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Journal ArticleDOI

Long-term Antipsychotic Treatment and Brain Volumes: A Longitudinal Study of First-Episode Schizophrenia

07 Feb 2011-Archives of General Psychiatry (American Medical Association)-Vol. 68, Iss: 2, pp 128-137
TL;DR: It is suggested that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.
Abstract: Context Progressive brain volume changes in schizophrenia are thought to be due principally to the disease. However, recent animal studies indicate that antipsychotics, the mainstay of treatment for schizophrenia patients, may also contribute to brain tissue volume decrement. Because antipsychotics are prescribed for long periods for schizophrenia patients and have increasingly widespread use in other psychiatric disorders, it is imperative to determine their long-term effects on the human brain. Objective To evaluate relative contributions of 4 potential predictors (illness duration, antipsychotic treatment, illness severity, and substance abuse) of brain volume change. Design Predictors of brain volume changes were assessed prospectively based on multiple informants. Setting Data from the Iowa Longitudinal Study. Patients Two hundred eleven patients with schizophrenia who underwent repeated neuroimaging beginning soon after illness onset, yielding a total of 674 high-resolution magnetic resonance scans. On average, each patient had 3 scans (≥2 and as many as 5) over 7.2 years (up to 14 years). Main Outcome Measure Brain volumes. Results During longitudinal follow-up, antipsychotic treatment reflected national prescribing practices in 1991 through 2009. Longer follow-up correlated with smaller brain tissue volumes and larger cerebrospinal fluid volumes. Greater intensity of antipsychotic treatment was associated with indicators of generalized and specific brain tissue reduction after controlling for effects of the other 3 predictors. More antipsychotic treatment was associated with smaller gray matter volumes. Progressive decrement in white matter volume was most evident among patients who received more antipsychotic treatment. Illness severity had relatively modest correlations with tissue volume reduction, and alcohol/illicit drug misuse had no significant associations when effects of the other variables were adjusted. Conclusions Viewed together with data from animal studies, our study suggests that antipsychotics have a subtle but measurable influence on brain tissue loss over time, suggesting the importance of careful risk-benefit review of dosage and duration of treatment as well as their off-label use.

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Citations
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Journal ArticleDOI
TL;DR: The relatively new field of HR research in psychosis has the potential to shed light on the development of major psychotic disorders and to alter their course and provides a rationale for service provision to those in need of help who could not previously access it.
Abstract: Context During the past 2 decades, a major transition in the clinical characterization of psychotic disorders has occurred. The construct of a clinical high-risk (HR) state for psychosis has evolved to capture the prepsychotic phase, describing people presenting with potentially prodromal symptoms. The importance of this HR state has been increasingly recognized to such an extent that a new syndrome is being considered as a diagnostic category in the DSM-5. Objective To reframe the HR state in a comprehensive state-of-the-art review on the progress that has been made while also recognizing the challenges that remain. Data Sources Available HR research of the past 20 years from PubMed, books, meetings, abstracts, and international conferences. Study Selection and Data Extraction Critical review of HR studies addressing historical development, inclusion criteria, epidemiologic research, transition criteria, outcomes, clinical and functional characteristics, neurocognition, neuroimaging, predictors of psychosis development, treatment trials, socioeconomic aspects, nosography, and future challenges in the field. Data Synthesis Relevant articles retrieved in the literature search were discussed by a large group of leading worldwide experts in the field. The core results are presented after consensus and are summarized in illustrative tables and figures. Conclusions The relatively new field of HR research in psychosis is exciting. It has the potential to shed light on the development of major psychotic disorders and to alter their course. It also provides a rationale for service provision to those in need of help who could not previously access it and the possibility of changing trajectories for those with vulnerability to psychotic illnesses.

1,213 citations

Journal ArticleDOI
TL;DR: The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period.
Abstract: Context A substantial proportion of people at clinical high risk of psychosis will develop a psychotic disorder over time. However, the risk of transition to psychosis varies between centers, and some recent work suggests that the risk of transition may be declining. Objective To quantitatively examine the literature to date reporting the transition risk to psychosis in subjects at clinical high risk. Data Sources The electronic databases were searched until January 2011. All studies reporting transition risks in patients at clinical high risk were retrieved. Study Selection Twenty-seven studies met the inclusion criteria, comprising a total of 2502 patients. Data Extraction Transition risks, as well as demographic, clinical, and methodologic variables, were extracted from each publication or obtained directly from its authors. Data Synthesis There was a consistent transition risk, independent of the psychometric instruments used, of 18% after 6 months of follow-up, 22% after 1 year, 29% after 2 years, and 36% after 3 years. Significant moderators accounting for heterogeneity across studies and influencing the transition risks were the age of participants, publication year, treatments received, and diagnostic criteria used. There was no publication bias, and a sensitivity analysis confirmed the robustness of the core findings. Conclusions The state of clinical high risk is associated with a very high risk of developing psychosis within the first 3 years of clinical presentation, and the risk progressively increases across this period. The transition risk varies with the age of the patient, the nature of the treatment provided, and the way the syndrome and transition to psychosis are defined.

1,159 citations

Journal ArticleDOI
TL;DR: A concordance is identified in terms of integrity of an anterior insula/dorsal anterior cingulate-based network, which may relate to executive function deficits observed across diagnoses, which provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology.
Abstract: Importance Psychiatric diagnoses are currently distinguished based on sets of specific symptoms. However, genetic and clinical analyses find similarities across a wide variety of diagnoses, suggesting that a common neurobiological substrate may exist across mental illness. Objective To conduct a meta-analysis of structural neuroimaging studies across multiple psychiatric diagnoses, followed by parallel analyses of 3 large-scale healthy participant data sets to help interpret structural findings in the meta-analysis. Data Sources PubMed was searched to identify voxel-based morphometry studies through July 2012 comparing psychiatric patients to healthy control individuals for the meta-analysis. The 3 parallel healthy participant data sets included resting-state functional magnetic resonance imaging, a database of activation foci across thousands of neuroimaging experiments, and a data set with structural imaging and cognitive task performance data. Data Extraction and Synthesis Studies were included in the meta-analysis if they reported voxel-based morphometry differences between patients with an Axis I diagnosis and control individuals in stereotactic coordinates across the whole brain, did not present predominantly in childhood, and had at least 10 studies contributing to that diagnosis (or across closely related diagnoses). The meta-analysis was conducted on peak voxel coordinates using an activation likelihood estimation approach. Main Outcomes and Measures We tested for areas of common gray matter volume increase or decrease across Axis I diagnoses, as well as areas differing between diagnoses. Follow-up analyses on other healthy participant data sets tested connectivity related to regions arising from the meta-analysis and the relationship of gray matter volume to cognition. Results Based on the voxel-based morphometry meta-analysis of 193 studies comprising 15 892 individuals across 6 diverse diagnostic groups (schizophrenia, bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety), we found that gray matter loss converged across diagnoses in 3 regions: the dorsal anterior cingulate, right insula, and left insula. By contrast, there were few diagnosis-specific effects, distinguishing only schizophrenia and depression from other diagnoses. In the parallel follow-up analyses of the 3 independent healthy participant data sets, we found that the common gray matter loss regions formed a tightly interconnected network during tasks and at resting and that lower gray matter in this network was associated with poor executive functioning. Conclusions and Revelance We identified a concordance across psychiatric diagnoses in terms of integrity of an anterior insula/dorsal anterior cingulate–based network, which may relate to executive function deficits observed across diagnoses. This concordance provides an organizing model that emphasizes the importance of shared neural substrates across psychopathology, despite likely diverse etiologies, which is currently not an explicit component of psychiatric nosology.

1,033 citations

Journal ArticleDOI
TL;DR: Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches, and validates that collaborative data analyses can readily be used across brain phenotypes and disorders.
Abstract: The profile of brain structural abnormalities in schizophrenia is still not fully understood, despite decades of research using brain scans. To validate a prospective meta-analysis approach to analyzing multicenter neuroimaging data, we analyzed brain MRI scans from 2028 schizophrenia patients and 2540 healthy controls, assessed with standardized methods at 15 centers worldwide. We identified subcortical brain volumes that differentiated patients from controls, and ranked them according to their effect sizes. Compared with healthy controls, patients with schizophrenia had smaller hippocampus (Cohen's d=-0.46), amygdala (d=-0.31), thalamus (d=-0.31), accumbens (d=-0.25) and intracranial volumes (d=-0.12), as well as larger pallidum (d=0.21) and lateral ventricle volumes (d=0.37). Putamen and pallidum volume augmentations were positively associated with duration of illness and hippocampal deficits scaled with the proportion of unmedicated patients. Worldwide cooperative analyses of brain imaging data support a profile of subcortical abnormalities in schizophrenia, which is consistent with that based on traditional meta-analytic approaches. This first ENIGMA Schizophrenia Working Group study validates that collaborative data analyses can readily be used across brain phenotypes and disorders and encourages analysis and data sharing efforts to further our understanding of severe mental illness.

919 citations

Journal ArticleDOI
TL;DR: It is shown that developmental alterations secondary to variant genes, early hazards to the brain, and childhood adversity sensitise the dopamine system, and result in excessive presynaptic dopamine synthesis and release.

624 citations

References
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Book
01 Jan 1996
TL;DR: This is the first in a planned series of 10 volumes that will attempt to "summarize epidemiological knowledge about all major conditions and most risk factors" and use historical trends in main determinants to project mortality and disease burden forward to 2020.
Abstract: This is the first in a planned series of 10 volumes that will attempt to "summarize epidemiological knowledge about all major conditions and most risk factors;...generate assessments of numbers of deaths by cause that are consistent with the total numbers of deaths by age sex and region provided by demographers;...provide methodologies for and assessments of aggregate disease burden that combine--into the Disability-Adjusted Life Year or DALY measure--burden from premature mortality with that from living with disability; and...use historical trends in main determinants to project mortality and disease burden forward to 2020." This first volume includes chapters summarizing results from the project as a whole. (EXCERPT)

7,154 citations


"Long-term Antipsychotic Treatment a..." refers background or methods in this paper

  • ...The 211 patients (152 men and 59 women) in this report were selected from the larger ILS sample on the basis of having (1) a DSM-IV diagnosis of schizophrenia (n=192) or schizoaffective disorder (n=19) (verified at follow-up by psychiatrists’ consensus), and (2) undergone 2 or more MRI brain scans....

    [...]

  • ...S CHIZOPHRENIA, A COMMON mental illness affecting 1% of the worldwide population, remains a leading cause of chronic disability among young adults.(1) Antipsychotic medications are the mainstay of treatment because there is strong empirical evidence that...

    [...]

Journal ArticleDOI
TL;DR: The relative simplicity, reliability, and validity of the GAS suggests that it would be useful in a wide variety of clinical and research settings.
Abstract: † The Global Assessment Scale (GAS) is a rating scale for evaluating the overall functioning of a subject during a specified time period on a continuum from psychological or psychiatric sickness to health. In five studies encompassing the range of populations to which measures of overall severity of illness are likely to be applied, the GAS was found to have good reliability. GAS ratings were found to have greater sensitivity to change over time than did other ratings of overall severity or specific symptom dimensions. Former inpatients in the community with a GAS rating below 40 had a higher probability of readmission to the hospital than did patients with higher GAS scores. The relative simplicity, reliability, and validity of the GAS suggests that it would be useful in a wide variety of clinical and research settings.

4,799 citations

Journal ArticleDOI
TL;DR: A significant, nonlinear decline in GMD with age is found over dorsal frontal and parietal association cortices on both the lateral and interhemispheric surfaces, indicating that the posterior temporal cortices have a more protracted course of maturation than any other cortical region.
Abstract: We used magnetic resonance imaging and cortical matching algorithms to map gray matter density (GMD) in 176 normal individuals ranging in age from 7 to 87 years. We found a significant, nonlinear decline in GMD with age, which was most rapid between 7 and about 60 years, over dorsal frontal and parietal association cortices on both the lateral and interhemispheric surfaces. Age effects were inverted in the left posterior temporal region, where GMD gain continued up to age 30 and then rapidly declined. The trajectory of maturational and aging effects varied considerably over the cortex. Visual, auditory and limbic cortices, which are known to myelinate early, showed a more linear pattern of aging than the frontal and parietal neocortices, which continue myelination into adulthood. Our findings also indicate that the posterior temporal cortices, primarily in the left hemisphere, which typically support language functions, have a more protracted course of maturation than any other cortical region.

2,233 citations


"Long-term Antipsychotic Treatment a..." refers background in this paper

  • ...As a group, patients with the least treatment showed WM volume increases over time that would be expected of individuals during their third and fourth decades of life.(58) Bartzokis and colleagues(59) previously found that patients with schizophrenia do not show the normal agerelated WM volume expansion during early to midadulthood....

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Journal ArticleDOI
TL;DR: Research strategies suggest that investigators should maintain a flexible database to permit them to adapt to changes in diagnostic systems, to do comparative nosological studies, and, ultimately, to develop new diagnostic systems based on knowledge concerning the underlying neurobiological nature of disorders.
Abstract: • The Comprehensive Assessment of Symptoms and History was developed for research studies of schizophrenia spectrum conditions and affective spectrum conditions. It is designed to provide a comprehensive information base concerning current and past signs and symptoms, premorbid functioning, cognitive functioning, sociodemographic status, treatment, and course of illness. Because the information base is broad, it is not wedded to a specific diagnostic system but rather permits clinicians and investigators to make diagnoses using a wide range of systems, including Research Diagnostic Criteria,DSM-III, DSM-III-R, and theInternational Classification of Diseases. Given the fact that disorders in psychiatry are not defined at the etiological or pathophysiological level, diagnostic criteria are prone to ongoing revision as our knowledge base changes. Research strategies suggest that investigators should maintain a flexible database to permit them to adapt to changes in diagnostic systems, to do comparative nosological studies, and, ultimately, to develop new diagnostic systems based on knowledge concerning the underlying neurobiological nature of disorders. Because it provides a comprehensive information base, the Comprehensive Assessment of Symptoms and History facilitates research of this type. Extensive developmental work has been done with the Comprehensive Assessment of Symptoms and History, including interrater and test-retest reliability studies, validity studies, training programs, and data entry programs.

1,237 citations

Journal ArticleDOI
TL;DR: Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia.
Abstract: Background: In the past two decades, gross morphologic changes have been uncovered in the schizophrenic brain, eg, increased ventricular width and decreased cortical volume; however, relatively little is known about the area-specific and laminar density of cells in the schizophrenic cortex, particularly in prefrontal areas. Method: A direct, three-dimensional counting method was used to determine cell density in 16 brains from patients with schizophrenia, 19 from normal subjects, six from patients with schizoaffective disorder, and nine from patients with advanced-stage Huntington's disease. Results: Increased neuronal density was found in prefrontal area 9 (17%) and occipital area 17 (10%) in the schizophrenic brains. In area 9, neuronal density was increased in layers III to VI; cell packing of pyramidal and nonpyramidal neurons was elevated. Cortical thickness in the schizophrenic brains was slightly but not significantly reduced in both areas, with a disproportionate reduction in layer V in area 9. In contrast, brains with Huntington's disease exhibited markedly higher glial density Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia. Conclusion: Abnormally high density in the cerebral cortices of schizophrenics suggests that neuronal atrophy is the anatomic substrate for deficient information processing in schizophrenia.

874 citations