The neurocognitive literature on test performance in schizophrenia is reviewed quantitatively. The authors report 22 mean effect sizes from 204 studies to index schizophrenia versus control differences in global and selective verbal memory, nonverbal memory, bilateral and unilateral motor performance, visual and auditory attention, general intelligence, spatial ability, executive function, language, and interhemispheric tactile-transfer test performance. Moderate to large raw effect sizes (d > .60) were obtained for all 22 neurocognitive test variables, and none of the associated confidence intervals included zero. The results indicate that schizophrenia is characterized by a broadly based cognitive impairment, with varying degrees of deficit in all ability domains measured by standard clinical tests.

Neurocognitive Deficit in Schizophrenia: A Quantitative Review of the Evidence

Psychiatric comorbidities are common among patients with schizophrenia. Substance abuse comorbidity predominates. Anxiety and depressive symptoms are also very common throughout the course of illness, with an estimated prevalence of 15% for panic disorder, 29% for posttraumatic stress disorder, and 23% for obsessive-compulsive disorder. It is estimated that comorbid depression occurs in 50% of patients, and perhaps (conservatively) 47% of patients also have a lifetime diagnosis of comorbid substance abuse. This article chronicles these associations, examining whether these comorbidities are "more than chance" and might represent (distinct) phenotypes of schizophrenia. Among the anxiety disorders, the evidence at present is most abundant for an association with obsessive-compulsive disorder. Additional studies in newly diagnosed antipsychotic-naive patients and their first-degree relatives and searches for genetic and environmental risk factors are needed to replicate preliminary findings and further investigate these associations.

Psychiatric Comorbidities and Schizophrenia

Clinical and experimental research have provided anatomical, pharmacological, and behavioral evidence for a prominent prefrontal dysfunction in schizophrenia. Negative symptoms and behavioral disorganization in the disorder can be understood as a failure in the working memory functions of the prefrontal cortex by which information is updated on a moment-to-moment basis or retrieved from long-term stores, held in mind, and used to guide behavior by ideas, concepts, and stored knowledge. This article recounts efforts to dissect the cellular and circuit basis of working memory with the goal of extending the insights gained from the study of normal brain organization in animal models to an understanding of the clinical disorder; it includes recent neuropathological findings that indicate that neural dystrophy rather than cell loss predominates in schizophrenia. Evidence from a variety of studies is accumulating to indicate that dopamine has a major role in regulating the excitability of the cortical neurons upon which the working memory function of the prefrontal cortex depends. Interactions between monoamines and a compromised cortical circuitry may hold the key to the salience of frontal lobe symptoms in schizophrenia, in spite of widespread pathological changes. We outline several direct and indirect intercellular mechanisms for modulating working memory function in the prefrontal cortex based on the localization of dopamine receptors on the distal dendrites and spines of glutamatergic pyramidal cells and on gamma-aminobutyric acid (GABA) ergic interneurons in the prefrontal cortex. Understanding the interactions between the major cellular constituents of cortical circuits-pyramidal and nonpyramidal cells-is a necessary step in unraveling the receptor mechanisms, which could lead to an effective pharmacological treatment of negative and cognitive symptoms, as well as improved insight into the pathophysiological basis of the disorder.

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Functional and Anatomical Aspects of Prefrontal Pathology in Schizophrenia

The maturation of corticolimbic systems that neurobiologically mediate essential affective and social regulatory functions is experience dependent. During the first and second years of life, the infant's affective experiences, especially those embedded in the relationship with the primary caregiver, elicit patterns of psychobiological alterations that influence the activity of subcortically produced trophic bioamines, peptides, and steroids that regulate the critical period growth and organization of the developing neocortex. Interactive attachment experiences of psychobiological attunemcnt, stressful misattunement, and stress-regulating repair and reattunement that maximize positive and minimize negative affect are imprinted into the orbitofrontal cortex — the hierarchical apex of the limbic system that is expanded in the early developing right hemisphere. During the critical period of maturation of this system , prolonged episodes of intense and unregulated interactive stress are manifest in disorganizing experiences of heightened negative affect and altered levels of stress hormones, and this chaotic biochemical alteration of the internal environment triggers an extensive apoptotic panellation of corticolimbic circuitries. In this manner less than optimal affect-regulating experiences with the primary caregiver are imprinted into the circuits of this frontolimbic system that is instrumental to attachment functions, thereby producing orbitofrontal organizations that neurobiologically express different patterns of insecure attachments. Such pathomorphogenetic outcomes result in structurally defective systems that, under stress, inefficiently regulate subcortical mechanisms that mediate the physiological processes that underlie emotion. The functional impairments of the cortical-subcortical circuitries of this prefrontal system are implicated in an enduring vulnerability to and the pathophysiology of various later forming psychiatric disorders.

The experience-dependent maturation of a regulatory system in the orbital prefrontal cortex and the origin of developmental psychopathology

Background Relatively few magnetic resonance imaging studies of schizophrenia have investigated the entire cerebral cortex. Most focus on only a few areas within a lobe or an entire lobe. To assess expected regional alterations in cortical volumes, we used a new method to segment the entire neocortex into 48 topographically defined brain regions. We hypothesized, based on previous empirical and theoretical work, that dorsolateral prefrontal and paralimbic cortices would be significantly volumetrically reduced in patients with schizophrenia compared with normal controls. Methods Twenty-nine patients with DSM-III-R schizophrenia were systematically sampled from 3 public outpatient service networks in the Boston, Mass, area. Healthy subjects, recruited from catchment areas from which the patients were drawn, were screened for psychopathologic disorders and proportionately matched to patients by age, sex, ethnicity, parental socioeconomic status, reading ability, and handedness. Analyses of covariance of the volumes of brain regions, adjusted for age- and sex-corrected head size, were used to compare patients and controls. Results The greatest volumetric reductions and largest effect sizes were in the middle frontal gyrus and paralimbic brain regions, such as the frontomedial and fronto-orbital cortices, anterior cingulate and paracingulate gyri, and the insula. In addition, the supramarginal gyrus, which is densely connected to prefrontal and cingulate cortices, was also significantly reduced in patients. Patients also had subtle volumetric increases in other cortical areas with strong reciprocal connections to the paralimbic areas that were volumetrically reduced. Conclusion Findings using our methods have implications for understanding brain abnormalities in schizophrenia and suggest the importance of the paralimbic areas and their connections with prefrontal brain regions.

Cortical abnormalities in schizophrenia identified by structural magnetic resonance imaging.

Obsessive and compulsive symptoms in chronic schizophrenia.

Neuropsychological probes of fronto-limbic system dysfunction in schizophrenia. Olfactory identification and Wisconsin Card Sorting performance.

Experimental and clinical neuropsychological measures of prefrontal dysfunction in schizophrenia.

Mr. A is a 50-year-old single man with a 38-year history of psychiatric difficulties, presently a patient on our Research and Evaluation Unit, whose case has stimulated active (and at times angry) debate among those caring for him regarding his diagnosis and most appropriate treatment. His case is presented to elucidate how a drug washout period can help establish a diagnosis, which for him has vacillated between psychosis (schizophrenia or bipolar disorder) and antisocial personality disorder.

https://ajp.psychiatryonline.org/doi/pdfplus/10.1176/ajp.154.12.1747

Anthony Kalinowski

Papers

Obsessive and compulsive symptoms in chronic schizophrenia.

Neuropsychological probes of fronto-limbic system dysfunction in schizophrenia. Olfactory identification and Wisconsin Card Sorting performance.

Experimental and clinical neuropsychological measures of prefrontal dysfunction in schizophrenia.

Evaluation of a Complex Case: The Value of a Drug Washout Period

Patient evaluation through live video transmission.