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The use of over-the-counter analgesics (OTCA) has been found to alter various aspects of emotional processing and has been linked to increased anxiety and depression symptoms. Attentional bias is an aspect of emotional processing that is closely related to anxiety and depression. Although OTCA and attentional bias have both been linked to anxiety and depression, the potential links between OTCA usage and attentional bias are not yet investigated. The present study aimed to determine whether the frequency of OTCA usage is associated with differences in attentional bias by comparing response-based measures of attentional bias in 62 women aged 19-30 years. The findings showed that the small group reporting high OTCA usage demonstrated more orientation avoidance to fearful stimuli than those reporting no or low usage. Based on these preliminary findings, further research on attentional bias and its relationship to high OTCA usage is recommended., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life., Methods: Interregional profiles of group differences in surface area between cases and controls were generated using T1-weighted magnetic resonance imaging from 27,359 individuals including those with attention-deficit/hyperactivity disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, schizophrenia, and high general psychopathology (through the Child Behavior Checklist). Similarity of interregional profiles of group differences in surface area and prenatal cell-specific gene expression was assessed., Results: Across the 11 cortical regions, group differences in cortical area for attention-deficit/hyperactivity disorder, schizophrenia, and Child Behavior Checklist were dominant in multimodal association cortices. The same interregional profiles were also associated with interregional profiles of (prenatal) gene expression specific to proliferative cells, namely radial glia and intermediate progenitor cells (greater expression, larger difference), as well as differentiated cells, namely excitatory neurons and endothelial and mural cells (greater expression, smaller difference). Finally, these cell types were implicated in known pre/perinatal risk factors for psychosis. Genes coexpressed with radial glia were enriched with genes implicated in congenital abnormalities, birth weight, hypoxia, and starvation. Genes coexpressed with endothelial and mural genes were enriched with genes associated with maternal hypertension and preterm birth., Conclusions: Our findings support a neurodevelopmental model of vulnerability to mental illness whereby prenatal risk factors acting through cell-specific processes lead to deviations from typical brain development during pregnancy., (Copyright © 2022 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Abnormal default mode network (DMN) connectivity has been found in schizophrenia and other psychotic disorders. However, there are limited studies on early onset psychosis (EOP), and their results show lack of agreement. Here, we investigated within-network DMN connectivity in EOP compared to healthy controls (HC), and its relationship to clinical characteristics. A sample of 68 adolescent patients with EOP (mean age 16.53 ± 1.12 [SD] years, females 66%) and 95 HC (mean age 16.24 ± 1.50 [SD], females 60%) from two Scandinavian cohorts underwent resting state functional magnetic resonance imaging (rsfMRI). A group independent component analysis (ICA) was performed to identify the DMN across all participants. Dual regression was used to estimate spatial maps reflecting each participant's DMN network, which were compared between EOP and HC using voxel-wise general linear models and permutation-based analyses. Subgroup analyses were performed within the patient group, to explore associations between diagnostic subcategories and current use of psychotropic medication in relation to connectivity strength. The analysis revealed significantly reduced DMN connectivity in EOP compared to HC in the posterior cingulate cortex, precuneus, fusiform cortex, putamen, pallidum, amygdala, and insula. The subgroup analysis in the EOP group showed strongest deviations for affective psychosis, followed by other psychotic disorders and schizophrenia. There was no association between DMN connectivity strength and the current use of psychotropic medication. In conclusion, the findings demonstrate weaker DMN connectivity in adolescent patients with EOP compared to healthy peers, and differential effects across diagnostic subcategories, which may inform our understanding of underlying disease mechanisms in EOP., (Copyright © 2021. Published by Elsevier Inc.)

Background: Over-the-counter analgesics (OTCA) such as Paracetamol and Ibuprofen are frequently used by adolescents, and the route of administration and access at home allows unsupervised use. Psychological distress and pain occur simultaneously and are more common among females than among males. There is a dynamic interplay between on-label pain indications and psychological distress, and frequent OTCA use or misuse can exacerbate symptoms. No studies have to date provided an overview of frequent OTCA use in a larger population-based study. The current study used survey data to explore associations between and the relative predictive value of on-label pain indication and measures of psychological distress, together with sex differences for weekly OTCA use., Methods: This study included 349,528 adolescents aged 13-19. The data was collected annually between January 2014 and December 2018 as part of the Norwegian Young Data survey. Performance analysis was conducted to explore the relative roles and associations between on-label pain indication and psychological distress in weekly OTCA use. A mixed-effects logistic regression model was used to explore the unique contributions from four domains of on-label pain indication and psychological distress as measured by a combined measure of anxiety and depression (HSCL-10) and peer-bullying involvement as victims or bullies., Results: Thirty percent of females and 13 % of males use OTCA weekly. Headache is the strongest on-label pain predictor of weekly OTCA use, followed by abdominal pain. Depression and anxiety are the strongest psychological predictor of weekly OTCA use, and higher symptom levels and being female increase the strength of this association. Anxiety and depression also predict weekly OTCA use after controlling for physiological pain., Conclusions: Sex, pain and anxiety and depression are inter-correlated and strong predictors of frequent OTCA use. Frequent OTCA use in the context of psychological distress may be a form of self-medication that can exacerbate symptoms and decrease psychosocial function. Longitudinal studies that explore causal trajectories between frequent on-label OTCA use and psychological distress are required. OTCA use among adolescents, and particularly among females, with anxiety and depression should be administered with caution and closely monitored., (© 2021. The Author(s).)

Abnormalities in amygdala volume are well-established in schizophrenia and commonly reported in bipolar disorders. However, the specificity of volumetric differences in individual amygdala nuclei is largely unknown. Patients with schizophrenia disorders (SCZ, N = 452, mean age 30.7 ± 9.2 [SD] years, females 44.4%), bipolar disorders (BP, N = 316, 33.7 ± 11.4, 58.5%), and healthy controls (N = 753, 34.1 ± 9.1, 40.9%) underwent T1-weighted magnetic resonance imaging. Total amygdala, nuclei, and intracranial volume (ICV) were estimated with Freesurfer (v6.0.0). Analysis of covariance and multiple linear regression models, adjusting for age, age2, ICV, and sex, were fitted to examine diagnostic group and subgroup differences in volume, respectively. Bilateral total amygdala and all nuclei volumes, except the medial and central nuclei, were significantly smaller in patients relative to controls. The largest effect sizes were found for the basal nucleus, accessory basal nucleus, and cortico-amygdaloid transition area (partial η2 > 0.02). The diagnostic subgroup analysis showed that reductions in amygdala nuclei volume were most widespread in schizophrenia, with the lateral, cortical, paralaminar, and central nuclei being solely reduced in this disorder. The right accessory basal nucleus was marginally smaller in SCZ relative to BP (t = 2.32, P = .05). Our study is the first to demonstrate distinct patterns of amygdala nuclei volume reductions in a well-powered sample of patients with schizophrenia and bipolar disorders. Volume differences in the basolateral complex (lateral, basal, and accessory basal nuclei), an integral part of the threat processing circuitry, were most prominent in schizophrenia., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center.)

A recent meta-analysis has questioned the relevance of attention bias modification (ABM) for depression outcomes. However, there might be patient characteristics not yet accounted for, that are relevant to the outcome. In the context of personalized treatment, the lack of moderator studies have limited the potential for matching ABM-treatment to individual patient characteristics. Subjects (N = 301) were randomly assigned 1:1 to receive either active or placebo Attention Bias Modification (ABM) twice daily for 14 days in a double-blind design (placebo n = 148; ABM n = 153). The outcome was change in symptoms based on the Hamilton Depression Rating Scale (HDRS). Moderator variables were self-reported depression (Beck Depression Inventory-II; BDI-II), anxiety (Beck Anxiety Inventory; BAI) and attentional bias (AB) assessed at baseline. This trial was registered with ClinicalTrials.gov, number NCT02658682. Only BAI (p for interaction = .01, Bootstrap 95% CI [0.046, 0.337]) moderated the effects of ABM on change in clinician rated depressive symptoms. Interactions were significant for BAI scores ≥8. The relative effect of the intervention increased with the highest symptom load. ABM was not effective in patients with the lowest symptom load. Future research should validate this finding and continue investigating moderators of the ABM-intervention to further enhance personalization of treatment to individual symptom characteristics., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Importance: Large-scale neuroimaging studies have revealed group differences in cortical thickness across many psychiatric disorders. The underlying neurobiology behind these differences is not well understood., Objective: To determine neurobiologic correlates of group differences in cortical thickness between cases and controls in 6 disorders: attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), bipolar disorder (BD), major depressive disorder (MDD), obsessive-compulsive disorder (OCD), and schizophrenia., Design, Setting, and Participants: Profiles of group differences in cortical thickness between cases and controls were generated using T1-weighted magnetic resonance images. Similarity between interregional profiles of cell-specific gene expression and those in the group differences in cortical thickness were investigated in each disorder. Next, principal component analysis was used to reveal a shared profile of group difference in thickness across the disorders. Analysis for gene coexpression, clustering, and enrichment for genes associated with these disorders were conducted. Data analysis was conducted between June and December 2019. The analysis included 145 cohorts across 6 psychiatric disorders drawn from the ENIGMA consortium. The numbers of cases and controls in each of the 6 disorders were as follows: ADHD: 1814 and 1602; ASD: 1748 and 1770; BD: 1547 and 3405; MDD: 2658 and 3572; OCD: 2266 and 2007; and schizophrenia: 2688 and 3244., Main Outcomes and Measures: Interregional profiles of group difference in cortical thickness between cases and controls., Results: A total of 12 721 cases and 15 600 controls, ranging from ages 2 to 89 years, were included in this study. Interregional profiles of group differences in cortical thickness for each of the 6 psychiatric disorders were associated with profiles of gene expression specific to pyramidal (CA1) cells, astrocytes (except for BD), and microglia (except for OCD); collectively, gene-expression profiles of the 3 cell types explain between 25% and 54% of variance in interregional profiles of group differences in cortical thickness. Principal component analysis revealed a shared profile of difference in cortical thickness across the 6 disorders (48% variance explained); interregional profile of this principal component 1 was associated with that of the pyramidal-cell gene expression (explaining 56% of interregional variation). Coexpression analyses of these genes revealed 2 clusters: (1) a prenatal cluster enriched with genes involved in neurodevelopmental (axon guidance) processes and (2) a postnatal cluster enriched with genes involved in synaptic activity and plasticity-related processes. These clusters were enriched with genes associated with all 6 psychiatric disorders., Conclusions and Relevance: In this study, shared neurobiologic processes were associated with differences in cortical thickness across multiple psychiatric disorders. These processes implicate a common role of prenatal development and postnatal functioning of the cerebral cortex in these disorders.

A key objective in the field of translational psychiatry over the past few decades has been to identify the brain correlates of major depressive disorder (MDD). Identifying measurable indicators of brain processes associated with MDD could facilitate the detection of individuals at risk, and the development of novel treatments, the monitoring of treatment effects, and predicting who might benefit most from treatments that target specific brain mechanisms. However, despite intensive neuroimaging research towards this effort, underpowered studies and a lack of reproducible findings have hindered progress. Here, we discuss the work of the ENIGMA Major Depressive Disorder (MDD) Consortium, which was established to address issues of poor replication, unreliable results, and overestimation of effect sizes in previous studies. The ENIGMA MDD Consortium currently includes data from 45 MDD study cohorts from 14 countries across six continents. The primary aim of ENIGMA MDD is to identify structural and functional brain alterations associated with MDD that can be reliably detected and replicated across cohorts worldwide. A secondary goal is to investigate how demographic, genetic, clinical, psychological, and environmental factors affect these associations. In this review, we summarize findings of the ENIGMA MDD disease working group to date and discuss future directions. We also highlight the challenges and benefits of large-scale data sharing for mental health research.

Background: Mental disorders and individual characteristics such as intelligence and personality are complex traits sharing a largely unknown neuronal basis. Their genetic architectures are highly polygenic and overlapping, which is supported by heterogeneous phenotypic expression and substantial clinical overlap. Brain network analysis provides a noninvasive means of dissecting biological heterogeneity, yet its sensitivity, specificity, and validity in assessing individual characteristics relevant for brain function and mental health and their genetic underpinnings in clinical applications remain a challenge., Methods: In a machine learning approach, we predicted individual scores for educational attainment, fluid intelligence and dimensional measures of depression, anxiety, and neuroticism using functional magnetic resonance imaging-based static and dynamic temporal synchronization between large-scale brain network nodes in 10,343 healthy individuals from the UK Biobank. In addition to using age and sex to serve as our reference point, we also predicted individual polygenic scores for related phenotypes and 13 different neuroticism traits and schizophrenia., Results: Beyond high accuracy for age and sex, supporting the biological sensitivity of the connectome-based features, permutation tests revealed above chance-level prediction accuracy for trait-level educational attainment and fluid intelligence. Educational attainment and fluid intelligence were mainly negatively associated with static brain connectivity in frontal and default mode networks, whereas age showed positive correlations with a more widespread pattern. In contrast, prediction accuracy was at chance level for depression, anxiety, neuroticism, and polygenic scores across traits., Conclusions: These novel findings provide a benchmark for future studies linking the genetic architecture of individual and mental health traits with functional magnetic resonance imaging-based brain connectomics., (Copyright © 2019 Society of Biological Psychiatry. All rights reserved.)

Previous structural and functional neuroimaging studies have implicated distributed brain regions and networks in depression. However, there are no robust imaging biomarkers that are specific to depression, which may be due to clinical heterogeneity and neurobiological complexity. A dimensional approach and fusion of imaging modalities may yield a more coherent view of the neuronal correlates of depression. We used linked independent component analysis to fuse cortical macrostructure (thickness, area, gray matter density), white matter diffusion properties and resting-state functional magnetic resonance imaging default mode network amplitude in patients with a history of depression (n = 170) and controls (n = 71). We used univariate and machine learning approaches to assess the relationship between age, sex, case-control status, and symptom loads for depression and anxiety with the resulting brain components. Univariate analyses revealed strong associations between age and sex with mainly global but also regional specific brain components, with varying degrees of multimodal involvement. In contrast, there were no significant associations with case-control status, nor symptom loads for depression and anxiety with the brain components, nor any interaction effects with age and sex. Machine learning revealed low model performance for classifying patients from controls and predicting symptom loads for depression and anxiety, but high age prediction accuracy. Multimodal fusion of brain imaging data alone may not be sufficient for dissecting the clinical and neurobiological heterogeneity of depression. Precise clinical stratification and methods for brain phenotyping at the individual level based on large training samples may be needed to parse the neuroanatomy of depression., (© 2019 The Authors. Human Brain Mapping published by Wiley Periodicals, Inc.)

Background: Attentional bias modification (ABM) may lead to more adaptive emotion perception and emotion regulation. Understanding the neural basis of these effects may lead to greater precision for the development of future treatments. Task-related functional MRI (fMRI) after ABM training has not been investigated in depression so far. The main aim of this randomized controlled trial was to explore differences in brain activity after ABM training, in response to emotional stimuli., Methods: A total of 134 people with previous depression, who had been treated for depression and had various degrees of residual symptoms, were randomized to 14 days of active ABM or a closely matched placebo training, followed by an fMRI emotion regulation task. The training procedure was a classical dot–probe task with emotional face stimuli. In the active ABM condition, the probes replaced the more positively valenced face of a given pair. As participants implicitly learned to predict the probe location, this would be likely to induce a more positive attentional bias. The placebo condition was identical, except for the contingency of the probe, which appeared equally behind positive and negative stimuli. We compared depression symptoms and subjective ratings of perceived negativity during fMRI between the training groups. We explored brain activation in predefined regions of interest and across the whole brain. We explored activation in areas associated with changes in attentional bias and degree of depression., Results: Compared with the placebo group, the ABM group showed reduced activation in the amygdala and the anterior cingulate cortex when passively viewing negative images. We found no group differences in predefined regions of interest associated with emotion regulation strategies. Response in the temporal cortices was associated with the degree of change in attentional bias and the degree of depressive symptoms in ABM versus placebo., Limitations: These findings should be replicated in other samples of patients with depression, and in studies using fMRI designs that allow analyses of within-group variability from baseline to follow-up., Conclusion: Attentional bias modification training has an effect on brain function in the circuitry associated with emotional appraisal and the generation of affective states., Clinicaltrials.gov Identifier: NCT02931487, (© 2020 Joule Inc. or its licensors)

Background: Following treatment, many depressed patients have significant residual symptoms. However, large randomised controlled trials (RCT) in this population are lacking. When Attention bias modification training (ABM) leads to more positive emotional biases, associated changes in clinical symptoms have been reported. A broader and more transparent picture of the true advantage of ABM based on larger and more stringent clinical trials have been requested. The current study evaluates the early effect of two weeks ABM training on blinded clinician-rated and self-reported residual symptoms, and whether changes towards more positive attentional biases (AB) would be associated with symptom reduction., Method: A total of 321 patients with a history of depression were included in a preregistered randomized controlled double-blinded trial. Patients were randomised to an emotional ABM paradigm over fourteen days or a closely matched control condition. Symptoms based on the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory II (BDI-II) were obtained at baseline and after ABM training., Results: ABM training led to significantly greater decrease in clinician-rated symptoms of depression as compared to the control condition. No differences between ABM and placebo were found for self-reported symptoms. ABM induced a change of AB towards relatively more positive stimuli for participants that also showed greater symptom reduction., Conclusion: The current study demonstrates that ABM produces early changes in blinded clinician-rated depressive symptoms and that changes in AB is linked to changes in symptoms. ABM may have practical potential in the treatment of residual depression., Trial Registration: ClinicalTrials.gov ID: NCT02658682 (retrospectively registered in January 2016).

Background: Depression is a complex disorder with large interindividual variability in symptom profiles that often occur alongside symptoms of other psychiatric domains, such as anxiety. A dimensional and symptom-based approach may help refine the characterization of depressive and anxiety disorders and thus aid in establishing robust biomarkers. We use resting-state functional magnetic resonance imaging to assess the brain functional connectivity correlates of a symptom-based clustering of individuals., Methods: We assessed symptoms using the Beck Depression and Beck Anxiety Inventories in individuals with or without a history of depression (N = 1084) and high-dimensional data clustering to form subgroups based on symptom profiles. We compared dynamic and static functional connectivity between subgroups in a subset of the total sample (n = 252)., Results: We identified five subgroups with distinct symptom profiles, which cut across diagnostic boundaries with different total severity, symptom patterns, and centrality. For instance, inability to relax, fear of the worst, and feelings of guilt were among the most severe symptoms in subgroups 1, 2, and 3, respectively. The distribution of individuals was 32%, 25%, 22%, 10%, and 11% in subgroups 1 to 5, respectively. These subgroups showed evidence of differential static brain-connectivity patterns, in particular comprising a frontotemporal network. In contrast, we found no significant associations with clinical sum scores, dynamic functional connectivity, or global connectivity., Conclusions: Adding to the pursuit of individual-based treatment, subtyping based on a dimensional conceptualization and unique constellations of anxiety and depression symptoms is supported by distinct patterns of static functional connectivity in the brain., (Copyright © 2018 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Alterations in resting state networks (RSNs) are associated with emotional- and attentional control difficulties in depressed individuals. Attentional bias modification (ABM) training may lead to more adaptive emotional processing in depression, but little is known about the neural underpinnings associated with ABM. In the current study a sample of 134 previously depressed individuals were randomized into 14 days of computerized ABM- or a closely matched placebo training regime followed by a resting state magnetic resonance imaging (MRI) scan. Using independent component analysis (ICA) we examined within-network connectivity in three major RSN's, the default mode network (DMN), the salience network (SN) and the central executive network (CEN) after 2 weeks of ABM training. We found a significant difference between the training groups within the SN, but no difference within the DMN or CEN. Moreover, a significant symptom improvement was observed in the ABM group after training. Clinical Trial Registration : www.ClinicalTrials.gov, identifier NCT02931487.

Background: Anorexia nervosa (AN) is a severe mental illness, with an unknown etiology. Magnetic resonance imaging studies show reduced brain volumes and cortical thickness in patients compared to healthy controls. However, findings are inconsistent, especially concerning the anatomical location and extent of the differences. The purpose of this study was to estimate and compare brain volumes and regional cortical thickness in young females with AN and healthy controls., Methods: Magnetic resonance imaging data was acquired from young females with anorexia nervosa (n = 23) and healthy controls (n = 28). Two different scanner sites were used. BMI varied from 13.5 to 20.7 within the patient group, and 11 patients had a BMI > 17.5. FreeSurfer was used to estimate brain volumes and regional cortical thickness., Results: There were no differences between groups in total cerebral cortex volume, white matter volume, or lateral ventricle volume. There were also no volume differences in subcortical grey matter structures. However the results showed reduced cortical thickness bilaterally in the superior parietal gyrus, and in the right inferior parietal and superior frontal gyri., Conclusions: The functional significance of the findings is undetermined as the majority of the included patients was already partially weight-restored. We discuss whether these regions could be related to predisposing factors of the illness, or whether they are regions that are more vulnerable to starvation, malnutrition or associated processes in AN.

Functional neuroimaging studies consistently report language-related cerebellar activations, but evidence from the clinical literature is less conclusive. Here, we attempt to bridge this gap by testing the effect of focal cerebellar lesions on cerebral activations in a reading task previously shown to involve distinct cerebellar regions. Patients (N=10) had lesions primarily affecting medial cerebellum, overlapping cerebellar regions activated during the presentation of random word sequences, but distinct from activations related to semantic prediction generation and prediction error processing. In line with this pattern of activation-lesion overlap, patients did not differ from matched healthy controls (N=10) in predictability-related activations. However, whereas controls showed increased activation in bilateral auditory cortex and parietal operculum when silently reading familiar words relative to viewing letter strings, this effect was absent in the patients. Our results highlight the need for careful lesion mapping and suggest possible roles for the cerebellum in visual-to-auditory mapping and/or inner speech., Competing Interests: The authors declare no competing financial interests., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: In studies employing physiological measures such as magnetic resonance imaging (MRI), it is often hard to distinguish what constitutes risk-resilience factors to posttraumatic stress disorder (PTSD) following trauma exposure and what the effects of trauma exposure and PTSD are., Objective: We aimed to investigate whether there were observable morphological differences in cortical and sub-cortical regions of the brain, 7-8 years after a single potentially traumatic event., Methods: Twenty-four participants, who all directly experienced the 2004 Indian Ocean Tsunami, and 25 controls, underwent structural MRI using a 3T scanner. We generated cortical thickness maps and parcellated sub-cortical volumes for analysis., Results: We observed greater cortical thickness for the trauma-exposed participants relative to controls, in a right lateralized temporal lobe region including anterior fusiform gyrus, and superior, middle, and inferior temporal gyrus., Conclusions: We observed greater thickness in the right temporal lobe which might indicate that the region could be implicated in resilience to the long-term effects of a traumatic event. We hypothesize this is due to altered emotional semantic memory processing. However, several methodological and confounding issues warrant caution in interpretation of the results.

The immunohistochemistry (IHC) performance of 4 anti-HER-2/neu antibodies was compared with fluorescent in situ hybridization (FISH) analysis of HER-2/neu gene expression in breast cancer patients considered for Herceptin (Trastuzumab) therapy. Interobserver variability in IHC interpretation was measured. Formalin-fixed tissue was received from 24 provincial hospital laboratories. The following anti-Her-2 antibodies were used: DAKO A0485 (polyclonal), Novacastra CB11 (monoclonal), Zymed TAB250 (monoclonal), and DAKO HercepTest (polyclonal). Additional sections were analyzed by FISH (Vysis). Three pathologists blinded to FISH results independently interpreted invasive tumor cell membranous staining on a scale of 0 to +3. The HER-2/neu gene was considered amplified when the FISH signal ratio of HER-2/CEP-17 was > or =2.0. Blocks from all hospitals and of all ages were suitable for IHC and FISH analysis. No interlaboratory analysis variability was noted. The interobserver agreement (kappa) for stain intensity for each antibody was good for 0 and +3 but poor for +1 and +2. Reasonable concordance between IHC and FISH was found with three of the four antibodies. TAB250 was the most sensitive antibody. For the three pathologists, the IHC sensitivities and specificities compared with FISH using 0/+1 as negative and +2/+3 as positive were as follows: A0485, 63-84/95-98; CB11, 63-66/97-98; TAB-250, 82-100/94-95; HercepTest, 59-77/91-93. The positive and negative predictive values varied by stain intensity. Stain scores of 0 and +3 were highly predictive of gene status. Stain scores of +1 and +2 were not sufficiently predictive to classify cases as amplified versus nonamplified. IHC is a reasonable first test to assess HER-2/neu status in patients with breast cancer. For most cases, DAKO A0485, TAB250, and HercepTest adequately predicted gene status. In cases with stain intensity of +1 or +2, the interobserver agreement is poor, and the predictive value is unsatisfactory for clinical use. Additional testing, preferably with FISH, is recommended.