hallucinations,antipsychotics failed to enhance full recovery and reintegration of the patient into the work force andsociety at large possibly because of the disabling cognitive deficits that were not addressed by theantipsychotic medication(11). Thus the cognitive theory of schizophrenia was introduced trying toaddress simultaneously both cognition and psychosis.The cognitive theory of schizophrenia seems to validate Kraepelin’s dementia praecox model in statingthat schizophrenia is primarily a cognitive disorder and that lack of insight is part of the cognitivedeficit(6). This shifted the emphasis from the “dopamine disorder” to the “glutamate disorder”(9) andit brought the recognition that negative and cognitive symptoms do not respond to antipsychoticmedications(91). Glutamate agonists such as glycine, d-cycloserine, as well as acethylcholine receptorligands such as ispronicline and others (12 ) were studied, but the results were disappointing in terms ofimproving cognition in schizophrenia(13).Where we are nowSchizophrenia continues to remain a major challenge for psychiatry. Even with the new and improvedantipsychotics and supportive psychotherapy sustained recovery occurs in less than 14% within the firstfive years following a psychotic episode (14). Nearly 20% of people with schizophrenia arehomeless(92). Lack of curative or preventative approaches reflect the lack of basic understanding of thepathophysiology of schizophrenia (9).
  • 3. After the completion of the Human Genome Project, a new era is gradually ushered in – the molecularparadigm. For the past decade the search for causes of schizophrenia has been going into twodirections: genetics(nature) and environment(nurture).On the one hand psychiatric genetics combined with neuroimaging reveal brain wiring during thedevelopment(93). Factors that influence neuronal migration, differentiation and apoptosis are beingidentified and studied(15)(83). A list of risk-genes for schizophrenia is gradually emerging (16). Geneticrisk factors combined with environmental stressors (epigenetic factors) are seen as instrumental intilting the balance of vulnerability and resilience toward schizophrenia (17). Like most major scientificdiscoveries, genetics seems to raise more questions than offer answers and this caused an initialdisappointment. Genomic and other research tools are available to help us come to grips with thesefindings. Gradually it became obvious that the genetic basis of schizophrenia is more complex thaninitially envisioned (18), however a new look at the risk genes revealed unrecognized sources of geneticvariability such as Copy Number Variation (CNV). Indeed, CNVs are recognized to contribute both tonormal genomic variability and to risk for human diseases, they seem to narrow down previous findingsfrom genome wide association studies and point more directly at abnormal neuropathologic substrates(95). This and other novel genetic data is being corroborated with neuroimaging and with post mortembrain studies supporting the recognition held for some time that schizophrenia is a neurodevelopmentalcondition(19)(84).On the other hand the study of the environment (nurture) focused on the two “epis”: epigenetics andepidemiology.Epigenetic studies of discordant twins revealed that people with schizophrenia present with changes ingene activity expressed or silenced by the environmental factors. Their identical DNA is expresseddifferently in the ill twin due to epigenetic markings such as methylation, hypomethylation, oracetylation. These findings were corroborated and confirmed with post-mortem brain tissue studies ofpeople with schizophrenia (20).A list of epidemiologic risk factors for schizophrenia is emerging(21)(22)(23), addressing ways in whichindividual (genetic) vulnerability is influenced by broader socio-environmental variables(31). There areestablished environmental risk factors for Schizophrenia such as pregnancy or birth complications(24)(25)(26)(27)(28), growing up in large cities, immigrant status(29) and drug consumption, especiallycannabis( 30). However, the odds ratios around 2 and each of these factors appears to increase thelifetime risk of the disease only slightly(32)(33). Thus, the currently known risk factors, either alone ortaken together, cannot be used for prediction and prevention without a more complete knowledge ofthe predispositional basis and the gene-gene and gene-environment interaction(34). More studies areneeded regarding ranking the risk factors according to their liability in disease causation(35)(36)(37).Genetic, epigenetic and epidemiologic data along with findings from various sciences such as moleculargenetics, cell biology, neurophysiology, brain structural and functional imaging and neuropsychology aprogressive evolution of schizophrenia in four stages: premorbid, prodromal, manifest and deficit orburn out stage(38)(39)(40)(41)(42).
  • 4. An “oncology model” of stage specific treatment is gradually taking shape in schizophrenia(43) and willprobably continue to develop as more neuropathological data becomes available(44)(45)(46)(47).Premorbid stage represents the genetic vulnerability with no signs or symptoms of illness. Prodromal stage ushers in softsigns and symptoms such as social isolation, decreased working memory, recent functional decline, unusual thought content,suspicion, etc. Stage of onset/deterioration is the stage of manifest disease, usually with multiple hospitalizations andgradual decline. Residual stage is the stage of deficit manifested by negative, cognitive and deficit symptoms.The premorbid stage is the stage of risk or genetic vulnerability(9). As mentioned earlier the recognizedneurobiologic risk factors are not sufficiently predictive at this time as to allow the development andapplication of preventive measures(48)(49)(50). Only very few genes such as DISC1 or chromosomaldeletions such as velo-cardio-facial syndrome (deletion 22q11) are certain high risk factors(51)(52).However deficient neuronal migration is emerging as link between many human neurologic diseases. Inepilepsy, schizophrenia and some neurodevelopmental conditions there is evidence that disorderedneuronal migration may contribute to the pathogenesis, as one of the more frequent findings in theseconditions is heterotopically located neurons in various positions throughout the CNS (53). In the nextdecade or two we might be able to study and classify variants of schizophrenia into categories likeNeuronal Migration Disorders (NMD) or myelination disorders, synaptic elimination disorders orcytoskeletal disorders(54)(55(56)(57)(58).The premorbid stage is an area where epidemiologic findings are beginning to emerge and are beingcorroborated with the neuroimaging such as the Human Connectom Project early results reveal a
  • 5. picture of deficient connectivity in schizophrenia, autism and many neurodevelopmental andneurodegenerative disorders(59)(60)(61)(62)(63).The prodromal stageFirst episode of psychosis (FEP) research has shown that the outbreak of the disease is preceded inabout 70% to 100% of cases by an initial prodrome, which lasts for an average of five to six years(34).After the initial episode even in the highly developed health care systems, an average of one yearelapses before the initiation of treatment(64)(65).Centers for early recognition and prevention of schizophrenia were established in Melbourne, Australiaand elsewhere in the mid 1990s(66)(67)(68). They conducted retrospective research of the early courseof psychosis. They showed that psychosis occurs late in the course of schizophrenia and is preceded byidentifiable disturbances in behavior and working memory(9)(62). The works of McGorry and Thompsonreveal a dynamic wave of tissue loss in the prodromal stage that starts initially the parietal cortex thanspreads to the temporal and prefrontal cortex in the following years(59)(65), offering a window ofopportunity for therapeutic interventions(60)(61)(63).A recent study of 291 adolescents followed for 2.5 years reported that the prodrome represents a 405-fold increase in risk (relative to the general population(9). A combination of three factors such asgenetic risk, recent functional decline, unusual thought content, suspicion/paranoia or reduced socialfunctioning) resulted in a positive predictive power for conversion to psychosis of 74-81%(56).Novel neuropsychological tools such as Prodromal Syndromes (SIPS), COGDIS or COOPER are able todistinguish schizophrenia risk factors from other causes (63)(64)(85). The detection and predictivepower can be increased by the addition of biological markers detected with functional or structuralneuroimaging(86)(87) and the above neuropsychological tests(69)(70)(71)(72). Early identification ofcognitive changes such as reductions in working memory are highly predictive of prodromal conversioninto psychosis(73)(74)(75)(34). COPER(cognitive perceptive basic symptoms), COGDIS(cognitivedisturbances)(34)(76)(78) are continuously improving and becoming increasingly more sensitive inidentifying the earliest cognitive deficits.Onset/Deterioration phase (manifest disease phase)First Psychotic Episode(FPE) usually occurs after a 5-6 years prodrome and is a common endpoint formany different pathological processes and even a variant of normal human experience in states of stressor restricted consciousness(95). Social, behavioral and cognitive abnormalities, which also feature inschizophrenia, overlap prominently with other disorders including learning disability, autistic spectrumdisorders [8], developmental disabilities, neurodegenerative disorders, substance dependence andseveral medical/metabolic conditions (19). This symptom overlap causes ongoing controversy abouthow the clinical boundaries of schizophrenia should be drawn and brings into question current
  • 6. psychiatric taxonomy. NIMH Research Domain Criteria – or RDoC – represents a new organizationalframework that would help researchers match molecular findings with neuropathologic changes anddomains of psychiatric syndromes and thus classify mental disorders accordingly.Several molecular mechanisms have been proposed regarding conversion from the prodrome to FPE.They include: apoptosis(110), oxidative stress(111), glutamate toxicity(112), stress sensitization(113),dysfunctional neurotropin pathways(115)(116). A consensus is forming about the role ofneuroprotective agents in schizophrenia(2). Neuroprotection refers to any type of therapeutic modality,usually pharmacological, that can prevent, delay or even reverse neuronal damage, axonal degenerationor any other form of neuronal injury( 2). For example agents such as estrogen(117 ), erythropoietin(118), piracetam(121 ), modafinil(119 ) omega 3 fatty acids(120 ) added to the regular antipsychotictreatment might improve the outcome of schizophrenia( 2 ) . Neuroprotective psychotropic agents inuse today include: Olanzapine(102) and clozapine (102). Valproate (122) and lithium(123) as well asantidepressants(116).More studies are needed to clarify types of interventions during the prodromal phase(77) that wouldprevent or delay first episode psychosis (FEP)psychosis(80)(81), but preliminary data point to the factthat small dose antipsychotics(79 ) antidepressants(83 ), lithium (90 ) , cognitive behavioral therapy(90)(91) or omega 3 polyunsaturated fatty acids(89 ) and other neuroprotective agents during theprodromal phase might decrease conversion to psychosis(88)(89). After the FEP aggressive treatmentwith antipsychotics including long acting neuroleptics was shown to decrease further progression of thedisease(93).Residual stage of schizophrenia or burnout phaseThis stage involves stabilization into deficit, negative and cognitive symptoms as well as significantdisability are the hallmark of this stage. Neuroimaging studies show that schizophrenic patients losearound 0.5% of their brain volume per year (as opposed to around 0.2% in normal controls), especially(but not only) in the frontal and temporal areas (96). Loss of brain volume seems to be due to both thepathologic disease process as well as some antipsychotic medications(97).Poor response to antipsychotic medications or treatment resistance characterizes this stage ofschizophrenia(97). This is probably due to the presence of predominantly negative and cognitivesymptoms of schizophrenia, there is a general consensus that these symptoms (including poor insight )do not respond to antipsychotic treatment(11)(12).It is also possible that continuous use of high dose antipsychotic drugs in this stage may cause moreharm than good since brain volume loss has been associated with long term use of antipsychoticmedications in schizophrenia (97). The intermittent, as needed or targeted use of antipsychotics(98 )(99) (100 ) (101 ) needs to be revisited for this stage (according to the model of chemotherapy inoncology or corticotherapy in rheumatology) as well as the use of neuroprotective agents. Morestudies are necessary about the use of antipsychotics in this stage, especially since obesity andmetabolic syndrome led to a decreased life expectancy ( of approximately 56 years) in individuals with
  • 7. schizophrenia. Neuroprotective psychotropic drugs such as clozapine, olanzapine or lithium may bemore justified in case of overt psychotic symptoms(102)Where we are goingThe future interventions in schizophrenia are based on two facts:1. schizophrenia is neurodevelopmental disorder2. psychosis is a common endpoint for schizophrenia and other neurological diseases as well as a lateoccurrence in the course of the disease (9). This recognition will shift emphasis on prevention whichincludes:1. early detection and treatment of prodromal symptoms2. avoidance or delaying first episode of psychosis (FEP)3. aggressive treatment and follow up of first episode psychosis(FEP)These steps are already applied in an NIMH research project called Recovery after an InitialSchizophrenia Episode (RAISE). This innovative project is attempting to change the trajectory andprognosis of schizophrenia through coordinated and aggressive treatment in the earliest stages ofillness. RAISE is designed to reduce the likelihood of long-term disability as well as enhance outcome.As mentioned earlier, phase specific schizophrenia treatments might be gradually developed withemphasis on prevention in the early phases and neuroprotection in later ones. Neuropsychologicalinstruments such as SIPS (Structural Interview for Prodromal Syndromes), and neurocognitive test-batteries for at risk mental states (ARMS)(51)(43) will become increasingly more powerful and able todetect deficits of working memory earlier.Neurorotective treatments as well as early psychotherapy (including CBT and family interventions) willbe integrated with the early prevention and follow up with the aim at slowing down disease progressionand possibly even achieving primary prevention in recognized prodromal states(103).Rather than being considered a homogeneous disease entity, schizophrenia will most likely bediagnosed and treated by separate domains of pathology (104)(105)(106)(107). For example geneticstudies will shift from the genetics of schizophrenia as a syndrome to the genetics of pathologicaldomains such as neuronal migration, myelination, cell loss, disconnection, synaptic strength/plasticity,dendritic spine and microtubular pathology. This may help clarify the apparent genetic overlap betweenmajor psychiatric syndromes as well a psychiatric taxonomy. NIMH Research Domain Criteria (RDoC) isstep in that direction, it is designing a framework for creating a new way to classify mental disorders;one built on decades of neuroscience-based research that is changing researchers’ understanding ofhow the brain produces adaptive behavior and how a patient’s functionality turns from normal toabnormal in forms of various mental disorders.
  • 8. The etiology and treatment of cognitive and negative symptoms of schizophrenia will be diagnosed andtreated differently with drugs targeting cognition(108).Integration of care is an area in which we are underperforming today. Medical care is currentlyseparated from psychiatric and psychosocial care such as family education, employment and familysupport(9). A new paradigm needs to be developed in which family members play a pivotal role in thetherapeutric process. Rather than excluding family members (in the interest of confidentiality) from theprocess of psychiatric treatment, an addiction medicine model needs to be adopted in which familymembers are considered allies in the therapeutic process (109).Conclusions:Schizophrenia is a syndrome comprised of many conditions (hence the plural used by Bleuler) some ofwhich are reversible while others invariably progress towards cognitive deficit.Recent genetic, epigenetic, neuroimaging and post mortem studies reveal subtle molecular and whitematter changes in the brains of individuals diagnosed with schizophrenia, placing this disease in therealm of neurological conditions.Schizophrenia originates during the embryonal development, but psychosis is a lateoccurrence/complication, offering an opportunity for early preventive treatment during the prodromalphase and after the first psychotic episode.Preventive approaches need to become mainstream interventions in schizophrenia, but they must bebased on genetic, epigenetic and epidemiologic risk factors confirmed with novel neuropsychologicaltools in order to assure early detection and aggressive treatment of prodromal and first psychoticepisode symptoms thus preventing relapse and chronicity.Novel psychopharmacologic and research therapies must address cognitive and negative symptomswhich do not respond to current treatments and prevent patient’s reintegration into the society andwork force.REFERENCES:1.PhillippePinel. Atreatise of insanity. Sheffield:W.Todd;18062.M.S. Ritsner(ed.) Brain Protection in Schizophrenia, Mood and Cognitive Disorders,DOI 10.1007/978-90-481-8553-5-1, Springer Science/business Media B.V.20103.HendlerT, Bleich-CohenM, Sharon H. Neurofunctional view of psychiatry: clinical brain imagingrevisited, CurrOpin Psychiatry. 2009 May;22(3):300-54.Washington (DC): National Academies Press (US); 2010nstitute of Medicine (US) Forum on DrugDiscovery, Development, and Translation. Washington (DC): National Academies Press (US); 2010.
  • 9. 5. Bleuler E. Dementia Praecox oderGruppe der Schizophrenien. Leipzig, Germany: Deuticke; 1911.6.Kreaepelin E. Dementia Precox and Paraphrenia, Edinburgh, UK: Livingstone; 19197.CarlG.Jung, Man and his symbols, 1964, Aldus Books Limited, London8.Bleuler E, (1913). Die Kritik der FreudschenTheorie. AllgemeineZeitschriftfürPsychiatrie undpsychischgerichtlicheMedizin, 52 (5), 665-718.9.Thoms R. Insel, Rethinking schizophrenia, Nature, 468,187-193(11November 2010)doi:10.1038/nature0955210. Jeffrey Liberman, Robin M. Murray; Comprehensive Care of Schizophrenia: A Textbook of ClinicalManagement, 212, Oxford University Press.11. Marvin S. Swartz; Diana O. Perkins; T. Scott Stroup; Sonia M. Davis; George Capuano; Robert A.Rosenheck; Fred Reimherr; Mark F. McGee; Richard S.E. Keefe; Joseph P. McEvoy; John K. Hsiao; JeffreyA. Lieberman; Effects of Antipsychotic Medications on Psychosocial Functioning in Patients With ChronicSchizophrenia: Findings From the NIMH CATIE Study ,Am J Psychiatry 2007;164:428-436.10.1176/appi.ajp.164.3.42812.Keefe RS, Sweeney JA, Gu H, Hamer RM et al.Effects of olanzapine, quetiapine, and risperidone onneurocognitive function in early psychosis: a randomized, double-blind 52-week comparison. Am JPsychiatry2007 Jul;164(7):1061-71.13.Stahls Essential Psychopharmacology: Neuroscientific Basis and Practical Applications by Stephen M.Stahl, Published April 1st 2008 by Cambridge University Press14.Delbert G. Robinson, Margaret G. Woerner, Howard M. Delman; Pharmacological Treatments forFirst-Episode Schizophrenia; Schizophrenia Bulletin vol. 31 no. 3 pp. 705–722,2005,doi:10.1093/schbul/sbi03215.Gill M; Donohoe G; Corvin A: What have the genomics ever done for the psychoses? Psychol Med2010; 40:529–54016.McGrath J; Saha S; Welham J; El Saadi O; MacCauley C; Chant D: A systematic review of theincidence of schizophrenia: the distribution of rates and the influence of sex, urbanicity, migrant statusand methodology. BMC Med 2004; 2:1317.Kirkbride J; Coid JW; Morgan C; Fearon P; Dazzan P; Yang M; Lloyd T; Harrison GL; MurrayRM; Jones PB: Translating the epidemiology of psychosis into public mental health: evidence,challenges and future prospects. J Public Ment Health 2010; 9:4–1418.Neurocognitive Outcomes in the Treatment of Early-Onset Schizophrenia Spectrum Disorders Study,Jean A. Frazier, M.D., Anthony J. Giuliano, Ph.D., Jacqueline L. Johnson, Dr.P.H., Lauren Yakutis, B.A., EricA. Youngstrom, Ph.D., David Breiger, Ph.D., LinmarieSikich, M.D., Robert L. Findling, M.D., M.B.A., Jon
  • 10. McClellan, M.D., Robert M. Hamer, Ph.D., Benedetto Vitiello, M.D., Jeffrey A. Lieberman, M.D., StephenR. Hooper, Ph.D.; February 2012. published online 15 March 2012.19.Susan Moore, Eric Kelleher and Aiden Corvin, The Shock of the New: Progress in SchizophreniaGenomics, Current Genomics, 2011, 12, 516-52420. Dempster, E. et al. ‘Disease-associated epigenetic changes in monozygotic twins discordant forschizophrenia and bipolar disorder’, Human Molecular Genetics doi: 10.1093/hmg/ddr41621.McGorry P. The prodromal or ultra-high risk stage of schizophrenia and related psychoses: a windowfor understanding and intervention. Programs and abstracts of the American Psychiatric Association2008 Annual Meeting; May 3-8, 2008; Washington, DC. ISS07.22.McGrath JJ: Myths and plain truths about schizophrenia epidemiology: the NAPE lecture 2004.ActaPsychiatrScand 2005; 111:4–1123.Davey Smith G; Ebrahim S: Epidemiology: is it time to call it a day? Int J Epidemiol 2001; 30:1–1124.Veling W; Hoek HW; Selten J-P; Susser E: Age at migration and future risk of psychotic disordersamong immigrants in the Netherlands: a 7-year incidence study. Am J Psychiatry 2011; 168:1278–128525. Clarke MC; Tanskanen A; Huttunen M; Leon DA; Murray RM; Jones PB; Cannon M: Increasedrisk of schizophrenia from additive interaction between infant motor developmental delay and obstetriccomplications: evidence from a population-based longitudinal study. Am J Psychiatry 2011; 168:1295–130226. Heins M; Simons C; Lataster T; Pfeifer S; Versmissen D; Lardinois M; Marcelis M; Delespaul P;Krabbendam L; van Os J; Myin-GermeysI;the GROUP Project: Childhood trauma and psychosis: a case-control and case-sibling comparison across different levels of genetic liability, psychopathology, andtype of trauma. Am J Psychiatry 2011; 168:1286–129427.Patterson PH: Maternal infection: window on neuroimmune interactions in fetal brain developmentand mental illness. CurrOpinNeurobiol 2002; 12:115–11828. Scott J; Varghese D; McGrath J: As the twig is bent, the tree inclines: adult mental healthconsequences of childhood adversity. Arch Gen Psychiatry 2010; 67:111–11229.Selten JP; Cantor-Graae E: Social defeat: risk factor for schizophrenia? Br J Psychiatry 2005;187:101–10230.Louise Arseneault, lecturera, Mary Cannon, Wellcome Trust advanced fellowb, Richie Poulton,director, Dunedin multidisciplinary health and development studyc, Robin Murray, professor,AvshalomCaspi, professora, Terrie E Moffitt, professor, Cannabis use in adolescence and risk for adultpsychosis: longitudinal prospective study; BMJ 2002; 325:1212 doi: 10.1136/bmj.325.7374.1212.
  • 11. 31.Lawlor DA; Davey Smith G; Kundu D; Bruckdorfer KR; Ebrahim S: Those confounded vitamins:what can we learn from the differences between observational versus randomised trial evidence?Lancet 2004; 363:1724–172732.Benros ME; Nielsen PR; Nordentoft M; Eaton WW; Dalton SO; Mortensen PB: Autoimmunediseases and severe infections as risk factors for schizophrenia: a 30-year population-based registerstudy. Am J Psychiatry 2011; 168:1303–131033. Marcelis M, Takei N, van Os J, Urbanization and risk for schizophrenia: does the effect operatebefore or around the time of illness onset? Psychol Med. 1999 Sep;29(5):1197-203.34.JoachimKlosterkotter et al. Prediction and prevention of schizophrenia: what has been achieved andwhere to go next? World Psychiatry. 2011 October; 10(3): 165–17435. Commonwealth Department of Health and Aged Care.Promotion, prevention and early interventionfor mental health – a monograph. Canberra: Commonwealth Department of Health and Aged Care;2000.36. European Commission. Green Paper – Improving mental health of the population: towards a strategyon mental health for the European Union. Brussels: European Commission; 200537. Rössler W, Salize HJ, van Os J. Size of burden of schizophrenia and psychotic disorders.EurNeuropsychopharmacol. 2005;15:399–40938. Hilleke E. Hulshoff Pol1 and René S. Kahn What Happens After the First Episode? A Review ofProgressive Brain Changes in Chronically Ill Patients With Schizophrenia. Published by Oxford University39.Brown AS; McGrath JJ: The prevention of schizophrenia. Schizophr Bull 2011; 37:257–261 Presson behalf of the Maryland Psychiatric Research Center.40.McGrath J: Is it time to trial vitamin D supplements for the prevention of schizophrenia?ActaPsychiatrScand 2010; 121:321–32441. Schultze-Lutter F, Ruhrmann S, Berning J. Basic symptoms and ultrahigh risk criteria: symptomdevelopment in the initial prodromal state. Schizophr Bull. 2010;36:182–191.42. Jeffrey Liberman, Robin M. Murray; Comprehensive Care of Schizophrenia: A Textbook of ClinicalManagement, 212, Oxford University Press.43. Schultze-Lutter F, Ruhrmann S, Klosterkötter J. Evolving psychosis. In: Johannessen JO, Martindale B,Cullberg J, editors. Different stages, different treatments. London: Routledge; 2006. pp. 104–123.
  • 12. 44. Schultze-Lutter F, Klosterkötter J, Picker H. Predicting first-episode psychosis by basic symptomcriteria. Clin Neuropsychiatry. 2007;4:11–22.45. Yung AR, Phillips LJ, McGorry PD. Prediction of psychosis. Br J Psychiatry. 1998;172(Suppl. 33):14–20.46. Miller TJ, McGlashan TH, Rosen JL. Prospective diagnosis of the initial prodrome for schizophreniabased on the structured interview for prodromal syndromes: preliminary evidence of interraterreliability and predictive validity. Am J Psychiatry. 2002;159:863–86547. Yung AR, Yuen HP, McGorry PD. Mapping the onset of psychosis: the comprehensive assessment ofat-risk mental states. Aust N Z J Psychiatry. 2005;39:964–971.48. McGlashan T, Walsh B, Woods S, editors. The psychosis-risk syndrome.Handbook for diagnosis andfollow-up. New York: Oxford University Press; 2010.49. Cornblatt B. The New York High-Risk Project to the Hillside Recognition and Prevention (RAP)Program.Am J Med Genet. 2002;114:956–966. [PubMed]50. Riecher-Rössler A, Geschwandtner U, Aston J. The Basel early-detection-of-psychosis (FEPSY)-study –design and preliminary results. ActaPsychiatr Scand. 2007;115:114–12551. Klosterkötter J, Hellmich M, Steinmeyer EM. Diagnosing schizophrenia in the initial prodromalphase.Arch Gen Psychiatry. 2001;58:158–16452. Marshall M, Lewis S, Lockwood A. Association between duration of untreated psychosis andoutcome in cohorts of first-episode patients: a systematic review. Arch Gen Psychiatry. 2005;62:975–98353. Gualtieri, C. Thomas, Brain Injury and Mental Retardation: Psychopharmacology andNeuropsychiatry, LIPPINCOTT RAVEN,200254.Yung AR, McGorry PD, Francey SM, et al. PACE: A specialised service for young people at risk ofpsychotic disorders. Med J Aust. 2007;187:S43-S46. Abstract55.Mrazek PJ, Haggerty RJ, eds. Reducing Risks for Mental Disorders: Frontiers for PreventiveIntervention Research . Washington DC: National Academy Press, 1994.56.Cannon TD, Cadenhead K, Cornblatt B, et al. Prediction of psychosis in youth at high clinical risk: amultisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65:28-37.57.Okasha A, et al. The emergence of subthreshold psychiatry.Programs and abstracts of the AmericanPsychiatric Association 2008 Annual Meeting; International symposium; May 3-8, 2008; Washington, DC.58.Rucci P, Gherardi S, Tansella M, et al. Subthreshold psychiatric disorders in primary care: Prevalenceand associated characteristics. J Affect Disord. 2003;76:171-181. Abstract
  • 13. 59.Paul M. Thompson et Mapping adolescent brain change reveals dynamic wave of accelerated graymatter loss in very early-onset schizophrenia ai.ProcNatlAcadSci U S A. 2001 September 25; 98(20):11650–11655. doi:10.1073/pnas.20124399860.Larsen TK, Melle I, Auestad B, et al. Early detection of first-episode psychosis: the effect on 1-yearoutcome. Schizophr Bull. 2006;32:758-764. Abstract61.Beardslee WR, et al. Recent advances in prevention science: implications for practice and DSM-V.Programs and abstracts of the American Psychiatric Association 2008 Annual Meeting; symposium 6;May 3-8, 2008; Washington, DC.62. Yung AR, Phillips LJ, Yuen HP. Risk factors for psychosis in an ultra high-risk group: psychopathologyand clinical features. Schizophr Res. 2004;67:131–142. [PubMed]63. Cannon TD, Cadenhead K, Cornblatt B. Prediction of psychosis in youth at high clinical risk: amultisite longitudinal study in North America. Arch Gen Psychiatry. 2008;65:28–37.64.Schultze-Lutter F, Ruhrmann S, Klosterkötter J. Evolving psychosis. In: Johannessen JO, Martindale B,Cullberg J, editors. Different stages, different treatments. London: Routledge; 2006. pp. 104–123.65. World Health Organization. Prevention of mental disorders: effective interventions and policyoptions. Geneva: World Health Organization; 2004.66. McGorry PD, Yung AR, Phillips LJ. Randomized controlled trial of interventions designed to reducethe risk of progression to first-episode psychosis in a clinical sample with subthreshold symptoms. ArchGen Psychiatry. 2002;59:921–928. [PubMed]67. Phillips LJ, McGorry PD, Yuen HP. Medium-term follow-up of a randomized controlled trial ofinterventions for young people at ultra high risk of psychosis.Schizophr Res. 2007;96:25–3368. Häfner H, Maurer K, Ruhrmann S. Early detection and secondary prevention of psychosis: facts andvisions. Eur Arch Psychiatry ClinNeurosci. 2004;254:117–128.69. Seidman LJ, Giuliano AJ, Meyer EC. Neuropsychology of the prodrome to psychosis in the NAPLSconsortium: relationship to family history and conversion to psychosis.70. Schultze-Lutter F, Addington J, Ruhrmann S. Schizophrenia Proneness Instrument, Adult version (SPI-A) Rome: Fioriti; 2007.71. Schultze-Lutter F, Koch E. Schizophrenia Proneness Instrument, Child & Youth version (SPI-CY) Rome:Fioriti; 2010.72. Schultze-Lutter F, Steinmeyer EM, Ruhrmann S. The dimensional structure of self-reported‘prodromal’ disturbances in schizophrenia.Clin Neuropsychiatry. 2008;5:140–150.73. Yung AR, Nelson B, Stanford C. Validation of “prodromal” criteria to detect individuals at ultra highrisk of psychosis: 2 year follow-up. Schizophr Res. 2008;105:10–17.
  • 14. 74. Ruhrmann S, Schultze-Lutter F, Salokangas RK. Prediction of psychosis in adolescents and youngadults at high risk: results from the prospective European Prediction of Psychosis Study (EPOS). Arch GenPsychiatry. 2010;67:241–251. [PubMed]75. Kirkbride JB, Fearon P, Morgan C. Heterogeneity in incidence rates of schizophrenia and otherpsychotic syndromes: findings from the 3-center AESOP study. Arch Gen Psychiatry. 2006;63:250–258.76. Mason O, Startup M, Halpin S. Risk factors for transition to first episode psychosis among individualswith ‘at-risk mental states’ Schizophr Res. 2004;71:227–237.77. Harrison G, Hopper K, Craig T. Recovery from psychotic illness: a 15- and 25-year internationalfollow-up study. Br J Psychiatry. 2001;178:506–517.78. Lencz T, Smith CW, Auther A. The assessment of “prodromal schizophrenia”: unresolved issues andfuture directions. Schizophr Bull. 2003;29:717–72879. McGlashan TH, Zipursky RB, Perkins D. The PRIME North America randomized double-blind clinicaltrial of olanzapine versus placebo in patients at risk of being prodromally symptomatic for psychosis. I.Study rationale and design. Schizophr Res. 2003;61:7–18.80. Bechdolf A, Müller H, Stützer H. Rationale and baseline characteristics of PREVENT: a secondgeneration intervention trial in subjects at-risk (prodromal) of developing first episode psychosisevaluating cognitive behaviour therapy, aripiprazole and placebo for the prevention of psychosis.Schizophr Bull.81. Ruhrmann S, Schultze-Lutter F, Maier W. Pharmacological intervention in the initial prodromal phaseof psychosis. Eur Psychiatry. 2005;20:1–6.82. Cornblatt BA, Lencz T, Smith CW. Can antidepressants be used to treat the schizophrenia prodrome?Results of a prospective, naturalistic treatment study of adolescents. J Clin Psychiatry. 2007;68:546–557.83. Borgwardt SJ, McGuire PK, Aston J. Structural brain abnormalities in individuals with an at-riskmental state who later develop psychosis.Br J Psychiatry. 2007;191(Suppl. 51):69–75.84. Pantelis C, Velakoulis D, Wood SJ. Neuroimaging and emerging psychotic disorders: the Melbourneultra-high risk studies. Int Rev Psychiatry. 2007;19:371–38185. Pukrop R, Schultze-Lutter F, Ruhrmann S. Neurocognitive functioning in subjects at risk for a firstepisode of psychosis compared with first- and multiple-episode schizophrenia. J ClinExpNeuropsychiatry. 2006;28:1388–1407.86. Witthaus H, Kaufmann C, Bohner G. Gray matter abnormalities in subjects at ultra-high risk forschizophrenia and first-episode schizophrenic patients compared to healthy controls. Psychiatry Res.2008;173:163–169. [PubMed]
  • 15. 87. The European Network of Schizophrenia Networks for the Study of Gene-Environment Interactions(EU-GEI) Schizophrenia aetiology: do gene-environment interactions hold the key? Schizophr Res.2008;102:21–2688. Berger G, Dell’Olio M, Amminger P. Neuroprotection in emerging psychotic disorders. Early IntervPsychiatry. 2007;1:114–127.89. Amminger GP, Schäfer MR, Papageorgiou K. Long-chain omega-3 fatty acids for indicated preventionof psychotic disorders: a randomized, placebo-controlled trial. Arch Gen Psychiatry. 2010;67:146–15490. Berger G, Wood SJ, Dell’Olio M. Neuroprotective effects of low dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study.Schizophr Res. 2008;102:39–40.91. Nelson B, McGorry P, Yung A. The NEURAPRO (North America, Europe, Australia Prodrome) Study: amulticenter RCT of treatment strategies for symptomatic patients at ultra-high risk for progression toschizophrenia and related disorders. Design and study plan. Schizophr Res. 2008;102(Suppl. 2):295–295.92.Folsom DP, McCahill M, Bartels SJ, Lindamer LA, Ganiats TG, JesteDV.Medical comorbidity and receiptof medical care by older homeless people with schizophrenia or depression. Psychiatr Serv. 2002Nov;53(11):1456-60.93.Leucht S, et al "Antipsychotic drugs versus placebo for relapse prevention in schizophrenia: asystematic review and meta-analysis" Lancet 2012; DOI: 10.1016/S0140-6736(12)60239-6.94.R.Grant Steen,Courtney Mull, Robert Mc Lure, Robert M. Hamer, Jeffrey A.Liberman;Brain volume infirst-episode schizophrenia;The British Journal of Psychiatry (2006) 188: 510-518 doi:10.1192/bjp.188.6.51095.Anne S. Bassett, M.D.; Stephen W. Scherer, Ph.D.; Linda M. Brzustowicz, M.D.Copy NumberVariations in Schizophrenia: Critical Review and New Perspectives on Concepts of Genetics andDisease,The American Journal of Psychiatry, VOL. 167, No. 8, Am J Psychiatry 2010;167:899-914.10.1176/appi.ajp.2009.0907101696.Brans RG, van HarenNE, van Baal GC, Schnack HG, Kahn RS, Hulshoff Pol HE;Heritability of changes inbrain volume over time in twin pairs discordant for schizophrenia; Arch Gen Psychiatry. 2008Nov;65(11):1259-68.97. Beng-Choon Ho, MRCPsych; Nancy C. Andreasen, MD, PhD; Steven Ziebell, BS; Ronald Pierson, MS;Vincent Magnotta, PhD, Long-term antipsychotic treatment and brain volumes;Arch Gen Psychiatry.2011;68(2):128-137. doi:10.1001/archgenpsychiatry.2010.19998.McCreadie, R.G.; Dingwall, J.M.; Wiles, D.H.; and Heykants, J.J.P. Intermittent pimozide versusfluphenazinedecanoate as maintenance therapy in chronic schizophrenia. British Journal of Psychiatry,137:510–517, 1980
  • 16. 99.Herz, M.I., and Melville, C. Relapse in schizophrenia. American Journal of Psychiatry, 137:801–805,1980.[100.Carpenter, W.T., Jr.; Heinrichs, D.W.; and Hanlon, T.E. A comparative trial of pharmacologicstrategies in schizophrenia. American Journal of Psychiatry, 144:1466–1470, 1987101.Carpenter, W.T., Jr.; Hanlon, T.E.; Heinrichs, D.W.; Summerfelt, A.T.; Kirkpatrick, B.; Levine, J., andBuchanan, R.W. "Continuous vs. Targeted Medication in Schizophrenic Outpatients: Outcome Results."Report of study conducted at Maryland Psychiatric Research Center, University of Maryland School ofMedicine, Baltimore, MD, 1990b102.Cahn W, Rais M. et al.Psychosis and brain volume changes during the first five years ofschizophrenia. EurNeuropsychopharmacol. 2009 feb;19(2):147-51.Epub 2008 .103. Morrison AP, French P, Walford L, et al. Cognitive therapy for the prevention of psychosis in peopleat ultra-high risk: randomised controlled trial. Br J Psychiatry. 2004;185:291-297.104.Carpenter WT Jr. Deficit psychopathology and a paradigm shift in schizophrenia research. BiolPsychiatry 1999;46:352-360 105.Carpenter WT Jr. Clinical constructs and therapeutic discovery.Schizophr Res 2004;72:69-73106.Carpenter WT Jr. The schizophrenia paradigm: A hundred-year challenge. The Journal of Nervousand Mental Disease 2006;194:639-643107.Carpenter WT Jr, Koenig JI. The Evolution of Drug Development in Schizophrenia: Past Issues andFuture Opportunities. Neuropsychopharmacol 2008;33:2061-2079108.Celso Arango, Robert W. Buchanan, Brian Kirkpatrick, William T. Carpenter; The deficit syndrome inschizophrenia: implications for the treatment of negative symptoms;European Psychiatry, Volume 19,Issue 1, Pages 21-26109. Shannon Miller, David Fiellin, Richard Saitz Principles of Addiction Medicine / Edition 4 by Richard K.Ries, Shannon Miller, David Fiellin, Richard Saitz Lippincott Williams & Wilkins, 2009110.Antonio AM, Druse MJ. Antioxidants prevent ethanol-associated apoptosis in fetal rhombencephalicneurons. Brain Res. 2008 Apr 14;1204:16-23. Epub 2008111.Warner DS, Sheng H, Batinic-HaberleI,Oxidants, antioxidants and the ischemic brain. J Exp Biol. 2004Aug;207(Pt 18):3221-31.112.Vardimon L. Neuroprotection by glutamine synthetase. Isr Med Assoc J. 2000 Jul;2 Suppl:46- 51.Review.113.DinaCollip, Inez Myin-Germeys, Jim Van Os, Does the Concept of “Sensitization” Provide aPlausible Mechanism for the Putative Link Between the Environment and Schizophrenia? Schizophr Bull(2008)34(2): 220-225. doi: 10.1093/schbul/sbm163 First published online: January 18, 2008
  • 17. 114.Lang U.E., Jockers-Scherubl M.C.; HellwegR.;State of the art of the neurotrophin hypothesis inpsychiatric disorders: implications and limitations 2004, vol. 111, no3, pp. 387-411.115. De-Maw Chuang,TheAntiapoptotic Actions of Mood Stabilizers,Article first published online: 28 JUN2008,DOI: 10.1111/j.1749-6632.2005.tb00026.116.McKernan DP, Dinan TG, Cryan JF. "Killing the Blues": a role for cellular suicide (apoptosis) indepression and the antidepressant response? ProgNeurobiol. 2009 August 88:246-263117. Green PS, Simpkins JW. Neuroprotective effects of estrogen: potential mechanisms of action. Int JDevNeurscci 2000; 18:347-358118.Ehrenreich H, Aust C, Krampe H et al. Erythropoietin: novel approaches to neuroprotection inhuman brain disease. Metab Brain Dis 2004; 19:195-206.119. Minzenberg MJ, Carter CS. Modafinil: a review of neurochemical actions and effects on cognition.Neuropsychopharmacology 2008; 33:1477-1502.120. Freeman MP, Hibbeln JR, Wisner KL et al. Omega 3 fatty acids: evidence basis for treatment andfuture research in psychiatry. J Clin Psychiatry 2006; 67:1954-1967121.Muller WE, Eckert GP,Eckert A. Piracetam: novelty in a unique mode of action; Pharmacopsychiatry1999;32:2-9.122. Chuang DM, The antiapoptotic actions of mood stabilizers:molecular mechanisms and therapeuticpotentials. Ann NY AcadSci 2005; 1053:195-204.123. Marmol F, Lithium: bipolar disorder and neurodegenerative diseases Possible cellular mechanismsof the therapeutic effects of lithium. Prog.NeuropsychopharmacolBiol Psychiatry 2008; 32:1761-1771.