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OBJECTIVE: The prevalence and significance of schizophrenia-related phenotypes at the population level is debated in the literature. Here, the authors assessed whether two recently reported neuroanatomical signatures of schizophrenia—signature 1, with widespread reduction of gray matter volume, and signature 2, with increased striatal volume—could be replicated in an independent schizophrenia sample, and investigated whether expression of these signatures can be detected at the population level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk. METHODS: This cross-sectional study used an independent schizophrenia-control sample (N=347; ages 16–57 years) for replication of imaging signatures, and then examined two independent population-level data sets: typically developing youths and youths with psychosis spectrum symptoms in the Philadelphia Neurodevelopmental Cohort (N=359; ages 16–23 years) and adults in the UK Biobank study (N=836; ages 44–50 years). The authors quantified signature expression using support-vector machine learning and compared cognition, psychopathology, and polygenic risk between signatures. RESULTS: Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youths with psychosis spectrum symptoms than in typically developing youths, whereas signature 2 frequency was similar in the two groups. In both youths and adults, signature 1 was associated with worse cognitive performance than signature 2. Compared with adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2. CONCLUSIONS: The authors successfully replicated two neuroanatomical signatures of schizophrenia and describe their prevalence in population-based samples of youths and adults. They further demonstrated distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

Genome-wide association studies (GWAS) have uncovered susceptibility loci associated with psychiatric disorders like bipolar disorder (BP) and schizophrenia (SCZ). However, most of these loci are in non-coding regions of the genome with unknown causal mechanisms of the link between genetic variation and disease risk. Expression quantitative trait loci (eQTL) analysis of bulk tissue is a common approach to decipher underlying mechanisms, though this can obscure cell-type specific signals thus masking trait-relevant mechanisms. While single-cell sequencing can be prohibitively expensive in large cohorts, computationally inferred cell type proportions and cell type gene expression estimates have the potential to overcome these problems and advance mechanistic studies. Using bulk RNA-Seq from 1,730 samples derived from whole blood in a cohort ascertained for individuals with BP and SCZ this study estimated cell type proportions and their relation with disease status and medication. We found between 2,875 and 4,629 eGenes for each cell type, including 1,211 eGenes that are not found using bulk expression alone. We performed a colocalization test between cell type eQTLs and various traits and identified hundreds of associations between cell type eQTLs and GWAS loci that are not detected in bulk eQTLs. Finally, we investigated the effects of lithium use on cell type expression regulation and found examples of genes that are differentially regulated dependent on lithium use. Our study suggests that computational methods can be applied to large bulk RNA-Seq datasets of non-brain tissue to identify disease-relevant, cell type specific biology of psychiatric disorders and psychiatric medication.

Using machine learning, we recently decomposed the neuroanatomical heterogeneity of established schizophrenia to discover two volumetric subgroups—a ‘lower brain volume’ subgroup (SG1) and an ‘higher striatal volume’ subgroup (SG2) with otherwise normal brain structure. In this study, we investigated whether the MRI signatures of these subgroups were also already present at the time of the first-episode of psychosis (FEP) and whether they were related to clinical presentation and clinical remission over 1-, 3-, and 5-years. We included 572 FEP and 424 healthy controls (HC) from 4 sites (Sao Paulo, Santander, London, Melbourne) of the PHENOM consortium. Our prior MRI subgrouping models (671 participants; USA, Germany, and China) were applied to both FEP and HC. Participants were assigned into 1 of 4 categories: subgroup 1 (SG1), subgroup 2 (SG2), no subgroup membership (‘None’), and mixed SG1 + SG2 subgroups (‘Mixed’). Voxel-wise analyses characterized SG1 and SG2 subgroups. Supervised machine learning analyses characterized baseline and remission signatures related to SG1 and SG2 membership. The two dominant patterns of ‘lower brain volume’ in SG1 and ‘higher striatal volume’ (with otherwise normal neuromorphology) in SG2 were identified already at the first episode of psychosis. SG1 had a significantly higher proportion of FEP (32%) vs. HC (19%) than SG2 (FEP, 21%; HC, 23%). Clinical multivariate signatures separated the SG1 and SG2 subgroups (balanced accuracy = 64%; p

ImportanceAutism spectrum disorder (ASD) is associated with significant clinical, neuroanatomical, and genetic heterogeneity that limits precision diagnostics and treatment.ObjectiveTo assess distinct neuroanatomical dimensions of ASD using novel semisupervised machine learning methods and to test whether the dimensions can serve as endophenotypes also in non-ASD populations.Design, Setting, and ParticipantsThis cross-sectional study used imaging data from the publicly available Autism Brain Imaging Data Exchange (ABIDE) repositories as the discovery cohort. The ABIDE sample included individuals diagnosed with ASD aged between 16 and 64 years and age- and sex-match typically developing individuals. Validation cohorts included individuals with schizophrenia from the Psychosis Heterogeneity Evaluated via Dimensional Neuroimaging (PHENOM) consortium and individuals from the UK Biobank to represent the general population. The multisite discovery cohort included 16 internationally distributed imaging sites. Analyses were performed between March 2021 and March 2022.Main Outcomes and MeasuresThe trained semisupervised heterogeneity through discriminative analysis models were tested for reproducibility using extensive cross-validations. It was then applied to individuals from the PHENOM and the UK Biobank. It was hypothesized that neuroanatomical dimensions of ASD would display distinct clinical and genetic profiles and would be prominent also in non-ASD populations.ResultsHeterogeneity through discriminative analysis models trained on T1-weighted brain magnetic resonance images of 307 individuals with ASD (mean [SD] age, 25.4 [9.8] years; 273 [88.9%] male) and 362 typically developing control individuals (mean [SD] age, 25.8 [8.9] years; 309 [85.4%] male) revealed that a 3-dimensional scheme was optimal to capture the ASD neuroanatomy. The first dimension (A1: aginglike) was associated with smaller brain volume, lower cognitive function, and aging-related genetic variants (FOXO3; Z = 4.65; P = 1.62 × 10−6). The second dimension (A2: schizophrenialike) was characterized by enlarged subcortical volumes, antipsychotic medication use (Cohen d = 0.65; false discovery rate–adjusted P = .048), partially overlapping genetic, neuroanatomical characteristics to schizophrenia (n = 307), and significant genetic heritability estimates in the general population (n = 14 786; mean [SD] h2, 0.71 [0.04]; P −4). The third dimension (A3: typical ASD) was distinguished by enlarged cortical volumes, high nonverbal cognitive performance, and biological pathways implicating brain development and abnormal apoptosis (mean [SD] β, 0.83 [0.02]; P = 4.22 × 10−6).Conclusions and RelevanceThis cross-sectional study discovered 3-dimensional endophenotypic representation that may elucidate the heterogeneous neurobiological underpinnings of ASD to support precision diagnostics. The significant correspondence between A2 and schizophrenia indicates a possibility of identifying common biological mechanisms across the 2 mental health diagnoses.

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Background: Normative modeling is a statistical approach to quantify the degree to which a particular individual-level measure deviates from the pattern observed in a normative reference population. When applied to human brain morphometric measures it has the potential to inform about the significance of normative deviations for health and disease. Normative models can be implemented using a variety of algorithms that have not been systematically appraised. Methods: To address this gap, eight algorithms were compared in terms of performance and computational efficiency using brain regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) collated from 87 international MRI datasets. Performance was assessed with the mean absolute error (MAE) and computational efficiency was inferred from central processing unit (CPU) time. The algorithms evaluated were Ordinary Least Squares Regression (OLSR), Bayesian Linear Regression (BLR), Generalized Additive Models for Location, Scale, and Shape (GAMLSS), Parametric Lambda, Mu, Sigma (LMS), Gaussian Process Regression (GPR), Warped Bayesian Linear Regression (WBLG), Hierarchical Bayesian Regression (HBR), and Multivariable Fractional Polynomial Regression (MFPR). Model optimization involved testing nine covariate combinations pertaining to acquisition features, parcellation software versions, and global neuroimaging measures (i.e., total intracranial volume, mean cortical thickness, and mean cortical surface area). Findings: Statistical comparisons across models at PFDR

The prevalence and significance of schizophrenia-related phenotypes at the population-level are debated in the literature. Here we assess whether two recently reported neuroanatomical signatures of schizophrenia, signature 1 with widespread reduction of gray matter volume, and signature 2 with increased striatal volume, could be replicated in an independent schizophrenia sample, and investigate whether expression of these signatures can be detected at the population-level and how they relate to cognition, psychosis spectrum symptoms, and schizophrenia genetic risk. This cross-sectional study used an independent schizophrenia-control sample (n=347; age 16-57 years) for replication of imaging signatures, and then examined two independent population-level datasets: Philadelphia Neurodevelopmental Cohort [PNC; n=359 typically developing (TD) and psychosis-spectrum symptoms (PS) youth] and UK Biobank (UKBB; n=836; age 44-50 years) adults. We quantified signature expression using support-vector machine learning, and compared cognition, psychopathology, and polygenic risk between signatures. Two neuroanatomical signatures of schizophrenia were replicated. Signature 1 but not signature 2 was significantly more common in youth with PS than TD youth, whereas signature 2 frequency was similar. In both youth and adults, signature 1 had worse cognitive performance than signature 2. Compared to adults with neither signature, adults expressing signature 1 had elevated schizophrenia polygenic risk scores, but this was not seen for signature 2. We successfully replicate two neuroanatomical signatures of schizophrenia, and describe their prevalence in population-based samples of youth and adults. We further demonstrate distinct relationships of these signatures with psychosis symptoms, cognition, and genetic risk, potentially reflecting underlying neurobiological vulnerability.

Subjective well-being (SWB) is associated with treatment adherence and symptom outcome in people with psychotic disorders. Also, it is associated with psychosis susceptibility and it is partly hereditable. The SWN-20 is a widely used tool to assess subjective well-being in patients; it was also found to be suitable for assessing SWB in healthy populations. Yet it is unclear how this retrospectively measured construct may be associated with momentary affective state, which is the proposed underlying mechanism of subjective well-being. This study therefore investigated the ecological validity of the SWN-20 in people at different risk for psychosis. In 63 patients with a psychotic disorder and 61 siblings of patients with a psychotic disorder we assessed whether subjective well-being as measured with the SWN-20, was associated with momentary positive affect, negative affect, reward experience and stress-sensitivity as measured by the experience sample method (ESM). Higher subjective well-being was associated with higher momentary positive affect and lower negative affect, and this association was not conditional on psychosis vulnerability. Subjective well-being was not associated with stress sensitivity or reward-experience. SWN-20 is an easy-to-use and ecologically valid tool to measure subjective well-being in people with different vulnerability for psychosis.

The authors regret that the GROUP-investigators were not acknowledged for their work due to a missing affiliation in the original publication. The new authorship line is: Annemarie P.M. Stiekema a,b Md Atiqul Islam c,d,e Edith J. Liemburg c,d,f Stynke Castelein c,g Edwin R. van den Heuvel h Jaap van Weeghel i,j Andre Aleman f,k Richard Bruggeman c,d Lisette van der Meer a,c GROUP-investigators l a Lentis Psychiatric Institute, Department of Rehabilitation, Zuidlaren, The Netherlands b School for Mental Health and Neuroscience, Faculty of Health, Medicine and Life Sciences, Maastricht University Medical Centre, Maastricht, The Netherlands c University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Groningen, The Netherlands d University of Groningen, University Medical Center Groningen, Groningen, Rob Giel Research center, The Netherlands e Department of Statistics, Shahjalal University of Science and Technology, Sylhet 3114, Bangladesh f University of Groningen, University Medical Center Groningen, Department of Neuroscience, Groningen, The Netherlands g Lentis Psychiatric Institute, Research Department, Groningen, The Netherlands h Department of Mathematics and Computer Science, Eindhoven University of Technology, Eindhoven, The Netherlands i Parnassia Group, Dijk en Duin Mental Health Center, Castricum, The Netherlands j Department of TRANZO, Tilburg School of Social and Behavioral Sciences, Tilburg University, The Netherlands k University of Groningen, Department of Clinical Psychology and Experimental Psychopathology, Groningen, The Netherlands l GROUP investigators are: Behrooz Z. Alizadeh m , Agna A. Bartels-Velthuis n , Nico J. van Beveren o,p,q , Richard Bruggeman n , Wiepke Cahn r , Lieuwe de Haan s , Philippe Delespaul t , Carin J. Meijer s , Inez Myin-Germeys u , Rene S. Kahn r , Frederike Schirmbeck s , Claudia J.P. Simons t,v , Neeltje E.M. van Haren r,w , Jim van Os t,x , Ruud van Winkel u m University of Groningen, University Medical Center Groningen, Department of Epidemiology, Groningen, The Netherlands n University of Groningen, University Medical Center Groningen, University Center for Psychiatry, Rob Giel Research center, Groningen, The Netherlands o Antes Center for Mental Health Care, Rotterdam, The Netherlands p Erasmus MC, Department of Psychiatry, Rotterdam, The Netherlands q Erasmus MC, Department of Neuroscience, Rotterdam, The Netherlands r University Medical Center Utrecht, Department of Psychiatry, Brain Centre Rudolf agnus, Utrecht, The Netherlands s Academic Medical Center, University of Amsterdam, Department of Psychiatry, Amsterdam, The Netherlands t Maastricht University Medical Center, Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht, The Netherlands u KU Leuven, Department of Neuroscience, Research Group Psychiatry, Center for Clinical Psychiatry, Leuven, Belgium v GGzE, Institute for Mental Health Care Eindhoven and De Kempen, Eindhoven, The Netherlands w Department of Child and Adolescent Psychiatry/Psychology, Erasmus Medical Centre, Rotterdam, Netherlands x King's College London, King's Health Partners, Department of Psychosis Studies, Institute of Psychiatry, London, United Kingdom The authors apologise for any inconvenience caused.

Polygenic risk scores have shown great promise in predicting complex disease risk and will become more accurate as training sample sizes increase. The standard approach for calculating risk scores involves linkage disequilibrium (LD)-based marker pruning and applying a p value threshold to association statistics, but this discards information and can reduce predictive accuracy. We introduce LDpred, a method that infers the posterior mean effect size of each marker by using a prior on effect sizes and LD information from an external reference panel. Theory and simulations show that LDpred outperforms the approach of pruning followed by thresholding, particularly at large sample sizes. Accordingly, predicted R-2 increased from 20.1% to 25.3% in a large schizophrenia dataset and from 9.8% to 12.0% in a large multiple sclerosis dataset. A similar relative improvement in accuracy was observed for three additional large disease datasets and for non-European schizophrenia samples. The advantage of LDpred over existing methods will grow as sample sizes increase. Refereed/Peer-reviewed

Patients with schizophrenia show symptom reduction early after the initiation of drug treatment, but no consensus has been reached on the number of weeks after which a nonresponding patient should be switched to an alternative treatment. We aimed to test whether patients should be switched to an alternative treatment at 2, 4, or 6 weeks from treatment initiation. Remission within 12 months was assessed in 299. first-episode patients who completed the full 12-month European First-Episode Schizophrenia Trial. Logistic regression analyses were used to test whether the prediction of remission was improved by including assessments obtained 4 or 6 weeks from treatment initiation compared with a prediction based on baseline and 2-week measures only. Based on baseline and 2-week assessments, remission status was correctly predicted in 61% of the patients (positive and negative predictive power, 0.61 and 0.58, respectively; sensitivity, 0.94; and specificity, 0.12). This percentage increased to 63% (positive and negative predictive power, 0.67 and 0.55, respectively; sensitivity, 0.73; and specificity, 0.47) and 68% (positive and negative predictive power, 0.73 and 0.61, respectively; sensitivity, 0.73; and specificity, 0.60) by the inclusion of 4- and 6-week assessments, respectively. Although we confirmed earlier. findings that 2-week measures of response are associated with remission, the prediction of remission is significantly improved by the inclusion of 4- and 6- week assessments. However, as the increase in prediction accuracy is modest, it is uncertain whether this improvement is clinically relevant.

There has been an increasing interest in the identification of genetic variants causing individual differences in human behavior. Psychiatrists have contributed to the genetics field by defining the most important behavioral characteristics and by studying the association between genetic variants and behavioral differences within phenotypically well‐characterized samples in which detailed assessments have been collected (e.g. neuroimaging). These samples are typically limited in size and are therefore not suitable for a genome‐wide association analysis. Instead, gene association studies conducted in such samples typically focus on a few genes of interest, allowing smaller sample sizes. However, the selection of high‐priority genes is not always straightforward and psychiatrists will usually have a limited background in genetics. We aim to fill this gap by (i) providing a basic introduction to genetics; (ii) showing how the selection of genes of interest can be optimized by the use of two web tools: Polysearch and Gene Prospector; (iii) illustrating how statistical power analyses can be performed and discussing the importance of sufficiently powered studies. This guide can help psychiatrists with limited experience in genetics in designing genetic studies that allow identification of specific behavioral, cognitive, or neural correlates of genetic risk variants, while avoiding common pitfalls. Copyright © 2015 John Wiley & Sons, Ltd.

Healthy aging is associated with a progressive decline across a range of cognitive functions. An important factor underlying this decline may be the age‐related impairment in stimulus–reward processing. Several studies have investigated age‐related effects, but compared young versus old subjects. This is the first study to investigate the effect of aging on brain activation during reward processing within a continuous segment of the adult life span. We scanned 49 healthy adults aged 40–70 years, using functional MRI. We adopted a simple reward task, which allowed separate evaluation of neural responses to reward anticipation and receipt. The effect of reward on performance accuracy and speed was not related to age, indicating that all subjects could perform the task correctly. We identified a whole‐brain significant age‐related decline of ventral striatum activation during reward anticipation as compared to neutral anticipation. Importantly, the specificity of this finding was underscored by the observation that there was no general decline in activation during anticipation. Activation in the ventral striatum increased with age during reward receipt as compared to receiving neutral outcome. Finally, activation in the ventromedial prefrontal cortex during outcome was not affected by age. Our data demonstrate that the typical shift in striatal activation from reward receipt to reward anticipation in young adults disappears with healthy aging. These changes are consistent the well‐ocumented age‐related decline of striatal dopamine availability, and may provide a stepping stone for further research of age‐related neurodegenerative diseases. Hum Brain Mapp 36:2305–2317, 2015. © 2015 Wiley Periodicals, Inc.

The long-standing notion of schizophrenia as a disorder of connectivity is supported by emerging evidence from recent neuroimaging studies, suggesting impairments of both structural and functional connectivity in schizophrenia. However, investigations are generally restricted to supratentorial brain regions, thereby excluding the cerebellum. As increasing evidence suggests that the cerebellum contributes to cognitive and affective processing, aberrant connectivity in schizophrenia may include cerebellar dysconnectivity. Moreover, as schizophrenia is highly heritable, unaffected family members of schizophrenia patients may exhibit similar connectivity profiles. The present study applies resting-state functional magnetic resonance imaging to determine cerebellar functional connectivity profiles, and the familial component of cerebellar connectivity profiles, in 62 schizophrenia patients and 67 siblings of schizophrenia patients. Compared to healthy control subjects, schizophrenia patients showed impaired functional connectivity between the cerebellum and several left-sided cerebral regions, including the hippocampus, thalamus, middle cingulate gyrus, triangular part of the inferior frontal gyrus, supplementary motor area, and lingual gyrus (all p< 0.0025, whole-brain significant). Importantly, siblings of schizophrenia patients showed several similarities to patients in cerebellar functional connectivity, suggesting that cerebellar dysconnectivity in schizophrenia might be related to familial factors. In conclusion, our findings suggest that dysconnectivity in schizophrenia involves the cerebellum and that this defect may be related to the risk to develop the illness.

To identify and control renal factors affecting plasma homovanillic acid (HVA), a dopamine metabolite and an indicator of brain dopamine activity in clinical research, nine healthy subjects were studied on 5 nonconsecutive days. First study day was the baseline and on the other days base, salt, water, or probenecid loads were given. On each day serial concentrations of HVA and serotonin metabolite 5-hyroxyindoleacetic acid (HIAA), another organic anion, in plasma were measured. Results suggested that base, salt, and water loads did not affect plasma concentrations of either metabolite. Probenecid, which partially blocks renal organic anion transport, induced similar increases in plasma HVA and HIAA. When plasma HVA:HIAA ratio was used to control for the effect of probenecid, differences between baseline and probenecid days were no longer significant. Results suggest that HVA and HIAA are similarly handled by the kidney and that simultaneously measured plasma HIAA could be used to distinguish renal influences in plasma HVA studies.

A placebo-controlled dose-response study of the direct serotonin receptor agonist m-chlorophenylpiperazine (MCPP), intravenously infused over 90 s in 0.06 and 0.08 mg/kg doses, was conducted in nine normal male subjects. Cortisol, prolactin, MCPP serum levels and behavioral responses were measured over a 210-min period. Both doses caused significant cortisol and prolactin release and were associated with significantly greater behavioral effects as compared to placebo. Though the two doses were associated with different MCPP serum levels, they did not significantly differ in their hormonal and behavioral effects.

In a neuroendocrine challenge paradigm, the present study investigated responses of schizophrenic patients to m-chlorophenylpiperazine (MCPP), a serotonin (5-hydroxytryptamine, 5HT) agonist. In an oral dose of 0.25 mg/kg, MCPP was administered in a placebo-controlled double-blind design to male schizophrenic patients (n = 7) and normal male controls (n = 8). Behavioral (Positive and Negative Syndrome Scale; PANSS) and hormonal (cortisol, prolactin) variables were measured over the subsequent 210 min. The schizophrenic patients experienced an overall exacerbation of psychopathology on MCPP as compared with placebo (p less than 0.05), with specific worsening of PANSS-positive symptoms (p less than 0.025) and PANSS activation (p less than 0.001). In addition, the schizophrenic patients showed significantly lower cortisol (p less than 0.05) and prolactin (p less than 0.05) responses than the normal subjects. The schizophrenic patients had lower peak MCPP blood levels than the normal subjects, although this difference was not statistically significant. The findings are discussed in terms of 5HT receptor(s) sensitivity and the pharmacokinetics of MCPP in schizophrenia.

Apart from imipramine (IMI), the efficacy of tricyclic antidepressants in panic disorder (PD) has received surprisingly little investigation. The authors report on a 6 week open trial of desipramine (DMI) preceded by a 10 day placebo lead-in, in 15 patients with PD. By week 6, 80% of the patients were globally rated as much or very much improved on a mean dose of 198 mg. Much of the improvement resulted from a reduction in non-panic attack symptomatology (i.e., psychic, somatic and phobic anxiety). Longer duration of illness, male gender and residual psychic anxiety were associated with poorer response in a subgroup of patients. DMI caused minimal intolerable side effects, suggesting possible compliance advantages in comparison to IMI. Beyond supporting the efficacy of DMI in PD, the results of the study point to a significant medication responsive non-panic illness component and caution against over-relying on panic attacks in assessing both illness severity and treatment response.

The response of a hormone allegedly under 5-hydroxytryptaminergic (5-HT-ergic) control to a compound stimulating or inhibiting serotonergic activity has been used as a measure of the functional state of central serotonergic systems. The relevant literature is reviewed, and based on that, it is concluded that, as yet, no reliable hormonal 5-HT probe exists. The main problems are nonselectivity of the challengers and noncomparability of individual studies because of variations in dose and route of administration. An acceptable hormonal 5-HT probe should at least have passed the following three tests. 1. (1) The influence of the challenger on catecholaminergic (CA) systems must be rendered unlikely in humans to avoid the pitfalls of, say, the 5-HT precursors whose CA-ergic influences have been overlooked. 2. (2) Dose-response relationships must be established to avoid the confusion caused by different investigators using the challenger in different doses. 3. (3) It must be demonstrated that the effect of the challenger is counteracted by its functional opponent.

Serotonin (5hydroxytryptamine; 5-HT) was first discovered in 1948 in blood platelets and a few years later in the brain. Since then, investigations of 5-HT involvement in mental disorders have contributed to major advances in psychiatry. 5-m distances were initially linked to the p~ogenesis of depression. A subgroup of depressed patients was noted to have decreased 5-HT metabolism in the central nervous system (CNS) (van Praag and Korf 1971). Further studies indicated that lowered 5-HT metabolism correlated with particular dimensions of psychopathology that may occur within depressive disorders but likewise within other syndromes. One of these dimensions is dyscontrol of aggression, leading to suicide or to outwardly directed aggression (van Praag 1986). A second psychopathological dimension appears to be related to anxiety. Evidence relevant to this latter conclusion will be summarized in this article. Most data on the relationship of 5-HT to anxiety are derived from animal studies. Research using human subjects has only recently begun. We think that the substanti~ body of animal findings and the exciting new human data warrant a reexamination of the role of 5-HT in the pathogenesis of anxiety. We will propose a 5-HT hypothesis of anxiety that takes into account 5-HT availability as well as receptor sensitivity. H-IT Systems in the Brain The raphe nuclei in the brain stem, encompassing the dorsal raphe and medial raphe nuclei, contain the cell bodies of 5-HT-producing neurons. From there, six major projections ascend to the forebrain, two tracts within the median forebrain bundle and four outside of it. Cortex, hypothalamus, thalamus, basal ganglia, substantia nigra, caudate, putamen, amygdala, hippocampus, septum, tegmentum, and mamillary bodies are all innervated by 5-HT neurons (Azmitia and Segal 1978). Two major subcategories of 5HT receptors have been identified in the CNS, labeled 5-HTr (Perot&a 1984) and 5-HT2 (Leysen et al. 1984). 5-HTr receptors are further su~Iassifi~ as 5-HTr,, 5-HTu,, 5HTr,, and 5-HTrd receptors. 5-HT,, receptors display a very high affinity for 8-hydroxyNJV-dipropyl-2-aminotetralin (80HDAP) and are found in the human frontal cortex and

5-Hydroxytraptamine (5-HT) disorders have been reported to occur in a variety of psychiatric disorders. The situation has been called chaotic, the disturbances non-specific. We reject this viewpoint. 5-HT disturbances are non-specific only from a nosological/categorical viewpoint; they seem rather specific from a functional/dimensional point of view, correlating as they do with particular psychopathological dimensions, i.e. aggression-, anxiety- and possibly mood-disregulation, across diagnosis. The evolution of 5-HT research in psychiatry illustrates the importance of what we have called the functional approach, implying dissection of a given psychopathological syndrome in its component parts, i.e., the psychological dysfunctions, and searching for correlations between biological and psychological dysfunctions. The rigid preoccupation of biological psychiatry with the search for markets of disease entities has hampered progress. The functional approach should be incorporated in biological psychiatry, not as an alternative for the nosological approach but as its complement.

Normal controls (NC) (n = 15), patients with panic disorder (PD) (n = 13) and patients with major depression (MD) (n = 17) were challenged with a single, oral dose (0.25 mg/kg) of the selective 5HT agonist m-chlorophenyl-piperazine (MCPP) or placebo. Blood samples were assayed for cortisol and MCPP levels every 30 min. The PD group had an augmented cortisol release when compared to the other two groups. Finally, a significant correlation was found across all subjects between clinical anxiety level and cortisol release on MCPP. These data support the hypothesis of 5HT receptor hypersensitivity in PD.