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Schizophrenia: the fundamental questions
Brain Research Reviews 31 Ž2000. 106–112 www.elsevier.comrlocaterbres
Interactive report
Schizophrenia: the fundamental questions 1 Nancy C. Andreasen
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UniÕersity of Iowa Hospitals and Clinics, Mental Health Clinical Research Center, 2911 JPP, 200 Hawkins DriÕe, Iowa City, IA 52242-1057, USA Accepted 29 September 1999
Abstract Identifying the correct phentotype of schizophrenia is perhaps the most important goal of modern research in schizophrenia. This identification is the necessary antecedent of indentifying the pathophysiology and etiology. A working model is proposed, which suggests that the phenotype should be defined on the basis of abnormalities in neural circuits and a fundamental cognitive process. This type of unitary model may be more heuristic than early ones that were based on heterogeneous signs and symptoms. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Neural circuits; Creativity; Cognition; Disease phenotypes
Contents 1. Introduction .
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2. The definition of the phenotype 3. Clues from epidemiology .
4. The etiology and pathophysiology of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Hypothesis one: The etiologies are multiple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Hypothesis two: The pathophysiology is an abnormality in the regulation and expression of neurodevelopment 4.3. Hypothesis three: The pathology is a ‘disease of neuronal connectivity’ . . . . . . . . . . . . . . . . . . . . . 4.4. Hypothesis four: The phenotype is defined by a mental metaprocess rather than by clinical symptoms . . . . . References
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1. Introduction Schizophrenia is one of the most important public health problems that human society confronts. It is a very common disorder, affecting 1% of the world population. People who develop schizophrenia experience severe suffering: approximately 10% commit suicide. The treatments available in the late 1990s reduce this suffering consider) Tel.: q1-319-356-1553; Fax: q1-319-353-8300; E-mail: [email protected] 1 Published on the World Wide Web on 28 October 1999.
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ably, but approximately 2r3 of those who develop schizophrenia require public assistance from governmental social security systems within a few years after onset w45x. The majority of people who develop schizophrenia are unable to return to work or to school and have relatively minimal social interactions. The costs to society are counted in billions of dollars w21x. This serious mental illness manifests itself in signs and symptoms that encompass the entire range of human mental activity. Because schizophrenia is a brain disease that manifests itself in the activities of the mind, it damages a variety of functions that we regard as specifically human.
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Schizophrenia impairs the ability to think creatively and imaginatively, to have close social relationships with other human beings, to use language to express ideas with clarity, or to experience and express a variety of emotions such as love and fear. People with schizophrenia are tormented by intrusive experiences such as hearing voices or by beliefs that they are being persecuted or injured by those around them or by alien external forces. No single sign or symptom defines schizophrenia. It is defined by the fact that people who suffer from it experience abnormalities in many different kinds of mental activities. Attempts to understand schizophrenia are shaped by several fundamental questions, which provide themes for this Nobel Symposium. Some questions addressed by this symposium are: What is the correct basis for identifying the phenotype? What does epidemiology tell us about its etiologyrpathophysiology? How many etiologies are there? This chapter provides a brief introduction to these questions, which will be amplified in the presentations of the other participants.
2. The definition of the phenotype The first of these questions, and perhaps the most fundamental of all of them, is the definition of the phenotype Ži.e., the core or true manifestation of the disease.. The definition of the phenotype in schizophrenia is particularly difficult because patients with this illness suffer from such a diversity of symptoms. Some mental illnesses, such as depression, are defined by an abnormality in a single mental system — i.e. depressed or dysphoric mood in the case of depression. Schizophrenia, on the other hand, is characterized by symptoms that reflect multiple mental processes: hallucinations, or abnormalities in perception; delusions, or abnormalities in inferential thinking; disorganized speech, or abnormalities in language; disorganized behavior, or abnormalities in behavioral monitoring and control. Those four symptoms are the classic ‘positive symptoms’ of schizophrenia in which normal functions are distorted or exaggerated. The various ‘negative symptoms’ of schizophrenia are another important aspect of the illness w6,7,33x. They represent a diminution or absence of mental functions that are normally present. Alogia Žliterally an absence of words. is a decrease in the fluency of ideas and language; affective blunting is a diminution in the ability to express emotions; avolition is a decrease in the ability to initiate and pursue goal-directed activity; anhedonia is a decrease in the ability to seek out and experience pleasurable activities, and attentional impairment is a decrease in the ability to focus attention. These various symptoms are present in patients suffering from schizophrenia in patterns that may not overlap at all. One person with schizophrenia may have hallucina-
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tions and affective blunting, while another may have delusions and attentional impairment. This non-overlapping pattern of symptoms raises an obvious question: is there a core or fundamental theme that unites this diversity of symptoms and that can provide a more general conceptualization of the phenotype? This fundamental question raises an even more fundamental question: What is the correct basis for defining the phenotype of schizophrenia? While the answer to this question seems simple and obvious at first glance, closer inspection suggests that probing deeply below the surface may be necessary. The obvious answer is that the phenotype of schizophrenia is defined by the criterion-based diagnostic symptoms that have been developed in the past several decades. The fourth Diagnostic and Statistical Manual of the American Psychiatric Association Ž1994. ŽDSM IV. w2x is perhaps the most widely used, although the definition in the 10th edition of the International Classification of Disease Ž1990. ŽICD 10. w68x provides a similar alternative. Both these criterion-based systems take a purely descriptive approach and define schizophrenia on the basis of presenting clinical signs and symptoms. Instead of trying to account for the diversity of symptoms, they emphasize psychotic symptoms as the defining feature Ži.e., delusions and hallucinations.. While the criterion-based systems are clinically useful, in that they have provided a reliable means for physicians around the world to communicate with one another, their validity is less well established. By focusing on only a few of the symptoms with which patients present, they have identified those that are easy to operationalize, but this narrow approach has probably sacrificed validity for the sake of reliability. If the long-term goal is to identify the pathophysiology and etiology of schizophrenia, then the definition of the phenotype must emphasize a definition that is heuristic for studying mechanisms of illness. With their excessive emphasis on positive or psychotic symptoms, criterion-based approaches such as DSM may have distracted investigators away from the ‘real illness’ by over-emphasizing clinical signs and symptoms, and perhaps even by over-emphasizing the wrong ones. When schizophrenia was delineated at the beginning of the 20th century by Emil Kraepelin w49x and Eugen Bleuler w22x, both of these clinician scientists stressed the importance of defining the illness by attempting to identify a fundamental ‘morbid process’. Both emphasized that psychotic symptoms, such as delusions and hallucinations, are not specific to schizophrenia, but occur in many other illnesses such as mood disorders or dementias. For both Kraepelin and Bleuler, the most important defining feature was an impairment in the ability to think in a clear, fluent, and logical way. The person with schizophrenia suffers primarily from a fragmenting in cognitive processes. Kraepelin highlighted this aspect when he named the illness ‘‘dementia praecox’’, or a serious cognitive illness with an
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onset at a relatively young age. He saw the diversity of symptoms as unified by the underlying destruction of cognitive processes:
Although the clinicians who originally delineated and defined schizophrenia emphasized that the disorder was not defined by clinical symptoms, this perspective has been lost in DSM IV and ICD 10. Both define schizophrenia using a polythetic clustering of symptoms. While useful clinically, the improved reliability of these recent standardized diagnostic manuals may exact a large price in terms of validity. Defining schizophrenia as a polythetic cluster makes the search for mechanisms more difficult, since it leads to a fragmented model: i.e., hallucinations are usually explained by one mechanism and negative symptoms by another. The alternative proposed by Kraepelin and Bleuler — that schizophrenia is defined by an abnormality in a fundamental mental process — makes the search simpler and more tractable. Consequently, several recent investigators have proposed ‘cognitive models’ of schizophrenia w16x.
‘‘Dementia praecox consists of a series of states, the common characteristic of which is a peculiar destruction of internal connections of the psychic personality . . . . The majority of the clinical pictures are the expression of a single morbid process, though outwardly they often diverge very far from one another.’’ Bleuler highlighted the same concept when he renamed the illness ‘‘schizophrenia’’. Bleuler’s new name referred to the ‘fragmenting of the mind’ that he believed to be the fundamental abnormality. Bleuler emphasized that the person with schizophrenia had lost the capacity to have his thought processes guided by concepts that were correctly linked together:
3. Clues from epidemiology ‘‘Of the thousands of associative threads that guide our thinking, this disease seems to interrupt, quite haphazardly, sometimes single threads, sometimes a whole group, and sometimes whole segments of them.’’
As we search for ‘the holy grail’ — the etiology and pathophysiology of schizophrenia — we can be guided by some simple and very consistent observations concerning the epidemiology of the disorder w21x. These include the following: 1. Schizophrenia has a similar clinical presentation and a similar prevalence throughout the world — a lifetime prevalence of approximately 1%. Because schizophrenia is at present a lifetime disorder, the lifetime prevalence and the point prevalence are essentially the same. 2. Schizophrenia has been present for centuries, as inferred from literary descriptions. 3. ‘Classic’ cases begin in young adult life. 4. Males are more frequently and severely affected. 5. The illness tends to run in families. 6. Despite the fact that the majority of people with schizophrenia do not marry or have children, the disease persists in the human population.
Thus the ‘founding fathers’ of schizophrenia believed that they had identified a disease that had many different kinds of symptomatic manifestations at the clinical level, but that was in fact defined by an abnormality in a more basic mental process. Their thinking, reshaped in 21st century terms, would be expressed by a ‘working model’ similar to that shown below. Schizophrenia is a disease that is characterized by multiple different symptoms when assessed at the clinical level Že.g., hallucinations, avolition. and multiple disturbances in cognitive processes when assessed at the systems level Že.g., memory, language.. However, schizophrenia is ultimately a disease of the mind that is characterized by a ‘disturbance in thinking’ — an abnormality in a fundamental cognitive process.
Working Model DNA
y
Gene Expression
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Etiology: Multiple convergent factors such as Viruses Toxins Nutrition Birth Injury
y
y
y
y
Psychological Experiences
Pathophysiology: Brain development from conception to early adulthood Že.g., neuron formation, migration, synaptogenesis, pruning, apoptosis, activity dependent changes.
y
Anatomic and functional disruption in neuronal connectivity and communication
y
Impairment in a fundamental cognitive process
y
Impairment in one or more second-order cognitive processes Že.g., attention, memory, language, emotion.
y
Symptoms of schizophrenia Že.g., hallucinations, delusions, negative symptoms, disorganized speech.
y
N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
The existence of schizophrenia is not defined by geography. Unlike some illnesses Že.g., multiple sclerosis., prevalence rates are the same throughout the world. The similar clinical presentation and lifetime prevalence has been documented in several international studies. The largest and most influential of these has been the WHO International Collaborative Study w60x. Conducted in multiple countries with different cultures and different levels of industrialization, it documented that the rate of schizophrenia varied slightly but that most countries had similar rates in the expected range. Although it has sometimes been suggested that schizophrenia could be ‘a disease of civilization’, this seems unlikely. Although schizophrenia was only demarcated as a specific diagnostic entity at the end of the 19th century, earlier accounts appear in literature. Many characters ‘become mad’ in classical tragedy, although the patterns of illness do not map precisely on the modern conceptions of schizophrenia — a fact probably due to both literary license and to the fact that the nosology of mental illness was not highly refined at that time. By the era of Elizabethan drama, however, we have portrayals of schizophrenia that closely resemble the modern concept w5x. The madness of Ophelia in Hamlet is quite similar to modern schizophrenia, and the portrayal of ‘Poor Tom’, son of Gloucester pretending to be a ‘Bedlam beggar’ escaped from the large Bethlehem Hospital where mental patients were housed, is a near-perfect portrayal of both hallucinations and disorganized speech: Who gives anything to Poor Tom? Whom the foul fiend hath led through fire and through flame . . . ? Tom’s a-cold,,— O, do de, do de, do de . . . Do poor Tom some charity, whom the foul fiend vexes. There I could have him now, — and there, and there again, and there.King Lear III.iv.51 ‘Classic’ schizophrenia usually has its onset in the late teens or early twenties, and it occurs more often in males and affects them more severely than females. These observations may contain important clues about pathophysiology and etiology. The age of onset is too late for the mechanism to be simply one of fetal or early childhood brain development. Whatever the factors are that lead to this illness, their effects must be cumulative, or must require a ‘releasing phenomenon’, or both. Because human brain development is an ongoing process that continues into early adulthood, the age of onset suggests that the development of schizophrenia must be influenced by molecular mechanisms involved in the regulation of brain maturation and that adolescence is a critical period during which these mechanisms exert their influence. The male predominance — a clue that is rarely pursued — suggests that at least one molecular influence may be x-linked. Schizophrenia is also familial. It clearly has a genetic component, although it does not appear to be a purely
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genetic disease, as Huntington’s disease, Tay Sachs disease, or cystic fibrosis are. Solid and well-designed studies, conducted since early in this century, have shown that the disease tends to run in families w52x. As compared with the population prevalence of approximately 1%, the prevalence among siblings and parents is increased approximately tenfold to around 10%. The prevalence in the adopted offspring of schizophrenic mothers, reared by ‘normal mothers’, is also around 10%, indicating that the familiality of the disorder cannot be explained by the family environment or the stress of living with a schizophrenic family member. Twin studies have shown a concordance rate of approximately 40% in monozygotic twins, as compared to a 10% concordance in dizygotic twins. Thus schizophrenia cannot be due only to genetic factors. Further, it does not follow classical Mendelian patterns of inheritance. In fact, schizophrenia often co-exists in familial pedigrees with other psychotic illnesses, such as severe mood disorders. Nor do symptoms breed true within families. Thus, as a genetic disorder, schizophrenia is ‘complex’, much as hypertension or cancer are. It probably cannot be explained by a single gene, or by genetic factors alone. The fact that schizophrenia persists in the human population despite the fact that the majority of people who develop it do not marry or procreate is fascinating. This observation should perhaps be coupled with another that has been less frequently noted and has not yet been systematically investigated: a substantial number of highly creative individuals have family members who are in the schizophrenia spectrum. The association between manicdepressive illness and creativity is well-established, but most of this work has focused on literary or artistic creativity w4,9,47x. In the case of schizophrenia, there may be a link with scientific creativity instead, although the evidence at present is only anecdotal. However, an impressive number of Nobel Laureates have an association with schizophrenia. Bertrand Russell had a son and granddaughter who suffered from schizophrenia, as well as an aunt and uncle who probably also suffered from this illness when it was simply called ‘insanity’ w53x. Albert Einstein had a son by his first wife who developed schizophrenia w27x. John Nash, a recent Nobel laureate in economics, developed schizophrenia himself in his early 30s and also has a son who suffers from schizophrenia w55x. James Joyce was emotionally aloof and cold and became increasingly disorganized artistically; his daughter Lucia suffered from hebephrenic schizophrenia w3x. Isaac Newton was a solitary, chronically suspicious, and socially aloof man who had a variety of unusual interests and beliefs; he would probably be called schizotypal using modern nomenclature; however, he also had a psychotic break at age 40 w66x. Coupled with the persistence of schizophrenia throughout history despite decreased fertility and procreation, this modest association between schizophrenia and ‘genius’
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suggests that, perhaps like sickle cell anemia, a predisposition to schizophrenia may convey a biological advantage.
4. The etiology and pathophysiology of schizophrenia We can formulate several hypotheses about the illness, based on its epidemiology, although these are necessarily speculative. These hypotheses provide a structure on which ‘the search for the holy grail’ may be based.
about pathophysiology and etiology by suggesting the importance of examining the molecular processes that regulate and shape brain development and the external factors that may influence those processes w1x. The most typical age of onset is during the late teens and early twenties, a time when brain maturation is reaching completion w19x, suggesting that one component of the etiology must involve a neurodevelopmental process related to these final stages of ‘brain sculpturing’, such as pruning or activity-dependent changes Žpsychological experiences that affect plasticity..
4.1. Hypothesis one: The etiologies are multiple Because the prevalence appears to be distributed fairly evenly throughout space and time, the etiology of schizophrenia is not linked to a particular place or to a particular time in history. This suggests, but does not require, that the etiologies are probably multiple. This concept is portrayed in the Working Model. Most cases probably occur as a consequence of multiple hits, much like cancer — an accumulation of genetic and non-genetic influences ranging from genes coded within DNA to exposure to toxins or drugs Že.g., radiation, amphetamines., viruses and other pathogens, injuries to the brain occurring at the time of birth or later, nutrition, or psychological experiences that produce somatic effects such as exposure to stress. Conceivably, some forms in some individuals could be due to a single ‘necessary and sufficient’ factor. More likely Žand more daunting in terms of identifying etiologies of schizophrenia. is the possibility that the phenotype of schizophrenia is produced by the influence of multiple factors that lead to a final common pathway in the brain. That is, the schizophrenia of ‘poor Tom’ and of the last patient that I saw in Iowa could be caused by a different and even non-overlapping constellation of factors that produce a similar brain injury, hypothesized in the Working Model to be an abnormality in neural connectivity that occurs as the brain develops and modifies itself in response to a variety of internal and external influences. 4.2. Hypothesis two: The pathophysiology is an abnormality in the regulation and expression of neurodeÕelopment Schizophrenia differs from the classical dementias in that there is no visible neuropathological marker such as plaques, tangles, or Lewy bodies. Importantly, the gliosis that is seen as a marker of neuronal death in neurodegenerative diseases is not present in schizophrenia w59x. This suggests that the pathophysiology and etiology must be related to a maturational or developmental brain process Že.g., neurite formation, synaptogenesis, neuronal pruning, apoptosis. w8,23,34,35,48,54,64,65,69 x. This sets the time period for the etiology of schizophrenia as some time between the beginning of neuron formation and migration Žaround the second trimester. and young adult life. Although this is a long time period, it focuses our thinking
4.3. Hypothesis three: The pathology is a ‘disease of neuronal connectiÕity’ The study of the neuropathology of schizophrenia is sometimes called a ‘graveyard’. The search for a single neuropathology, which began with Kraepelin’s team Žand included Alzheimer, Nissl, and Brodmann., has not been successful in finding a ‘marker’. Perhaps this is because we have been looking in the wrong place or thinking in the wrong way. The brain abnormalities that have been identified in schizophrenia, using techniques that range from neuropathology to neuroimaging, have implicated multiple regions throughout the brain: frontal cortex, temporal cortex, thalamus, hippocampal complex, basal ganglia, and even the cerebellum w10–15,20,24,28–31,36,40,44,50, 57,58,61–63x. This suggests that the pathology of the illness is probably not focal or ‘localizable’ to a single region. Coupled with the absence of a pathological neural marker such as plaques and tangles, research to date suggests that the pathology may involve distributed neural circuits and neurotransmitter systems w15,17,18,31,38,41, 42,61x. That is, schizophrenia is ‘a disease of neuronal connectivity’. Perhaps the search must refocus on those mechanisms that influence and continually shape and reshape neural connectivity at the level of dendrites, spines, synapses, neurotransmitters, and signal transducers. These mechanisms cannot be visualized and measured using the traditional methods of neuropathology, which is why those methods led to a ‘graveyard’. However, a host of newer tools are now being applied to this question, with increasingly interesting results, as evidenced by many presentations at this symposium. 4.4. Hypothesis four: The phenotype is defined by a mental metaprocess rather than by clinical symptoms When the connectivity and communication within neural circuitry is disrupted, patients display diverse impairments in cognition and diverse symptoms, the complex and varied signs and symptoms of schizophrenia. This clinically observed presentation of schizophrenia may not in fact represent the true phenotype, since it is comprised of varied symptoms that derive from diverse systems, occurs in non-overlapping patterns, and does not breed true. In-
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stead, the phenotype may perhaps be best defined by a process that lies behind the symptoms, or a metaprocess, sometimes also referred to as an endophenotype, which is a ‘final common pathway’ that defines the illness. This way of thinking about schizophrenia is very similar to the way that we think about cancer, which is also a disease with diverse clinical presentations that are due to a more fundamental process. For cancer it is misregulation of cell proliferation. For schizophrenia it is misregulation of information processing in the brain. Several different models have been proposed to define or describe this mental metaprocess. Following the search for unitary processes originally suggested by Bleuler and Kraepelin, these models seek to identify a single fundamental process that defines the illness. Examples provided in this Nobel symposium include the work of Frith w39x, Holzman w46x, and Goldman-Rakic w43x. Our work and that of others provide additional alternative examples w17,25,26,32,37,51,56,67x. This strategy may offer a more powerful method for identifying the neural and molecular mechanisms of the illness and for developing animal models for molecular and pharmacologic research.
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N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112 Evidence for an inherited, congenital neurointegrative defect, Arch. Gen. Psychiatry 125 Ž1977. 1–24. M. Flaum, D.S. O’Leary, V.W. Swayze, D.D. Miller, S. Arndt, N.C. Andreasen, Symptom dimensions and brain morphology in schizophrenia and related psychotic disorders, J. Psychiatr. Res. 29 Ž1995. 261–276. R. Freedman, L.E. Adler, M.C. Waldo, E. Pachtman, R.D. Franks, Neurophysiological evidence for a defect in inhibitory pathways in schizophrenia: comparison of medicated and drug-free patients, Biol. Psychiatry 18 Ž1983. 537–551. K.J. Friston, C.D. Frith, P. Fletcher, P.F. Liddle, R.S.J. Frakowiak, Functional tomography: multidimensional scaling and functional connectivity in the brain, Cereb. Cortex 6 Ž1996. 156–164. C.D. Frith, The Cognitive Neuropsychology of Schizophrenia, Lawrence Erlbaum, East Sussix, 1992. C.D. Frith, K.J. Friston, S. Herold, D. Silbersweig, P. Fletcher, C. Cahill, R.J. Dolan, R.S.J. Frackowiak, P.F. Liddle, Regional brain activity in chronic schizophrenic patients during performance of a verbal fluency task, Br. J. Psychiatry 167 Ž1995. 343–349. P.S. Goldman-Rakic, Changing concepts of cortical connectivity: Parallel distributed cortical networks, in: P. Rakic, W. Singer ŽEds.., Neurobiology of Neocortex, Wiley, New York, 1988, pp. 177–202. P.S. Goldman-Rakic, Topography of cognition: Parallel distributed networks in primate association cortex, Annu. Rev. Neurosci. 11 Ž1988. 137–156. P.S. Goldman-Rakic, Working memory dysfunction in schizophrenia, J. Neuropsych. Clin. Neurosci. 6 Ž1994. 348–357. R.E. Gur, P. Cowell, B.I. Turetsky et al., A follow-up magnetic resonance imaging study of schizophrenia: Relationship of neuroanatomical changes to clinical and neurobehavioral measures, Arch. Gen. Psychiatry 55 Ž1998. 145–152. B.C. Ho, N.C. Andreasen, M. Flaum, Dependence on public financial support early in the course of schizophrenia, Psychiatr. Serv. 48 Ž1997. 948–950. P.S. Holzman, D.L. Levy, L.R. Proctor, Smooth pursuit eye movements, attention, and schizophrenia, Arch. Gen. Psychiatry 45 Ž1976. 641–647. K.R. Jamison, Mood disorders and patterns of creativity in British writers and artists, Psychiatry 52 Ž2. Ž1989. 125–134. P. Jones, R.M. Murray, The genetics of schizophrenia is the genetics of neurodevelopment, Br. J. Psychiatry 158 Ž1991. 615–623. E. Kraepelin, R.M. Barclay, G.M. Robertson, Dementia Praecox and Paraphrenia, E and S Livingstone, Edinburgh, 1919. P.F. Liddle, K.J. Friston, C.D. Frith, S.R. Hirsch, T. Jones, R.S.J. Frackowiak, Patterns of cerebral blood flow in schizophrenia, Br. J. Psychiatry 60 Ž1992. 179–186. R.W. McCarley, S.F. Faux, M.E. Shenton, P.G. Nestor, J. Adams, Event-related potentials in schizophrenia: Their biological and clinical correlates and a new model of schizophrenic pathophysiology, Schizophr. Res. 4 Ž1991. 209–231. S.O. Moldin, I.I. Gottesman, At issue: genes, experience, and chance in schizophrenia-positioning for the 21st century, Schizophr. Bull. 23 Ž4. Ž1997. 547–561.
w53x C. Moorehead, Bertrand Russell: A Life, Viking, New York, 1992. w54x R.M. Murray, S.W. Lewis, Is schizophrenia a neurodevelopmental disorder? Br. Med. J. 295 Ž1987. 681–682. w55x S. Nasar, A Beautiful Mind, Simon and Shuster, New York, 1998. w56x K.H. Neuchterlein, M.E. Dawson, Information processing and attentional function in the developmental course of schizophrenic disorders, Schizophr. Bull. 10 Ž1988. 160–203. w57x P. Nopoulos, I. Torres, M. Flaum, N.C. Andreasen, J.C. Ehrhardt, W.T.C. Yuh, Brain morphology in first episode schizophrenia, Am. J. Psychiatry 152 Ž12. Ž1995. 1721–1724. w58x B. Pakkenberg, Pronounced reduction of total neuron number in mediodorsal thalamic nucleus and nucleus accumens in schizophrenics, Arch. Gen. Psychiatry 47 Ž1990. 1023–1028. w59x G.W. Roberts, N. Colter, R. Lofthouse, E.C. Johnstone, T.J. Crowe, Is there gliosis in schizophrenia? Investigation of the temporal lobe, Biol. Psychiatry 22 Ž1987. 1459–1468. w60x N. Sartorius, A. Jablensky, A. Korten, Early manifestations and first contact incidence of schizophrenia in different cultures: a preliminary report on the evaluation of the WHO collaborative study in the determinants of outcome of severe mental disorders, Psychol. Med. 16 Ž1986. 909–928. w61x L.D. Selemon, P.S. Goldman-Rakic, The reduced neuropil hypothesis: A circuit based model of schizophrenia, Biol. Psychiatry 45 Ž1999. 17–25. w62x M.E. Shenton, R. Kikinis, F.A. Jolesz, S.D. Pollak, M. LeMay, C.G. Wible, H. Hokama, J. Martin, D. Metcalf, M. Coleman, R.W. McCarley, Abnormalities of the left temporal lobe and thought disorder in schizophrenia: A quantitative magnetic resonance imaging study, N. Engl. J. Med. 327 Ž1992. 604–612. w63x D.R. Weinberger, K.F. Berman, R.F. Zec, Physiological dysfunction of dorsolateral prefrontal cortex in schizophrenia I: regional cerebral blood flow ŽrCBF. evidence, Arch. Gen. Psychiatry 43 Ž1986. 114–124. w64x D. Weinberger, Implications of normal brain development for the pathogenesis of schizophrenia, Arch. Gen. Psychiatry 44 Ž1987. 660–669. w65x D.R. Weinberger, B.K. Lipska, Cortical maldevelopment, anti-psychotic drugs, and schizophrenia: a search for common ground, Schizophr. Res. 16 Ž1995. 87–110. w66x M. White, Isaac Newton: The Last Sorcerer, Addison-Wesley, Reading, Mass, 1997. w67x A.K. Wiser, N.C. Andreasen, D.S. O’Leary, G.L. Watkins, L.L.B. Ponto, R.D. Hichwa, Dysfunctional cortico-cerebellar circuits cause ‘cognitive dysmetria’ in schizophrenia, NeuroReport 9 Ž1998. 1895– 1899. w68x World Health Organization, Chapter V, Mental and Behavioral Disorders Žincluding disorders of psychological development.: Diagnosis Criteria for Research, International Classification of Diseases, Tenth Edition ŽICD-10., Geneva, 1990. w69x B.T. Woods, Is schizophrenia a progressive neurodevelopmental disorder? Toward a unitary pathogenetic mechanism, Am. J. Psychiatry 155 Ž12. Ž1998. 1661–1670.
Interactive report
Schizophrenia: the fundamental questions 1 Nancy C. Andreasen
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UniÕersity of Iowa Hospitals and Clinics, Mental Health Clinical Research Center, 2911 JPP, 200 Hawkins DriÕe, Iowa City, IA 52242-1057, USA Accepted 29 September 1999
Abstract Identifying the correct phentotype of schizophrenia is perhaps the most important goal of modern research in schizophrenia. This identification is the necessary antecedent of indentifying the pathophysiology and etiology. A working model is proposed, which suggests that the phenotype should be defined on the basis of abnormalities in neural circuits and a fundamental cognitive process. This type of unitary model may be more heuristic than early ones that were based on heterogeneous signs and symptoms. q 2000 Elsevier Science B.V. All rights reserved. Keywords: Schizophrenia; Neural circuits; Creativity; Cognition; Disease phenotypes
Contents 1. Introduction .
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2. The definition of the phenotype 3. Clues from epidemiology .
4. The etiology and pathophysiology of schizophrenia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1. Hypothesis one: The etiologies are multiple . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Hypothesis two: The pathophysiology is an abnormality in the regulation and expression of neurodevelopment 4.3. Hypothesis three: The pathology is a ‘disease of neuronal connectivity’ . . . . . . . . . . . . . . . . . . . . . 4.4. Hypothesis four: The phenotype is defined by a mental metaprocess rather than by clinical symptoms . . . . . References
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1. Introduction Schizophrenia is one of the most important public health problems that human society confronts. It is a very common disorder, affecting 1% of the world population. People who develop schizophrenia experience severe suffering: approximately 10% commit suicide. The treatments available in the late 1990s reduce this suffering consider) Tel.: q1-319-356-1553; Fax: q1-319-353-8300; E-mail: [email protected] 1 Published on the World Wide Web on 28 October 1999.
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ably, but approximately 2r3 of those who develop schizophrenia require public assistance from governmental social security systems within a few years after onset w45x. The majority of people who develop schizophrenia are unable to return to work or to school and have relatively minimal social interactions. The costs to society are counted in billions of dollars w21x. This serious mental illness manifests itself in signs and symptoms that encompass the entire range of human mental activity. Because schizophrenia is a brain disease that manifests itself in the activities of the mind, it damages a variety of functions that we regard as specifically human.
0165-0173r00r$ - see front matter q 2000 Elsevier Science B.V. All rights reserved. PII: S 0 1 6 5 - 0 1 7 3 Ž 9 9 . 0 0 0 2 7 - 2
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Schizophrenia impairs the ability to think creatively and imaginatively, to have close social relationships with other human beings, to use language to express ideas with clarity, or to experience and express a variety of emotions such as love and fear. People with schizophrenia are tormented by intrusive experiences such as hearing voices or by beliefs that they are being persecuted or injured by those around them or by alien external forces. No single sign or symptom defines schizophrenia. It is defined by the fact that people who suffer from it experience abnormalities in many different kinds of mental activities. Attempts to understand schizophrenia are shaped by several fundamental questions, which provide themes for this Nobel Symposium. Some questions addressed by this symposium are: What is the correct basis for identifying the phenotype? What does epidemiology tell us about its etiologyrpathophysiology? How many etiologies are there? This chapter provides a brief introduction to these questions, which will be amplified in the presentations of the other participants.
2. The definition of the phenotype The first of these questions, and perhaps the most fundamental of all of them, is the definition of the phenotype Ži.e., the core or true manifestation of the disease.. The definition of the phenotype in schizophrenia is particularly difficult because patients with this illness suffer from such a diversity of symptoms. Some mental illnesses, such as depression, are defined by an abnormality in a single mental system — i.e. depressed or dysphoric mood in the case of depression. Schizophrenia, on the other hand, is characterized by symptoms that reflect multiple mental processes: hallucinations, or abnormalities in perception; delusions, or abnormalities in inferential thinking; disorganized speech, or abnormalities in language; disorganized behavior, or abnormalities in behavioral monitoring and control. Those four symptoms are the classic ‘positive symptoms’ of schizophrenia in which normal functions are distorted or exaggerated. The various ‘negative symptoms’ of schizophrenia are another important aspect of the illness w6,7,33x. They represent a diminution or absence of mental functions that are normally present. Alogia Žliterally an absence of words. is a decrease in the fluency of ideas and language; affective blunting is a diminution in the ability to express emotions; avolition is a decrease in the ability to initiate and pursue goal-directed activity; anhedonia is a decrease in the ability to seek out and experience pleasurable activities, and attentional impairment is a decrease in the ability to focus attention. These various symptoms are present in patients suffering from schizophrenia in patterns that may not overlap at all. One person with schizophrenia may have hallucina-
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tions and affective blunting, while another may have delusions and attentional impairment. This non-overlapping pattern of symptoms raises an obvious question: is there a core or fundamental theme that unites this diversity of symptoms and that can provide a more general conceptualization of the phenotype? This fundamental question raises an even more fundamental question: What is the correct basis for defining the phenotype of schizophrenia? While the answer to this question seems simple and obvious at first glance, closer inspection suggests that probing deeply below the surface may be necessary. The obvious answer is that the phenotype of schizophrenia is defined by the criterion-based diagnostic symptoms that have been developed in the past several decades. The fourth Diagnostic and Statistical Manual of the American Psychiatric Association Ž1994. ŽDSM IV. w2x is perhaps the most widely used, although the definition in the 10th edition of the International Classification of Disease Ž1990. ŽICD 10. w68x provides a similar alternative. Both these criterion-based systems take a purely descriptive approach and define schizophrenia on the basis of presenting clinical signs and symptoms. Instead of trying to account for the diversity of symptoms, they emphasize psychotic symptoms as the defining feature Ži.e., delusions and hallucinations.. While the criterion-based systems are clinically useful, in that they have provided a reliable means for physicians around the world to communicate with one another, their validity is less well established. By focusing on only a few of the symptoms with which patients present, they have identified those that are easy to operationalize, but this narrow approach has probably sacrificed validity for the sake of reliability. If the long-term goal is to identify the pathophysiology and etiology of schizophrenia, then the definition of the phenotype must emphasize a definition that is heuristic for studying mechanisms of illness. With their excessive emphasis on positive or psychotic symptoms, criterion-based approaches such as DSM may have distracted investigators away from the ‘real illness’ by over-emphasizing clinical signs and symptoms, and perhaps even by over-emphasizing the wrong ones. When schizophrenia was delineated at the beginning of the 20th century by Emil Kraepelin w49x and Eugen Bleuler w22x, both of these clinician scientists stressed the importance of defining the illness by attempting to identify a fundamental ‘morbid process’. Both emphasized that psychotic symptoms, such as delusions and hallucinations, are not specific to schizophrenia, but occur in many other illnesses such as mood disorders or dementias. For both Kraepelin and Bleuler, the most important defining feature was an impairment in the ability to think in a clear, fluent, and logical way. The person with schizophrenia suffers primarily from a fragmenting in cognitive processes. Kraepelin highlighted this aspect when he named the illness ‘‘dementia praecox’’, or a serious cognitive illness with an
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onset at a relatively young age. He saw the diversity of symptoms as unified by the underlying destruction of cognitive processes:
Although the clinicians who originally delineated and defined schizophrenia emphasized that the disorder was not defined by clinical symptoms, this perspective has been lost in DSM IV and ICD 10. Both define schizophrenia using a polythetic clustering of symptoms. While useful clinically, the improved reliability of these recent standardized diagnostic manuals may exact a large price in terms of validity. Defining schizophrenia as a polythetic cluster makes the search for mechanisms more difficult, since it leads to a fragmented model: i.e., hallucinations are usually explained by one mechanism and negative symptoms by another. The alternative proposed by Kraepelin and Bleuler — that schizophrenia is defined by an abnormality in a fundamental mental process — makes the search simpler and more tractable. Consequently, several recent investigators have proposed ‘cognitive models’ of schizophrenia w16x.
‘‘Dementia praecox consists of a series of states, the common characteristic of which is a peculiar destruction of internal connections of the psychic personality . . . . The majority of the clinical pictures are the expression of a single morbid process, though outwardly they often diverge very far from one another.’’ Bleuler highlighted the same concept when he renamed the illness ‘‘schizophrenia’’. Bleuler’s new name referred to the ‘fragmenting of the mind’ that he believed to be the fundamental abnormality. Bleuler emphasized that the person with schizophrenia had lost the capacity to have his thought processes guided by concepts that were correctly linked together:
3. Clues from epidemiology ‘‘Of the thousands of associative threads that guide our thinking, this disease seems to interrupt, quite haphazardly, sometimes single threads, sometimes a whole group, and sometimes whole segments of them.’’
As we search for ‘the holy grail’ — the etiology and pathophysiology of schizophrenia — we can be guided by some simple and very consistent observations concerning the epidemiology of the disorder w21x. These include the following: 1. Schizophrenia has a similar clinical presentation and a similar prevalence throughout the world — a lifetime prevalence of approximately 1%. Because schizophrenia is at present a lifetime disorder, the lifetime prevalence and the point prevalence are essentially the same. 2. Schizophrenia has been present for centuries, as inferred from literary descriptions. 3. ‘Classic’ cases begin in young adult life. 4. Males are more frequently and severely affected. 5. The illness tends to run in families. 6. Despite the fact that the majority of people with schizophrenia do not marry or have children, the disease persists in the human population.
Thus the ‘founding fathers’ of schizophrenia believed that they had identified a disease that had many different kinds of symptomatic manifestations at the clinical level, but that was in fact defined by an abnormality in a more basic mental process. Their thinking, reshaped in 21st century terms, would be expressed by a ‘working model’ similar to that shown below. Schizophrenia is a disease that is characterized by multiple different symptoms when assessed at the clinical level Že.g., hallucinations, avolition. and multiple disturbances in cognitive processes when assessed at the systems level Že.g., memory, language.. However, schizophrenia is ultimately a disease of the mind that is characterized by a ‘disturbance in thinking’ — an abnormality in a fundamental cognitive process.
Working Model DNA
y
Gene Expression
y
Etiology: Multiple convergent factors such as Viruses Toxins Nutrition Birth Injury
y
y
y
y
Psychological Experiences
Pathophysiology: Brain development from conception to early adulthood Že.g., neuron formation, migration, synaptogenesis, pruning, apoptosis, activity dependent changes.
y
Anatomic and functional disruption in neuronal connectivity and communication
y
Impairment in a fundamental cognitive process
y
Impairment in one or more second-order cognitive processes Že.g., attention, memory, language, emotion.
y
Symptoms of schizophrenia Že.g., hallucinations, delusions, negative symptoms, disorganized speech.
y
N.C. Andreasenr Brain Research ReÕiews 31 (2000) 106–112
The existence of schizophrenia is not defined by geography. Unlike some illnesses Že.g., multiple sclerosis., prevalence rates are the same throughout the world. The similar clinical presentation and lifetime prevalence has been documented in several international studies. The largest and most influential of these has been the WHO International Collaborative Study w60x. Conducted in multiple countries with different cultures and different levels of industrialization, it documented that the rate of schizophrenia varied slightly but that most countries had similar rates in the expected range. Although it has sometimes been suggested that schizophrenia could be ‘a disease of civilization’, this seems unlikely. Although schizophrenia was only demarcated as a specific diagnostic entity at the end of the 19th century, earlier accounts appear in literature. Many characters ‘become mad’ in classical tragedy, although the patterns of illness do not map precisely on the modern conceptions of schizophrenia — a fact probably due to both literary license and to the fact that the nosology of mental illness was not highly refined at that time. By the era of Elizabethan drama, however, we have portrayals of schizophrenia that closely resemble the modern concept w5x. The madness of Ophelia in Hamlet is quite similar to modern schizophrenia, and the portrayal of ‘Poor Tom’, son of Gloucester pretending to be a ‘Bedlam beggar’ escaped from the large Bethlehem Hospital where mental patients were housed, is a near-perfect portrayal of both hallucinations and disorganized speech: Who gives anything to Poor Tom? Whom the foul fiend hath led through fire and through flame . . . ? Tom’s a-cold,,— O, do de, do de, do de . . . Do poor Tom some charity, whom the foul fiend vexes. There I could have him now, — and there, and there again, and there.King Lear III.iv.51 ‘Classic’ schizophrenia usually has its onset in the late teens or early twenties, and it occurs more often in males and affects them more severely than females. These observations may contain important clues about pathophysiology and etiology. The age of onset is too late for the mechanism to be simply one of fetal or early childhood brain development. Whatever the factors are that lead to this illness, their effects must be cumulative, or must require a ‘releasing phenomenon’, or both. Because human brain development is an ongoing process that continues into early adulthood, the age of onset suggests that the development of schizophrenia must be influenced by molecular mechanisms involved in the regulation of brain maturation and that adolescence is a critical period during which these mechanisms exert their influence. The male predominance — a clue that is rarely pursued — suggests that at least one molecular influence may be x-linked. Schizophrenia is also familial. It clearly has a genetic component, although it does not appear to be a purely
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genetic disease, as Huntington’s disease, Tay Sachs disease, or cystic fibrosis are. Solid and well-designed studies, conducted since early in this century, have shown that the disease tends to run in families w52x. As compared with the population prevalence of approximately 1%, the prevalence among siblings and parents is increased approximately tenfold to around 10%. The prevalence in the adopted offspring of schizophrenic mothers, reared by ‘normal mothers’, is also around 10%, indicating that the familiality of the disorder cannot be explained by the family environment or the stress of living with a schizophrenic family member. Twin studies have shown a concordance rate of approximately 40% in monozygotic twins, as compared to a 10% concordance in dizygotic twins. Thus schizophrenia cannot be due only to genetic factors. Further, it does not follow classical Mendelian patterns of inheritance. In fact, schizophrenia often co-exists in familial pedigrees with other psychotic illnesses, such as severe mood disorders. Nor do symptoms breed true within families. Thus, as a genetic disorder, schizophrenia is ‘complex’, much as hypertension or cancer are. It probably cannot be explained by a single gene, or by genetic factors alone. The fact that schizophrenia persists in the human population despite the fact that the majority of people who develop it do not marry or procreate is fascinating. This observation should perhaps be coupled with another that has been less frequently noted and has not yet been systematically investigated: a substantial number of highly creative individuals have family members who are in the schizophrenia spectrum. The association between manicdepressive illness and creativity is well-established, but most of this work has focused on literary or artistic creativity w4,9,47x. In the case of schizophrenia, there may be a link with scientific creativity instead, although the evidence at present is only anecdotal. However, an impressive number of Nobel Laureates have an association with schizophrenia. Bertrand Russell had a son and granddaughter who suffered from schizophrenia, as well as an aunt and uncle who probably also suffered from this illness when it was simply called ‘insanity’ w53x. Albert Einstein had a son by his first wife who developed schizophrenia w27x. John Nash, a recent Nobel laureate in economics, developed schizophrenia himself in his early 30s and also has a son who suffers from schizophrenia w55x. James Joyce was emotionally aloof and cold and became increasingly disorganized artistically; his daughter Lucia suffered from hebephrenic schizophrenia w3x. Isaac Newton was a solitary, chronically suspicious, and socially aloof man who had a variety of unusual interests and beliefs; he would probably be called schizotypal using modern nomenclature; however, he also had a psychotic break at age 40 w66x. Coupled with the persistence of schizophrenia throughout history despite decreased fertility and procreation, this modest association between schizophrenia and ‘genius’
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suggests that, perhaps like sickle cell anemia, a predisposition to schizophrenia may convey a biological advantage.
4. The etiology and pathophysiology of schizophrenia We can formulate several hypotheses about the illness, based on its epidemiology, although these are necessarily speculative. These hypotheses provide a structure on which ‘the search for the holy grail’ may be based.
about pathophysiology and etiology by suggesting the importance of examining the molecular processes that regulate and shape brain development and the external factors that may influence those processes w1x. The most typical age of onset is during the late teens and early twenties, a time when brain maturation is reaching completion w19x, suggesting that one component of the etiology must involve a neurodevelopmental process related to these final stages of ‘brain sculpturing’, such as pruning or activity-dependent changes Žpsychological experiences that affect plasticity..
4.1. Hypothesis one: The etiologies are multiple Because the prevalence appears to be distributed fairly evenly throughout space and time, the etiology of schizophrenia is not linked to a particular place or to a particular time in history. This suggests, but does not require, that the etiologies are probably multiple. This concept is portrayed in the Working Model. Most cases probably occur as a consequence of multiple hits, much like cancer — an accumulation of genetic and non-genetic influences ranging from genes coded within DNA to exposure to toxins or drugs Že.g., radiation, amphetamines., viruses and other pathogens, injuries to the brain occurring at the time of birth or later, nutrition, or psychological experiences that produce somatic effects such as exposure to stress. Conceivably, some forms in some individuals could be due to a single ‘necessary and sufficient’ factor. More likely Žand more daunting in terms of identifying etiologies of schizophrenia. is the possibility that the phenotype of schizophrenia is produced by the influence of multiple factors that lead to a final common pathway in the brain. That is, the schizophrenia of ‘poor Tom’ and of the last patient that I saw in Iowa could be caused by a different and even non-overlapping constellation of factors that produce a similar brain injury, hypothesized in the Working Model to be an abnormality in neural connectivity that occurs as the brain develops and modifies itself in response to a variety of internal and external influences. 4.2. Hypothesis two: The pathophysiology is an abnormality in the regulation and expression of neurodeÕelopment Schizophrenia differs from the classical dementias in that there is no visible neuropathological marker such as plaques, tangles, or Lewy bodies. Importantly, the gliosis that is seen as a marker of neuronal death in neurodegenerative diseases is not present in schizophrenia w59x. This suggests that the pathophysiology and etiology must be related to a maturational or developmental brain process Že.g., neurite formation, synaptogenesis, neuronal pruning, apoptosis. w8,23,34,35,48,54,64,65,69 x. This sets the time period for the etiology of schizophrenia as some time between the beginning of neuron formation and migration Žaround the second trimester. and young adult life. Although this is a long time period, it focuses our thinking
4.3. Hypothesis three: The pathology is a ‘disease of neuronal connectiÕity’ The study of the neuropathology of schizophrenia is sometimes called a ‘graveyard’. The search for a single neuropathology, which began with Kraepelin’s team Žand included Alzheimer, Nissl, and Brodmann., has not been successful in finding a ‘marker’. Perhaps this is because we have been looking in the wrong place or thinking in the wrong way. The brain abnormalities that have been identified in schizophrenia, using techniques that range from neuropathology to neuroimaging, have implicated multiple regions throughout the brain: frontal cortex, temporal cortex, thalamus, hippocampal complex, basal ganglia, and even the cerebellum w10–15,20,24,28–31,36,40,44,50, 57,58,61–63x. This suggests that the pathology of the illness is probably not focal or ‘localizable’ to a single region. Coupled with the absence of a pathological neural marker such as plaques and tangles, research to date suggests that the pathology may involve distributed neural circuits and neurotransmitter systems w15,17,18,31,38,41, 42,61x. That is, schizophrenia is ‘a disease of neuronal connectivity’. Perhaps the search must refocus on those mechanisms that influence and continually shape and reshape neural connectivity at the level of dendrites, spines, synapses, neurotransmitters, and signal transducers. These mechanisms cannot be visualized and measured using the traditional methods of neuropathology, which is why those methods led to a ‘graveyard’. However, a host of newer tools are now being applied to this question, with increasingly interesting results, as evidenced by many presentations at this symposium. 4.4. Hypothesis four: The phenotype is defined by a mental metaprocess rather than by clinical symptoms When the connectivity and communication within neural circuitry is disrupted, patients display diverse impairments in cognition and diverse symptoms, the complex and varied signs and symptoms of schizophrenia. This clinically observed presentation of schizophrenia may not in fact represent the true phenotype, since it is comprised of varied symptoms that derive from diverse systems, occurs in non-overlapping patterns, and does not breed true. In-
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stead, the phenotype may perhaps be best defined by a process that lies behind the symptoms, or a metaprocess, sometimes also referred to as an endophenotype, which is a ‘final common pathway’ that defines the illness. This way of thinking about schizophrenia is very similar to the way that we think about cancer, which is also a disease with diverse clinical presentations that are due to a more fundamental process. For cancer it is misregulation of cell proliferation. For schizophrenia it is misregulation of information processing in the brain. Several different models have been proposed to define or describe this mental metaprocess. Following the search for unitary processes originally suggested by Bleuler and Kraepelin, these models seek to identify a single fundamental process that defines the illness. Examples provided in this Nobel symposium include the work of Frith w39x, Holzman w46x, and Goldman-Rakic w43x. Our work and that of others provide additional alternative examples w17,25,26,32,37,51,56,67x. This strategy may offer a more powerful method for identifying the neural and molecular mechanisms of the illness and for developing animal models for molecular and pharmacologic research.
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