The concept of progressive brain change in schizophrenia: implications for understanding schizophrenia

Kraepelin originally defined dementia praecox as a progressive brain disease, although this concept has received various degrees of acceptance and rejection over the years since his famous published textbooks appeared. This article places an historical perspective on the current renewal of Kraepelin's concept in brain imaging literature that supports progressive brain change in schizophrenia from its earliest stages through its chronic course. It is concluded that a great deal of future research is needed focusing on the longitudinal course of change, the extent to the regions of change within each individual and the underlying mechanism and implications of brain change through functional and neurochemical imaging, combined with structural studies in the same individuals.     

Bipolar illness and schizophrenia as oligogenic diseases: implications for the future.

As with most complex inheritance diseases, there are at this time no identified susceptibility genes for schizophrenia, bipolar manic-depressive illness, major depression, childhood autism, and other inherited brain disorders whose manifestations are primarily behavioral. Nonetheless, progress has occurred. Genetic epidemiologic research, based on reliable phenotypic definitions, has demonstrated the heritability of many of these disorders. Genetic linkages and associations have been reported and replicated, although there have been inconsistencies between studies, apparently due to the low statistical power of the samples studied to detect small effects genes. Nonreplications of early linkage reports in manic-depressive illness in the 1980s occurred when new cases developed in the same large families in which the linkage was originally reported, and the newly ill persons had the wrong genetic markers in the linkage region. This appears to have resulted from applying inappropriate analytic assumptions of single-gene dominant inheritance of a rare gene, which implied that new cases must arise from the same ancestral gene within the pedigree. When new cases arose in family members not sharing that chromosomal region, the initial linkage report was proved invalid. Under oligogenic inheritance, on the other hand, susceptibility genes are expected to be common, and have a substantial probability of being brought into the pedigree by persons marrying in. Nonspecific psychopathology genes may exist, shared by schizophrenia and bipolar illness, diagnoses which do not co-aggregate in families. The discovery of susceptibility mutations may be expected.     

Self-evaluation in schizophrenia: an fMRI study with implications for the understanding of insight

ABSTRACT: BACKGROUND: Lack of insight is a core feature of schizophrenia and is associated with structural brain abnormalities. The functional neuroanatomy of insight has only recently been investigated. When people evaluate their personality traits compared to those of another, activation is seen in central midline structures (CMS) of the brain. This study set out to compare cerebral activation in schizophrenia patients versus controls during a self-evaluation task which included positive and negative traits as well as mental and physical illness terms. METHODS: Eleven schizophrenia patients and 8 healthy controls, matched for age were studied. Insight was assessed using the Schedule for the Assessment of Insight-expanded version (SAI-E). FMRI data were obtained with a 1.5 Tesla GE system and interactions between participant group, self versus other, significant at the cluster level, were recorded. RESULTS: Significant hypoactivation in the medial superior frontal gyrus (dorsomedial prefrontal cortex) was observed in patients vs. controls during self-evaluation of all traits combined. A second cluster of hypoactivation in the posterior cingulate was also detected. When the response to individual traits was explored, underactivation in other frontal regions plus right inferior parietal lobule emerged and this tended to correlate, albeit weakly with lower insight scores. Further, there were areas of hyperactivation relative to controls in anterior cingulate, frontal and parietal regions (especially precuneus) which showed moderate inverse correlations with insight scores. CONCLUSIONS: We have demonstrated that the CMS, identified as a key system underpinning self-evaluation, is dysfunctional in patients with schizophrenia, particularly dorso-medial PFC. This may have implications for lack of insight in schizophrenia. Hypofunction within the dorsomedial prefrontal region seems to be particularly important although other posterior and lateral cortical regions play a part and may modulate self-evaluative responses depending on the type of trait under consideration.     

GABA neurons and the mechanisms of network oscillations: implications for understanding cortical dysfunction in schizophrenia

Synchronization of neuronal activity in the neocortex may underlie the coordination of neural representations and thus is critical for optimal cognitive function. Because cognitive deficits are the major determinant of functional outcome in schizophrenia, identifying their neural basis is important for the development of new therapeutic interventions. Here we review the data suggesting that phasic synaptic inhibition mediated by specific subtypes of cortical gamma-aminobutyric acid (GABA) neurons is essential for the production of synchronized network oscillations. We also discuss evidence indicating that GABA neurotransmission is altered in schizophrenia and propose mechanisms by which such alterations can decrease the strength of inhibitory connections in a cell-type-specific manner. We suggest that some alterations observed in the neocortex of schizophrenia subjects may be compensatory responses that partially restore inhibitory synaptic efficacy. The findings of altered neural synchrony and impaired cognitive function in schizophrenia suggest that such compensatory responses are insufficient and that interventions aimed at augmenting the efficacy of GABA neurotransmission might be of therapeutic value.     

Visual gamma oscillations in schizophrenia: implications for understanding neural circuitry abnormalities.

Gamma oscillations may play an important role in the representation of information in the brain by synchronizing the firing of neurons in local and distributed neural circuits. The Bleulerian conceptualization of schizophrenia as "disintegration of thought and personality" suggests that neural mechanisms responsible for the integration of neural activity, such as gamma oscillations, might be particularly disrupted in this disorder. Here we review studies of gamma oscillations in healthy and schizophrenic individuals performing visual perception tasks. The findings suggest that schizophrenia is associated with a variety of abnormalities of visual gamma oscillations, which appear to be linked to core symptoms and cognitive deficits of schizophrenia. The relationships between these abnormalities and neural circuitry abnormalities in schizophrenia are discussed.     

Gender differences in the relationship of childhood trauma and the course of illness in schizophrenia

IntroductionDifferent types of childhood trauma have been repeatedly shown to contribute to psychotic symptoms. Gender differences in schizophrenia are well known. Some studies argue that trauma history means a significantly higher risk of psychosis for women than men. However, there is evidence of early adverse life events to be associated with higher stress-sensitivity in men. Little is known about the connection of specific type of trauma and specific psychotic symptoms as well as the course of illness with explicit regard to gender differences.Methods102 men and women with schizophrenia spectrum disorder were tested using Structured Clinical Interview for DSM-IV-TR Axis I Disorders, Scale for Assessing Positive Symptoms, Early Trauma Inventory-SR.ResultsAlthough, women had a later age at onset without regarding trauma history (d = 0.74), this difference became non-significant when introducing trauma variables. Patients reporting physical abuse had a significantly earlier age at onset, regardless of their sex (V = 0.13, F = 3.11, p = 0.03. Physical abuse predicted an earlier age at onset only in women (R² = 0.23). History of general trauma predicted more frequent hospitalizations only in men (R² = 0.55).ConclusionsAlthough women generally tend to have a more favorable course of illness including a later age at onset men, women with CPA seem to lose this “advantage”. It is necessary to investigate the contribution of gender interacting with adverse life events in contribution to the phenomenology and etiology of schizophrenia.     

DUF1220 copy number is associated with schizophrenia risk and severity: implications for understanding autism and schizophrenia as related diseases

The copy number of DUF1220, a protein domain implicated in human brain evolution, has been linearly associated with autism severity. Given the possibility that autism and schizophrenia are related disorders, the present study examined DUF1220 copy number variation in schizophrenia severity. There are notable similarities between autism symptoms and schizophrenia negative symptoms, and divergence between autism symptoms and schizophrenia positive symptoms. We therefore also examined DUF1220 copy number in schizophrenia subgroups defined by negative and positive symptom features, versus autistic individuals and controls. In the schizophrenic population (N=609), decreased DUF1220 copy number was linearly associated with increasing positive symptom severity (CON1 P=0.013, HLS1 P=0.0227), an association greatest in adult-onset schizophrenia (CON1 P=0.00155, HLS1 P=0.00361). In schizophrenic males, DUF1220 CON1 subtype copy number increase was associated with increased negative symptom severity (P=0.0327), a finding similar to that seen in autistic populations. Subgroup analyses demonstrated that schizophrenic individuals with predominantly positive symptoms exhibited reduced CON1 copy number compared with both controls (P=0.0237) and schizophrenic individuals with predominantly negative symptoms (P=0.0068). These findings support the view that (1) autism and schizophrenia exhibit both opposing and partially overlapping phenotypes and may represent a disease continuum, (2) variation in DUF1220 copy number contributes to schizophrenia disease risk and to the severity of both disorders, and (3) schizophrenia and autism may be, in part, a harmful by-product of the rapid and extreme evolutionary increase in DUF1220 copy number in the human species.     

Gender and the expression of schizophrenia

The expression of schizophrenia was examined in 169 DSM-III diagnosed schizophrenics. Restricted maximum likelihood factor analysis was used to test the invariance of the hypothesized symptom model across gender. Findings indicated that schizophrenic women not only expressed more impulsivity and affective symptomatology than did men, but their psychotic symptoms covaried consistently with the expression of impulsivity, anger and other affective symptomatology. Men's expression of schizophrenia covaried positively with withdrawal/isolation and an inability to function, suggesting a possible negative symptom pattern. Gender differences were not attributable to misclassification, differences in diagnostic subtypes, nor to selection. Results are discussed in light of their implications for understanding the heterogeneity of schizophrenia.     

Symptoms and the genetics of schizophrenia: implications for diagnosis

To determine whether genetic influences in schizophrenia are related to the symptoms specified by diagnostic criteria, the case histories of 151 pairs of monozygotic twins from five twin studies of schizophrenia were rated for positive and negative symptoms. Concordance rates in monozygotic twins were significantly higher when probands had a greater number of negative symptoms; no evidence of a similar relationship was found for positive symptoms. The data indicate that negative symptoms may be characteristic of schizophrenia in which there is a greater genetic component. The results have important implications for determining diagnostic criteria and understanding the pathogenesis of schizophrenia.     

Genetics of schizophrenia: implications for treatment

Schizophrenia is a common, debilitating illness for which treatment is empirical and unsatisfactory. Intense efforts to identify etiological factors have been launched in order to facilitate rational therapy. Such efforts have included gene-mapping studies since a significant heritability has been proved. In common with other polygenic/multifactorial disorders, mapping efforts for schizophrenia pose daunting challenges. Faced with such complexities, attempts to detect genetic associations with pharmacological response have been initiated. Although intriguing associations have been reported, formal replication is required. Suggestions for the design of replicate studies are proposed. This review is restricted to studies that investigated response to clozapine (Clozaril, Novartis) and other novel antipsychotic medications.     

Conceptualization of the liability for schizophrenia: clinical implications

Historically, the Diagnostic and Statistical Manual of Mental Disorders (DSM) diagnostic criteria for schizophrenia have emphasized several features, including symptoms of psychosis, a dissociation of symptoms from their etiology, a reliance on clinical symptoms, and a categorical approach to classifying the disorder. Although these emphases are quite useful, they have limitations. We review these here, and stress the importance of incorporating recent data on the genetic /biological and neurodevelopmental origins of schizophrenia into current conceptions of the disorder. We also review "schizotaxia, " which is a concept thai embodies this point of view, occurs before the onset of psychosis, and is hypothesized to represent the liability for schizophrenia. If our hypothesis on this point is correct, the identification of schizotaxic individuals will eventually facilitate the development of prevention strategies by identifying a premorbid (but clinically significant) condition for schizophrenia. Moreover, the identification of biological or neuropsychological components of schizotaxia will provide more specific bases for developing novel treatment interventions. Our initial attempts to develop protocols for the assessment and treatment of schizotaxia are encouraging, and will be reviewed.     

Maternal infection and schizophrenia: implications for prevention

Accumulating evidence suggests that maternal infection is a risk factor for schizophrenia. Prospective epidemiological studies indicate that maternal influenza, toxoplasmosis, and genital/reproductive infection are associated with this disorder in offspring. Preclinical models of maternal immune activation have supported the neurobiological plausibility of these microbes in schizophrenia. Previous studies suggest that treatment or prophylactic efforts targeting these and other infections could have significant effects on reducing the incidence of schizophrenia, given that they are common in the population and the effect sizes derived from epidemiological studies of these and other microbial pathogens and schizophrenia, to date, are not small. Fortunately, the occurrence of many of these infections can be reduced with relatively practical and inexpensive interventions that are scalable to large populations given adequate resources. Hence, in the present article, we focus on the potential for prevention of schizophrenia by control of infection, using these 3 categories of infection as examples. Lessons learned from previous successful public health efforts targeting these infections, including the relative advantages and disadvantages of these measures, are reviewed.     

Neurological signs and the heterogeneity of schizophrenia

OBJECTIVE: More than 20 studies of schizophrenia have found a three-factor model of symptom complexes or syndromes consisting of hallucinations/delusions, disorganization of thought and behavior, and negative symptoms. Several lines of evidence suggest that these syndromes relate to neurobiological differences. We examined the relationship of these three syndromes to neurological signs. METHOD: The relationships among the subscales of the Neurological Evaluation Scale and hallucinations/delusions, disorganization, and the deficit syndrome were examined in 83 clinically stable outpatients with schizophrenia. Patients with the deficit syndrome have enduring, idiopathic (or primary) negative symptoms. RESULTS: Each of the three syndromes had a distinctive pattern of relationships to neurological signs. Disorganization was significantly related to the total score on the Neurological Evaluation Scale, to sensory integration, and to the sequencing of complex motor acts. The deficit syndrome was significantly related to sensory integration only. Neither hallucinations/delusions nor a continuous measure of negative symptoms derived from the Brief Psychiatric Rating Scale (that measured both primary and secondary negative symptoms, as well as enduring and transient symptoms) was related to any of the Neurological Evaluation Scale subscales or total score. Drug treatment was not related to neurological impairment. CONCLUSIONS: The results further support the neurobiological significance of the three clinical syndromes of schizophrenia. Ratings on a scale measuring negative symptoms appear to be less sensitive to neurobiological correlates than is the categorization of the presence or absence of the deficit syndrome.     

Physical illness and schizophrenia: a review of the literature

OBJECTIVE: The lifespan of people with schizophrenia is shortened compared to the general population. We reviewed the literature on comorbid physical diseases in schizophrenia to provide a basis for initiatives to fight this unacceptable situation. METHOD: We searched MEDLINE (1966 - May 2006) combining the MeSH term of schizophrenia with the 23 MeSH terms of general physical disease categories to identify relevant epidemiological studies. RESULTS: A total of 44 202 abstracts were screened. People with schizophrenia have higher prevalences of HIV infection and hepatitis, osteoporosis, altered pain sensitivity, sexual dysfunction, obstetric complications, cardiovascular diseases, overweight, diabetes, dental problems, and polydipsia than the general population. Rheumatoid arthritis and cancer may occur less frequently than in the general population. Eighty-six per cent of the studies came from industrialized countries limiting the generalizability of the findings. CONCLUSION: The increased frequency of physical diseases in schizophrenia might be on account of factors related to schizophrenia and its treatment, but undoubtedly also results from the unsatisfactory organization of health services, from the attitudes of medical doctors, and the social stigma ascribed to the schizophrenic patients.