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  • 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.
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