Psychology Psychotic Disorders
Deborah J. Walder, Marta Statucka, Maureen Daly, Beril Yaffe
  • LAST REVIEWED: 09 May 2017
  • LAST MODIFIED: 28 April 2014
  • DOI: 10.1093/obo/9780199828340-0151


The term “psychotic disorders” refers to a broad conceptualization of conditions including primary psychoses, such as schizophrenia and psychotic mood disorders, other disorders that are sometimes marked by psychotic features (e.g., borderline personality disorder, body dysmorphic disorder), and secondary psychotic disorders due to medical conditions or substances (e.g., alcohol withdrawal delirium). As addressed in Ketter, et al. 2004 (“Psychotic Bipolar Disorders: Dimensionally Similar to or Categorically Different from Schizophrenia?,” cited in the Debate of Dimensional versus Categorical), controversy regarding relationships among mood disorders (particularly bipolar and depressive disorders with psychotic features) and schizophrenia is ongoing. The authors argue that while the respective dimensional (e.g., psychotic bipolar disorder as intermediate between non-psychotic bipolar and schizophrenia spectrum disorders) versus categorical debate persists, a mixed dimensional/categorical approach may best help elucidate pathophysiology and treatment options. Schizophrenia, specifically, is a severe and persistent form of mental illness often marked by positive symptoms (such as excesses and distortions in thoughts and sensory/perceptual experiences such as hallucinations and delusions), negative symptoms (behavioral deficits such as avolition, asociality, anhedonia, blunted affect, and alogia), disorganized symptoms (such as disorganized speech and behavior), movement symptoms (or grossly abnormal psychomotor behavior such as catatonia), and impairments in cognition (such as memory and frontal/executive functions that include, for example, planning ability and initiation). Kring, et al. 2014 (Abnormal Psychology, cited under the Schizophrenia Spectrum) provides an excellent introductory-level overview of schizophrenia and other psychotic disorders. The etiological (or causal) basis of schizophrenia and related psychotic disorders remains not wholly determined. Prevailing theories, however, ascribe to a diathesis-stress model, whereby biological factors (e.g., predispositions such as genetic liability) are believed to interact with adverse environmental factors (e.g., obstetric complications; adverse, stressful life events) over the course of development toward the manifestation of illness. This article offers a historical perspective of psychotic disorders, a review of etiological/theoretical models, a description of illness epidemiology and issues pertaining to sex differences and comorbidity, an outline of diagnostic considerations, a description of the schizophrenia spectrum, an examination of available assessment tools, the role of cognition/social cognition, a review of current evidence of neurobiological disruptions in psychosis (e.g., genetics, structural and functional neuroimaging, hormones, neurotransmitters, other aspects of maldevelopment in the central nervous system), other laboratory markers (e.g., perceptual and attentional abnormalities, smooth-pursuit eye movement dysfunction), environmental factors (such as stress, toxins, and familial-expressed emotion), the importance of gene-environment interactions in psychotic disorders, and, finally, current directions pertaining to prevention and treatment (pharmacological and psychosocial). While various psychotic-related disorders are addressed, this article focuses on the schizophrenia spectrum.

Historical Context

These papers introduce the work of Emil Kraepelin and Eugen Bleuler, two integral figures in the conceptualization of schizophrenia. Palha and Esteves 1997 presents a short history of psychiatry, from ancient civilizations through the 19th century, describing how Kraepelin synthesized previous work to form his nosologic system of psychopathology. Palm and Möller 2011 reviews Kraepelin’s nosology and its reception by his peers during the early 20th century, after its initial publication. A comparison of Kraepelin and Bleuler in terms of personality and personal history, approach to patients, and sociohistorical factors that influenced their unique conceptualizations of schizophrenia is provided in Kaplan 2008. Though Kraepelin’s nosologic system remains the basis for modern psychiatry, Hoff 2012 argues that Bleuler’s conceptualization of schizophrenia represented a drastic progression from Kraepelin’s work, by introducing a multidimensional approach and a precursor to modern diathesis-stress models. For a summary of Bleuler’s contributions to our understanding of schizophrenia, refer to Cuesta and Peralta 2011, the special edition of Schizophrenia Bulletin celebrating the centennial of Bleuler’s Dementia Praecox or the Group of Schizophrenias. This issue of Schizophrenia Bulletin also contains relevant contributions by Berrios 2011 and McGlashan 2011. However, over the years Bleuler’s conceptualization has been simplified and distorted, leading to many misinterpretations and unfounded criticisms of his work, as outlined in Moskowitz and Heim 2011. As argued in McNally 2009, this is especially true of the “Four A’s,” which has been used as a mnemonic of Bleuler’s work for many years but inaccurately summarizes his conceptualization of schizophrenia. From a historical and sociological perspective, additional important theoretical considerations are those posited by the “antipsychiatry” movement. Nasrallah 2011 briefly reviews the antipsychiatry movement, its primary propagators, and their claims. Nasrallah emphasizes that despite the assertions of antipsychiatry, which are largely believed to be “. . . unfair exaggerations based on events and primitive conditions of more than a century ago,” it is important because it helps keep the field of psychiatry “. . . honest and rigorous about what we do, motivating us to relentlessly seek better diagnostic models and treatment paradigms.” At present, the schizophrenia spectrum is conceptualized as including not only major psychotic disorders such as schizophrenia and schizoaffective disorder, but also the cluster A (“odd, eccentric”) personality disorders, each of which approximates some features of schizophrenia in an attenuated form. Cluster A personality disorders include paranoid personality disorder (characterized by a pervasive lack of trust in others), schizoid personality disorder (characterized by a tendency to be socially isolated and not interested in close relationships), and schizotypal personality disorder (SPD; characterized by a tendency to be socially isolated, reserved, and distant, accompanied by frequently experienced perceptual abnormalities). There are higher rates of SPD among family members of patients with schizophrenia than in the general population, and there is a relatively higher rate of transition to psychosis among individuals with SPD (see the Schizophrenia Spectrum).

  • Berrios, G. E. 2011. Eugen Bleuler’s place in the history of psychology. Schizophrenia Bulletin 37.6: 1095–1098.

    DOI: 10.1093/schbul/sbr132Save Citation »Export Citation »E-mail Citation »

    An editorial advocating for Bleuler’s place in the “pantheon of psychiatry” and encouraging further research into his concept of schizophrenia as well as his other works.

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    • Cuesta, M. J., and Peralta, V., eds. 2011. Theme: Bleuler’s contribution to contemporary psychiatry. Schizophrenia Bulletin 37.6: 1118–1146.

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      Issue celebrating the publication of Bleuler’s Dementia Praecox or the Group of Schizophrenias in 1911. Contains articles outlining Bleuler’s seven main contributions (Peralta and Cuesta, pp. 1118–1120), tracing the descriptive features of schizophrenia introduced by Kraepelin and Bleuler to the current diagnostic criterion (Parnas, pp. 1121–1130), and proposing progress toward a neurobiological understanding of schizophrenia (Heckers, pp. 1131–1135).

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      • Hoff, P. 2012. Eugen Bleuler’s concept of schizophrenia and its relevance to present-day psychiatry. Neuropsychobiology 66.1: 6–13.

        DOI: 10.1159/000337174Save Citation »Export Citation »E-mail Citation »

        Outlines how Bleuler was influenced by Kraepelin, Johann Friedrich Herbart, and Sigmund Freud. Argues that Bleuler’s conceptualization of schizophrenia represents clear progress from previous conceptualizations (including Kraepelin’s), citing his multidimensional approach and his introduction of a framework suggestive of modern diathesis-stress models.

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        • Kaplan, R. M. 2008. Being Bleuler: The second century of schizophrenia. Australasian Psychiatry 16.5: 305–311.

          DOI: 10.1080/10398560802302176Save Citation »Export Citation »E-mail Citation »

          Provides brief biographies of Kraepelin and Bleuler and describes and contrasts the historical, cultural, and social factors influencing their work. Also provides a brief but compelling comparison of their personalities, relationships with patients, and conceptualization of schizophrenia.

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          • McGlashan, T. H. 2011. Eugen Bleuler: Centennial anniversary of his 1911 publication of Dementia Praecox of the Group of Schizophrenias. Schizophrenia Bulletin 37.6: 1101–1103.

            DOI: 10.1093/schbul/sbr130Save Citation »Export Citation »E-mail Citation »

            An article that clearly and concisely summarizes Bleuler’s diagnostic and therapeutic contributions.

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            • McNally, K. 2009. Eugene Bleuler’s Four As. History of Psychology 12.2: 43–59.

              DOI: 10.1037/a0015934Save Citation »Export Citation »E-mail Citation »

              Describes how Bleuler’s complex theory was gradually simplified and distorted into the Four A’s (disturbed Affect and Associations, Ambivalence, Autism). Demonstrates how this led to misinterpretation and unfounded criticism of Bleuler, and emphasizes the importance of other symptoms in Bleuler’s conceptualization (especially splitting of personality).

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              • Moskowitz, A., and G. Heim. 2011. Eugen Bleuler’s Dementia praecox or the group of schizophrenias (1911): A centenary appreciation and reconsideration. Schizophrenia Bulletin 37.3: 471–479.

                DOI: 10.1093/schbul/sbr016Save Citation »Export Citation »E-mail Citation »

                Clarifies four myths regarding Bleuler’s conceptualization, including the inadequacy of the Four A’s. Argues that DSM-5 requires a neo-Bleulerian perspective deemphasizing the importance of psychotic symptoms.

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                • Nasrallah, H. A. 2011. The antipsychiatry movement: Who and why. Current Psychiatry 10.12: 4, 6, 53.

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                  Briefly reviews the antipsychiatry movement, its primary propagators (such as Michel Foucault, David Cooper, Erich Fromm, R. D. Laing, and Thomas Szasz) and their claims, which question the legitimacy of the concept of schizophrenia. Highlights that despite the inaccurate claims of antipsychiatry, which are based on obsolete information, these views help keep the field of psychiatry “. . . honest and rigorous about what we do, motivating us to relentlessly seek better diagnostic models and treatment paradigms.”

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                  • Palha, A. P., and M. F. Esteves. 1997. The origin of dementia praecox. Schizophrenia Research 28.2–3: 99–103.

                    DOI: 10.1016/S0920-9964(97)00117-5Save Citation »Export Citation »E-mail Citation »

                    Short historical review of psychiatry’s origins in ancient civilizations, the church’s influence during the Middle Ages, the resurgence of psychiatry during the Enlightenment, the first biological models of mental illness in the 19th century, and how Kraepelin synthesized others’ work and created his nosologic system.

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                    • Palm, U., and H.-J. Möller. 2011. Reception of Kraepelin’s ideas 1900–1960. Psychiatry and Clinical Neurosciences 65.4: 318–325.

                      DOI: 10.1111/j.1440-1819.2011.02226.xSave Citation »Export Citation »E-mail Citation »

                      While Kraepelin’s nosology received harsh criticism from 1900 to 1926, it was quickly and broadly accepted thereafter and forms the basis of current diagnostic tools. Presents several criticisms of Kraepelin’s system but argues that it is the foundation of modern psychiatry due to its simplicity and clarity.

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                      Etiological/Theoretical Models

                      The following papers represent a snapshot of etiological models of schizophrenia (and psychotic disorders more broadly), to date, largely reflecting diathesis-stress and neurodevelopmental perspectives. The vulnerability model put forth in Zubin and Spring 1977 laid the groundwork for understanding individual differences in illness susceptibility and adaptability to stressors as multidimensional and occurring across development. Norman and Malla 1993 further clarifies the interaction of stressful life events and symptom exacerbation among individuals with schizophrenia. The neural diathesis-stress model put forward in Walker and Diforio 1997 outlines the effects of the hypothalamic-pituitary-adrenal (HPA) axis on dopaminergic pathways, linking illness vulnerability (e.g., diathesis) and hyperresponsivity to stress to exacerbation of symptoms. Murray, et al. 1992 addresses the heterogeneity of schizophrenia and posits classifications, by examining indicators of neurodevelopmental deviance (e.g., prenatal insults), sex differences, and illness onset and course. With an aim of increasing specificity of neurodevelopmental indicators of risk for schizophrenia, Rapoport, et al. 2005 synthesizes longitudinal research examining prenatal disruptions, brain maturation, age of onset, and genetics. Piper, et al. 2012 focuses on the critical prenatal period and subsequent neurodevelopment to better characterize mechanisms contributing to illness onset in adulthood. The transition from adolescence to adulthood is also a critical period of neurodevelopment, marked by alterations in the organization, structure, and functions of cortical networks disrupted in schizophrenia, as reviewed in Uhlhaas and Singer 2011 in the context of neural oscillations.

                      • Murray, R. M., E. O’Callaghan, D. J. Castle, and S. W. Lewis. 1992. A neurodevelopmental approach to the classification of schizophrenia. Schizophrenia Bulletin 18.2: 319–332.

                        DOI: 10.1093/schbul/18.2.319Save Citation »Export Citation »E-mail Citation »

                        Provides a theoretical framework for conceptualizing congenital schizophrenia from a neurodevelopmental perspective and as a distinct diagnostic construct apart from affective psychoses that manifest later in adulthood. The authors’ conclusions arose from evidence of etiological heterogeneity, sex differences, structural brain abnormalities, and cognitive deficits.

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                        • Norman, R. M., and A. K. Malla. 1993. Stressful life events and schizophrenia, I: A review of the research. British Journal of Psychiatry 162:161–166.

                          DOI: 10.1192/bjp.162.2.161Save Citation »Export Citation »E-mail Citation »

                          Consistent with a vulnerability-stress perspective, this review clarifies that schizophrenia patients’ levels of stress are associated with variations in symptom severity. To a lesser extent, schizophrenia patients experience greater stressful life events relative to control groups, but no more than other psychiatric patients (e.g., depressed).

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                          • Piper, M., M. Beneyto, T. H. J. Burne, D. W. Eyles, D. A. Lewis, and J. J. McGrath. 2012. The neurodevelopmental hypothesis of schizophrenia: Convergent clues from epidemiology and neuropathology. Psychiatric Clinics of North America 35.3: 571–584.

                            DOI: 10.1016/j.psc.2012.06.002Save Citation »Export Citation »E-mail Citation »

                            Focuses on critical periods during which prenatal and perinatal risk factors interact with candidate genes associated with schizophrenia to alter the trajectory of brain development. Basic neuroscience, using animal models, has revealed biological mechanisms that may underlie these interactions, such as disruptions in cortical GABAergic interneurons and their corresponding pathways.

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                            • Rapoport, J. L., A. M. Addington, S. Frangou, and M. R. C. Psych. 2005. The neurodevelopmental model of schizophrenia: Update 2005. Molecular Psychiatry 10.5: 434–449.

                              DOI: 10.1038/ Citation »Export Citation »E-mail Citation »

                              Synthesizes epidemiological, imaging, and genetics findings to illustrate the variability and interactions of etiologic risk factors for psychosis, while taking into account the age of onset. The timing of developmental disruptions and their associations with brain morphology and gene expression are outlined, with an eye toward increasing specificity of illness trajectories.

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                              • Uhlhaas, P. J., and W. Singer. 2011. The development of neural synchrony and large-scale cortical networks during adolescence: Relevance for the pathophysiology of schizophrenia and neurodevelopmental hypothesis. Schizophrenia Bulletin 37.3: 514–523.

                                DOI: 10.1093/schbul/sbr034Save Citation »Export Citation »E-mail Citation »

                                The critical period of adolescence and corresponding maturational changes related to neural network connectivity are discussed in relation to psychosis. Deficits in cortical oscillatory synchronization associated with schizophrenia may represent developmental abberations in neurotransmitter system modifications (e.g., GABAergic interactions), white-matter tracts (e.g., corticocortical pathways), myelination, or synaptic pruning.

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                                • Walker, E. F., and D. Diforio. 1997. Schizophrenia: A neural diathesis-stress model. Psychological Review 104.4: 667–685.

                                  DOI: 10.1037/0033–295X.104.4.667Save Citation »Export Citation »E-mail Citation »

                                  An emphasis on the HPA axis provides an elegant model of how dysregulated stress responses influence illness vulnerability, exacerbation of symptoms, and the pathophysiology of schizophrenia throughout development. The effects of HPA activation (specifically cortisol release) on dopaminergic and glutamatergic neurotransmission, and hippocampal structure and function, are elucidated.

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                                  • Zubin, J., and B. Spring. 1977. Vulnerability—a new view of schizophrenia. Journal of Abnormal Psychology 86.2: 103–126.

                                    DOI: 10.1037//0021-843X.86.2.103Save Citation »Export Citation »E-mail Citation »

                                    This seminal paper suggests that increased vulnerability and compromised resiliency in response to adverse events decrease the threshold of developing schizophrenia. The authors’ vulnerability approach aims to incorporate a range of putative risk factors (e.g., genetics, prenatal and perinatal events), to define and measure indices of risk, and to identify episodic stressors.

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                                    Epidemiology, Sex Differences, and Comorbidity

                                    These papers collectively provide an overview of descriptive epidemiology of schizophrenia. Brown 2011 addresses incidence and prevalence rates as well as variability as a function of factors such as season of birth and urban versus rural setting. Buckley, et al. 2009 discusses the high comorbidity of schizophrenia spectrum disorders with other psychiatric symptoms and disorders such as substance abuse and anxiety and mood disorders (e.g., depression, post-traumatic stress disorder). The authors review the degree to which such comorbidities are due to chance versus reflecting separable phenotypes. Seeman 2012 outlines the ways in which research efforts have expanded with respect to inclusion of female subjects (animals and humans), who were largely neglected until the early 21st century. Salem and Kring 1998 outlines sexual differentiation in schizophrenia, with respect to factors such as age at onset, course of symptoms, and premorbid history. Ochoa, et al. 2012 provides an updated and extended review of sex differences in schizophrenia and first-episode psychosis. Lastly, Walder, et al. 2013 examines sex differences with respect to risk factors for conversion among those at clinical high risk. The convergence of these findings points to new directions for treatment and preventive interventions that may be differentially tailored by gender.

                                    • Brown, A. S. 2011. The environment and susceptibility to schizophrenia. Progress in Neurobiology 93.1: 23–58.

                                      DOI: 10.1016/j.pneurobio.2010.09.003Save Citation »Export Citation »E-mail Citation »

                                      The first part of this paper reviews the descriptive epidemiology of schizophrenia, including general studies on incidence, prevalence, and differences in these measures by urban-rural, neighborhood, migrant, and season-of-birth status, as well as time trends.

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                                      • Buckley, P. F., B. J. Miller, D. S. Lehrer, and D. J. Castle. 2009. Psychiatric comorbidities and schizophrenia. Schizophrenia Bulletin 35.2: 383–402.

                                        DOI: 10.1093/schbul/sbn135Save Citation »Export Citation »E-mail Citation »

                                        Discusses common psychiatric comorbidities in schizophrenia patients and examines whether they occur more than by chance, possibly representing separable phenotypes.

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                                        • Ochoa, S., J. Usall, J. Cobo, X. Labad, and J. Kulkarni. 2012. Gender differences in schizophrenia and first-episode psychosis: A comprehensive literature review. Schizophrenia Research and Treatment 2012:916198.

                                          DOI: 10.1155/2012/916198Save Citation »Export Citation »E-mail Citation »

                                          Reviews gender differences in schizophrenia and first-episode psychosis. Evidence suggests higher incidence, earlier age of onset, and more-common substance abuse in men, whereas premorbid and social functioning, remission, and relapse rates are better in females. Symptoms are mixed, cognition remains inconclusive, and no gender differences were observed in familial risk and obstetric complications.

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                                          • Salem, J. E., and A. M. Kring. 1998. The role of gender differences in the reduction of etiologic heterogeneity in schizophrenia. Clinical Psychology Review 18.7: 795–819.

                                            DOI: 10.1016/S0272-7358(98)00008-7Save Citation »Export Citation »E-mail Citation »

                                            Discusses gender differences in schizophrenia, with respect to incidence, age of onset, course and medication response, premorbid social and intellectual function, affective symptoms, familial morbid risk of schizophrenia and affective disorders, obstetric complications, and structural brain abnormalities. Also discusses the role of potential contributing factors such as estrogen, neurodevelopment, and family history of affective disorders and critically evaluates the possibility of a neurodevelopmental subtype that is sexually differentiated.

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                                            • Seeman, M. V. 2012. Women and psychosis. Women’s Health 8.2: 215–224.

                                              DOI: 10.2217/whe.11.97Save Citation »Export Citation »E-mail Citation »

                                              Highlights the historical exclusion of female animals and women in research, and how the early-21st-century inclusion of women in psychosis research helps address the (until recently) relatively neglected issue of sex differences. Reviews the relevant literature and emphasizes the need to develop treatments that address illness-related factors differentiated by sex.

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                                              • Walder, D. J., C. W. Holtzman, J. Addington, et al. 2013. Sexual dimorphisms and prediction of conversion in the NAPLS psychosis prodrome. Schizophrenia Research 144.1–3: 43–50.

                                                DOI: 10.1016/j.schres.2012.11.039Save Citation »Export Citation »E-mail Citation »

                                                As part of the North American Prodrome Longitudinal Study (NAPLS), examines sexual dimorphisms in clinical high-risk symptoms, childhood academic and social functioning, baseline social and role functioning, and conversion to psychosis. Results demonstrate sex effects that illuminate early psychosis vulnerability, with implications for understanding etiology and development of preventive interventions.

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                                                Diagnostic Considerations

                                                In North America, the diagnosis of schizophrenia or other schizophrenia spectrum disorders is made using the diagnostic criteria outlined in American Psychiatric Association 2013, the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Diagnosis largely relies on identification of positive (e.g., hallucinations, delusions), negative (e.g., social withdrawal, apathy, anhedonia), disorganized (e.g., disorganized speech, disorganized behavior), and movement symptoms (e.g., motor abnormalities). Kring, et al. 2014 (cited under the Schizophrenia Spectrum) outlines how the DSM-5 criteria for schizophrenia differ from the fourth-edition text update (DSM-IV-TR) criteria, in the following ways: (1) no subtypes, (2) negative symptoms are described in greater detail, (3) one symptom no longer needs to be hallucinations, delusions, or disorganized speech, (4) no longer requires only one symptom to be present if delusion is bizarre, and (5) subtypes (paranoid, disorganized, catatonic, undifferentiated) were removed due to questionable usefulness, poor reliability, considerable overlap between subtypes, and poor predictive validity. Also, DSM-5 includes schizophrenia in a chapter titled “Schizophrenia Spectrum and Other Psychotic Disorders,” consisting of the following diagnoses: schizophrenia, schizoaffective disorder, delusional disorder, schizophreniform disorder, and brief psychotic disorder. Crow 1980 suggests that symptoms may represent distinct pathological processes. Differentiating clusters of symptoms may be important because numerous authors, including Nancy Andreasen and Scott Olsen (Andreasen and Olsen 1982) reported that patients with a predominance of negative symptoms often have poorer premorbid functioning, more chronic disease course, and poorer prognosis. The current diagnostic criteria do not consider cognitive deficits, though Addington, et al. 1991 demonstrates that cognitive deficits are often associated with negative symptoms of schizophrenia (see Cognition). Keefe and Fenton 2007 recommends the addition of cognitive impairments as diagnostic criteria to future diagnostic manuals. Tandon 2012 proposes a number of additional changes to improve the diagnosis of schizophrenia, and Harvey, et al. 2012 rigorously reviews the reliability, validity, and stability over time of the diagnosis of schizophrenia. Finally, van Os and Kapur 2009 provides an overview of schizophrenia, including information pertaining to course of illness and long-term clinical and functional outcome, which help inform and guide treatment.

                                                • Addington, J., D. Addington, and E. Maticka-Tyndale. 1991. Cognitive functioning and positive and negative symptoms in schizophrenia. Schizophrenia Research 5.2: 123–134.

                                                  DOI: 10.1016/0920-9964(91)90039-TSave Citation »Export Citation »E-mail Citation »

                                                  During acute psychosis and at six-month follow-up, cognitive deficits were associated with negative symptoms, and executive functioning deficits were largely stable. Symptoms generally improved over time, and improved cognitive functioning was related to declining positive symptoms.

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                                                  • American Psychiatric Association. 2013. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA: American Psychiatric Association.

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                                                    Most recent edition of the diagnostic manual of the American Psychiatric Association. Provides current diagnostic criteria for schizophrenia and other schizophrenia spectrum disorders such a delusional disorder and schizoaffective disorder. Suggests that “attenuated psychosis syndrome” requires further research before clinical use is appropriate (see Psychosis Prodrome and Clinical High Risk).

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                                                    • Andreasen, N. C., and S. Olsen. 1982. Negative v positive schizophrenia: Definition and validation. Archives of General Psychiatry 39.7: 789–794.

                                                      DOI: 10.1001/archpsyc.1982.04290070025006Save Citation »Export Citation »E-mail Citation »

                                                      Explores validity of classifying schizophrenia as positive, negative, or mixed. Patients with predominantly negative symptomatology were characterized by poor premorbid adjustment, lower general functioning, impaired cognition, abnormal computed tomography (CT) scans, less education, lower employment rates, and more intense treatment course compared to patients with positive and mixed symptoms.

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                                                      • Crow, T. J. 1980. Positive and negative schizophrenic symptoms and the role of dopamine. British Journal of Psychiatry 137:379–386.

                                                        DOI: 10.1192/bjp.137.4.379Save Citation »Export Citation »E-mail Citation »

                                                        Outlines classification of schizophrenia into type I (characterized by positive symptoms, good treatment response and prognosis, and neurochemical imbalance) and type II (characterized by negative symptoms, poor treatment response and chronic course, and neuroanatomical changes) syndromes, reflecting two distinct pathological processes.

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                                                        • Harvey, P. D., R. K. Heaton, W. T. Carpenter Jr., M. F. Green, J. M. Gold, and M. Schoenbaum. 2012. Diagnosis of schizophrenia: Consistency across information sources and stability of the condition. Schizophrenia Research 140.1–3: 9–14.

                                                          DOI: 10.1016/j.schres.2012.03.026Save Citation »Export Citation »E-mail Citation »

                                                          This review, based on an expert meeting convened by the National Institute of Mental Health and the Social Security Administration (SSA), examines reliability and validity of a schizophrenia diagnosis, including valid diagnosis and diagnostic stability over time—toward assisting SSA in considering whether schizophrenia warrants inclusion in their new “Compassionate Allowance” process.

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                                                          • Keefe, R. S. E., and W. S. Fenton. 2007. How should DSM-V criteria for schizophrenia include cognitive impairment? Schizophrenia Bulletin 33.4: 912–920.

                                                            DOI: 10.1093/schbul/sbm046Save Citation »Export Citation »E-mail Citation »

                                                            Recommends adding cognitive impairments to DSM criteria because impairments are more universal, severe, and stable in schizophrenia than in affective psychosis, are present before psychosis onset, and have implications for treatment. Inclusion may assist in making differential diagnoses and lead to more accurate prognosis and better treatment.

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                                                            • Tandon, R. 2012. The nosology of schizophrenia: Toward DSM-5 and ICD-11. Psychiatric Clinics of North America 35.3: 557–569.

                                                              DOI: 10.1016/j.psc.2012.06.001Save Citation »Export Citation »E-mail Citation »

                                                              Proposes changes for DSM-5 and the eleventh edition of International Classification of Diseases (ICD-11), including elimination of schizophrenia subtypes, reduced emphasis on first-rank symptoms such as auditory hallucinations and delusions, addition of dimensional measurement of symptom severity, and better delineation of schizoaffective disorder, to differentiate it from schizophrenia with mood symptoms.

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                                                              • van Os, J., and S. Kapur. 2009. Schizophrenia. Lancet 374.9690: 635–645.

                                                                DOI: 10.1016/S0140-6736(09)60995-8Save Citation »Export Citation »E-mail Citation »

                                                                Reviews key biological, epidemiological, and pharmacological developments pertaining to schizophrenia and provides a syndromal framework. Discusses neuroanatomic and neurotransmitter changes associated with schizophrenia, and pharmacological, vocational, and psychological interventions that improve functional outcome. Biological mechanisms underlying illness, and moderating psychosocial factors, are also addressed.

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                                                                The Debate of Dimensional versus Categorical

                                                                Though the diagnosis of schizophrenia has traditionally relied on the identification of positive and negative symptoms (see Diagnostic Considerations), research suggests that this dichotomy does not adequately classify the symptoms of schizophrenia. Peralta, et al. 1992 proposes that positive symptoms are heterogeneous and that a three-syndrome model (e.g., negative, delusion-hallucination, and disorganization) is more appropriate. Other studies, such as Serretti and Olgiati 2004, found that in addition to the traditional dichotomy, disorganization, mania, and depression characterize the symptomatology of schizophrenia. Furthermore, given research supporting the clinical relevance of the dimensional approach, Widiger and Samuel 2005 outlines the validity and clinical utility of a dimensional classification of psychological disorders in general, concluding that future diagnostic manuals should incorporate dimensional models with the current categorical systems. Similarly, Potuzak, et al. 2012 argues that a hybrid of dimensional and categorical classification systems may be best suited to diagnose psychotic disorders. Van Os, et al. 1999 presents a rationale for why a dimensional model is superior to traditional categorical representations of psychopathology. The dimensional versus categorical controversy extends beyond identification of symptomatology within schizophrenia, to conceptualization and classification distinctions across schizophrenia and mood disorders (bipolar, depression) with psychotic features, as discussed in Ketter, et al. 2004. The controversy emphasizes commonalities across these various presentations, which highlights the heterogeneity of disorders. Ketter, et al. 2004 argues that a mixed dimensional/categorical approach may best help elucidate pathophysiology and treatment options.

                                                                • Ketter, T. A., P. W. Wang, O. V. Becker, C. Nowakowska, and Y. Yang. 2004. Psychotic bipolar disorders: Dimensionally similar to or categorically different from schizophrenia? Journal of Psychiatric Research 38.1: 47–61.

                                                                  DOI: 10.1016/S0022-3956(03)00099-2Save Citation »Export Citation »E-mail Citation »

                                                                  Discusses the controversy regarding how best to conceptualize primary psychoses, which include psychotic mood disorders and schizophrenia. Authors address commonalities and distinctions in phenomenology, biology, therapeutic response, and findings from brain imaging. Argues for utility of a mixed dimensional/categorical approach to understanding pathophysiology and treatment.

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                                                                  • Peralta, V., J. de Leon, and M. J. Cuesta. 1992. Are there more than two syndromes in schizophrenia? A critique of the positive-negative dichotomy. British Journal of Psychiatry 161.3: 335–343.

                                                                    DOI: 10.1192/bjp.161.3.335Save Citation »Export Citation »E-mail Citation »

                                                                    Factor analysis demonstrates that a positive-negative dichotomy does not adequately classify symptoms of schizophrenia because positive symptoms do not represent a homogeneous syndrome. Argues a three-syndrome model (negative, delusion-hallucination, and disorganization syndromes) is more psychometrically robust.

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                                                                    • Potuzak, M., C. Ravichandran, K. E. Lewandowski, D. Ongür, and B. M. Cohen. 2012. Categorical vs dimensional classifications of psychotic disorders. Comprehensive Psychiatry 53.8: 1118–1129.

                                                                      DOI: 10.1016/j.comppsych.2012.04.010Save Citation »Export Citation »E-mail Citation »

                                                                      Most dimensional studies report four psychosis dimensions: positive, negative, disorganization, and affective. Categorical studies are less common and typically report three to seven psychosis classes. There is a dearth of studies comparing or combining these approaches, though a hybrid approach may provide the best system of classification.

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                                                                      • Serretti, A., and P. Olgiati. 2004. Dimensions of major psychoses: A confirmatory factor analysis of six competing models. Psychiatry Research 127.1–2: 101–109.

                                                                        DOI: 10.1016/j.psychres.2003.07.005Save Citation »Export Citation »E-mail Citation »

                                                                        Confirmatory factor analysis demonstrates that the symptomatology of psychosis (in schizophrenia, bipolar disorder, and delusional disorder) appears to be composed of five factors: mania, positive symptoms, disorganization, depression, and negative symptoms.

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                                                                        • van Os, J., C. Gilvarry, R. Bale, et al. 1999. A comparison of the utility of dimensional and categorical representations of psychosis. Psychological Medicine 29.3: 595–606.

                                                                          DOI: 10.1017/S0033291798008162Save Citation »Export Citation »E-mail Citation »

                                                                          Compares dimensional and categorical representations of psychopathology with regard to their ability to predict important clinical features that usually assist treatment planning. The dimensional model was superior, and high scores on more dimensions increased the impact on clinical measures. Provides thoughtful rationale for the dimensional representation’s superiority.

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                                                                          • Widiger, T. A., and D. B. Samuel. 2005. Diagnostic categories or dimensions? A question for the Diagnostic and statistical manual of mental disorders—fifth edition. In Special section: Toward a dimensionally based taxonomy of psychopathology. Journal of Abnormal Psychology 114.4: 494–504.

                                                                            DOI: 10.1037/0021-843X.114.4.494Save Citation »Export Citation »E-mail Citation »

                                                                            Presents an overview of the limitations of the categorical model, with illustrative examples and research supporting the validity and clinical utility of dimensional classification of mental disorders. Suggests future editions of the DSM should incorporate dimensional models in addition to the categorical diagnostic system.

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                                                                            The Schizophrenia Spectrum

                                                                            Importantly, as outlined in Kring, et al. 2014, one important change in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; American Psychiatric Association 2013, cited under Diagnostic Considerations) from the fourth-edition text revision (DSM-IV-TR) is that schizophrenia is now part of a chapter titled “Schizophrenia Spectrum and Other Psychotic Disorders,” which also includes schizoaffective disorder, delusional disorder, schizophreniform disorder, and brief psychotic disorder. The dimensional model of schizophrenia proposes that psychopathology exists along a continuum and that psychotic symptoms differ only quantitatively from normal experience such that individuals in the general population may carry a genetic vulnerability to schizophrenia or may experience psychotic-like symptoms without developing psychosis. Refer to seminal papers such as Meehl 1962 and Meehl 1990 for an introduction to Paul Meehl’s taxonic model, which posited the existence of a discrete taxon (or class of individuals) associated with genetic vulnerability to schizophrenia, superimposed by dimensional variation (e.g., from polygenic potentiators). Also see Lenzenweger 2006 for a review of common misunderstandings of Meehl’s model. Tsuang, et al. 2002 shows that first-degree relatives of patients with schizophrenia (e.g., those at increased genetic vulnerability for schizophrenia) exhibit symptoms and impairments in keeping with Meehl’s theory of schizotaxia. Faraone, et al. 2001 reports that 20–50 percent of first-degree relatives of schizophrenia patients have schizotaxia, a clinically significant syndrome characterized by negative symptoms (see Diagnostic Considerations) as well as cognitive (see Cognition) and social-cognitive deficits (see Social Cognition). As described in Faraone, et al. 2001 and Tsuang, et al. 2002, these schizotaxic symptoms may be ameliorated through intervention.

                                                                            • Faraone, S. V., A. I. Green, L. J. Seidman, and M. T. Tsuang. 2001. “Schizotaxia”: Clinical implications and new directions for research. Schizophrenia Bulletin 27.1: 1–18.

                                                                              DOI: 10.1093/oxfordjournals.schbul.a006849Save Citation »Export Citation »E-mail Citation »

                                                                              Approximately 20–50 percent of relatives of schizophrenia patients, though non-schizotypal and non-psychotic, are schizotaxic. Schizotaxia is a clinically consequential condition characterized by negative symptoms and neuropsychological and psychosocial deficits. Schizotaxia may compromise family members’ ability to participate in family interventions. Argues that psychological or pharmacological approaches should focus on alleviating presenting symptoms of schizotaxia.

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                                                                              • Kring, A. M., S. L. Johnson, G. C. Davison, and J. M. Neale. 2014. Abnormal psychology. 12th ed. Hoboken, NJ: Wiley.

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                                                                                Update of DSM-5. In chapter 9 (pp. 250–283), provides a comprehensive introductory overview of schizophrenia and psychotic disorders, including a review of cardinal features, etiology, and treatment.

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                                                                                • Lenzenweger, M. F. 2006. Schizotaxia, schizotypy, and schizophrenia: Paul E. Meehl’s blueprint for the experimental psychopathology and genetics of schizophrenia. Journal of Abnormal Psychology 115.2: 195–200.

                                                                                  DOI: 10.1037/0021-843X.115.2.195Save Citation »Export Citation »E-mail Citation »

                                                                                  Clarifies frequent misconceptions of Meehl’s dimension model. Accordingly, Lenzenweger clarifies that the following are correct: (1) Meehl’s schizotypy is not the same as schizotypal personality disorder, (2) schizotypal personality disorder is not inherited but results from the interaction between schizotaxia and the environment, (3) schizotypal personality disorder is heterogeneous, and (4) not all individuals with schizotypal personality disorder develop schizophrenia.

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                                                                                  • Meehl, P. E. 1962. Schizotaxia, schizotypy, schizophrenia. American Psychologist 17.12: 827–838.

                                                                                    DOI: 10.1037/h0041029Save Citation »Export Citation »E-mail Citation »

                                                                                    Seminal paper introducing a neurodevelopmental and dimensional model explaining the cause and pathogenesis of schizophrenia. Briefly, a genetic defect (schizotaxia) causes a brain anomaly, which leads to a schizotypal personality organization, and given the proper constellation of personality and environmental factors, the individual may develop schizophrenia.

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                                                                                    • Meehl, P. E. 1990. Toward an integrated theory of schizotaxia, schizotypy, and schizophrenia. Journal of Personality Disorders 4.1: 1–99.

                                                                                      DOI: 10.1521/pedi.1990.4.1.1Save Citation »Export Citation »E-mail Citation »

                                                                                      Extends position paper, elaborating and updating Meehl 1962. Proposes that schizotaxia occurs in 10 percent of the general population; however, if exposed to a healthy environment, not all schizotaxic individuals develop schizotypy.

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                                                                                      • Tsuang, M. T., W. S. Stone, S. I. Tarbox, and S. V. Faraone. 2002. An integration of schizophrenia with schizotypy: Identification of schizotaxia and implications for research on treatment and prevention. Schizophrenia Research 54.1–2: 169–175.

                                                                                        DOI: 10.1016/S0920-9964(01)00364–4Save Citation »Export Citation »E-mail Citation »

                                                                                        Reviews evidence supporting the existence of schizotaxia in first-degree relatives of patients: (1) schizotaxic individuals have poorer clinical and social functioning than non-schizotaxic individuals, (2) schizotaxic individuals have more negative symptoms than non-schizotaxic individuals, and (3) schizotaxic cognitive deficits and negative symptoms improve with risperidone. Discusses clinical implications.

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                                                                                        Psychosis Prodrome and Clinical High Risk

                                                                                        Since the turn of the 21st century, there has been a significant increase in research examining the psychosis prodrome or individuals at clinical high risk (CHR) for developing psychosis. Addington, et al. 2007 describes efforts of the North American Prodrome Longitudinal Study (NAPLS) to combine data sets across research institutions to create the largest sample of CHR subjects worldwide. The NAPLS sites (with corresponding principal investigators) include Emory University, the University of Calgary, the University of California–San Diego, Zucker Hillside Hospital, Yale University, the University of North Carolina, and Harvard Medical School. This initial project led to a five-year prospective study, described in Addington, et al. 2012, which recruits a large-enough sample to address many important questions pertaining to the psychosis prodrome. NAPLS demonstrated strong diagnostic validity of the prospective “prodromal risk syndrome” (Woods, et al. 2009), though this diagnosis was not included in the DSM-5 (see Criticisms, Controversies, and Ethical Considerations). In Australia, Yung, et al. 2003 reports that 40.8 percent of CHR individuals converted to psychosis after twelve months. In North America, Cannon, et al. 2008 reports that 35 percent converted to psychosis after 2.5 years. In Europe, Ruhrmann, et al. 2010 reports only 19 percent converted to psychosis after eighteen months. Some variability in conversion rates can be explained by differences in assessing prodromal symptoms at different sites. Clearly, however, not all individuals identified as CHR develop psychosis. This has led these research groups to develop prediction models to help improve the ability to predict who will develop psychosis and who will not. For a review of predictors, including positive symptoms, social functioning, and genetic risk, which collectively carry strong predictive power upward of over 80 percent, see Gee and Cannon 2011.

                                                                                        • Addington, J., K. S. Cadenhead, T. D. Cannon, et al. 2007. North American Prodrome Longitudinal Study: A collaborative multisite approach to prodromal schizophrenia research. Schizophrenia Bulletin 33.3: 665–672.

                                                                                          DOI: 10.1093/schbul/sbl075Save Citation »Export Citation »E-mail Citation »

                                                                                          Describes collaborative efforts among eight independently conceived research projects to combine previously collected data sets toward creation of the largest sample of longitudinally followed CHR subjects worldwide. Allows investigators to establish diagnostic reliability in CHR subjects and to explore fundamental questions such as conversion rates, predictors of onset, and impact of early treatment.

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                                                                                          • Addington, J., K. S. Cadenhead, B. A. Cornblatt, et al. 2012. North American Prodrome Longitudinal Study (NAPLS 2): Overview and recruitment. Schizophrenia Research 142.1–3: 77–82.

                                                                                            DOI: 10.1016/j.schres.2012.09.012Save Citation »Export Citation »E-mail Citation »

                                                                                            Describes the methodology of a five-year prospective study consisting of a consortium of eight programs examining CHR individuals. The study aims to recruit a large-enough sample to address questions regarding neurobiological correlates of psychosis development.

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                                                                                            • Cannon, T. D., K. Cadenhead, B. Cornblatt, et al. 2008. Prediction of psychosis in youth at high clinical risk: A multisite longitudinal study in North America. Archives of General Psychiatry 65.1: 28–37.

                                                                                              DOI: 10.1001/archgenpsychiatry.2007.3Save Citation »Export Citation »E-mail Citation »

                                                                                              In this NAPLS sample, 35 percent of CHR individuals converted to psychosis after 2.5 years. Considering genetic risk for schizophrenia with recent functional decline, higher levels of unusual beliefs or suspiciousness and greater social impairment improved the ability to predict which individuals would convert to psychosis.

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                                                                                              • Gee, D. G., and T. D. Cannon. 2011. Prediction of conversion to psychosis: Review and future directions. Revista Brasileira de Psiquiatria 33.S2: S129–S142.

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                                                                                                Reviews predictors of conversion to psychosis among youth at ultrahigh risk and suggests rates of conversion of 30–40 percent over two–three-year follow-up. Severity of subthreshold positive symptoms, poorer social functioning, and genetic risk for schizophrenia collectively achieve positive predictive power greater than 80 percent. Symptoms that predict recovery are also reviewed.

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                                                                                                • Ruhrmann, S., F. Schultze-Lutter, R. K. R. Salokangas, et al. 2010. Prediction of psychosis in adolescents and young adults at high risk: Results from the prospective European Prediction of Psychosis Study. Archives of General Psychiatry 67.3: 241–251.

                                                                                                  DOI: 10.1001/archgenpsychiatry.2009.206Save Citation »Export Citation »E-mail Citation »

                                                                                                  Prospective, multicenter, naturalistic field study where 19 percent of CHR individuals developed psychosis after eighteen months. Individuals with a diagnosis based on a structured interview (see Assessment Tools) and cognitive disturbances had higher conversion rates. A prediction model including positive symptoms, bizarre thinking, sleep disturbances, schizotypal personality disorder, global functioning, and education was created.

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                                                                                                  • Woods, S. W., J. Addington, K. S. Cadenhead, et al. 2009. Validity of the prodromal risk syndrome for first psychosis: Findings from the North American Prodrome Longitudinal Study. Schizophrenia Bulletin 35.5: 894–908.

                                                                                                    DOI: 10.1093/schbul/sbp027Save Citation »Export Citation »E-mail Citation »

                                                                                                    Demonstrates strong diagnostic validity of the prospective “prodromal risk syndrome” construct, by comparing individuals in NAPLS (assessed using the Structured Interview for Prodromal Syndromes) with these groups: normal, help-seeking comparisons, familial high risk, and schizotypal personality disorder.

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                                                                                                    • Yung, A. R., L. J. Phillips, H. P. Yuen, et al. 2003. Psychosis prediction: 12-month follow up of a high-risk (“prodromal”) group. Schizophrenia Research 60.1: 21–32.

                                                                                                      DOI: 10.1016/S0920-9964(02)00167-6Save Citation »Export Citation »E-mail Citation »

                                                                                                      At the PACE Clinic in Australia, 40.8 percent of CHR individuals converted to psychosis within twelve months. Predictors of psychosis included long duration of prodromal symptoms, poor functioning at baseline, attenuated psychotic symptoms, depression, and disorganization.

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                                                                                                      Criticisms, Controversies, and Ethical Considerations

                                                                                                      Until the publication of the DSM-5 (American Psychiatric Association 2013), there was considerable controversy and discussion in the field regarding whether to add the psychosis prodrome as a diagnostic category. Some researchers argued that this category may help advance research and treatment, whereas others raised several concerns. For example, Corcoran, et al. 2005 outlines potential concerns for individuals identified as CHR, focusing on risks to individuals who are incorrectly identified as CHR (e.g., false positives), because these individuals may suffer from medication side effects, stigma, and discrimination without any benefit from interventions. Yang, et al. 2010 reviews various ways in which being labeled “at risk” may lead to stigma and discrimination, and the authors propose that future research should include measurement of stigma encountered by CHR individuals. These controversies, coupled with evidence of lower conversion rates, led the authors of Corcoran, et al. 2010 and Shrivastava, et al. 2011, as well as others in the field, to conclude it was premature to include the psychosis prodrome as a diagnostic category in the DSM-5. Shrivastava, et al. 2011 also includes a response from the chair of the DSM-5 Psychosis Work Group addressing the concerns raised by the authors. Ultimately, DSM-5 (American Psychiatric Association 2013) excludes the psychosis prodrome as a diagnostic category.

                                                                                                      • American Psychiatric Association. 2013. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA: American Psychiatric Association.

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                                                                                                        Provides a universal definition and classification system of mental disorders, to be used by clinicians and researchers in order to improve diagnosis, treatment, and research of mental disorders.

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                                                                                                        • Corcoran, C., M. B. First, and B. Cornblatt. 2010. The psychosis risk syndrome and its proposed inclusion in the DSM-V: A risk-benefit analysis. Schizophrenia Research 120.1–3: 16–22.

                                                                                                          DOI: 10.1016/j.schres.2010.03.018Save Citation »Export Citation »E-mail Citation »

                                                                                                          Benefits of including the psychosis risk syndrome in DSM-5 include improved identification and preventive treatment, reduced misdiagnosis and inappropriate treatment, and reduced stigma. Risks are as outlined in Corcoran, et al. 2005. Authors propose a research agenda to improve understanding of this risk syndrome before inclusion in future DSM.

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                                                                                                          • Corcoran, C., D. Malaspina, and L. Hercher. 2005. Prodromal interventions for schizophrenia vulnerability: The risks of being “at risk.” Schizophrenia Research 73.2–3: 173–184.

                                                                                                            DOI: 10.1016/j.schres.2004.05.021Save Citation »Export Citation »E-mail Citation »

                                                                                                            Outlines several controversies in identifying psychosis risk, including substantial false-positive rates. These individuals may be unnecessarily exposed to medication, potentially leading to social stigma and health risks, a change in life plans, facing insurability problems, etc. Draws analogies to other at-risk populations (e.g., diabetes, breast cancer).

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                                                                                                            • Shrivastava, A., P. D. McGorry, M. Tsuang, et al. 2011. “Attenuated psychotic symptoms syndrome” as a risk syndrome of psychosis, diagnosis in DSM-V: The debate. Indian Journal of Psychiatry 53.1: 57–65.

                                                                                                              DOI: 10.4103/0019-5545.75560Save Citation »Export Citation »E-mail Citation »

                                                                                                              Authors support inclusion of prodromal syndrome in a DSM-5 appendix to promote further research. Though inclusion of a diagnostic category may advance treatment and research, the dearth of data and high false-positive rates remain a concern. Includes response from the chair of the DSM-5 Psychosis Work Group, addressing concerns raised.

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                                                                                                              • Yang, L. H., A. J. Wonpat-Borja, M. G. Opler, and C. M. Corcoran. 2010. Potential stigma associated with inclusion of the psychosis risk syndrome in the DSM-V: An empirical question. Schizophrenia Research 120.1–3: 42–48.

                                                                                                                DOI: 10.1016/j.schres.2010.03.012Save Citation »Export Citation »E-mail Citation »

                                                                                                                Evaluates potential effects of stigma from psychosis risk labeling. Identification commonly occurs during adolescence, when the degree and effects of stigma may be severe and may interfere with identity formation. Stigma may also lead to structural (e.g., insurance, education, housing) and familial discrimination. Authors recommend stigma measurement strategies for future research.

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                                                                                                                Genetic/Familial High Risk and First Episode

                                                                                                                Given that the age of onset of schizophrenia is typically not until late adolescence or early adulthood, a number of methodological approaches have been engineered toward identifying individuals at risk for psychosis prior to illness onset, and then following them prospectively over time. The goal is to better understand etiology and to identify predictors of conversion to illness. One such approach is the family (or genetic) high-risk study design. Diwadkar, et al. 2004 reviews the import of the family high-risk paradigm and then-recent relevant findings. Agnew-Blais and Seidman 2013 specifically reviews neurocognitive evidence in youth and adults at familial risk for schizophrenia.

                                                                                                                • Agnew-Blais, J., and L. J. Seidman. 2013. Neurocognition in youth and young adults under age 30 at familial risk for schizophrenia: A quantitative and qualitative review. In Special issue: Cognitive antecedents of psychiatric disorders. Cognitive Neuropsychiatry 18.1–2: 44–82.

                                                                                                                  DOI: 10.1080/13546805.2012.676309Save Citation »Export Citation »E-mail Citation »

                                                                                                                  Provides a combined quantitative and qualitative review of the literature (up to May 2011), examining neurocognition among youth and young adults at familial risk for schizophrenia. The paper concludes that, in general, young individuals at familial high risk demonstrate moderate deficits relative to healthy comparisons, with effect sizes varying across domains.

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                                                                                                                  • Diwadkar, V. A., K. M. Prasad, and M. S. Keshavan. 2004. Approaches for adolescents with an affected family member with schizophrenia. Current Psychiatry Reports 6.4: 296–302.

                                                                                                                    DOI: 10.1007/s11920-004-0080-2Save Citation »Export Citation »E-mail Citation »

                                                                                                                    Discusses the import of the family high-risk paradigm (e.g., studying offspring and siblings of patients), toward understanding the etiology and underlying pathophysiology of, and predicting, schizophrenia. Reviews some literature on high-risk individuals, including neurobehavioral, neuroanatomic, physiologic, and neurochemical alterations in adolescent high-risk relatives, to elucidate early developmental indicators of the schizophrenia diathesis.

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                                                                                                                    Psychometric High-Risk/Psychotic-Like Symptoms in the General Population

                                                                                                                    In support of the dimensional approach, van Os, et al. 2000 finds that psychotic symptoms (e.g., hallucinations and delusions) are common in the general population. Verdoux and van Os 2002 further demonstrates that these symptoms are associated with an increased risk for psychopathology. Lenzenweger 1994 proposes a psychometric high-risk research paradigm to be used as an adjunct to traditional studies examining relatives of patients. Psychometrically high-risk individuals are also clinically relevant, and the longitudinal study in Chapman, et al. 1994 demonstrates that these individuals are at increased risk for psychosis and other forms of psychopathology; Rössler, et al. 2007 also shows that psychometric risk is associated with impairments in social functioning. Through the use of experience-sampling methodologies, Kwapil, et al. 2012 further bolsters construct validity of a multidimensional model of schizotypy, and ecological validity of positive and negative schizotypy dimensions. For a review of research supporting the dimensional approach, see Johns and van Os 2001.

                                                                                                                    • Chapman, L. J., J. P. Chapman, T. R. Kwapil, M. Eckblad, and M. C. Zinser. 1994. Putatively psychosis-prone subjects 10 years later. Journal of Abnormal Psychology 103.2: 171–183.

                                                                                                                      DOI: 10.1037//0021-843X.103.2.171Save Citation »Export Citation »E-mail Citation »

                                                                                                                      Longitudinal study demonstrating that high schizotypy scores predicted higher frequency of psychosis, psychotic-like experiences, and mood disorders over ten years. Schizotypal individuals also had poorer overall functioning at follow-up.

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                                                                                                                      • Johns, L. C., and J. van Os. 2001. The continuity of psychotic experiences in the general population. Clinical Psychology Review 21.8: 1125–1141.

                                                                                                                        DOI: 10.1016/S0272-7358(01)00103-9Save Citation »Export Citation »E-mail Citation »

                                                                                                                        Reviews research findings supporting the dimensional approach. Concludes that clinical psychosis represents a minor selection of the phenotypic continuum. Reviews implications for acceptance of the dimensional model in research and clinical practice.

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                                                                                                                        • Kwapil, T. R., L. H. Brown, P. J. Silvia, I. Myin-Germeys, and N. Barrantes-Vidal. 2012. The expression of positive and negative schizotypy in daily life: An experience sampling study. Psychological Medicine 42.12: 2555–2566.

                                                                                                                          DOI: 10.1017/S0033291712000827Save Citation »Export Citation »E-mail Citation »

                                                                                                                          Used experience-sampling methodology (ESM) to assess positive and negative schizotypy in daily life among nonclinical young adults. Findings bolster construct validity of a multidimensional model of schizotypy, and ecological validity of positive and negative schizotypy dimensions.

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                                                                                                                          • Lenzenweger, M. F. 1994. Psychometric high-risk paradigm, perceptual aberrations, and schizotypy: An update. Schizophrenia Bulletin 20.1: 121–135.

                                                                                                                            DOI: 10.1093/schbul/20.1.121Save Citation »Export Citation »E-mail Citation »

                                                                                                                            Reviews psychometrically identified schizotypy research using Meehl’s theoretical framework. Proposes that such research is a useful adjunct to traditional genetic high-risk methods and that it can elucidate etiologic and pathophysiological processes in schizophrenia. Presents eleven conceptualization and methodological issues inherent to the psychometric high-risk paradigm.

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                                                                                                                            • Rössler, W., A. Riecher-Rössler, J. Angst, et al. 2007. Psychotic experiences in the general population: A twenty-year prospective community study. Schizophrenia Research 92.1–3: 1–14.

                                                                                                                              DOI: 10.1016/j.schres.2007.01.002Save Citation »Export Citation »E-mail Citation »

                                                                                                                              First longitudinal study examining subclinical psychotic symptoms in a community cohort over twenty years. Subclinical symptoms were associated with impairments in social functioning. Though symptoms generally decreased with age, cannabis use during early adulthood predicted continuously high symptoms.

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                                                                                                                              • van Os, J., M. Hanssen, R. V. Bijl, and A. Ravelli. 2000. Strauss (1969) revisited: A psychosis continuum in the general population? Schizophrenia Research 45.1–2: 11–20.

                                                                                                                                DOI: 10.1016/S0920-9964(99)00224-8Save Citation »Export Citation »E-mail Citation »

                                                                                                                                Psychotic symptoms are common in the general population. In a large random sample, 17.5 percent self-reported psychotic experiences (e.g., hallucinations or delusions), but only 2 percent of these people had a diagnosis of nonaffective psychosis.

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                                                                                                                                • Verdoux, H., and J. van Os. 2002. Psychotic symptoms in non-clinical populations and the continuum of psychosis. Schizophrenia Research 54.1–2: 59–65.

                                                                                                                                  DOI: 10.1016/S0920-9964(01)00352-8Save Citation »Export Citation »E-mail Citation »

                                                                                                                                  Reviews the prevalence of psychotic symptoms in the general population, and outcomes of these “psychosis-prone” individuals. “Psychosis proneness” lacks diagnostic specificity because it is associated with increased risk for mood disorders. Research is needed to determine whether it is a nonspecific risk factor for psychopathology or an attenuated form of psychosis.

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                                                                                                                                  Psychotic Mood Disorders

                                                                                                                                  There remains an interest in better delineating commonalties and distinctions (etiologically, pathophysiologically, and otherwise) between schizophrenia and primary mood disorders with psychotic features. This is important clinically, given that psychotic symptoms lead to a relatively worse prognosis. Tsuang, et al. 2004 addresses how major differences between bipolar disorder and unipolar depression lie not only in symptom profile, but also in that the former is generally (though not always) more severe than the latter. Severity in part depends on presence of psychotic features and raises the possibility that mood disorders with psychotic features are distinct illnesses. Authors explore this possibility on the basis of genetic evidence. Ketter, et al. 2004 reviews phenomenology, biology, therapeutic responses, and findings from brain imaging, to identify similarities and dissociations between psychotic bipolar disorders and schizophrenia; conclusions support the dimensional view. Kelleher, et al. 2013 extends early-21st-century community-based research to a clinical sample of adolescents, suggesting that psychotic experiences among youth with a range of psychiatric disturbances are an important marker of risk for severe psychopathology.

                                                                                                                                  • Kelleher, I., N. Devlin, J. T. W. Wigman, et al. 2013. Psychotic experiences in a mental health clinic sample: Implications for suicidality, multimorbidity and functioning. Psychological Medicine: FirstView: 1–10.

                                                                                                                                    DOI: 10.1017/S0033291713002122Save Citation »Export Citation »E-mail Citation »

                                                                                                                                    Examined prevalence of attenuated or frank psychotic experiences (in a clinical sample of adolescents) in relation to affective, anxiety, and behavioral disorders; multimorbid psychopathology; global functioning; and suicidal behavior. Findings point to psychotic experiences as important markers of risk for severe psychopathology.

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                                                                                                                                    • Ketter, T. A., P. W. Wang, O. V. Becker, C. Nowakowska, and Y. Yang. 2004. Psychotic bipolar disorders: Dimensionally similar to or categorically different from schizophrenia? Journal of Psychiatric Research 38.1: 47–61.

                                                                                                                                      DOI: 10.1016/S0022-3956(03)00099-2Save Citation »Export Citation »E-mail Citation »

                                                                                                                                      Discusses phenomenology, biology, therapeutic responses, and findings from brain imaging, to identify commonalties and dissociations between psychotic bipolar disorders and schizophrenia. Concludes that findings (predominantly) support a dimensional view, where psychotic bipolar disorders are intermediate between non-psychotic bipolar disorders and schizophrenia spectrum disorders. Utility of the categorical approach, however, is not excluded.

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                                                                                                                                      • Tsuang, M. T., L. Taylor, and S. V. Faraone. 2004. An overview of the genetics of psychotic mood disorders. Journal of Psychiatric Research 38.1: 3–15.

                                                                                                                                        DOI: 10.1016/S0022-3956(03)00096-7Save Citation »Export Citation »E-mail Citation »

                                                                                                                                        Reviews genetic underpinnings of psychotic mood disorders, including evidence from epidemiological, linkage, and associated studies that include serotonin and dopamine genes. Points to studies suggesting a genetic link between schizophrenia and bipolar disorder as undermining the Kraepelinian dichotomous classification of psychotic disorders. Argues for future examination of psychotic mood disorders by using epidemiological and molecular approaches.

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                                                                                                                                        Other Disorders with Psychotic Features

                                                                                                                                        There are a wide range of secondary psychotic disorders caused by general medical conditions and substance use. Substance-induced psychotic disorders may result from substances such as amphetamines, cannabis, and alcohol (e.g., alcohol withdrawal delirium) (see American Psychiatric Association 2013). Moreover, several neurological disorders and non-psychotic psychiatric disorders are accompanied by psychosis or psychotic features, such as Parkinson’s disease, Alzheimer’s disease, borderline personality disorder (BPD), and body dysmorphic disorder (BDD). A comprehensive overview of all possible secondary psychotic disorders and non-psychotic disorders with psychotic features is beyond the scope of this article. Barnow, et al. 2010 reviews one example; namely, the prevalence of psychotic symptoms in BPD, the role of comorbidity, and comparative results among BPD, schizophrenia, and other psychotic disorders with respect to genetic and neurobiological findings. Another example is examined in Reese, et al. 2011, which reports on the degree to which individuals with BDD demonstrated reality-monitoring deficits; findings suggest intact reality monitoring despite elevated focal delusionality. Friedman 2010 reviews psychotic symptoms that occur in Parkinson’s disease and treatment options. Finally, Awissi, et al. 2013 reviews literature examining prevalence, risk factors, screening tools, prophylactic and treatment strategies, and outcomes for alcohol withdrawal syndrome (AWS) and delirium tremens (DT) in the critically ill.

                                                                                                                                        • American Psychiatric Association. 2013. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Arlington, VA: American Psychiatric Association.

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                                                                                                                                          Most recent edition of the diagnostic manual of the American Psychiatric Association. Provides current diagnostic criteria for schizophrenia and other schizophrenia spectrum disorders such a delusional disorder and schizoaffective disorder, as well as substance-induced and other psychotic disorders (and non-psychotic disorders with psychotic features).

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                                                                                                                                          • Awissi, D.-K., G. Lebrun, D. B. Coursin, R. R. Riker, and Y. Skrobik. 2013. Alcohol withdrawal and delirium tremens in the critically ill: A systematic review and commentary. Intensive Care Medicine 39.1: 16–30.

                                                                                                                                            DOI: 10.1007/s00134-012-2758Save Citation »Export Citation »E-mail Citation »

                                                                                                                                            This review examines prevalence, risk factors, screening tools, prophylactic and treatment strategies, and outcomes for AWS and DT in the critically ill.

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                                                                                                                                            • Barnow, S., E. A. Arens, S. Sieswerda, R. Dinu-Biringer, C. Spitzer, and S. Lang. 2010. Borderline personality disorder and psychosis: A review. Current Psychiatry Reports 12.3: 186–195.

                                                                                                                                              DOI: 10.1007/s11920-010-0107-9Save Citation »Export Citation »E-mail Citation »

                                                                                                                                              Reviews prevalence of psychotic symptoms in BPD, comorbidity (e.g., mood disorders, post-traumatic stress disorder) and its link with psychotic symptoms, the role of stress, the (unlikely) possibility of shared genetic vulnerability between BPD and psychosis (versus an indirect link via a third variable or the alternative possibility of common underlying personality dimensions such as neuroticism), overlapping and distinct neurobiological (neuroimaging and pathophysiological) findings, and treatment (e.g., antipsychotics), and respective study limitations to be considered. Concludes that BPD psychotic symptoms, although not necessarily predictive of a psychotic disorder, require close clinical attention toward diagnosis and treatment.

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                                                                                                                                              • Friedman, J. H. 2010. Parkinson’s disease psychosis 2010: A review article. Parkinsonism & Related Disorders 16.9: 553–560.

                                                                                                                                                DOI: 10.1016/j.parkreldis.2010.05.004Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                This review article describes psychotic symptoms that occur in Parkinson’s disease, treatment options, and the need to identify etiological factors.

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                                                                                                                                                • Reese, H. E., R. J. McNally, and S. Wilhelm. 2011. Reality monitoring in patients with body dysmorphic disorder. Behavior Therapy 42.3: 387–398.

                                                                                                                                                  DOI: 10.1016/j.beth.2010.10.001Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                  Studies degree of impairment in reality monitoring in BDD as compared to obsessive-compulsive disorder and healthy comparisons. Findings revealed absence of a reality-monitoring deficit in BDD, though elevated levels of focal delusionality.

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                                                                                                                                                  Assessment Tools

                                                                                                                                                  In North America, the diagnosis of schizophrenia or other schizophrenia spectrum disorders is made by using the diagnostic criteria outlined in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5; see American Psychiatric Association 2013, cited under Diagnostic Considerations). The Structured Clinical Interview for the fourth-edition text revision of the manual (DSM-IV-TR), developed by the authors of First, et al. 2002, remains the principal measure used for assessing axis I disorders. The Positive and Negative Syndrome Scale (PANSS) is an assessment tool used in research and clinically to measure the severity of schizophrenia symptoms (Kay, et al. 1987). The Structured Interview for Prodromal Syndromes (SIPS) and the Scale of Prodromal Symptoms (SOPS) in Miller, et al. 2003 measure prodromal symptoms in research participants, and these tools have good interrater reliability and predictive validity. Loewy, et al. 2012 demonstrates that the SIPS together with the Prodromal Questionnaire constitute an efficient two-stage screening process for prodromal psychosis. However, despite these assessment techniques, high positive rates remain a concern (see Criticisms, Controversies, and Ethical Considerations). The authors of Nurnberger, et al. 1994 developed the Diagnostic Interview for Genetic Studies (DIGS) as an alternative measure for the assessment of major mood and psychotic disorders and related spectrum conditions. Together with the DIGS, the Family Interview for Genetics Studies (FIGS; Maxwell 1992) is often used to identify individuals at familial/genetic risk for psychosis.

                                                                                                                                                  • First, M. B., R. L. Spitzer, M. Gibbon, and J. B. Williams. 2002. User’s guide for the Structured Clinical Interview for DSM-IV-TR axis I disorders: SCID-I/P. Research Version. New York: Biometrics Research Department, New York State Psychiatric Institute.

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                                                                                                                                                    This is a semistructured interview for making psychiatric diagnoses based on DSM-IV-TR diagnostic criteria. Contents include modules covering mood, psychotic, anxiety, substance use, somatoform, eating, and adjustment modules, as well as optional modules. Alternate editions such as a non-patient edition are also available.

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                                                                                                                                                    • Kay, S. R., A. Fiszbein, and L. A. Opler. 1987. The Positive and Negative Syndrome Scale (PANSS) for schizophrenia. Schizophrenia Bulletin 13.2: 261–276.

                                                                                                                                                      DOI: 10.1093/schbul/13.2.261Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                      Describes the development and standardization of PANSS, currently one of the most widely used, standardized assessment tools for symptom severity in schizophrenia.

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                                                                                                                                                      • Loewy, R. L., S. Therman, M. Manninen, M. O. Huttunen, and T. D. Cannon. 2012. Prodromal psychosis screening in adolescent psychiatry clinics. Early Intervention in Psychiatry 6.1: 69–75.

                                                                                                                                                        DOI: 10.1111/j.1751-7893.2011.00286.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                        Examines concurrent validity of the Prodromal Questionnaire against clinical risk status and preliminary predictive validity for later psychotic disorder among adolescents in mental health clinics in Finland. Results suggest that combined use of SIPS with the Prodromal Questionnaire constitutes an efficient two-stage screening process for prodromal psychosis.

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                                                                                                                                                        • Maxwell, M. E. 1992. Family Interview for Genetic Studies (FIGS): A manual for FIGS. Bethesda, MD: National Institute of Mental Health, Clinical Neurogenetic Branch, Intramural Research Program.

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                                                                                                                                                          FIGS is a method of assessing family history of psychiatric disorders, often for the purpose of studies on familial/genetic high risk. The measure combines use of a pedigree drawing, screening questions, and completion of checklists on the basis of an informant’s responses.

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                                                                                                                                                          • Miller, T. J., T. H. McGlashan, J. L. Rosen, et al. 2003. Prodromal assessment with the Structured Interview for Prodromal Syndromes and the Scale of Prodromal Symptoms: Predictive validity, interrater reliability, and training to reliability. Schizophrenia Bulletin 29.4: 703–715.

                                                                                                                                                            DOI: 10.1093/oxfordjournals.schbul.a007040Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                            Describes two research instruments developed to rate and track the symptoms of three prodromal syndromes. SIPS is a structured diagnostic interview used to diagnose syndromes; SOPS measures severity and change of symptoms. Both have excellent diagnostic interrater reliability and good predictive validity.

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                                                                                                                                                            • Nurnberger, J. I., M. C. Blehar, C. A. Kaufmann, et al. 1994. Diagnostic Interview for Genetic Studies: Rationale, unique features, and training. Archives of General Psychiatry 51.11: 849–859.

                                                                                                                                                              DOI: 10.1001/archpsyc.1994.03950110009002Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                              DIGS is a clinical interview constructed for the assessment of major mood and psychotic disorders and spectrum conditions. It was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health Genetics Initiative and has some unique features.

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                                                                                                                                                              Cognitive deficits in patients with schizophrenia appear to be pervasive and stable. For a summary of the course, profile, and severity of cognitive deficits in schizophrenia and a discussion of potential neurobiological factors causing these deficits, see Harvey 2012. Importantly, Nuechterlein, et al. 2012 demonstrates that milder attention deficits are evident in first-degree relatives of patients. Together, this line of research suggests that cognitive deficits are not attributable to the deleterious effects of chronic illness and treatment and may in fact represent a genetic-vulnerability factor for schizophrenia (Bilder, et al. 2011). An early meta-analysis conducted by the authors of Aylward, et al. 1984 evidenced that both early- and adult-onset schizophrenia is associated with intellectual deficits across the life-span, and the results implicated important sex effects. Reichenberg, et al. 2010 also suggests the possibility of a developmental course of cognitive dysfunction, whereby early-childhood abilities for verbal reasoning are followed by a lag in working memory, attention, and processing speed. Furthermore, Green, et al. 2000 demonstrates that deficits in attention, executive functioning, and memory are related to poor functional outcome. Given this relationship, the amelioration of cognitive deficits in patients with schizophrenia has become a major target for intervention since the turn of the 21st century. Nuechterlein, et al. 2004 includes a cognitive-assessment battery to improve the evaluation of cognition in future treatment trials targeting the cognitive deficits in patients with schizophrenia. Importantly, Sheffield, et al. 2013, comparing data from the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) and Cognitive Neuroscience Test Reliability and Clinical Applications for Schizophrenia (CNTRACS) batteries, suggests “both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia.”

                                                                                                                                                              • Aylward, E., E. Walker, and B. Bettes. 1984. Intelligence in schizophrenia: Meta-analysis of the research. Schizophrenia Bulletin 10.3: 430–459.

                                                                                                                                                                DOI: 10.1093/schbul/10.3.430Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                Meta-analysis of IQ in schizophrenia provides evidence suggesting that both early- and adult-onset schizophrenia is associated with intellectual deficits across the life-span. Results raise the issue regarding whether IQ independently may mitigate susceptibility to schizophrenia versus a manifestation of constitutional predisposition. Sex differences point to more-prevalent premorbid IQ deficits among males.

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                                                                                                                                                                • Bilder, R. M., A. Howe, N. Novak, F. W. Sabb, and D. S. Parker. 2011. The genetics of cognitive impairment in schizophrenia: A phenomic perspective. In Special issue: The genetics of cognition. Trends in Cognitive Sciences 15.9: 428–435.

                                                                                                                                                                  DOI: 10.1016/j.tics.2011.07.002Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                  Provides a brief synopsis regarding the genetic basis of cognitive deficits in schizophrenia, highlights important conceptual issues in this area, and introduces CogGene, a freely available resource that may help researchers aggregate, visualize, and analyze evidence (among healthy people) relevant to genetic bases of cognitive function in schizophrenia and other disorders.

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                                                                                                                                                                  • Green, M. F., R. S. Kern, D. L. Braff, and J. Mintz. 2000. Neurocognitive deficits and functional outcome in schizophrenia: Are we measuring the “right stuff”? Schizophrenia Bulletin 26.1: 119–136.

                                                                                                                                                                    DOI: 10.1093/oxfordjournals.schbul.a033430Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                    Meta-analysis demonstrating that neurocognition (particularly memory, vigilance, and executive functioning) is related to functional outcome in schizophrenia, with medium to large effect sizes. Future identification of mediators may help explain this relationship.

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                                                                                                                                                                    • Harvey, P. D. 2012. Cognitive impairment in schizophrenia: Profile, course, and neurobiological determinants. In Handbook of clinical neurology. Vol. 106, Neurobiology of psychiatric disorders. Edited by T. E. Schlaepfer and C. B. Nemeroff, 433–445. New York: Elsevier.

                                                                                                                                                                      DOI: 10.1016/B978-0-444-52002-9.00025-5Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                      Review of course, profile, and severity of cognitive impairments in schizophrenia. Suggests a pervasive, stable pattern of global impairment accompanied by abnormal cortical activation. Discussion of neurobiological etiological factors includes increased ventricular size, reduced volume of cortical gray matter, and white-matter and neurotransmitter abnormalities.

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                                                                                                                                                                      • Nuechterlein, K. H., D. M. Barch, J. M. Gold, T. E. Goldberg, M. F. Green, and R. K. Heaton. 2004. Identification of separable cognitive factors in schizophrenia. Schizophrenia Research 72.1: 29–39.

                                                                                                                                                                        DOI: 10.1016/j.schres.2004.09.007Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                        Describes the methodology used to derive the seven cognitive domains of the MATRICS, a consensus cognitive battery for use in clinical trials in order to improve standardized evaluation of new cognitive treatments.

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                                                                                                                                                                        • Nuechterlein, K. H., K. L. Subotnik, J. Ventura, M. F. Green, D. Gretchen-Doorly, and R. F. Asarnow. 2012. The puzzle of schizophrenia: Tracking the core role of cognitive deficits. Development and Psychopathology 24.2: 529–536.

                                                                                                                                                                          DOI: 10.1017/S0954579412000132Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                          Attentional deficits remain stable across the course of schizophrenia and are evidenced in first-degree relatives (e.g., children, parents, siblings) of patients, suggesting they may be an endophenotype or vulnerability factor for schizophrenia. Cognitive functioning is a strong predictor of functional outcome and thus is a critical target for intervention.

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                                                                                                                                                                          • Reichenberg, A., A. Caspi, H. Harrington, et al. 2010. Static and dynamic cognitive deficits in childhood preceding adult schizophrenia: A 30-year study. American Journal of Psychiatry 167.2: 160–169.

                                                                                                                                                                            DOI: 10.1176/appi.ajp.2009.09040574Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                            Follow-up study of cognitive development among children in Dunedin, New Zealand, who later developed schizophrenia or recurrent depression, and healthy comparisons. Results suggest two interrelated developmental processes underlying schizophrenia from ages seven to thirteen, marked by difficulties in early-childhood verbal reasoning and a later lag in working memory, attention, and processing speed.

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                                                                                                                                                                            • Sheffield, J. M., J. M. Gold, M. E. Strauss, et al. 2013. Common and specific cognitive deficits in schizophrenia: Relationships to function. Cognitive, Affective, & Behavioral Neuroscience.

                                                                                                                                                                              DOI: 10.3758/s13415-013-0211-5Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                              Demonstrates “both shared and specific variance across cognitive tasks related to cognitive and functional impairments in schizophrenia and that measures derived from cognitive neuroscience can predict functional capacity and status in schizophrenia.”

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                                                                                                                                                                              Social Cognition

                                                                                                                                                                              In addition to cognitive deficits in schizophrenia (see Cognition), since the late 20th century, researchers have begun to focus on the social-cognitive deficits in schizophrenia. For an operational definition of social cognition and differentiation between social cognition and neurocognition, see Penn, et al. 1997. More recently, the National Institute of Mental Health sponsored a meeting to establish definitions of social-cognition constructs that are relevant to schizophrenia research; as outlined in Green, et al. 2008, these include theory of mind, social perception, social knowledge, attributional bias, and emotional processing. Penn, et al. 2008 provides a concise summary of research examining social-cognitive deficits in patients with schizophrenia. Importantly, social cognition is an area of interest; Couture, et al. 2006 shows that social-cognitive constructs are related to various measures of social functioning. Fett, et al. 2011 finds that social cognition (especially theory of mind) is more strongly related to community functioning than neurocognition.

                                                                                                                                                                              • Couture, S. M., D. L. Penn, and D. L. Roberts. 2006. The functional significance of social cognition in schizophrenia: A review. Schizophrenia Bulletin 32.S1: S44–S63.

                                                                                                                                                                                DOI: 10.1093/schbul/sbl029Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                Qualitative review demonstrating that social and emotion perception are related to social behavior in the milieu and community functioning; social perception is also related to social problem solving, while emotion perception is related to social skills. Social and emotion perception may act as mediators between neurocognition and functional outcome.

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                                                                                                                                                                                • Fett, A.-K., W. Viechtbauer, Maria-de-Gracia Dominguez, D. L. Penn, J. van Os, and L. Krabbendam. 2011. The relationship between neurocognition and social cognition with functional outcomes in schizophrenia: A meta-analysis. Neuroscience & Biobehavioral Reviews 35.3: 573–588.

                                                                                                                                                                                  DOI: 10.1016/j.neubiorev.2010.07.001Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                  Meta-analysis demonstrating that social cognition is more strongly associated with community functioning than neurocognition. Theory of mind is more strongly associated with community functioning than all neurocognitive domains except one. Results support and quantify Couture, et al. 2006.

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                                                                                                                                                                                  • Green, M. F., D. L. Penn, R. Bentall, et al. 2008. Social cognition in schizophrenia: An NIMH workshop on definitions, assessment, and research opportunities. Schizophrenia Bulletin 34.6: 1211–1220.

                                                                                                                                                                                    DOI: 10.1093/schbul/sbm145Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                    Summary of National Institute of Mental Health–sponsored meeting to establish definitions of relevant social-cognition constructs, including theory of mind, social perception, social knowledge, attributional bias, and emotional processing. Identifies key research topics for researchers interested in social cognition in schizophrenia.

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                                                                                                                                                                                    • Penn, D. L., P. W. Corrigan, R. P. Bentall, J. M. Racenstein, and L. Newman. 1997. Social cognition in schizophrenia. Psychological Bulletin 121.1: 114–132.

                                                                                                                                                                                      DOI: 10.1037/0033-2909.121.1.114Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                      Provides a review of social cognition in schizophrenia. Differentiates social cognition from neurocognition and provides an operational definition of social cognition; namely, “the mental operations underlying social interactions, which include human ability and capacity to perceive the intentions and dispositions of others” (p. 116).

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                                                                                                                                                                                      • Penn, D. L., L. J. Sanna, and D. L. Roberts. 2008. Social cognition in schizophrenia: An overview. Schizophrenia Bulletin 34.3: 408–411.

                                                                                                                                                                                        DOI: 10.1093/schbul/sbn014Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                        Concise introductory summary of findings on social cognition in schizophrenia, especially emotion perception, theory of mind, and attributional style. Authors suggest psychosocial treatment programs may efficaciously ameliorate social-cognitive deficits.

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                                                                                                                                                                                        In Prodrome

                                                                                                                                                                                        Like patients with schizophrenia, individuals at clinical high risk (CHR) for developing psychosis demonstrate a similar pattern of cognitive deficits, as reported in Fusar-Poli, et al. 2012, a meta-analysis. The severity of cognitive deficits in CHR individuals appears to be intermediate between patients with schizophrenia and healthy controls, as shown in Giuliano, et al. 2012. Moreover, Kim, et al. 2011 reports that impairments in executive functioning and memory are related to a greater risk of developing psychosis. One large longitudinal study, Seidman, et al. 2010, found that CHRs (particularly those who convert to psychosis) have prominent neuropsychological difficulties. With regard to social cognition, Thompson, et al. 2011 finds that CHR individuals demonstrate impairments in theory of mind and facial-affect recognition. Thompson, et al. 2012 further shows that severity of these impairments is also intermediate between patients with schizophrenia and healthy controls. In addition to cognitive deficits predicting conversion to psychosis, Kim, et al. 2011 reports that performance on theory of mind also predicts conversion to psychosis in CHR individuals.

                                                                                                                                                                                        • Fusar-Poli, P., G. Deste, R. Smieskova, et al. 2012. Cognitive functioning in prodromal psychosis: A meta-analysis. Archives of General Psychiatry 69.6: 562–571.

                                                                                                                                                                                          DOI: 10.1001/archgenpsychiatry.2011.1592Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                          Meta-analysis demonstrating that CHR individuals are impaired on measures of general intelligence, attention, executive functioning, verbal fluency, working memory, memory, and social cognition, as compared to controls. Conversion to psychosis related to more-impaired verbal fluency, working memory, and memory.

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                                                                                                                                                                                          • Giuliano, A. J., H. Li, R. I. Mesholam-Gately, S. M. Sorenson, K. A. Woodberry, and L. J. Seidman. 2012. Neurocognition in the psychosis risk syndrome: A quantitative and qualitative review. Current Pharmaceutical Design 18.4: 399–415.

                                                                                                                                                                                            DOI: 10.2174/138161212799316019Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                            CHR individuals showed small to medium impairments on nine out of ten cognitive domains. Severity of cognitive deficits was intermediate between first-episode patients and healthy controls. In those who converted to psychosis, baseline cognitive functioning was more severely impaired compared to those who did not convert.

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                                                                                                                                                                                            • Kim, H. S., N. Y. Shin, J. H. Jang, et al. 2011. Social cognition and neurocognition as predictors of conversion to psychosis in individuals at ultra-high risk. Schizophrenia Research 130.1–3: 170–175.

                                                                                                                                                                                              DOI: 10.1016/j.schres.2011.04.023Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                              Compared CHR individuals who converted to psychosis with those who did not and with healthy controls. Groups differed on theory of mind, executive functioning, working memory, and visual and verbal memory at baseline, with converters being most impaired. Performance in these domains predicted time to conversion to psychosis.

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                                                                                                                                                                                              • Seidman, L. J., A. J. Giuliano, E. C. Meyer, et al. 2010. Neuropsychology of the prodrome to psychosis in the NAPLS consortium: Relationship to family history and conversion to psychosis. Archives of General Psychiatry 67.6: 578–588.

                                                                                                                                                                                                DOI: 10.1001/archgenpsychiatry.2010.66Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                This longitudinal study examines the relationship of neuropsychological function with conversion to psychosis and family history of psychosis, as well as whether baseline neuropsychological function predicts subsequent psychosis, among individuals at clinical high risk for psychosis (CHR). Findings suggest CHRs (particularly those who convert to psychosis) have prominent neuropsychological difficulties.

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                                                                                                                                                                                                • Thompson, A., A. Papas, C. Bartholomeusz, et al. 2012. Social cognition in clinical “at risk” for psychosis and first episode psychosis populations. Schizophrenia Research 141.2–3: 204–209.

                                                                                                                                                                                                  DOI: 10.1016/j.schres.2012.08.007Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                  First-episode patients performed significantly worse than controls on all social-cognition measures; CHR individuals perform significantly worse than controls on a task involving theory of mind but do not differ from first-episode patients on social-cognition tasks. CHR individuals’ performance is intermediate between healthy controls and schizophrenia patients.

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                                                                                                                                                                                                  • Thompson, A. D., C. Bartholomeusz, and A. R. Yung. 2011. Social cognition deficits and the “ultra high risk” for psychosis population: A review of literature. Early Intervention in Psychiatry 5.3: 192–202.

                                                                                                                                                                                                    DOI: 10.1111/j.1751-7893.2011.00275.xSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                    Four out of seven studies reported social-cognition deficits in CHR individuals that were similar to deficits in schizophrenia patients, especially on tasks involving theory of mind and facial-affect recognition. Authors propose that social-cognition deficits may be trait characteristics for schizophrenia.

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                                                                                                                                                                                                    These articles were selected to provide an overview of the genetics of schizophrenia, including with respect to the diathesis-stress model and the intersection of psychosocial and neurobiological factors, outlined in Gottesman, et al. 1987. Tsuang 2000 emphasizes the role of genetic factors that may interfere with brain development and interact with environmental (e.g., psychosocial) stressors, toward yielding schizophrenia vulnerability. Wray and Gottesman 2012 reports heritability estimates of schizophrenia, bipolar disorder, and major depressive disorder on the basis of national population data in Denmark. Owen 2012 emphasizes the import of cross-diagnostic considerations toward understanding pathogenesis of schizophrenia. Claes, et al. 2012 provides an overview of various methods currently used to identify genetic factors such as genetic linkage and genome-wide association studies, and consideration of other genetic indices. Gejman, et al. 2011 emphasizes the import of combining different study methods, together with future resequencing programs in better elucidating molecular genetics of schizophrenia. Finally, Popov, et al. 2012 discusses epigenetic mechanisms—that is, DNA modifications thought to be involved in schizophrenia—with a specific focus on DNA methylation and post-translational histone modifications.

                                                                                                                                                                                                    • Claes, S., Y.-L. Tang, C. F. Gillespie, and J. F. Cubells. 2012. Human genetics of schizophrenia. In Handbook of clinical neurology. Vol. 106, Neurobiology of psychiatric disorders. Edited by T. E. Schlaepfer and C. B. Nemeroff, 37–52. New York: Elsevier.

                                                                                                                                                                                                      DOI: 10.1016/B978-0-444-52002-9.00003-6Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                      Reviews findings from genetic studies in schizophrenia, including linkage studies and examination of candidate genes, cytogenetic abnormalities, the role of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs), and future directions for genetics research in psychopathology. Discusses the role of candidate genes, indicating that they may not be exclusively related to schizophrenia and that the combination of other factors is likely to be necessary for the vulnerability of schizophrenia.

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                                                                                                                                                                                                      • Gejman, P. V., A. R. Sanders, and K. S. Kendler. 2011. Genetics of schizophrenia: New findings and challenges. Annual Review of Genomics and Human Genetics 12:121–144.

                                                                                                                                                                                                        DOI: 10.1146/annurev-genom-082410-101459Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                        Reviews the role of family, twin, and adoption studies; major and non-major histocompatibility complex loci; genome-wide association studies; polygenic contributions and rare CNVs in schizophrenia; and the combination of these factors in schizophrenia. Discusses the role of current and upcoming resequencing programs in combination with more-informative genotyping arrays toward illuminating molecular genetics of schizophrenia.

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                                                                                                                                                                                                        • Gottesman, I. I., P. McGuffin, and A. E. Farmer. 1987. Clinical genetics as clues to the “real” genetics of schizophrenia (a decade of modest gains while playing for time). Schizophrenia Bulletin 13.1: 23–47.

                                                                                                                                                                                                          DOI: 10.1093/schbul/13.1.23Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                          Reviews genetics research on schizophrenia, with an emphasis on the diathesis-stress model and consideration of epigenetics (interaction of psychosocial and neurobiological factors). Discusses needs of the clinical-genetic-epidemiological perspective and emphasizes the phenotypic heterogeneity of schizophrenia. This early paper presents a seminal perspective that influenced current conceptualizations.

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                                                                                                                                                                                                          • Owen, M. J. 2012. Implications of genetic findings for understanding schizophrenia. Schizophrenia Bulletin 38.5: 904–907.

                                                                                                                                                                                                            DOI: 10.1093/schbul/sbs103Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                            Conveys the importance of current genetic findings in schizophrenia. Discusses the involvement of a large number of genes with the risk of schizophrenia and focuses on the genetic overlap observed between schizophrenia and other neurodevelopmental disorders. Proposes a continuum approach to schizophrenia, by identifying cross-diagnostic processes across related neurodevelopmental disorders.

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                                                                                                                                                                                                            • Popov, N. T., V. K. Stoyanova, N. P. Madzhirova, and T. I. Vachev. 2012. Epigenetic aspects in schizophrenia etiology and pathogenesis. Folia Medica 54.2: 12–16.

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                                                                                                                                                                                                              Reviews epigenetic mechanisms (or chemical modifications of DNA) in schizophrenia; that is, how they mediate the interaction between environmental and genetic factors. Discusses the role of DNA methylation and post-translational histone modifications in schizophrenia etiology. Proposes future directions regarding the use of epigenetic therapy in relieving symptoms and cognitive deficits.

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                                                                                                                                                                                                              • Tsuang, M. 2000. Schizophrenia: Genes and environment. Biological Psychiatry 47.3: 210–220.

                                                                                                                                                                                                                DOI: 10.1016/S0006-3223(99)00289-9Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                Reviews historical and genetic foundations of schizophrenia. Reports on findings from various family, adoption, and twin studies, to identify genetic (which may interfere with brain development and synaptic connections) and environmental (e.g., psychosocial stressors, dysfunctional family communication) determinants of schizophrenia and their interactions. Discusses implications and future directions.

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                                                                                                                                                                                                                • Wray, N. R., and I. I. Gottesman. 2012. Using summary data from the Danish National Registers to estimate heritabilities for schizophrenia, bipolar disorder, and major depressive disorder. Frontiers in Genetics 3 (July): 118.

                                                                                                                                                                                                                  DOI: 10.3389/fgene.2012.00118Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                  Reports heritability estimates of schizophrenia, bipolar disorder, and major depressive disorder, by using national population data in Denmark. Heritability estimates are reported to be lower for schizophrenia and bipolar disorder compared to estimates, on the basis of twin samples. Discusses possible diverse environments as a contributing factor to lower heritability estimates.

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                                                                                                                                                                                                                  Structural and Functional Neuroanatomic Disruptions

                                                                                                                                                                                                                  This collection of papers focuses on the use of modern neuroimaging techniques to elucidate the underlying pathophysiology of schizophrenia. As part of a longitudinal study of first-episode patients, Andreasen, et al. 2011 identifies structural neuroimaging and cognitive findings. Szeszko, et al. 2012 similarly focuses on structural magnetic resonance imaging (MRI) among first-episode patients, with the goal of determining which brain measures best predict response to pharmacological intervention. By contrast, Goghari, et al. 2010 reviews functional MRI findings in relation to symptoms, whereas Jindal and Keshavan 2008 integrates findings across cognition, structural, and functional neuroanatomy and neurochemistry in early phases of schizophrenia, with consideration of complex gene-environment interactions. Shenton, et al. 2010 provides an extensive review of structural neuroanatomic abnormalities in schizophrenia and discusses important directions for future research. Karlsgodt, et al. 2010 reviews key structural and functional brain abnormalities implicated in cognition and schizophrenia (e.g., prefrontal and medial temporal-lobe regions) and the importance of critical periods of brain development. Finally, Lencz, et al. 2001 takes the unique perspective of “dual cytoarchitectonic trends theory of neurodevelopment” to understand the psychosis prodrome, in its review of neuroimaging findings in schizophrenia. Collectively, this body of literature emphasizes both the structural and functional approaches to examining the neurobiological basis of schizophrenia, including along the schizophrenia spectrum, with consideration of treatment implications and an emphasis on some key regions of interest, including during early development.

                                                                                                                                                                                                                  • Andreasen, N. C., P. Nopoulos, V. Magnotta, R. Pierson, S. Ziebell, and B.-C. Ho. 2011. Progressive brain change in schizophrenia: A prospective longitudinal study of first-episode schizophrenia. Biological Psychiatry 70.7: 672–679.

                                                                                                                                                                                                                    DOI: 10.1016/j.biopsych.2011.05.017Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                    Reports on structural neuroimaging (and cognitive) results from the Iowa Longitudinal Study of first-episode patients over eighteen years; specifically, significant age-by-group interaction main effects reflected significant decreases in multiple gray- and white-matter regions, with corresponding increases in cerebrospinal fluid. Findings were most prominent during early years following illness onset.

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                                                                                                                                                                                                                    • Goghari, V. M., S. R. Sponheim, and A. W. MacDonald III. 2010. The functional neuroanatomy of symptom dimensions in schizophrenia: A qualitative and quantitative review of a persistent question. Neuroscience & Biobehavioral Reviews 34.3: 468–486.

                                                                                                                                                                                                                      DOI: 10.1016/j.neubiorev.2009.09.004Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                      Reviews twenty-five task-related functional magnetic resonance imaging (fMRI) studies in relation to symptomatology. Findings indicate small to moderate relationships of specific symptom dimensions with regional brain activity in the ventrolateral prefrontal cortex, ventral striatum, medial prefrontal cortex, amygdala, hippocampus/parahippocampal region, and dorsolateral prefrontal cortex (though not middle or superior temporal regions).

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                                                                                                                                                                                                                      • Jindal, R. D., and M. S. Keshavan. 2008. Neurobiology of the early course of schizophrenia. Expert Review of Neurotherapeutics 8.7: 1093–1100.

                                                                                                                                                                                                                        DOI: 10.1586/14737175.8.7.1093Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                        Reviews key directions toward understanding the neurobiological basis of early schizophrenia, including alterations in cognition, structural, and functional neuroanatomy, and neurochemistry in early phases of schizophrenia. Discusses the role of genetic and environmental factors and their interactions in schizophrenia etiology (see Gene-Environment Interactions).

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                                                                                                                                                                                                                        • Karlsgodt, K. H., D. Sun, and T. D. Cannon. 2010. Structural and functional brain abnormalities in schizophrenia. Current Directions in Psychological Science 19.4: 226–231.

                                                                                                                                                                                                                          DOI: 10.1177/0963721410377601Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                          Reviews key structural and functional brain abnormalities implicated in cognition and schizophrenia, such as prefrontal and medial temporal-lobe regions, and the importance of critical periods of brain development. Emphasizes that schizophrenia involves disruptions in neural connectivity and that both genetic and environmental factors play a role in brain development.

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                                                                                                                                                                                                                          • Lencz, T., R. M. Bilder, and B. Cornblatt. 2001. The timing of neurodevelopmental abnormality in schizophrenia: An integrative review of the neuroimaging literature. CNS Spectrums 6.3: 233–255.

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                                                                                                                                                                                                                            Reviews neuroimaging research in schizophrenia and critically evaluates the nature and timing of underlying neuroanatomic abnormalities. Findings are considered from the perspective of “dual cytoarchitectonic trends theory of neurodevelopment,” and with respect to the schizophrenia prodrome. Argues for longitudinal neuroimaging studies of adolescents at clinical risk for schizophrenia.

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                                                                                                                                                                                                                            • Shenton, M. E., T. J. Whitford, and M. Kubicki. 2010. Structural neuroimaging in schizophrenia: From methods to insights to treatments. Dialogues in Clinical Neuroscience 12.3: 317–332.

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                                                                                                                                                                                                                              Reviews evidence of structural neuroimaging abnormalities in schizophrenia, including focal (primary gray matter) abnormalities and systemic/circuitry abnormalities, with a focus on white-matter connectivity. Future prospects warranting exploration, toward translation of current knowledge to novel treatments, are discussed.

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                                                                                                                                                                                                                              • Szeszko, P. R., K. L. Narr, O. R. Phillips, et al. 2012. Magnetic resonance imaging predictors of treatment response in first-episode schizophrenia. Schizophrenia Bulletin 38.3: 569–578.

                                                                                                                                                                                                                                DOI: 10.1093/schbul/sbq126Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                Uses structural magnetic resonance imaging (sMRI) to determine brain measures that predict treatment response (risperdone versus olanzapine) in first-episode patients. Findings support the hypothesis that plasticity and cortical thickness may be more preserved in responders and that sMRI imaging may help predict treatment response.

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                                                                                                                                                                                                                                Hormones, Neurotransmitters, and Other Neurobiological Factors

                                                                                                                                                                                                                                Various hormones, neurotransmitters, and psychophysiological and other neurobiological factors have been implicated in the etiology of schizophrenia. Core to current neurodevelopmental theories of psychosis is the role of neuroendocrine functioning, particularly neurohormones that trigger gene expression and alter adolescent brain maturation, put forward in Walker and Bollini 2002. Outlined in a review in Corcoran, et al. 2003, the primary neurohormone implicated in psychosis is cortisol, a byproduct of the hypothalamic-pituitary-adrenal (HPA) axis, the neural system involved in the mammalian biological stress response. Walker, et al. 2013 presents findings from the North American Prodrome Longitudinal Study (NAPLS) substantiating mounting evidence of heightened cortisol secretion in individuals at clinical high risk (CHR) for psychosis, and associations with symptom severity and progression. Riecher-Rössler and Kulkarni 2011 examines the important contributions of gonadal hormones to illness manifestation. Keshavan, et al. 2008 reviews abnormalities in brain structure, function, and connectivity; brain physiology; sleep abnormalities; and neurochemical alterations, and their implications as potential neurobiomarkers of risk, currently under rigorous investigation. Among some of the principal neurotransmitters of interest regarding schizophrenia etiology are dopamine and glutamate. Howes and Kapur 2009 reviews and updates the dopamine hypothesis of schizophrenia, which posits a role of hyperdopaminergic functioning (or excess dopamine activity) in illness manifestation. Kantrowitz and Javitt 2012 reviews disruptions in glutamatergic transmission associated with schizophrenia. The glutamate hypothesis posits hypofunction of glutamatergic signaling via N-methyl-D-aspartate (NMDA) receptors; it does not negate the dopamine hypothesis. It remains plausible that the origins of schizophrenia involve both dopaminergic and glutamatergic dysfunction.

                                                                                                                                                                                                                                • Corcoran, C., E. Walker, R. Huot, et al. 2003. The stress cascade and schizophrenia: Etiology and onset. Schizophrenia Bulletin 29.4: 671–692.

                                                                                                                                                                                                                                  DOI: 10.1093/oxfordjournals.schbul.a007038Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                  Reviews the HPA axis, principally involved in the biological stress response, how stress may serve as a potentiating factor for psychosis among those who are vulnerable, and the link between stress and psychotic symptoms. Proposes research design and statistical modeling to test the diathesis-stress model of psychosis among high-risk individuals.

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                                                                                                                                                                                                                                  • Howes, O. D., and S. Kapur. 2009. The dopamine hypothesis of schizophrenia: Version III—the final common pathway. Schizophrenia Bulletin 35.3: 549–562.

                                                                                                                                                                                                                                    DOI: 10.1093/schbul/sbp006Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                    Critically reviews the dopamine hypothesis of schizophrenia, including the more recently conceptualized role of subcortical hyperdopaminergic and prefrontal hypodopaminergic function—and the contribution of findings from studies on neurochemical imaging and genetics, environmental risk factors, and animal studies. Authors propose a new dopamine hypothesis (‘the final common pathway’) and discuss treatment implications.

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                                                                                                                                                                                                                                    • Kantrowitz, J., and D. C. Javitt. 2012. Glutamatergic transmission in schizophrenia: From basic research to clinical practice. Current Opinion in Psychiatry 25.2: 96–102.

                                                                                                                                                                                                                                      DOI: 10.1097/YCO.0b013e32835035b2Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                      Reviews the glutamatergic theory, including literature addressing assessment and genetic studies, and drug development in animals and humans.

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                                                                                                                                                                                                                                      • Keshavan, M. S., R. Tandon, N. N. Boutros, and H. A. Nasrallah. 2008. Schizophrenia, “just the facts”: What we know in 2008; Part 3; Neurobiology. Schizophrenia Research 106.2: 89–107.

                                                                                                                                                                                                                                        DOI: 10.1016/j.schres.2008.07.020Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                        Discusses the neurobiology of schizophrenia through an extensive review of neurochemical, psychophysiological, and imaging findings. These factors are reviewed in the context of serving as potential biomarkers of risk that collectively may shed light on the etiology of schizophrenia.

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                                                                                                                                                                                                                                        • Riecher-Rössler, A., and J. Kulkarni. 2011. Estrogens and gonadal function in schizophrenia and related psychoses. In Special issue: Biological basis of sex differences in psychopharmacology. Current Topics in Behavioral Neurosciences 8:155–171.

                                                                                                                                                                                                                                          DOI: 10.1007/7854_2010_100Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                          Discusses the importance of estrogens and the HPG axis in schizophrenia (including hormonal dysregulation), the potential protective effects and modes of action of estrogen in the brain, and preliminary results of treatment studies. Implications for clinical and research realms are discussed.

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                                                                                                                                                                                                                                          • Walker, E., and A. M. Bollini. 2002. Pubertal neurodevelopment and the emergence of psychotic symptoms. Schizophrenia Research 54.1: 17–23.

                                                                                                                                                                                                                                            DOI: 10.1016/S0920-9964(01)00347-4Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                            Examines normal adolescent neurodevelopmental processes and the role of hormones in regulating gene expression that directs brain maturation. Postpubertal hormonal changes are reviewed with respect to potentiating expression of genes that contribute to disruptions in brain development and, in turn, may potentiate psychosis.

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                                                                                                                                                                                                                                            • Walker, E. F., H. D. Trotman, B. D. Pearce, et al. 2013. Cortisol levels and risk for psychosis: Initial findings from the North American Prodrome Longitudinal Study. Biological Psychiatry 74.6: 410–417.

                                                                                                                                                                                                                                              DOI: 10.1016/j.biopsych.2013.02.016Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                              Presents findings from the NAPLS substantiating mounting evidence of heightened cortisol secretion in individuals at clinical high risk for psychosis, and associations with baseline symptom severity and progression. Findings demonstrate an effect of age on cortisol, with levels increasing through adolescence and adulthood, and higher baseline cortisol among CHRs who transitioned to psychotic-level symptoms as compared to healthy control subjects and CHRs who remitted.

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                                                                                                                                                                                                                                              Other Indicators of Maldevelopment in the Central Nervous System

                                                                                                                                                                                                                                              Research increasingly points to early disruptions in central nervous system (CNS) development in the etiology of schizophrenia. Among these indicators of maldevelopment are dermatoglyphic abnormalities, minor physical anomalies, and neurological soft signs. Reviews of the literature on research among schizophrenia patients in Golembo-Smith, et al. 2012, and among unaffected relatives of patients in Neelam, et al. 2011 and Xu, et al. 2011, relatively consistently point to disruptions in early CNS development. Additional support comes from Walker, et al. 1994, which examines other precursors such as early neuromotor development, and Niemi, et al. 2005, which examines neurological soft signs.

                                                                                                                                                                                                                                              • Golembo-Smith, S., D. J. Walder, M. P. Daly, et al. 2012. The presentation of dermatoglyphic abnormalities in schizophrenia: A meta-analytic review. Schizophrenia Research 142.1–3: 1–11.

                                                                                                                                                                                                                                                DOI: 10.1016/j.schres.2012.10.002Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                This meta-analysis examines dermatoglyphic features among individuals with schizophrenia, including studies published between 1968 and 2012. Results indicate total finger ridge count and total A-B ridge count appear most reliable in differentiating individuals with and without schizophrenia.

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                                                                                                                                                                                                                                                • Neelam, K., D. Garg, and M. Marshall. 2011. A systematic review and meta-analysis of neurological soft signs in relatives of people with schizophrenia. BMC Psychiatry 11.1: 139.

                                                                                                                                                                                                                                                  DOI: 10.1186/1471-244X-11-139Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                  Reviews whether soft signs in schizophrenia meet criteria for an endophenotype, particularly familial association. This meta-analysis reveals that neurological soft signs are more common in first-degree relatives of schizophrenia individuals than in controls, and more common in schizophrenia individuals than in their first-degree relatives. Results support the endophenotype criterion of familial association.

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                                                                                                                                                                                                                                                  • Niemi, L. T., J. M. Suvisaari, J. K. Haukka, and J. K. Lönnqvist. 2005. Childhood predictors of future psychiatric morbidity in offspring of mothers with psychotic disorder: Results from the Helsinki High-Risk Study. British Journal of Psychiatry 186.2: 108–114.

                                                                                                                                                                                                                                                    DOI: 10.1192/bjp.186.2.108Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                    As part of the Helsinki High-Risk Study, examines information from childhood and school health records to determine whether developmental abnormalities predict later mental disorders. Findings point to neurological, emotional, social, and behavioral vulnerability indicators of psychosis and other mental disorders, especially among youth at genetic high risk for psychosis.

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                                                                                                                                                                                                                                                    • Walker, E. F., T. Savoie, and D. Davis. 1994. Neuromotor precursors of schizophrenia. Schizophrenia Bulletin 20.3: 441–451.

                                                                                                                                                                                                                                                      DOI: 10.1093/schbul/20.3.441Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                      As part of a larger, landmark “archival-observational” project using childhood home movies to explore developmental precursors of schizophrenia, reports neuromotor abnormalities in children who developed schizophrenia and comparisons. Group differences were confined to the first two years of life and included choreoathetoid movements and posturing of the upper limbs.

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                                                                                                                                                                                                                                                      • Xu, T., R. C. K. Chan, and M. T. Compton. 2011. Minor physical anomalies in patients with schizophrenia, unaffected first-degree relatives, and healthy controls: A meta-analysis. PLoS ONE 6.9: e24129.

                                                                                                                                                                                                                                                        DOI: 10.1371/journal.pone.0024129Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                        This meta-analysis reviews the magnitude of differences in minor physical anomalies (MPAs) between schizophrenia patients and healthy controls, assesses manifestation in unaffected first-degree relatives, and examines sensitivity among individual MPA items. Findings support MPAs as a putative endophenotype of schizophrenia.

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                                                                                                                                                                                                                                                        Other Laboratory Markers

                                                                                                                                                                                                                                                        Beyond the various biological and environmental factors outlined in prior sections, there are numerous additional important laboratory “markers” of psychosis. For example, Yang, et al. 2013; Silverstein and Keane 2010; Ivleva, et al. 2013; and Fogelson, et al. 2010 are among those studies demonstrating perceptual (visual-context processing, perceptual organization) abnormalities, problems with smooth-pursuit eye movements, and span of apprehension and attentional abnormalities in psychosis.

                                                                                                                                                                                                                                                        • Fogelson, D. L., R. A. Asarnow, C. A. Sugar, et al. 2010. Avoidant personality disorder symptoms in first-degree relatives of schizophrenia patients predict performance on neurocognitive measures: The UCLA family study. Schizophrenia Research 120.1–3: 113–120.

                                                                                                                                                                                                                                                          DOI: 10.1016/j.schres.2009.12.004Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                          Finds a range of neurocognitive measures were linked with avoidant personality symptoms in first-degree relatives of schizophrenia patients; for example, worse performance on measures of span of apprehension (SPAN), attention (e.g., a continuous performance test), and complex attention / executive functioning (Trail Making Test-B) were associated with more avoidant symptoms.

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                                                                                                                                                                                                                                                          • Ivleva, E. I., A. F. Moates, J. P. Hamm, et al. 2013. Smooth pursuit eye movement, prepulse inhibition, and auditory paired stimuli processing endophenotypes across the schizophrenia–bipolar disorder psychosis dimension. Schizophrenia Bulletin.

                                                                                                                                                                                                                                                            DOI: 10.1093/schbul/sbt047Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                            Studies smooth-pursuit eye movement (SPEM), prepulse inhibition (PPI) and auditory event-related potentials (ERPs) across the schizophrenia–bipolar disorder dimension. Results suggest SPEM and ERP (though not PPI) are part of the schizophrenia and bipolar endophenotype.

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                                                                                                                                                                                                                                                            • Silverstein, S. M., and B. P. Keane. 2010. Perceptual organization impairment in schizophrenia and associated brain mechanisms: Review of research from 2005 to 2010. Schizophrenia Bulletin 37.4: 690–699.

                                                                                                                                                                                                                                                              DOI: 10.1093/schbul/sbr052Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                              Provides an updated literature review of perceptual-organization impairments in schizophrenia, incorporating behavioral, electrophysiological, and functional magnetic resonance imaging (fMRI) studies in patient and non-patient samples, as well as evidence of functional consequences of perceptual-organization impairments.

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                                                                                                                                                                                                                                                              • Yang, E., D. Tadin, D. M. Glasser, S. W. Hong, R. Blake, and S. Park. 2013. Visual context processing in schizophrenia. Clinical Psychological Science 1.1: 5–15.

                                                                                                                                                                                                                                                                DOI: 10.1177/2167702612464618Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                This important work demonstrates abnormal contextual modulation (on visual tasks) in schizophrenia individuals (compared to healthy participants), though it is selective. Findings suggest there is not a unitary contextual-processing dysfunction in schizophrenia.

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                                                                                                                                                                                                                                                                Environment, Stress, and Related Factors

                                                                                                                                                                                                                                                                The literature strongly supports a role of a range of environmental factors such as stress and toxins in psychosis and risk for psychosis. Holtzman, et al. 2013 reviews support for the relatively robust and well-established contributory role of stress to psychosis risk. As an example, as part of the North American Prodrome Longitudinal Study (NAPLS), the largest study of individuals at risk for psychosis, Addington, et al. 2013 demonstrates that childhood trauma and bullying are linked with greater subsequent subthreshold symptoms. Torrey, et al. 2012 reviews the role of maternal infection in risk for schizophrenia. Brown 2011 reviews the contributions of other environmental factors in relation to psychosis risk, some of which are mixed and tenuous. For example, as reviewed in Malchow, et al. 2013, the role of substances such as cannabis and alcohol in triggering psychosis onset and the link with brain integrity remain highly controversial. Wicks, et al. 2005 offers evidence that social adversity, during the prenatal period and in childhood, is associated with increased psychosis risk. Finally, Brown, et al. 1972 and Butzlaff and Hooley 1998 represent two examples among the seminal works demonstrating an important role of familial expressed emotion (EE) in psychosis. Collectively, this body of literature reflects the ongoing pursuit of identification of environmental and other precursors to psychosis, with important implications for preventive intervention.

                                                                                                                                                                                                                                                                • Addington, J., J. Stowkowy, K. S. Cadenhead, et al. 2013. Early traumatic experiences in those at clinical high risk for psychosis. Early Intervention in Psychiatry 7.3: 300–305.

                                                                                                                                                                                                                                                                  DOI: 10.1111/eip.12020Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                  As part of the NAPLS, examines the role of childhood trauma and bullying among youth at clinical high risk for psychosis. Findings link prior trauma and bullying with increased later subthreshold levels of depression and anxiety and poorer sense of self.

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                                                                                                                                                                                                                                                                  • Brown, A. S. 2011. The environment and susceptibility to schizophrenia. Progress in Neurobiology 93.1: 23–58.

                                                                                                                                                                                                                                                                    DOI: 10.1016/j.pneurobio.2010.09.003Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                    Reviews the putative role of environmental factors in schizophrenia, including those during fetal and perinatal periods (such as infections, nutritional deficiencies, paternal age, obstetric insults/complications, maternal stress), as well as cannabis use, socioeconomic status, trauma, and infections during childhood and adolescence. Discusses implications for prevention and understanding biological mechanisms, and directions for future research. (See Hormones, Neurotransmitters, and Other Neurobiological Factors.)

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                                                                                                                                                                                                                                                                    • Brown, G. W., J. L. Birley, and J. K. Wing. 1972. Influence of family life on the course of schizophrenic disorders: A replication. British Journal of Psychiatry: The Journal of Mental Science 121.562: 241–258.

                                                                                                                                                                                                                                                                      DOI: 10.1192/bjp.121.3.241Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                      This study principally confirms an association of high family EE with relapse among schizophrenia patients.

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                                                                                                                                                                                                                                                                      • Butzlaff, R. L., and J. M. Hooley. 1998. Expressed emotion and psychiatric relapse: A meta-analysis. Archives of General Psychiatry 55.6: 547–552.

                                                                                                                                                                                                                                                                        DOI: 10.1001/archpsyc.55.6.547Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                        Provides a meta-analysis of the literature on EE outcome and demonstrates that EE is a strong predictor of relapse in schizophrenia, more so for individuals with chronic schizophrenia. The effect size was greater for mood disorders and eating disorders than for schizophrenia, suggesting EE is important not only for psychosis but also other mental disorders.

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                                                                                                                                                                                                                                                                        • Holtzman, C. W., H. D. Trotman, S. M. Goulding, et al. 2013. Stress and neurodevelopmental processes in the emergence of psychosis. In Special issue: Stress and the adolescent brain. Neuroscience 249:172–191.

                                                                                                                                                                                                                                                                          DOI: 10.1016/j.neuroscience.2012.12.017Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                          Reviews the psychosocial stress–psychosis link (in patients and individuals at clinical high risk for psychosis), biological stress systems, and changes prior to and after illness onset. Discusses brain findings suggesting disruptions in normal adolescent neuromaturational processes as laying the foundation for psychosis. Neural mechanisms and future research directions are explored.

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                                                                                                                                                                                                                                                                          • Malchow, B., A. Hasan, P. Fusar-Poli, A. Schmitt, P. Falkai, and T. Wobrock. 2013. Cannabis abuse and brain morphology in schizophrenia: A review of the available evidence. European Archives of Psychiatry and Clinical Neuroscience 263.1: 3–13.

                                                                                                                                                                                                                                                                            DOI: 10.1007/s00406-012-0346-3Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                            Systematically reviews structural magnetic resonance imaging (sMRI) studies comparing high-risk and schizophrenia patients, with and without cannabis abuse. Results are inconclusive and suggest overall weak evidence of brain morphological abnormalities due to cannabis use preceding illness onset.

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                                                                                                                                                                                                                                                                            • Torrey, E. F., J. J. Bartko, and R. H. Yolken. 2012. Toxoplasma gondii and other risk factors for schizophrenia: An update. Schizophrenia Bulletin 38.3: 642–647.

                                                                                                                                                                                                                                                                              DOI: 10.1093/schbul/sbs043Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                              Provides an update to a 2007 meta-analysis on prevalence of Toxoplasma gondii antibodies in schizophrenia, including fifteen additional studies. Compares T. gondii to other risk factors, such as having an affected parent or sibling, cannabis use, minor physical anomalies, childhood sex abuse, obstetrical complications, maternal exposure to influenza, and prenatal stress.

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                                                                                                                                                                                                                                                                              • Wicks, S., A. Hjern, D. Gunnell, G. Lewis, and C. Dalman. 2005. Social adversity in childhood and the risk of developing psychosis: A national cohort study. American Journal of Psychiatry 162.9: 1652–1657.

                                                                                                                                                                                                                                                                                DOI: 10.1176/appi.ajp.162.9.1652Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                Describes social factors during childhood and the risk of later developing psychosis, in a national Swedish cohort. Results indicate that social adversity in childhood and the fetal period is linked with risk for schizophrenia and other psychoses. Consistent with a dose-response pattern, risks are increased with number of exposures.

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                                                                                                                                                                                                                                                                                Gene-Environment Interactions

                                                                                                                                                                                                                                                                                This section focuses on the role of gene-environment interactions in the development of schizophrenia. More specifically, Murray, et al. 1992 provides an early perspective on the interaction between genetic and environmental factors, from a neurodevelopmental perspective. Lewis and Levitt 2002 focuses on gene-environment interactions and subsequent disruptions in neuromaturational processes. Tsuang 2000 provides an etiological pathway resulting in schizophrenia. Contemporaneous findings bolstering these models include Cannon, et al. 2003 (a review of findings among prodromal and familial high-risk samples); Tienari, et al., 2004 (longitudinal findings of risk for schizophrenia spectrum disorders among a cohort of adoptees); and van Os, et al. 2008 (a review of methodological strengths and weaknesses, with an eye toward future research). Collectively, this body of research advocates for multidisciplinary approaches in the exploration of gene-environment interactions underlying psychosis.

                                                                                                                                                                                                                                                                                • Cannon, T. D., T. G. M. van Erp, C. E. Bearden, et al. 2003. Early and late neurodevelopmental influences in the prodrome to schizophrenia: Contributions of genes, environment, and their interactions. Schizophrenia Bulletin 29.4: 653–669.

                                                                                                                                                                                                                                                                                  DOI: 10.1093/oxfordjournals.schbul.a007037Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                  Neural changes leading up to the initiation of psychosis are discussed from a prodromal approach. Findings from family studies and high-risk studies are reported to better understand the etiology of schizophrenia. Implications of the interaction between genetics and environmental factors are discussed.

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                                                                                                                                                                                                                                                                                  • Lewis, D. A., and P. Levitt. 2002. Schizophrenia as a disorder of neurodevelopment. Annual Review of Neuroscience 25:409–432.

                                                                                                                                                                                                                                                                                    DOI: 10.1146/annurev.neuro.25.112701.142754Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                    Reviews evidence of neurobiological and environmental factors possibly underlying schizophrenia and respective neurodevelopmental mechanisms. Emphasizes the role of genetic predisposition, gene-environment interactions, disruptions in neuromaturational processes, and subsequent steady-state outcome in the development of schizophrenia.

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                                                                                                                                                                                                                                                                                    • Murray, R. M., P. Jones, E. O’Callaghan, N. Takei, and P. Sham. 1992. Genes, viruses and neurodevelopmental schizophrenia. In Special issue: Genetics and gene expression in mental illness. Journal of Psychiatric Research 26.4: 225–235.

                                                                                                                                                                                                                                                                                      DOI: 10.1016/0022-3956(92)90029-NSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                      This relatively earlier paper exploring neurodevelopmental processes underlying schizophrenia draws attention to the role of developmental brain abnormalities, early-childhood behavioral disruptions that predate illness onset, and the interaction of environmental hazards (such as maternal viral exposure and obstetric complications) with genetic factors. Attention is also paid to sex effects.

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                                                                                                                                                                                                                                                                                      • Tienari, P., L. C. Wynne, A. Sorri, et al. 2004. Genotype-environment interaction in schizophrenia-spectrum disorder: Long-term follow-up study of Finnish adoptees. British Journal of Psychiatry 184.3: 216–222.

                                                                                                                                                                                                                                                                                        DOI: 10.1192/bjp.184.3.216Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                        This is a twenty-one-year follow-up of a longitudinal study of Finnish adoptees at risk for schizophrenia, aimed at assessing genetic factors that moderate susceptibility to (family-related) environmental risks. Results indicate that the adoptive-family-rearing environment predicted risk among adoptees at high (but not low) genetic risk.

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                                                                                                                                                                                                                                                                                        • Tsuang, M. 2000. Schizophrenia: Genes and environment. Biological Psychiatry 47.3: 210–220.

                                                                                                                                                                                                                                                                                          DOI: 10.1016/S0006-3223(99)00289-9Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                          Reviews evidence of genetic and environmental factors that interact to enhance schizophrenia risk, and methods for studying gene-environment interactions. Addresses the role of genes in controlling embryonic neurodevelopment and, in turn, the modifying role of the environment. Presents target features of the proposed neurodevelopmental etiologic pathway to schizophrenia.

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                                                                                                                                                                                                                                                                                          • van Os, J., B. P. F. Rutten, and R. Poulton. 2008. Gene-environment interactions in schizophrenia: Review of epidemiological findings and future directions. Schizophrenia Bulletin 34.6: 1066–1082.

                                                                                                                                                                                                                                                                                            DOI: 10.1093/schbul/sbn117Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                            Reviews findings toward understanding the development of schizophrenia, with consideration of gene-environment interactions, from multiple perspectives. Addresses current methodological approaches and their respective advantages and disadvantages. Advocates for consideration of a multidisciplinary approach involving epidemiology, psychology, psychiatry, neuroimaging, pharmacology, biostatistics, and genetics, and, ultimately, the benefit of experimental ecogenetic approaches.

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                                                                                                                                                                                                                                                                                            Prevention and Intervention

                                                                                                                                                                                                                                                                                            There is growing appreciation of the role of early identification and preventive intervention in psychosis. Alvarez-Jimenez, et al. 2012 reviews risk factors for relapse following treatment in early psychosis. Cornblatt, et al. 2001 discusses ethical and scientific issues relevant to early intervention with the psychosis prodrome. Rector and Beck 2012 offers a meta-analytic review of randomized, controlled trial studies assessing efficacy of cognitive behavioral therapy (CBT) for schizophrenia. Fusar-Poli, et al. 2013 offers a meta-analysis of randomized controlled trials of second-generation, long-acting antipsychotic injections in schizophrenia. Correll, et al. 2011 examines the role and limitations of (and alternative approaches to) randomized controlled trials to assess pharmacological and nonpharmacological interventions in schizophrenia. Harvey and Bowie 2012 reviews the role of cognition in treatment, and Eack 2012 reviews cognitive remediation as a new approach to psychosocial intervention toward functional recovery. Hogarty, et al. 1986 offers some of the earlier evidence that family psychoeducation and social-skills training reduce relapse rates, in part as a function of a change from high to low expressed emotion (EE). Onwumere, et al. 2011 explores the efficacy of family interventions. Statucka and Walder 2013 reviews social-cognitive remediation in psychosis and the importance of targeting high-risk samples, with consideration of sex effects. Finally, Hamm, et al. 2013 offers a review of other new trends following the recovery movement.

                                                                                                                                                                                                                                                                                            • Alvarez-Jimenez, M., A. Priede, S. E. Hetrick, et al. 2012. Risk factors for relapse following treatment for first episode psychosis: A systematic review and meta-analysis of longitudinal studies. Schizophrenia Research 139.1–3: 116–128.

                                                                                                                                                                                                                                                                                              DOI: 10.1016/j.schres.2012.05.007Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                              Reviews risk factors for, and rates of relapse in, early psychosis. Nonadherence with medication, persistent substance use disorder, carers’ criticism, and poorer premorbid adjustment increase the risk for relapse, whereas clinical variables and general demographic variables have little impact.

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                                                                                                                                                                                                                                                                                              • Cornblatt, B. A., T. Lencz, and J. M. Kane. 2001. Treatment of the schizophrenia prodrome: Is it presently ethical? Schizophrenia Research 51.1: 31–38.

                                                                                                                                                                                                                                                                                                DOI: 10.1016/S0920-9964(01)00236-5Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                With recognition of the import of early intervention, argues that the psychosis prodrome is an important “retrospective construct,” and that defining signs and symptoms needs validation in naturalistic, longitudinal studies (including base rates) before evaluation of early treatment. Discusses other important ethical/scientific issues.

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                                                                                                                                                                                                                                                                                                • Correll, C. U., T. Kishimoto, and J. M. Kane. 2011. Randomized controlled trials in schizophrenia: Opportunities, limitations, and trial design alternatives. Dialogues in Clinical Neuroscience 13.2: 155–172.

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                                                                                                                                                                                                                                                                                                  Discusses clinical-trial design and methodology, including strengths of randomized controlled trials for assessment of pharmacological and nonpharmacological interventions, and potential complications and influences that hold potential to compromise success.

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                                                                                                                                                                                                                                                                                                  • Eack, S. M. 2012. Cognitive remediation: A new generation of psychosocial interventions for people with schizophrenia. Social Work 57.3: 235–246.

                                                                                                                                                                                                                                                                                                    DOI: 10.1093/sw/sws008Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                    Reviews cognitive remediation as a new approach to psychosocial intervention toward functional recovery. Provides an overview of one novel model and approach to cognitive remediation; namely, cognitive enhancement therapy.

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                                                                                                                                                                                                                                                                                                    • Fusar-Poli, P., M. J. Kempton, and R. A. Rosenheck. 2013. Efficacy and safety of second-generation long-acting injections in schizophrenia: A meta-analysis of randomized-controlled trials. International Clinic of Psychopharmacology 28.2: 57–66.

                                                                                                                                                                                                                                                                                                      DOI: 10.1097/YIC.0b013e32835b091fSave Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                      Offers a meta-analysis of randomized controlled trials of second-generation, long-acting antipsychotic injections (SGLAI) in schizophrenia. Results suggest that SGLAI do not reduce psychotic symptoms over oral medications. Their potential effects on relapse prevention should be better addressed by future randomized controlled trials.

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                                                                                                                                                                                                                                                                                                      • Hamm, J. A., I. Hasson-Ohayon, M. Kukla, and P. H. Lysaker. 2013. Individual psychotherapy for schizophrenia: Trends and developments in the wake of the recovery movement. Psychology Research and Behavior Management 6:45–54.

                                                                                                                                                                                                                                                                                                        DOI: 10.2147/PRBM.S47891Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                        Reviews new trends following the recovery movement, including new integrative psychotherapy treatments for schizophrenia. Outlines five integrative models of treatment.

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                                                                                                                                                                                                                                                                                                        • Harvey, P. D., and C. R. Bowie. 2012. Cognitive enhancement in schizophrenia: Pharmacological and cognitive remediation approaches. Psychiatric Clinics of North America 35.3: 683–698.

                                                                                                                                                                                                                                                                                                          DOI: 10.1016/j.psc.2012.06.008Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                          Discusses cognition measurement in schizophrenia and the role of cognition in determining disability and treatments such as pharmacological and behavioral interventions.

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                                                                                                                                                                                                                                                                                                          • Hogarty, G. E., C. M. Anderson, D. J. Reiss, et al. 1986. Family psychoeducation, social skills training, and maintenance chemotherapy in the aftercare treatment of schizophrenia, I: One-year effects of a controlled study on relapse and expressed emotion. Archives of General Psychiatry 43.7: 633–642.

                                                                                                                                                                                                                                                                                                            DOI: 10.1001/archpsyc.1986.01800070019003Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                            Provides evidence that family psychoeducation and social-skills training reduce relapse rates, in part as a function of a change from high to low EE. Remission was sustained among households with high EE only in the context of combined treatment.

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                                                                                                                                                                                                                                                                                                            • Onwumere, J., P. Bebbington, and E. Kuipers. 2011. Family interventions in early psychosis: Specificity and effectiveness. Epidemiology and Psychiatric Sciences 20.2: 113–119.

                                                                                                                                                                                                                                                                                                              DOI: 10.1017/S2045796011000187Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                              Discusses the rationale for recommending family interventions in early and late psychosis.

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                                                                                                                                                                                                                                                                                                              • Rector, N. A., and A. T. Beck. 2012. Cognitive behavioral therapy for schizophrenia: An empirical review. Journal of Nervous and Mental Disease 200.10: 832–839.

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                                                                                                                                                                                                                                                                                                                Reprinted from Journal of Nervous and Mental Disease 189.5 (2001): 278–287. Provides a meta-analytic review of randomized controlled trial studies assessing efficacy of CBT for schizophrenia. Results demonstrate large clinical effects on positive and negative symptoms, with benefits of adjunctive CBT surpassing routine care with adjunctive supportive therapy.

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                                                                                                                                                                                                                                                                                                                • Statucka, M., and D. J. Walder. 2013. Efficacy of social cognition remediation programs targeting facial affect recognition deficits in schizophrenia: A review and consideration of high-risk samples and sex differences. Psychiatry Research 206.2–3: 125–139.

                                                                                                                                                                                                                                                                                                                  DOI: 10.1016/j.psychres.2012.12.005Save Citation »Export Citation »E-mail Citation »

                                                                                                                                                                                                                                                                                                                  Provides a systematic review of efficacy of empirically based remediations in schizophrenia that target facial-affect recognition and potential functional benefits. Future directions are recommended, including examination of sexual dimorphisms and efficacy in clinical high-risk populations. See Epidemiology, Sex Differences, and Comorbidity.

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