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SRF Essay Contest 1 | P a g e

The Schizophrenia Research Forum

ESSAY CONTEST for the

2nd Schizophrenia International Research Society Conference

-------www.schizophreniaforum.org-


The Schizophrenia Research Forum Essay Contest for the 2nd Schizophrenia International Research Society Conference

April 10-14, Florence, Italy

Applicants were asked to choose five compelling facts from various fields and describe a unifying hypothesis for schizophrenia based upon these (to include predictions, i.e., testing hypotheses). Essays were scored independently for originality, argument and implementation.

Winner Rajiv Radhakrishnan, Yale University School of Medicine

Honorable Mention

Anna Docherty, University of Missouri-Columbia Thomas Whitford, University of Melbourne/Harvard Medical School

Rest of the Top 12

Pauline Belujon, University of Pittsburgh Kathryn Gill, University of Pittsburgh Richard Keefe, Duke University Medical Center Matcheri Keshavan, Harvard University El-Wui Loh, National Health Research Institutes, Taiwan Neely Myers, University of Virginia Nathalie Picard, Abbott Naren Rao, National Institute of Mental Health and Neuroscience Bangalore James Walters, Cardiff University


WINNER

Rajiv Radhakrishnan Yale University School of Medicine New Haven, Connecticut

Fact 1: Exposure to amphetamine can result in schizophrenia-like symptoms in some individuals. This effect is observed in chronic, but not acute, amphetamine use (Segal et al., 1997).

Fact 2: The electrophysiological characteristics of prefrontal cortex neurons begin to change after just a few doses of the drug, and amphetamine exposure has opposite effects in two subregions of prefrontal cortex—a progressive hyperactivation of orbitofrontal cortex and hypoactivation of medial prefrontal cortex (mPFC) (Homayoun et al., 2006).

Fact 3: mPFC abnormalities are present in schizophrenia on multimodal imaging (Pomarol-Clotet et al., 2010). In first-episode antipsychotic-naïve patients with schizophrenia, the mPFC is smaller compared to controls (Venkatasubramanian et al., 2008).

Fact 4: The mPFC is an important hub of the default mode network (DMN). An aberrant functional connectivity of the DMN is seen in schizophrenia (Garrity et al., 2007) involving the mPFC, in particular (Camchong et al., 2009).

Fact 5: The endocannabinoid system is abnormal in schizophrenia (Fernandez-Espejo et al., 2009). Inhibition of interneuron firing extends the spread of endocannabinoid signaling (as has been shown in the cerebellum) (Kreitzer et al., 2002). The rate of firing can determine if the endocannabinoid system causes a net inhibitory long-term depression (LTD) or disinhibitory LTD (Adermark et al., 2009).

Hypothesis Conversion from ultra high risk to schizophrenia is characterized by spread of activation of the mPFC to the dorsolateral prefrontal cortex (DLPFC), resulting in a disruption of the normal feedback regulation of the mPFC. This leads to progressive denervation of the mPFC. This process is mediated by the endocannabinoid system. It is predicted that: 1) There would be a decrease in activation of mPFC and increase in activation of DLPFC in both a working memory paradigm and a DMN paradigm as ultra high-risk patients progress to schizophrenia; 2) Cannabinoid receptor number and density will increase in the mPFC during progression from ultra high risk to schizophrenia and subsequently decrease with denervation.

Testing the Hypothesis 1. Characterization of the activity and volume of mPFC and DLPFC in DMN and working memory task paradigms in prodromal, ultra high-risk subjects over time to conversion to schizophrenia. The hypothesis suggests that the current discrepancy with regard to working memory tasks (with some studies showing hyperactivity and others showing hypoactivity in DLPFC) can be explained by the functional integrity of the mPFC; with progressive denervation of mPFC, DLPFC activity will decrease.

2. Characterization of temporal pattern of cannabinoid receptor (CB1, CB2) number and density in prodromal, ultra high-risk subjects until conversion to schizophrenia.


3. Demonstration of inhibitory LTD and disinhibitory LTD in the medial PFC in an animal model mediated by endocannabinoid signaling.

4. Demonstration of spread of activation from mPFC to DLPFC in an animal model by modulating endocannabinoid signaling.

References: Segal DS, Kuczenski R. An escalating dose ‘‘binge’’model of amphetamine psychosis: behavioral and neurochemical characteristics. J Neurosci. 1997;17:2551–2566. Abstract

Homayoun H, Moghaddam B. Progression of cellular adaptations in medial prefrontal and orbitofrontal cortex in response to repeated amphetamine.J Neurosci. 2006 Aug 2;26(31):8025-39. Abstract

Pomarol-Clotet E, Canales-Rodríguez EJ, Salvador R, Sarró S, Gomar JJ, Vila F, Ortiz-Gil J, Iturria-Medina Y, Capdevila A, McKenna PJ. Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Mol Psychiatry. 2010 Jan 12. Abstract

Venkatasubramanian G, Jayakumar PN, Gangadhar BN, Keshavan MS. Automated MRI parcellation study of regional volume and thickness of prefrontal cortex (PFC) in antipsychotic-naïve schizophrenia. Acta Psychiatr Scand. 2008 Jun;117(6):420-31. Abstract

Garrity AG, Pearlson GD, McKiernan K, Lloyd D, Kiehl KA, Calhoun VD. Aberrant "default mode" functional connectivity in schizophrenia.Am J Psychiatry. 2007 Mar;164(3):450-7. Abstract

Camchong J, Macdonald AW 3rd, Bell C, Mueller BA, Lim KO. Altered Functional and Anatomical Connectivity in Schizophrenia. Schizophr Bull. 2009 Nov 17. Abstract

Fernandez-Espejo E, Viveros MP, Núñez L, Ellenbroek BA, Rodriguez de Fonseca F. Role of cannabis and endocannabinoids in the genesis of schizophrenia. Psychopharmacology (Berl). 2009 Nov;206(4):531-49. Abstract

Kreitzer AC, Carter AG, Regehr WG. Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron. 2002 May 30;34(5):787-96. Abstract

Adermark L, Lovinger DM. Frequency-dependent inversion of net striatal output by endocannabinoid-dependent plasticity at different synaptic inputs. J Neurosci. 2009 Feb 4;29(5):1375-80. Abstract


Honorable Mention Anna Docherty University of Missouri-Columbia

There is growing evidence that anhedonia, or the extent to which an individual reports pleasure in social and physical stimuli, is associated with genetic liability in schizophrenia (Clementz, 1991; Kendler, 1996; Docherty and Sponheim, 2008) and predicts future development of schizophrenia-spectrum disorders (Kwapil, 1998; Gooding, 2005). At the same time, in patients with schizophrenia, anhedonia is associated with poor long-term outcome (Fenton and McGlashan, 1991) and anhedonia, as well as other negative symptoms, are found to be treatment-refractory to dopamine-inhibiting medication. Despite the apparent importance of anhedonia to schizophrenia, there are unanswered questions about what anhedonia is and how it fits into schizophrenia pathogenesis.

One hypothesis might be that anhedonia results in part from a decrease in dopamine, such that sporadic spikes in dopamine associated with positive symptoms may be superimposed on underlying, low levels of tonic dopamine. In characterizing anhedonia, it has long been thought that anhedonia might reflect emotion deficits (i.e., Burbridge and Barch, 2007), and previous research has consistently found evidence of that for an involvement of dopamine in the experience of positive affect (PA; DePue, 1999). In multiple studies using emotion stimuli, we have found that anhedonia in non-clinical individuals is associated with decreased self-reported PA intensity (Kerns et al., 2008). In addition, in one prior study we found that first-degree relatives with a high-activity polymorphism of the Val158Met COMT gene (rs4680; responsible for a significant decrease in dopamine to prefrontal cortex) have higher levels of anhedonia (Docherty and Sponheim, 2008). This also suggests that anhedonia is related to dopamine regulation.

While important for prefrontal function, dopamine also plays an important role in white matter development (i.e., Wahlstrom, 2009). Myelination projections, influenced by dopamine, result in a variation in right hemisphere (RH) white matter integrity, and some evidence of this association can be found in at least one study showing an association between COMT and RH white matter integrity (Thomason, 2010). In patients, deficit symptoms have been associated with white matter integrity between prefrontal and parietal areas in RH (Rowland, 2009). Moreover, in studies of patients, Berenbaum and colleagues have found anhedonia to be related to lateralized function (Berenbaum et al., 2009), and our studies of schizotypal anhedonia show a similar relationship (Docherty and Kerns, in preparation). Altogether, there is converging emotion, genetic, and cognitive evidence that dopamine may play a key role in the presence of anhedonia. The NIMH is currently seeking enhancements in studies of genetic etiology, and one promising avenue may be endophenotype research. Future research into anhedonia and dopamine could include a study of diffusion tensor imaging to examine an association of COMT, PA intensity, and white matter integrity in the context of schizotypal anhedonia in patients and relatives. References: Berenbaum, H., Kerns, J. G., Vernon, L. L., and Gomez, J. J. (2008). Cognitive correlates of schizophrenia signs and symptoms: II. Emotional disturbances. Psychiatry Res, 159(1-2), 157-162. Abstract Burbridge, J. A., and Barch, D. M. (2007). Anhedonia and the experience of emotion in individuals with schizophrenia. J Abnorm Psychol, 116(1), 30-42. Abstract


Clementz, B. A., Grove, W. M., Katsanis, J., and Iacono, W. G. (1991). Psychometric detection of schizotypy: perceptual aberration and physical anhedonia in relatives of schizophrenics. J Abnorm Psychol, 100(4), 607-612. Abstract Depue, R. A., and Collins, P. F. (1999). Neurobiology of the structure of personality: dopamine, facilitation of incentive motivation, and extraversion. Behav Brain Sci, 22(3), 491-517; discussion 518-69. Abstract Docherty, A. R., and Kerns, J.G. (in preparation). Anhedonia is associated with deficits in tasks of lateralized visual and motor function. Docherty, A. R., and Sponheim, S. R. (2008). Anhedonia as a phenotype for the Val158Met COMT polymorphism in relatives of patients with schizophrenia. J Abnorm Psychol, 117(4), 788-798. Abstract Fenton, W. S., and McGlashan, T. H. (1991). Natural history of schizophrenia subtypes. II. Positive and negative symptoms and long-term course. Arch Gen Psychiatry, 48(11), 978-986. Abstract Gooding, D. C., Tallent, K. A., and Matts, C. W. (2005). Clinical status of at-risk individuals 5 years later: further validation of the psychometric high-risk strategy. J Abnorm Psychol, 114(1), 170-175. Abstract Kendler, K. S., Thacker, L., and Walsh, D. (1996). Self-report measures of schizotypy as indices of familial vulnerability to schizophrenia. Schizophr Bull, 22(3), 511-520. Abstract Kerns, J. G., Docherty, A. R., and Martin, E. A. (2008). Social and physical anhedonia and valence and arousal aspects of emotional experience. J Abnorm Psychol, 117(4), 735-746. Abstract Kwapil, T. R. (1998). Social anhedonia as a predictor of the development of schizophrenia-spectrum disorders. J Abnorm Psychol, 107(4), 558-565. Abstract Rowland, L. M., Spieker, E. A., Francis, A., Barker, P. B., Carpenter, W. T., and Buchanan, R. W. (2009). White matter alterations in deficit schizophrenia. Neuropsychopharmacology, 34(6), 1514-1522. Abstract Thomason, M. E., Dougherty, R. F., Colich, N. L., Perry, L. M., Rykhlevskaia, E. I., Louro, H. M., et al. (2010). COMT genotype affects prefrontal white matter pathways in children and adolescents. Neuroimage. 2010 Jan 18. Abstract Wahlstrom, D., White, T., and Luciana, M. (2009). Neurobehavioral evidence for changes in dopamine system activity during adolescence. Neurosci Biobehav Rev. 2010 Apr;34(5):631-48. Abstract


Honorable Mention

Thomas Whitford University of Melbourne/Harvard Medical School Five compelling facts about schizophrenia: Fact 1. The symptoms of schizophrenia typically first present in adolescence/early adulthood (1). Fact 2. Structural abnormalities in the white matter have consistently been observed in schizophrenia patients (both in vitro [2] and in vivo [3-5]), particularly in fasciculi connecting the frontal lobe with the rest of the brain (e.g., uncinate, arcuate, cingulum).These fasciculi are among the last to mature, with myelination typically continuing through adolescence and early adulthood (6). Fact 3. The passivity experiences (including delusions of control and delusions of thought insertion) are among the most pathognomic symptoms of schizophrenia (7). At a basic level, these symptoms seem to reflect a difficulty in distinguishing between internally generated and externally generated actions (8). Fact 4. Schizophrenia patients typically exhibit subnormal levels of cortical suppression to self-generated sensations (9,10), ostensibly because of an abnormality in the “corollary discharge” mechanisms normatively involved in suppressing the sensory consequences of self-generated actions (11,12). Fact 5. Schizophrenia patients typically show elevated levels of the neurotransmitter dopamine—a primary role of which is to modulate the salience of otherwise neutral environmental stimuli (13). A unifying hypothesis (14): Schizophrenia is ultimately caused by abnormalities in the genetically triggered, neurodevelopmental processes of myelination that normatively occur in frontal fasciculi at peri-adolescence (Facts 1 and 2). Just as myelin damage to the optic nerve causes conduction delays in visually evoked potentials in patients with multiple sclerosis (15), myelin damage to the frontal fasciculi causes conduction delays in the corollary discharges that are normally initiated in the frontal lobe in response to willed actions, and arguably willed cognitions more generally (11). This causes the corollary discharges to arrive at their cortical destinations too late to suppress the sensory consequences of self-generated actions (Fact 4), which leads to these actions being perceived as externally generated (Fact 3) (16). This confusion of agency represents a neurologically salient event which causes a release of dopamine from brainstem nuclei. The resulting hyperdopaminergia (Fact 5) causes innocuous events to be perceived as salient, which worsens the passivity experiences and leads to other pathognomic symptoms such as delusions of reference 17. Predictions of the theory: 1. Delaying sensory feedback of self-generated actions by the length of the inferred conduction delay (i.e., in the order of milliseconds) will lead to the simultaneous arrival of the corollary discharge and the sensory-evoked activity in the sensory cortex, and hence a normalization of the supranormal cortical response typically exhibited by schizophrenia patients to self-generated sensations (for preliminary evidence, see reference 18).


2. Structural damage to the white-matter fasciculi connecting the frontal lobes with the rest of the brain will result in a) conduction delays and b) hyperdopaminergia (for preliminary evidence, see reference 19). 3. Remyelinating medications may be effective in preventing the onset of psychosis in people at high risk of developing schizophrenia. References: 1. McGrath, J., Saha, S., Chant, D. and Welham, J. Schizophrenia: a concise overview of incidence, prevalence, and mortality. Epidemiol Rev 30, 67-76 (2008). Abstract 2. Uranova, N., et al. The role of oligodendrocyte pathology in schizophrenia. Int J Neuropsychopharmacol 10, 537-545 (2007). Abstract 3. Price, G., et al. White matter tracts in first-episode psychosis: a DTI tractography study of the uncinate fasciculus. Neuroimage 39, 949-955 (2008). Abstract 4. Burns, J., et al. Structural disconnectivity in schizophrenia: a diffusion tensor magnetic resonance imaging study. Br J Psychiatry 182, 439-443 (2003). Abstract 5. Kubicki, M., et al. Cingulate fasciculus integrity disruption in schizophrenia: a magnetic resonance diffusion tensor imaging study. Biol Psychiatry 54, 1171-1180 (2003). Abstract 6. Yakovlev, P., Lecours, A. and Minkowski, A. The myelinogenetic cycles of regional maturation of the brain. in Regional development of the brain early in life 3-70. (Blackwell Scientific Publications, Boston, Massachusetts, 1967). 7. Schneider, K. Primary and secondary symptoms in schizophrenia. Fortschr Neurol Psychiatr 25, 487-490 (1957). Abstract 8. Frith, C.D. The cognitive neuropsychology of schizophrenia. (Lawrence Erlbaum Associates, Hove, UK, 1992). 9. Blakemore, S.J., Wolpert, D.M. and Frith, C.D. Central cancellation of self-produced tickle sensation. Nature Neuroscience 1, 635-640 (1998). Abstract 10. Ford, J.M., et al. Neurophysiological evidence of corollary discharge dysfunction in schizophrenia. Am J Psychiatry 158, 2069-2071. (2001). Abstract 11. Feinberg, I. Efference copy and corollary discharge: implications for thinking and its disorders. Schizophr Bull 4, 636-640 (1978). Abstract 12. Ford, J., Gray, M., Faustman, W., Roach, B. and Mathalon, D. Dissecting corollary discharge dysfunction in schizophrenia. Psychophysiology 44, 522-529 (2007). Abstract 13. Wise, R. Dopamine, learning and motivation. Nat Rev Neurosci 5, 483-494 (2004). Abstract 14. Whitford, T.J., Kubicki, M. and Shenton, M.E. The neuroanatomical underpinnings of schizophrenia and their implications as to the cause of the disorder: a review of the structural MR and


diffusion literature. In: Shenton ME and Turetsky B; Neuropsychiatric Imaging. (Cambridge University Press, New York, in press). 15. Cuypers, M., Dickson, K., Pinckers, A., Thijssen, J. and Hommes, O. Discriminative power of visual evoked potential characteristics in multiple sclerosis. Doc Ophthalmol 90, 247-257 (1995). Abstract 16. Fletcher, P. and Frith, C. Perceiving is believing: a Bayesian approach to explaining the positive symptoms of schizophrenia. Nat Rev Neurosci 10, 48-58 (2009). Abstract 17. Kapur, S. Psychosis as a state of aberrant salience: a framework linking biology, phenomenology, and pharmacology in schizophrenia. Am J Psychiatry 160, 13-23 (2003). Abstract 18. Whitford, T.J., et al. Electrophysiological and Diffusion-Tensor Imaging Evidence of Delayed Corollary Discharges in Patients with Schizophrenia. (Under review.) 19. Roy, K., et al. Loss of erbB signaling in oligodendrocytes alters myelin and dopaminergic function, a potential mechanism for neuropsychiatric disorders. Proc Natl Acad Sci U S A 104, 8131-8136 (2007). Abstract


Pauline Belujon University of Pittsburgh Premorbid cortical dysfunction signals vulnerability to stress and subsequent psychosis. Schizophrenia is a complex brain disorder which consists of a variable range of disturbances of perception, thought, emotion, motivation, and motor activity. Several studies have reported on abnormalities in the nervous system of individuals with schizophrenia, but information is limited on patients destined to develop schizophrenia but who are not psychotic yet. Some studies of high-risk individuals have focused on evaluating the changes that take place during this premorbid phase. Evidence suggests that individuals at risk for schizophrenia often show executive functioning deficits (Morey et al., 2005; Chung et al., 2008), suggesting that these cognitive changes may serve as a behavioral marker of genetic liability for schizophrenia (Park et al., 1995). Dysfunction of the medial prefrontal cortex (mPFC) has been shown to induce deficits comparable to those observed in schizophrenia (working memory deficits), suggesting that disruption of the mPFC might be involved in the early phase of the disease, and imaging studies showed hyperactivity within the hippocampus that correlates with psychosis in schizophrenia patients (Silbersweig et al., 1995). Evidence suggests that stress is a risk factor for schizophrenia and may trigger episodes of psychosis. Indeed, the Edinburgh study has shown that in high-risk individuals, people who develop psychosis are hyper-responsive to stressors (Miller et al., 2001; Johnstone et al., 2002). Moreover, prior to the onset of psychosis, there is an increase in pituitary volume, suggesting activation of the hypothalamic-pituitary-adrenal (HPA) axis that controls physiological reactions to stress (Garner et al., 2005) and, in addition, to hippocampal modifications that can lead to the onset of psychosis. The amygdala is known to be activated during stress responses (LeDoux, 2000), and the mPFC can modulate this response by inhibiting the amygdala (Rosenkranz et al., 2003). Thus, dysfunction of the mPFC can lead to hypersensitivity to stress as observed in high-risk individuals who develop psychosis. Prolonged exposure or hypersensitivity to stress will induce increased release of glucocorticoids that can lead to structural brain damage, especially in the hippocampus (Thompson et al., 2004). Damage to the hippocampus from stress has ramifications on HPA axis activity such that the stress response is constitutively active, leading to cognitive impairment (Hoschl and Hajek, 2001). Therefore, premorbid dysfunction of the mPFC might lead to unregulated stress inducing hippocampal damage that further exacerbates hyper-responsitivity to stress, hippocampal damage-induced hyperactivity leading to dysregulation of the dopamine system, thereby leading to psychosis. Thus, treating hypersensitivity to stress by enhancing extinction of fear using catecholamine pharmacotherapeutics may prevent the onset of psychosis and symptom severity. References: Chung YS, Kang DH, Shin NY, Yoo SY, Kwon JS (2008) Deficit of theory of mind in individuals at ultra-high-risk for schizophrenia. Schizophr Res 99:111-118. Abstract Garner B, Pariante CM, Wood SJ, Velakoulis D, Phillips L, Soulsby B, Brewer WJ, Smith DJ, Dazzan P, Berger GE, Yung AR, van den Buuse M, Murray R, McGorry PD, Pantelis C (2005) Pituitary volume predicts future transition to psychosis in individuals at ultra-high risk of developing psychosis. Biol Psychiatry 58:417-423. Abstract


Hoschl C, Hajek T (2001) Hippocampal damage mediated by corticosteroids--a neuropsychiatric research challenge. Eur Arch Psychiatry Clin Neurosci 251 Suppl 2:II81-88. Abstract Johnstone EC, Cosway R, Lawrie SM (2002) Distinguishing characteristics of subjects with good and poor early outcome in the Edinburgh High-Risk Study. Br J Psychiatry Suppl 43:s26-29. Abstract LeDoux JE (2000) Emotion circuits in the brain. Annu Rev Neurosci 23:155-184. Abstract Miller P, Lawrie SM, Hodges A, Clafferty R, Cosway R, Johnstone EC (2001) Genetic liability, illicit drug use, life stress and psychotic symptoms: preliminary findings from the Edinburgh study of people at high risk for schizophrenia. Social psychiatry and psychiatric epidemiology 36:338-342. Abstract Morey RA, Inan S, Mitchell TV, Perkins DO, Lieberman JA, Belger A (2005) Imaging frontostriatal function in ultra-high-risk, early, and chronic schizophrenia during executive processing. Arch Gen Psychiatry 62:254-262. Abstract Park S, Holzman PS, Goldman-Rakic PS (1995) Spatial working memory deficits in the relatives of schizophrenic patients. Arch Gen Psychiatry 52:821-828. Abstract Rosenkranz JA, Moore H, Grace AA (2003) The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli. J Neurosci 23:11054-11064. Abstract Silbersweig DA, Stern E, Frith C, Cahill C, Holmes A, Grootoonk S, Seaward J, McKenna P, Chua SE, Schnorr L, et al. (1995) A functional neuroanatomy of hallucinations in schizophrenia. Nature 378:176-179. Abstract Thompson JL, Pogue-Geile MF, Grace AA (2004) Developmental pathology, dopamine, and stress: a model for the age of onset of schizophrenia symptoms. Schizophr Bull 30:875-900. Abstract


Kathryn Gill University of Pittsburgh The preponderance of research on the neural underpinnings of schizophrenia has focused on cortical dysfunction and the association with dopaminergic and glutamatergic mechanisms. Like most psychiatric conditions, there is disruption across a broad network encompassing several brain regions, accounting for the complicated array of symptoms attributed to schizophrenia. Indeed, there are multiple sources of evidence that support a role of hippocampal dysfunction, in addition to cortical alterations, in the development of schizophrenia. Like volume changes observed in the prefrontal cortex, there is also a widespread atrophy of the hippocampus in patients diagnosed with schizophrenia measured postmortem (Brans et al., 2008). While it has not been ascertained whether hippocampal alterations precede those observed in the prefrontal cortex, it is possible that symptom severity increases as the disease progresses from an initial disturbance in the hippocampus. It has been shown that there are simultaneous, and opposing, changes in the activation of the prefrontal cortex and temporal lobe, encompassing the parahippocampal regions, in patients with schizophrenia during a word encoding and recognition task (Ragland et al., 2004). Patients demonstrated an underactivation of the prefrontal cortex along with a hyperactivation of parahippocampal regions. These data are consistent with evidence from the rodent MAM neurodevelopmental model of schizophrenia in which hyperactivation of the dopamine system is caused by an overactivation of the ventral hippocampus (Lodge and Grace, 2007). Ultimately, altered output from the ventral hippocampus can cause widespread changes in a broad neural network, encompassing the prefrontal cortex as well as subcortical dopamine systems. Intra-hippocampal oscillatory activity is disrupted in the MAM model of schizophrenia, and there are corresponding reductions in the number of parvalbumin-expressing (PV+) neurons (Lodge et al., 2009). Based on the evidence summarized above, we hypothesize that abnormal activation of the hippocampus in patients with schizophrenia is a result of aberrant interneuron activity, specifically PV+ interneurons. It has been shown elsewhere that PV+ interneurons are important for the synchronization of hippocampal networks during the processing, transfer, and storage of information during oscillatory activity (Buzsaki and Draguhn, 2004; Mann and Paulsen, 2007). This implicates a GABAergic mechanism in the hippocampus for the coordination of phasic activation of pyramidal neurons. Consequently, by stabilizing the activity of pyramidal neurons via selective manipulations of GABAergic interneurons, the hyperactivation of the hippocampus will be ameliorated and have downstream consequences on the dopamine system as well as cortical targets. References: Brans, R. G., N. E. van Haren, et al. (2008). "Heritability of changes in brain volume over time in twin pairs discordant for schizophrenia." Arch Gen Psychiatry. 65(11): 1259-1268. Buzsaki, G. and A. Draguhn (2004). "Neuronal oscillations in cortical networks." Science 304(5679): 1926-1929. Lodge, D. J., M. M. Behrens, et al. (2009). "A loss of parvalbumin-containing interneurons is associated with diminished oscillatory activity in an animal model of schizophrenia." J Neurosci. 29(8): 2344-2354.


Lodge, D. J. and A. A. Grace (2007). "Aberrant hippocampal activity underlies the dopamine dysregulation in an animal model of schizophrenia." J Neurosci. 27(42): 11424-11430. Mann, E. O. and O. Paulsen (2007). "Role of GABAergic inhibition in hippocampal network oscillations." Trends Neurosci. 30(7): 343-349. Ragland, J. D., R. C. Gur, et al. (2004). "Event-related fMRI of frontotemporal activity during word encoding and recognition in schizophrenia." Am J Psychiatry. 161(6): 1004-1015.


Richard Keefe (with Ranga Krishnan, Michael Kraus) Duke University Medical Center Schizophrenia Is a Disorder of Learning-Dependent Predictive Perception Facts: Fact 1. People with schizophrenia exhibit hallucinations and delusions. Fact 2. People with schizophrenia demonstrate a variety of cognitive and perceptual deficits. Fact 3. There is loss of both GABAergic and pyramidal neurons in multiple areas of the cerebral cortex. Fact 4. Many of the genes linked to schizophrenia such as DISC1 and neuregulin affect synaptic regulation in the cerebral neocortex. Fact 5. Famine during fetal development increases risk of schizophrenia. Model: The neocortex is arranged into repeating units of vertical columns of cell bodies. These cortical columns are highly interconnected and form strong connections with the thalamus and hippocampus. The circuitry’s basic function is learning-dependent predictive perception, in which bottom-up inputs are matched in a hierarchy of recognition. Each hierarchical level stores previously observed temporal sequences of input. Higher levels predict future input by projecting expectations to lower levels. When an input sequence matches a top-down prediction at a given layer of the hierarchy, a defined output is propagated up the hierarchy eliminating details. This process produces a more compact, efficient signal and increased invariance at higher levels. When a mismatch occurs, a more complete representation propagates upwards. This causes alternative “interpretations” to be activated at higher levels, in turn generating other predictions at lower levels. This process is fundamental to the perception of reality. The associative areas of the cortex, thalamus, and hippocampus are key regions in this process. We propose that in schizophrenia there is impairment in learning-dependent predictive perception due to neuronal loss or synaptic deregulation in higher-order association areas. Difficulty with formation and storage of invariant representations disrupts the capacity of higher levels to provide sufficient input to lower levels for solving the nature of stimuli. This impaired predictive process causes increases in inaccurate perceptions throughout development. It leads to incorrect beliefs about the nature of reality and a tendency to favor idiosyncratic interpretations of stimuli and their interactions. This, we hypothesize, is the mechanism behind hallucinations, delusions, and perceptual and cognitive impairment. This hypothesis can be tested, and we expect the following: 1. In high-risk individuals, impairment on tests of learning-dependent predictive perception, such as binocular depth inversion and closure paradigms, will predict later schizophrenia. 2. Changes in cortical development will occur in the higher-order hierarchical levels prior to illness onset. 3. Structure and function in the neocortex and hippocampus will be impaired.


4. Genetic risk factors will be those that affect development of structures involved in higher-order hierarchical recognition and those that affect synapse structure and regulation. 5. Early damage during neonatal development from injury or infection will contribute to the abnormal genesis of this crucial circuitry and function. References: Kraus MS, Keefe RSE, Krishnan RK. Memory-prediction errors and their consequences in schizophrenia. Neuropsychology Review, 2009; 19:336-352. Keefe RSE, Kraus MS. Measuring memory-prediction errors and their consequences in youth at risk for schizophrenia. Annals of the Academy of Medicine, Singapore, 2009; 38: 414-416. Krishnan RR, Keefe R, Kraus M. Schizophrenia is a disorder of higher order hierarchical processing. Medical Hypotheses, 2009; 72: 740-744. Reichenberg A, Caspi A, Harrington H, Houts R, Keefe RS, Murray RM, Poulton R, Moffitt TE. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: A 30-year study. American Journal of Psychiatry, 2010. Purves, D., R. B. Lotto, et al. (2001). "Why we see things the way we do: evidence for a wholly empirical strategy of vision." Philos Trans R Soc Lond B Biol Sci 356(1407): 285-97. Hawkins, J. and S. Blakeslee, On Intelligence January 1, 2004, New York, New York, U.S.A.: Times Books. Hirsch, J.A. and L.M. Martinez, Laminar processing in the visual cortical column. Curr Opin Neurobiol, 2006. 16(4): p. 377-84. Douglas, R.J. and K.A. Martin, Recurrent neuronal circuits in the neocortex. Curr Biol, 2007. 17(13): p. R496-500. Lewis, D.A., T. Hashimoto, and H.M. Morris, Cell and receptor type-specific alterations in markers of GABA neurotransmission in the prefrontal cortex of subjects with schizophrenia. Neurotox Res, 2008. 14(2-3): p. 237-48. Javitt, D.C., When doors of perception close: bottom-up models of disrupted cognition in schizophrenia. Annu Rev Clin Psychol, 2009. 5: p. 249-75. Butler, P.D., et al., Early-stage visual processing and cortical amplification deficits in schizophrenia. Arch Gen Psychiatry, 2005. 62(5): p. 495-504. Doniger, G.M., et al., Impaired sensory processing as a basis for object-recognition deficits in schizophrenia. Am J Psychiatry, 2001. 158(11): p. 1818-26. Kamiya, A., et al., DISC1-NDEL1/NUDEL protein interaction, an essential component for neurite outgrowth, is modulated by genetic variations of DISC1. Hum Mol Genet, 2006. 15(22): p. 3313-23. Duan, X., et al., Disrupted-In-Schizophrenia 1 regulates integration of newly generated neurons in the adult brain. Cell, 2007. 130(6): p. 1146-58. van Praag, H., et al., Functional neurogenesis in the adult


hippocampus. Nature, 2002. 415(6875): p. 1030-4.


Matcheri Keshavan Harvard University Pathophysiology of Schizophrenia: A Neurochemical Cascade Model Any theory that seeks to provide an integrative understanding of schizophrenia needs to explain known “facts” of this illness (1,2). Distilled into five key facts, these are: a) schizophrenia is heritable, with many glutamate-associated genes implicated; b) dopamine mesolimbic overactivation mediates pathogenesis of psychosis but glutamatergic alterations may be operant as well; c) psychosis begins during adolescence, while d) premorbid cognitive alterations date back to early childhood; and e) social, vocational, cognitive, and neurobiologic deterioration occur early during schizophrenia. Connecting these dots is critical to an integrative formulation of schizophrenia. The first two facts point to the role of glutamate and dopamine, and the last three facts strongly point to role of early (intra- or perinatal) or late (peri-adolescent) neurodevelopmental as well as post-illness onset neuroprogressive impairment in schizophrenia pathogenesis. We propose that a genetically mediated hypofunction of the excitatory glutamatergic system (via N-methyl D-aspartate, or NMDA receptors) leads to a downstream compensatory dopaminergic imbalance, parsimoniously connecting these “dots.” Hypofunctioning NMDA receptors could account for the premorbid cognitive and psychosocial dysfunction. Onset of psychosis in adolescence may be related to an excessive elimination of excitatory glutamatergic synapses and secondarily, phasic glutamatergic and limbic dopaminergic overactivity. Following illness onset, these neurochemical alterations in relation to continuing untreated psychosis may lead to further excitotoxic glutamatergic neuronal loss (3), perhaps explaining progressive gray and white matter alterations seen in some schizophrenia patients over time. Activity of the excitatory glutamatergic pyramidal neurons is under inhibitory regulation by cortical gamma amino butyric acid (GABA) interneurons; failure of such inhibition might cause unregulated glutamatergic function, disrupt neuronal synchronization at gamma frequencies, and thereby cause the characteristic cognitive deficits in schizophrenia (4). Thus, a genetically mediated alteration in the excitatory (glutamate)-inhibitory (GABA) balance in the corticolimbic networks might predispose to schizophrenia and the persistent cognitive impairments, while a phasic-dopaminergic and glutamatergic overactivity could be the proximal cause of psychosis beginning in adolescence and subsequent illness progression. This neurochemical “cascade” model of schizophrenia pathogenesis generates several key predictions: a) glutamatergic and GABA deficits in adolescents at high risk for schizophrenia using magnetic resonance spectroscopy (MRS) will predict conversion to psychosis; b) MRS and positron emission tomography (PET) studies will show increases in glutamatergic and dopaminergic activity during conversion to psychosis; and c) reversing the excitatory/inhibitory imbalance in the premorbid phase pharmacologically (e.g., with glycine, d-cycloserine, GABA-enhancing agents will reduce likelihood of conversion to full-fledged clinical psychosis. References: 1. Tandon R, Keshavan MS, Nasrallah HA. Schizophrenia, "Just the Facts": what we know in 2008 part 1: overview. Schizophr Res. 2008 Mar;100(1-3):4-19. MacDonald and Schultz 2009).


2. MacDonald AW, Schulz SC. What we know: findings that every theory of schizophrenia should explain. Schizophr Bull. 2009 May;35(3):493-508. 3. Keshavan MS. Development, disease and degeneration in schizophrenia: a unitary pathophysiological model. J Psychiatr Res. 1999 Nov-Dec;33(6):513-21. 4. Lewis DA, Hashimoto T. Deciphering the disease process of schizophrenia: the contribution of cortical GABA neurons. Int Rev Neurobiol. 2007;78:109-31.


El-Wui Loh National Health Research Institutes, Taiwan Metabolic Abnormality as a Differentiable Phenotype and in Schizophrenia The health issues associated with schizophrenia are not merely mental. The most frequent physical problems associated with schizophrenia are various types of metabolic abnormality, such as diabetes and metabolic syndrome, which are associated with the complex but commonly seen phenotype-obesity. A few studies have pointed to an increased risk of impaired fasting glucose or diabetes in younger schizophrenia patients, especially in female patients (Chien et al., 2009; Chiu et al., 2009; Hung et al., 2005; Huang et al., 2009). Compelling facts support that metabolic abnormality may play a role in the pathogenesis and pathology of a type of schizophrenia. First, antipsychotics, especially atypical antipsychotics, may induce metabolic abnormality in some schizophrenia patients but not other schizophrenia patients. Interestingly, the more potent the antipsychotics, the more likely they may induce metabolic abnormality (Girgis et al., 2008). Second, studies predating the invention of antipsychotics reported an increased prevalence of impaired glucose tolerance within schizophrenia (Kohen, 2004), and this supports that glucose metabolic abnormality can be a pre-schizophrenia sign, which is not necessary induced by the therapeutics. Third, family studies indicate a higher risk of diabetes in the relative of schizophrenia patients (Wright et al., 1996). The notion of prior glucose metabolic abnormality before onset of schizophrenia is strengthened by a study that observed an increased risk of diabetes among the parents of non-affective psychosis subjects (Fernandez-Egea et al., 2008a); a significant increase of the mean glucose level in the siblings of schizophrenic subjects compared to controls was also observed (Fernandez-Egea et al., 2008b). Such aggregation suggests a possibility of shared biological pathways between schizophrenia and diabetes and related phenotypes (e.g., obesity related phenotypes), which are possibly genetic in nature. Fourth, Kirkpatrick et al. found that non-deficit schizophrenia patients showed a higher glucose level in glucose tolerance tests than deficit schizophrenia patients, and normal controls (Kirkpatrick et al., 2009), suggesting that the degree of deficiency in glucose metabolism is not unique in some schizophrenia, but may be related to the cognitive deficits. Fifth, susceptibility genes that contribute to both diabetes and schizophrenia have been identified by unrelated genetic studies which investigated diabetes or schizophrenia, suggesting that schizophrenia with pre-metabolic abnormality may be caused by a set of shared bio-susceptibility genes (Bellivier, 2005; Chagnon et al., 2004). We hypothesized that metabolic functions of some schizophrenia patients may be dysregulated. Testing of the following hypotheses may help to resolve our unifying hypothesis: 1. Psychotic syndromes are associated with specific metabolic indexes. 2. Patterns of cognitive deficits in schizophrenia are associated with specific metabolic index. 3. Some diabetes-related genes may contribute to the development of schizophrenia.


References: Bellivier F. Schizophrenia, antipsychotics and diabetes: Genetic aspects. Eur Psychiatry 2005; 20 Suppl 4: S335-S339. Chagnon Y C, Merette C, Bouchard R H, Emond C, Roy M A, Maziade M. A genome wide linkage study of obesity as secondary effect of antipsychotics in multigenerational families of eastern Quebec affected by psychoses. Mol Psychiatry 2004; 9(12): 1067-1074. Chien I C, Hsu J H, Lin C H, Bih S H, Chou Y J, Chou P. Prevalence of diabetes in patients with schizophrenia in Taiwan: a population-based National Health Insurance study. Schizophr Res 2009; 111(1-3): 17-22. Chiu H J, Loh e, Lan T H, Sou J H, Hsieh H C, Hu T M. Increase of incidence of impaired fasting glucose in young schizophrenia patients. Psychiatry Clin Neurosci 2009; 63(1): 127-128. Fernandez-Egea E, Miller B, Bernardo M, Donner T, Kirkpatrick B. Parental history of type 2 diabetes in patients with nonaffective psychosis. Schizophr Res 2008a; 98(1-3): 302-306. Fernandez-Egea E, Bernardo M, Parellada E, Justicia A, Garcia-Rizo C, Esmatjes E, Conget I, Kirkpatrick B. Glucose abnormalities in the siblings of people with schizophrenia. Schizophr Res 2008b; 103(1-3): 110-113. Girgis R R, Javitch J A, Lieberman J A. Antipsychotic drug mechanisms: links between therapeutic effects, metabolic side effects and the insulin signaling pathway. Mol Psychiatry 2008; 13(10): 918-929. Huang M C, Lu M L, Tsai C J, Chen P Y, Chiu C C, Jian D L, Lin K M, Chen C H. Prevalence of metabolic syndrome among patients with schizophrenia or schizoaffective disorder in Taiwan. Acta Psychiatr Scand 2009. Hung C F, Wu C K, Lin P Y. Diabetes mellitus in patients with schizophrenia in Taiwan. Prog Neuropsychopharmacol Biol Psychiatry 2005; 29(4): 523-527. Kirkpatrick B, Fernandez-Egea E, Garcia-Rizo C, Bernardo M. Differences in glucose tolerance between deficit and nondeficit schizophrenia. Schizophr Res 2009; 107(2-3): 122-127. Kohen D. Diabetes mellitus and schizophrenia: historical perspective. Br J Psychiatry Suppl 2004; 47: S64-S66. Wright P, Sham P C, Gilvarry C M, Jones P B, Cannon M, Sharma T, Murray R M. Autoimmune diseases in the pedigrees of schizophrenic and control subjects. Schizophr Res 1996; 20(3): 261-267.


Neely Myers University of Virginia Three subsequent generations of World Health Organization studies (1-6), including follow-up studies of two to five years at 30 research sites in 19 countries “robustly” confirmed that the short- and long-term outcomes of people diagnosed with schizophrenia in “developing” countries are better than the short- and long-term outcomes of people with schizophrenia who live in “developed” countries (7-13). As Hopper (12) explained, there are “relatively constant . . . odds of recovery ratio of roughly 1:5 favoring the non-industrial group.” “Sociocultural factors” like increased family involvement, reduced expectations of economic independence, easier employment in an agrarian economy, community cohesion, and less stigmatization of the mentally ill in “developing” nations may explain some differences (14-18). People with schizophrenia in “developed” nations often live marginalized lives (19-23) cut off from their families and social worlds by stigma (24-27), unemployment (28,29), poverty, and homelessness (18,30,31). The differences in outcomes between the “developing” group and the “developed” group, I propose, may be summarized as resilience to stress. The “diathesis-stress model” of schizophrenia (32-34) maintains that people with schizophrenia have an increased vulnerability to everyday stress (35-41). Activation of the HPA axis, which governs the individual’s “stress response,” precipitates and exacerbates psychosis via a “stress cascade” of neural events (35,41-43). People diagnosed with schizophrenia may be intolerant of even normal amounts of everyday stress (36). Childhood trauma arrests vulnerable people’s ability to cope with stress (44). Experiences of political and economic disenfranchisement may also be experienced as chronic stress and increase the incidence of schizophrenia in those populations (45-51). Stressful sociocultural conditions exacerbate clinical symptoms. The difference between the people with schizophrenia in the “developed” and “developing” world may also depend on culturally available therapies for stress relief, such as built-in non-pharmacological stress reduction techniques that prevent symptom exacerbation and psychosis. Non-pharmacological mind-body therapies like meditation, yoga, participation in peer groups, and deep breathing techniques have been promoted for their symptom-stabilizing effects by people who are in recovery from schizophrenia in the U.S. (52-54). Practicing mind-body therapies may strengthen psychophysiological pathways that reduce the impact of stress (e.g., the HPA axis) and thereby modify clinical symptoms (55). I hypothesize that mind-body therapies that reduce the impact of stress may be able to prevent or modify clinical symptoms leading to psychosis. To test this, my colleagues must identify interventions used by people who experience “recovery” that may increase resilience to stress. What are the impacts of these therapies on, for example, the HPA axis? If they reduce overactivity of the HPA axis, can they prevent or reduce psychosis conversion? If so, we may be able to design early interventions that increase the resilience of people with schizophrenia and reduce their development of psychotic symptoms. References: 1. Jablensky, A., et al., Schizophrenia: manifestations, incidence and course in different cultures. Psychological Medicine, 1992. Monograph Supplement 20.


2. WHO, W.H.O., The International Pilot Study of Schizophrenia. 1973, New York: John Wiley and Sons. 3. WHO, W.H.O., Schizophrenia: an International Follow-Up Study. 1979, New York, NY: John Wiley and Sons. 4. Harrison, G., et al., Recovery from Psychotic Illness: A 15- and 25- year Follow-up Study. British Journal of Psychiatry, 2001. 178: p. 506-517. 5. Hopper, K.J. and J. Wanderling, Revisiting the Developed vs. Developing Country Distinction in Course and Outcome in Schizophrenia: Results from ISoS, the WHO-Collaborative Follow-up Project. Schizophrenia Bulletin, 2000. 26: p. 835-846. 6. Hopper, K., Outcomes elsewhere: course of psychosis in 'other cultures', in Society and Psychosis, C. Morgan, K. McKenzie, and P. Fearon, Editors. 2008, Cambridge University Press: Cambridge. 7. Cohen, A., et al., Questioning an Axiom: Better Prognosis for Schizophrenia in the Developing World? Schizophrenia Bulletin, 2007: p. sbm105. 8. Bhugra, D., Severe mental illness across cultures. Acta Psychiatrica Scandanivica, 2006. 113(429 supplement): p. 17-23. 9. Issac, M., P. Chand, and P. Murthy, Schizophrenia Outcome Measures in the Wider International Community. British Journal of Psychiatry, 2007. 191(suppl 50): p. s71-s77. 10. Kulhara, P. and S. Chakrabarti, Culture and schizophrenia and other psychotic disorders. Psychiatric Clinics of North America, 2001. 24: p. 449-464. 11. Mueser, K.T. and S.R. McGurk, Schizophrenia. The Lancet, 2004: p. 2063-2072. 12. Hopper, K., Outcomes elsewhere: course of psychosis in 'other cultures', in Society and Psychosis, C. Morgan, K. McKenzie, and P. Fearon, Editors. 2008, Cambridge University Press: Cambridge. p. 198-216. 13. Patel, V., et al., Is the outcome of schizophrenia really better in developing countries? . Revista Brasiliera Psiquiatria, 2006. 28(2): p. 129-152. 14. Bresnahan, M., et al., Geographical variation in incidence, course, and outcome of schizophrenia: a comparison of developing and developed countries, in The Epidemiology of Schizophrenia, R. Murray, et al., Editors. 2003, Cambridge University Press: Cambridge. 15. Cooper, J. and N. Sartorius, Cultural and Temporal Variations in Schizophrenia: a Speculation on the Importance of Industrialization. British Journal of Psychiatry, 1977. 130: p. 50-55. 16. Warner, R., Recovery from Schizophrenia: Psychiatry and Political Economy. 3rd ed. 2004, London: Brunner-Routledge. 408. 17. Hopper, K., Interrogating the Meaning of "Culture" in the WHO International Studies of Schizophrenia, in Schizophrenia, culture, and subjectivity: The edge of experience, J.H. Jenkins and R.J. Barrett, Editors. 2004, Cambridge University Press: Cambridge. p. 62-86.


18. Luhrmann, T., Social defeat and the culture of chronicity: or, why schizophrenia does so well over there and so badly here. Culture, Medicine, and Psychiatry, 2007. 31(2): p. 135-172. 19. Stefan, S., "Discredited" and "Discreditable": The Search for Political Identity by People with Psychiatric Diagnoses. William and Mary Law Review, 2002. 44: p. 1341-1383. 20. Estroff, S., Identity, Disability, and Schizophrenia: the Problem of Chronicity, in Knowledge, power and practice: the anthropology of medicine in everyday life, S. Lindenbaum and M. Lock, Editors. 1993, University of California Press: Los Angeles. p. 247-286. 21. Estroff, S.E., Making It Crazy: An Ethnography of Psychiatric Clients in an American Community. 1981, Los Angeles: University of California Press. 22. Estroff, S.E., Self, Identity, and Subjective Experiences of Schizophrenia: In Search of the Subject. Schizophrenia Bulletin, 1989. 15(2): p. 189-197. 23. Barrett, R.J., The 'Schizophrenic' and the Liminal Persona in Modern Society. Culture, Medicine, and Psychiatry, 1998. 22: p. 465-494. 24. Link, B.G. and J.C. Phelan, Stigma and its public health implications. The Lancet, 2006. 367(9509): p. 528. 25. Corrigan, P.W. and A.C. Watson, The Paradox of Self-Stigma and Mental Illness. Clinical Psychology: Science and Practice, 2002. 9(1): p. 35-53. 26. Hayward, P. and J. Bright, Stigma and Mental Illness: A Review and Critique. Journal of Mental Health, 1997. 6: p. 345-354. 27. Jenkins, J. and E. Carpenter-Song, Stigma despite recovery: Strategies for living in the aftermath of psychosis. Medical Anthropology Quarterly, 2008. 22(4): p. 381-409. 28. Cook, J.A., Employment barriers for persons with psychiatric disabilities: a report for the President's New Freedom Commission. Psychiatric Services, 2006. 57: p. 1391-1405. 29. Rutman, I., How psychiatric disability expresses itself as a barrier to employment. Psychosocial Rehabilitation Journal, 1994. 17(3): p. 15-35. 30. Hopper, K., Returning to the community—again. Psychiatric Services, 2002. 53(11): p. 1355. 31. Estroff, S.E., et al., Pathways to Disability Income among Persons with Severe, Persistent Psychiatric Disorders. The Milbank Quarterly, 1997. 74(4): p. 495-532. 32. Millon, T., P. Blaney, and R. Davis, eds. Oxford Textbook of Psychopathology. 1999, Oxford University Press: New York. 33. Norquist, G. and W. Narrow, Schizophrenia: Epidemiology, in Comprehensive Textbook of Psychiatry, I. Sadock and V. Sadock, Editors. 2000, Lippincott Williams and Wilkins: New York.


34. Walker, E. and D. Diforio, Schizophrenia: a neural diathesis-stress model. Psychological Review, 1997. 104: p. 667-685. 35. Corcoran, C., et al., The stress cascade and schizophrenia: etiology and onset. Schizophr Bull, 2003. 29(4): p. 671-92. 36. Yung, A., et al., Mapping the Onset of psychosis: the comprehensive assessment of at risk mental states (CAARMS). Schizophrenia Research, 2003. 60(1): p. 30-31. 37. Halsband, S.A., [Stress and psychosis]. Vertex, 2002. 13 Suppl 1: p. 12-6. 38. Phillips, L.J., et al., Stress, the hippocampus and the hypothalamic-pituitary-adrenal axis: implications for the development of psychotic disorders. Aust N Z J Psychiatry, 2006. 40(9): p. 725-41. 39. Nuechterlein, K., et al., Developmental processes in schizophrenia disorders: longitudinal studies of vulnerability and stress. Schizophrenia Bulletin, 1992. 18: p. 387-425. 40. Jones, S.R. and C. Fernyhough, A new look at the neural diathesis--stress model of schizophrenia: the primacy of social-evaluative and uncontrollable situations. Schizophr Bull, 2007. 33(5): p. 1171-7. 41. Walker, E., V. Mittal, and K. Tessner, Stress and the hypothalamic pituitary adrenal axis in the developmental course of schizophrenia. Annu Rev Clin Psychol, 2008. 4: p. 189-216. 42. Walker, E. Social Outcome and Schizophrenia: Back to the Future. in International Congress on Schizophrenia Research. 2009. San Diego, CA: Schizophrenia Research Forum News. 43. Walker, E.F. and D. Diforio, Schizophrenia: a neural diathesis-stress model. Psychol Rev, 1997. 104(4): p. 667-85. 44. Read, J., et al., The contribution of early traumatic events to schizophrenia in some patients: a traumagenic neurodevelopmental model. Psychiatry, 2001. 64(4): p. 319-45. 45. Adler, N.E. and K. Newman, Socioeconomic Disparities In Health: Pathways And Policies. Health Aff, 2002. 21(2): p. 60-76. 46. Harrison, G., et al., Increased incidence of psychotic disorders in migrants from the Caribbean to the United Kingdom. Psychological Medicine, 1997. 27: p. 799-806. 47. Boydell, J., et al., Incidence of Schizophrenia in Ethnic Minorities in London: Ecological Study into Interactions with Environment. British Medical Journal, 2001. 323: p. 1336-1338. 48. Baum, A., J.P. Garofalo, and A.M. Yali, Socioeconomic Status and Chronic Stress: Does Stress Account for SES Effects on Health? Ann NY Acad Sci, 1999. 896(1): p. 131-144. 49. Williams, D.R., et al., Racial Differences in Physical and Mental Health: Socio-economic Status, Stress and Discrimination. J Health Psychol, 1997. 2(3): p. 335-351. 50. Bhugra, D., Migration, distress, and cultural identity. British Medical Bulletin, 2004. 69: p. 129-141.


51. Kelly, B.D., Structural Violence and Schizophrenia. Social Science and Medicine, 2005. 61(3): p. 721-730. 52. Copeland, M.E., WRAP: Wellness Recovery Action Plan: WRAPPIn' Virginia in Recovery, M.R. Virginia Department of Mental Health, and Substance Abuse Services, Editor. 2008, VDMHMRS. 53. Ridgway, P., et al., Pathways to Recovery: A Strengths Recovery Self Help Workbook. 2002, Auburn Hills, MI: Data Production Corporation. 54. Romme, M., et al., Living with Voices: 50 Stories of Recovery. 2009, Gateshead, UK: Athaeneum Press. 55. Taylor, A.G., et al., Top-Down and Bottom-Up Mechanisms in Mind-Body Medicine: Development of an Integrative Framework for Psychophysiological Research. Explore, 2010. 6(1): p. 29-41.


Nathalie Picard Abbott Schizophrenia is often described in terms of positive, negative and cognitive symptoms, which are considered orthogonal since current antipsychotics cannot address all. Various theories have been formulated to model the etiology of schizophrenia including biochemical (dopamine, glutamate, serotonin, GABA), neurodevelopmental, gene-X-environment, and neurogenesis/synaptic plasticity hypotheses. However, none of these models accounts for all of the data available, and a unifying hypothesis for schizophrenia is still missing. Five major lines of evidence coming from independent fields suggest that this unifying hypothesis could stem from the DISC1/NDEL1 pathway. Genetic studies have linked DISC1 with schizophrenia (3-5,7,10,20,24,28) and shown epistasis interaction with NDEL1 (2,14,22). Animal models disrupting NDEL1/DISC1 interaction (11,16-18,25) display in adolescence, subtle behavioral and histological features reminiscent of positive, negative, cognitive, and anatomical symptoms of schizophrenia. Furthermore, the mild schizophrenia-like endophenotypes of Dn- DISC1 transgenic mice are boosted when combined with the induction of a strong neonatal innate immune, as expected by the GeneXEnvironment hypothesis (12). Consistent with the neurodevelopmental hypothesis, DISC1 and NDEL1 are neurodevelopmentally regulated (1), and their decrease impairs neurite outgrowth, dendrite orientation, and leads to retarded neuronal migration and abnormal corticogenesis (13,23). These processes depend on DISC1/NDEL1 interaction (14), DISC1-dependent stabilization of catenin (19) and on cycles of NDEL1 palmitoylation (26). In adults, DISC1 controls hippocampal neurogenesis by regulating the integration of new neurons in active neuronal networks (8). Loss of function of DISC1 leads to premature cell cycle exit and accelerated integration of glutamatergic and GABAergic newly generated neurons. Knockdown of NDEL1 leads to a milder phenotype with an additive effect observed when both genes are decreased (6). DISC1 and NDEL1 are acting as integrators of the cytoskeletal function. They both interact with the dynein molecular motor (13,15), regulate microtubule dynamics, intracellular trafficking (1,20), as well as the necessary cytoskeleton reorganization necessary to ensure cell proliferation, cell motility (27), and dendritic spine plasticity (9). DISC1 and NDEL1 affect neurosignaling: The cellular desensitization system for cAMP depends on both DISC1 and NDEL1 (1,21). DISC1 controls the multi-firing capability of GABAergic and glutamatergic synapses of adult-born neurons (6). Short-term loss of DISC1 potentiates NMDAR signaling, but continuous loss of DISC1 induces structural shrinkage of spines and functional alteration of NMDAR signaling (9). NDEL1’s role in spine function is yet to be published. The DISC1/NDEL1 pathway emerges as a promising unifying hypothesis for schizophrenia. To strengthen this hypothesis, additional studies are needed to elucidate the implication of DISC1 and NDEL1 in the mesocortical dopamine system. A better understanding of the NDEL1-dependent subcellular targeting of the scaffold protein DISC1 is also missing. Validation of this model in schizophrenic patients by the use of appropriate biomarkers is critical to guide the search for innovative therapeutic treatments for schizophrenia. References:


1. Brandon et al. (2004) Disrupted in Schizophrenia and NUDEL form a neurodevelopmentally regulated protein complex : implications for schizophrenia and other major neurological disorders. Mol.Cell Neurosci 25:42-55. 2. Burdik et al. (2008) Elucidating the relationship between DISC1, NDEL1 and NDE1 and the risk for schizophrenia : Evidence of epistasis and competitive binding. Human molecular genetics 17, (16): 2462-2473 3. Cannon et al. (2005) Association of DISC1/TRAX haplotypes with Schizophrenia, reduced prefrontal grey matter, and impaired short and long term memory; Arch. Gen. Psychiatry 62:1205-1213. 4. Chen et al (2007) Case control association study of Disrupted in schizophrenia (DISC1) gene and schizophrenia in the Chinese population. J. Psychiatr. Res 41: 428-434. 5. Devon RS et al. (2001) Identification of polymorphisms within Disrupted In Schizophrenia 1 and Disrupted In Schizophrenia 2 and an investigation of their assiociation with schizophrenia and bipolar affective disorder. Psychiatr Genet 11:1611-1617. 6. Duan et al. (2007) Disrupted in Schizophreniaregulates integration of newly generated neurons in the adult brain. Cell 130:1-13. 7. Ekelund et al. (2001) Chromosome 1 loci in Finnish schizophrenia families. Hum. Mol. Genet. 10:1611-1617 8. Faulkner et al. (2008) Development of hippocampal mossy fiber synaptic outputs by new neurons in the adult brain. PNAS 105:14157-14162. 9. Hayashi-Tagaki et al. (2010) Disrupted in schizophrenia 1 (DISC1) regulates spines of the glutamate synapse via Rac1. Nature Neuroscience (online advanced publication). 10. Hennah et al. (2009) DISC1 association, heterogeneity and interplay in schizophrenia and bipolar disorder. Mol Psychiatry 9:865-873. 11. Hikida et al. (2007) Dominant-negative DISC1 transgenic mice display schizophrenia-associated phenotypes detected by measures translatable to humans. PNAS 104 (36):14501-14506. 12. Ibi et al. (2010) Combined effect of neonatal immune activation and mutant DISC1 on phenotypic change in adulthood. Behavioral Brain Research 206:32-37. 13. Kamiya et al (2005) A schizophrenia-associated mutation of DISC1 perturbs cerebral cortex development; Nat. Cell. Biol 7:1167-1178. 14. Kamiya et al (2006) DISC1-NDEL1/NDEL1 protein interaction, an essential component for neurite outgrowth is modulated by genetic variation of DISC1. Human Molecular Genetics 3313-3323. 15. Liang et al. (2004) Nudel functions in membrane traffic mainly through association with Lis1 and cytoplasmic dynein. The journal of Cell Biology 164 (4): 557-565.


16. Koike et al. (2006) DISC1 is mutated in the 129S6/SvEv strain and modulates working memory in mice. PNAS 103:3693-3697. 17. Kvajo et al. (2008) A mutation in mouse DISC1 that models a schizophrenia risk allele leads to specific alterations in neuronal architecture and cognition. PNAS 105:7076-7081. 18. Li et al.(2007) Specific developmental disruption of disrupted in schizophrenia 1 function results in schizophrenia related phenotypes in mice. PNAS 104 (46):18280-18285. 19. Mao et al. (2009) DISC1 regulates neural progenitor proliferation via modulation of GSK3b/bcatenin signaling. Cell 136(6):1017-1031. 20. Millar JK et al. (2000) Disruption of two novel genes by a translocation cosegregating with Schizophrenia. Hum Mol. Genet 9:1415-1423. 21. Millar JK. Et al. (2005) Disrupted in Schizophrenia 1 (DISC1): Subcellular targeting and induction of ring mitochondria. Mol. Cell. Neurosc. 30: 477-484. 22. Nicodemus et al. (2010) Evidence of statistical epistasis between DISC1, CIT and NDEL1 impacting risk for schizophrenia: biological validation with functional imaging. Human genetics. Epub ahead of print. 23. Ozeki et al. (2003) Disrupted in Schizophrenia (DISC1): mutant truncation prevents binding to NUDE-like (NUDEL) and inhibits neurite outgrowth. Proc. Natl. Acad. Sci. USA 100: 289-294. 24. Sachs et al. (2005) A frameshift mutation in Disrupted in schizophrenia 1 in an American family with schizophrenia and schizoaffective disorder. Mol. Psychiatry 10:758-764. 25. Shen S. et al. (2008) Schizophrenia-related neural and behavioral phenotypes in transgenic mice expressing truncated DISC1. The Journal of Neuroscience 28(43): 10893-10904. 26. Shmueli et al. (2009). NDEL1 palmitoylation: a new mean to regulate cytoplasmic dynein activity. EMBO J. 1:1-13. 27. Shu et al. (2004) Ndel1 Operates in a Common Pathway with LIS1 and Cytoplasmic Dynein to Regulate Cortical Neuronal Positioning. Neuron 44 (2) 263-277. 28. Thomson et al. (2005) Association between the TRAX/DISC locus and both bipolar disorder and schizophrenia in the Scottish population. Mol. Psychiatry 10:657-668.


Naren Rao National Institute of Mental Health and Neuroscience Bangalore Neuroimmune-endocrine Model for Schizophrenia: Gene-Environment Crosstalk? Compelling evidence from different research studies over the past few decades has supported the notion of schizophrenia as a multi-systemic disorder. Data from different sources, namely epidemiological, neurobiological, and pharmacological studies, have documented aberrations in nervous, immune, and endocrine systems: 1. Prenatal maternal infections are associated with increased risk of development of schizophrenia (Brown and Derkits, 2010; Limosin et al., 2003). Stressful life events are known to precipitate psychotic episodes in patients with schizophrenia (Shevlin et al., 2008) possibly though neuro-immuno-endocrine interactions through cortisol (Docherty et al., 2009). 2. Various cytokine abnormalities are noted in patients with schizophrenia with increased activity of Th2 system and decreased activity of TH1 system, suggesting a hyperactive pro-inflammatory response (Meyer et al., 2009; Patterson, 2007). 3. Hyperactive pro-inflammatory response can induce a change in tryptophan metabolism through the kyneurenine pathway and cause glutamatergic-NMDA dysfunction, which in turn leads to development of schizophrenia symptoms (Kim et al., 2009). Different candidate genes implicated in schizophrenia like neuregulin, DAAO, G72, and RSG4 are linked to glutamatergic transmission through NMDA receptors (Harrison and Owen, 2003). 4. Antipsychotics have been shown to reverse these abnormalities in the immune system, decreasing TH2 activity (Pae et al., 2006). 5. There are elevated levels of left-handedness and impaired cerebral lateralization in schizophrenia with reversal of normal cerebral asymmetries (DeLisi et al., 1997). Recent studies also suggest left-handed individuals have increased risk for immune abnormalities (Lengen et al., 2009), supporting Geschwind’s hypothesis of prenatal sex hormone influence in cerebral lateralization and immune development (Geschwind and Behan, 1982; Geschwind and Galaburda,1985). Thus, with the available evidence, I propose a “neuro-immune-endocrine model” for schizophrenia: a developmental anomaly due to maternal infection and aberrant sex hormone levels could result in impaired lateralization and a dysfunctional immune-endocrine system. When vulnerable individuals are exposed to stressful situations later in life, it could initiate a cascade of immune-endocrine reaction with hyperactive pro-inflammatory response. This in turn could result in neurochemical aberrations through the kyneurenine pathway and subsequently the symptoms of schizophrenia. Antipsychotics reverse the imbalance in immune-endocrine pathways and result in symptom remission. A concurrent multilevel investigation involving neuroimaging (examining cerebral laterality using structural and functional imaging, neurochemical abnormality using magnetic resonance spectroscopy and ligand-based imaging) and immune-endocrine (cytokine-cortisol-related endocrine changes) assessments can yield insights into pathogenic mechanisms. Examining patients before and after treatment will help assess the mechanism of action of antipsychotics in immune modulation. This could have potential clinical implications in the development of newer molecules targeting immune pathways. Another important clinical utility will be identification of immune biomarkers for diagnosis and prediction of treatment response. In addition,


longitudinal studies in at-risk individuals can also yield significant information regarding gene environment interaction. In summary, this model has potential to unravel the pathogenesis of schizophrenia and could have preventive and therapeutic clinical utility. References: Brown A.S.,Derkits E.J., 2010. Prenatal infection and schizophrenia: a review of epidemiologic and translational studies. Am J Psychiatry 167, 261-80. DeLisi L.E., Sakuma M., Kushner M., Finer D.L., Hoff A.L.,Crow T.J., 1997. Anomalous cerebral asymmetry and language processing in schizophrenia. Schizophr Bull 23, 255-71. Docherty N.M., St-Hilaire A., Aakre J.M.,Seghers J.P., 2009. Life events and high-trait reactivity together predict psychotic symptom increases in schizophrenia. Schizophr Bull 35, 638-45. Geschwind N.,Behan P., 1982. Left-handedness: association with immune disease, migraine, and developmental learning disorder. Proc Natl Acad Sci U S A 79, 5097-100. Geschwind N.,Galaburda A.M., 1985. Cerebral lateralization. Biological mechanisms, associations, and pathology: I. A hypothesis and a program for research. Arch Neurol 42, 428-59. Harrison P.J.,Owen M.J., 2003. Genes for schizophrenia? Recent findings and their pathophysiological implications. Lancet 361, 417-9. Kim Y.K., Myint A.M., Verkerk R., Scharpe S., Steinbusch H.,Leonard B., 2009. Cytokine changes and tryptophan metabolites in medication-naive and medication-free schizophrenic patients. Neuropsychobiology 59, 123-9. Lengen C., Regard M., Joller H., Landis T.,Lalive P., 2009. Anomalous brain dominance and the immune system: do left-handers have specific immunological patterns? Brain Cogn 69, 188-93. Limosin F., Rouillon F., Payan C., Cohen J.M.,Strub N., 2003. Prenatal exposure to influenza as a risk factor for adult schizophrenia. Acta Psychiatr Scand 107, 331-5. Meyer U., Feldon J.,Yee B.K., 2009. A review of the fetal brain cytokine imbalance hypothesis of schizophrenia. Schizophr Bull 35, 959-72. Pae C.U., Yoon C.H., Kim T.S., Kim J.J., Park S.H., Lee C.U., Lee S.J., Lee C.,Paik I.H., 2006. Antipsychotic treatment may alter T-helper (TH) 2 arm cytokines. Int Immunopharmacol 6, 666-71. Patterson P.H., 2007. Neuroscience. Maternal effects on schizophrenia risk. Science 318, 576-7. Shevlin M., Houston J.E., Dorahy M.J.,Adamson G., 2008. Cumulative traumas and psychosis: an analysis of the national comorbidity survey and the British Psychiatric Morbidity Survey. Schizophr Bull 34, 193-9.


James Walters Cardiff University The last three years will be considered a tipping point for the molecular genetics of schizophrenia. During this time international collaboration has enabled research which, as well as identifying novel neurobiological pathways (1-4), has corroborated clinical experience (3-7) in questioning the demarcation between schizophrenia and related disorders (1-7). The genetic overlap between schizophrenia and bipolar disorder has been demonstrated on an epidemiological scale (8),and genetic studies suggest that the two disorders have in common polygenic variation (5). The shared risk between schizophrenia and autism seems to be conferred by structural genetic variation (1,2,5-7). One of the most interesting copy number variant (CNV) locations, 16p11.2, has also been shown to be associated with obesity (9,10). Whilst the underlying genetics of these findings requires further elucidation, now is an opportune time to consider the value of phenotype in this context. The theory promoted in this essay rests on the belief that the genetic dissection of schizophrenia, and hence its neurobiological underpinnings, will emerge by comparison of gene/phenotype association in schizophrenia and populations with phenotypic overlap. Comparisons thus far have been with healthy controls, and whilst such designs have provided crucial insights, they fail to differentiate between symptom domains or disorders. Comparative phenotype research across related disorders has the potential to address this shortcoming; it is this approach that this theory promotes. Testing this theory, researchers would investigate risk variants for schizophrenia and autism for association with candidate phenotypes that the conditions have in common (neurocognitive deficits or social cognitive impairment), comparing those with and without these deficits. This challenging but achievable approach relies upon reliable, comparable phenotype and endophenotype data being available across research centers and disorders (11). The theory could be criticized as naïve in assuming simple gene/phenotype relationships and ignoring issues of pleiotropy. There will undoubtedly be variants that have pleiotropic effects: risk variants for schizophrenia, autism, and learning disability that are “generalist” genes involved in processes central to neurodevelopment. However, it seems likely that in this scenario, additional factors will also be in operation, be they genetic (“second hits” [12]) or environmental, which are associated with endophenotypes or clinical features, and set an individual on a trajectory to a particular phenotype. Whilst pleiotropy may operate at the clinical phenotype level, it also seems reasonable to expect convergence of the action of risk variants at some endophenotypic level, be that gene expression or imaging/neurocognitive measures. Crucial to combing such levels of data and advancing this approach will be the increasing sophistication of systems biology, gene pathway, and network analysis. Not only will such a strategy inform better diagnosis, it will elucidate the neurobiology of dimensions of illness and ultimately could lead to the treatment of disorders in a domain-specific way. References: 1. Kirov G, Gumus D, Chen W et al. Comparative genome hybridization suggests a role for NRXN1 and APBA2 in schizophrenia. Hum Mol Genet. 2008;17(3):458-65. 2. Rujescu D, Ingason A, Cichon S, et al. Disruption of the neurexin 1 gene is associated with schizophrenia. Hum. Mol. Genet.2009;18(5):988-996.


3. The International Schizophrenia Consortium. Common polygenic variation contributes to risk of schizophrenia and bipolar disorder. Nature 2009;460:748 –52. 4. O’Donovan MC, Craddock N, Norton N, Williams H, Peirce T, Moskvina V, et al. Identification of loci associated with schizophrenia by genome-wide association and follow-up. Nat Genet 2008;40(9):1053–1055 5. McCarthy SE, Makarov V, Kirov G, et al. Microduplications of 16p11.2 are associated with schizophrenia. Nat Genet. 2009;41(11):1223-7. 6. Mefford HC, Sharp AJ, Baker C, et al. Recurrent rearrangements of chromosome 1q21.1 and variable pediatric phenotypes. N Engl J Med. 2008;359(16):1685-99. 7. Weiss LA, Shen Y, Korn JM, et al. Association between Microdeletion and Microduplication at 16p11.2 and Autism. N Engl J Med. 2008;358(7):667-675. 8. Lichtenstein P, Yip BH, Björk C et al. Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study. Lancet 2009;373:234-9. 9. Walters RG, Jacquemont S, Valsesia A, et al. A new highly penetrant form of obesity due to deletions on chromosome 16p11.2. Nature 2010;463(7281):671-675. 10. Bochukova EG, Huang N, Keogh J, et al. Large, rare chromosomal deletions associated with severe early-onset obesity. Nature 2010;463(7281):666-670. 11. Cross-Disorder Phenotype Group of the Psychiatric GWAS Consortium, Craddock N, Kendler K, Neale M, Nurnberger J, Purcell S, et al. Dissecting the phenotype in genome-wide association studies of psychiatric illness. Br J Psychiatry 2009;195:97 –9. 12. Girirajan S, Rosenfeld JA, Cooper GM, et al. A recurrent 16p12.1 microdeletion supports a two-hit model for severe developmental delay. Nature Genetics.42(3):203-209.

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