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This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of Biological Psychiatry Editor John H. Krystal, M.D., with agreement from all authors except Chen Chen and Emily Valente. These two co-authors moved and, with no forwarding information that was available or could be found, they were therefore unable to be contacted. The authors have uncovered irregularities and deviations from the approved protocol related to the work reported in this article. Treatment with antidepressant medications within the past 28 days was an exclusion criterion: “Subjects were excluded for… current treatment or treatment within the past 4 weeks with psychotropic or other medications known to affect dopamine.” Individuals taking an ineffective antidepressant medication who otherwise met study criteria were to undergo a study-supervised medication taper to discontinue their medication for the required period prior to study participation. The published article does not describe that a subgroup of participants (15 out of the 47 consented subjects) enrolled in the study while taking an ineffective antidepressant medication. Of this subgroup, 10 individuals were successfully tapered off their medication and were among the 36 subjects contributing data to the analyses described. In addition, the authors have found that 8 participants did not complete the required 28-day washout prior to beginning the study. For these 8 participants, the medication-free period ranged from 1 to 21 days, with a mean of 10.1 days. Separately, an inclusion criterion was that eligible subjects “had Center for Epidemiologic Studies—Depression Rating scale score ≤ 10.” However, the authors have found that 3 ineligible participants were included, each of whom had depressive symptom scores 1 point out of range for eligibility. Lastly, the CONSORT diagram in Figure S1 states that 11 participants were lost to follow-up. However, this is incorrect. Instead, 9 participants were lost to follow up and 2 participants were screen failures. The authors voluntarily informed the Journal of these honest errors upon discovery. Because of the extent of these issues, the editors and authors concluded that the only course of action was to retract this paper. However, the authors are revising the paper, which the Journal will consider further for publication., (Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

This paper reviews the evidence that antipsychotic drugs induce neuroplasticity. We outline how the synaptic changes induced by the antipsychotic drug haloperidol may help our understanding of the mechanism of action of antipsychotic drugs in general, and how they may help to elucidate the neurobiology of schizophrenia. Studies have provided compelling evidence that haloperidol induces anatomical and molecular changes in the striatum. Anatomical changes have been documented at the level of regional brain volume, synapse morphology, and synapse number. At the molecular level, haloperidol has been shown to cause phosphorylation of proteins and to induce gene expression. The molecular responses to conventional antipsychotic drugs are predominantly observed in the striatum and nucleus accumbens, whereas atypical antipsychotic drugs have a subtler and more widespread impact. We conclude that the ability of antipsychotic drugs to induce anatomical and molecular changes in the brain may be relevant for their antipsychotic properties. The delayed therapeutic action of antipsychotic drugs, together with their promotion of neuroplasticity suggests that modification of synaptic connections by antipsychotic drugs is important for their mode of action. The concept of schizophrenia as a disorder of synaptic organization will benefit from a better understanding of the synaptic changes induced by antipsychotic drugs.

This paper discusses the current practice of using single word labels for emotional states that ignore the nature of the incentive, cognitive representations, physiologic profile, and especially the developmental stage of the agent. The universal cognitive advances that are derivatives of brain maturation over the first dozen years are accompanied by significant emotional states that infants and young children cannot experience. The cognitive transitions at the end of the first year, the middle of the second year, 5-7 years and early adolescence have special implications for affect states.

This paper reviews prior research studies examining neurobiological correlates and treatment response of depression in children, adolescents, and adults. Although there are some similarities in research findings observed across the life cycle, both children and adolescents have been found to differ from depressed adults on measures of basal cortisol secretion, corticotropin stimulation post-corticotropin releasing hormone (CRH) infusion, response to several serotonergic probes, immunity indices, and efficacy of tricyclic medications. These differences are proposed to be due to 1) developmental factors, 2) stage of illness factors (e.g., number of episodes, total duration of illness), or 3) heterogeneity in clinical outcome (e.g., recurrent unipolar course vs. new-onset bipolar disorder). Relevant clinical and preclinical studies that provide support for these alternate explanations of the discrepant findings are reviewed, and directions for future research are discussed. To determine whether child-, adolescent-, and adult-onset depression represent the same condition, it is recommended that researchers 1) use the same neuroimaging paradigms in child, adolescent, and adult depressed cohorts; 2) carefully characterize subjects' stage of illness; and 3) conduct longitudinal clinical and repeat neurobiological assessments of patients of different ages at various stages of illness. In addition, careful attention to familial subtypes (e.g., depressive spectrum disorders vs. familial pure depressive disorders) and environmental factors (e.g., trauma history) are suggested for future investigations.

This paper considers the influence of temperamental factors on the development of anxious symptoms in children and adolescents. About 20 percent of healthy children are born with a temperamental bias that predisposes them to be highly reactive to unfamiliar stimulation as infants and to be fearful of or avoidant to unfamiliar events and people as young children. Experiences act on this initial temperamental bias and, by adolescence, about one-third of this group is likely to show signs of serious social anxiety. These children are also likely to have one or more biological features, including a sympathetically more reactive cardiovascular system, asymmetry of cortical activation in EEG favoring a more active right frontal area, more power in the EEG in the higher frequency range, and a narrower facial skeleton. The data imply that this temperamental bias should be conceptualized as constraining the probability of developing a consistently fearless and spontaneous profile rather than as determining an anxious or introverted phenotype.

Background: The high-risk strategy is one of the most powerful approaches for identifying premorbid risk factors and reducing etiologic and phenotypic heterogeneity characteristic of the major psychiatric disorders., Methods: This paper reviews the methods of high-risk research and findings from previous high-risk studies of anxiety. The preliminary results of the 6-8 year follow-up of a high-risk study of 192 offspring of probands with anxiety disorders, substance abuse, and unaffected controls are presented. The key study measures include comprehensive diagnostic interviews, symptom ratings, indirect measures of brain functioning (neuropsychologic, neurologic and psychophysiologic function), developmental measures, and family functioning measures., Results: The major findings reveal that there is specificity of familial aggregation of anxiety disorders among parents and children; children at high risk for anxiety have increased startle reflex, autonomic reactivity, and stress reactivity, higher verbal IQ, and deficits in paired associative learning as compared to other children., Conclusions: The finding that family environment and parenting do not differ between children at risk for anxiety disorders and other children, when taken together with the strong degree of specificity of transmission of anxiety disorders, suggests that there may be temperamental vulnerability factors for anxiety disorders in general that may already manifest in children prior to puberty.

The field of psychiatry has an opportunity to construct a more refined, perhaps more enduring understanding of the ethical basis of mental illness research. The aim of this paper is to help advance this understanding by 1) tracing the evolution of the emerging ethic for biomedical experimentation, including recent recommendations of the President's National Bioethics Advisory Commission, and 2) reviewing data and concepts related to compelling ethical questions now faced in the study of mental disorders. Empirical findings on informed consent, the ethical safeguards of institutional review and surrogate decision making, and the relationship between scientific and ethical imperatives are outlined. Psychiatric researchers will increasingly be called upon to justify their scientific approaches and to seek ways of safeguarding the well-being of people with mental illness who participate in experiments. Most importantly, psychiatric investigators will need to demonstrate their appreciation and respect for ethical dimensions of investigation with special populations. Further empirical study and greater sophistication with respect to the distinct ethical issues in psychiatric research are needed. Although such measures present many challenges, they should not interfere with progress in neuropsychiatric science so long as researchers in our field seek to guide the process of reflection and implementation.

Schizophrenia is likely to be caused by several susceptibility genes and may have environmental factors that interact with susceptibility genes and/or nongenetic causes. Recent evidence supports the likelihood that 22q11 Deletion Syndrome (22qDS) represents an identifiable genetic subtype of schizophrenia. 22qDS is an under-recognized genetic syndrome associated with microdeletions on chromosome 22 and a variable expression that often includes mild congenital dysmorphic features, hypernasal speech, and learning difficulties. Initial evidence indicates that a minority of patients with schizophrenia (approximately 2%) may have 22qDS and that prevalence may be somewhat higher in subpopulations with developmental delay. This paper proposes clinical criteria (including facial features, learning disabilities, hypernasal speech, congenital heart defects and other congenital anomalies) to aid in identifying patients with schizophrenia who may have this subtype and outlines features that may increase the index of suspicion for this syndrome. Although no specific causal gene or genes have yet been identified in the deletion region, 22qDS may represent a more homogeneous subtype of schizophrenia. This subtype may serve as a model for neurodevelopmental origins of schizophrenia that could aid in delineating etiologic and pathogenetic mechanisms.

The variation in functional outcome in schizophrenia appears to be exaggerated in late life. The cognitive and functional deficits commonly seen in younger schizophrenic patients appear to worsen in some cases in late life, while others patients appear to have a stable course of illness without functional decline, and still other patients have been reported to have essentially no residual symptoms in their later years. Cognitive and functional deficits appear to worsen more significantly in patients with a lifetime course of severe functional deficit. Despite the profound functional and cognitive deficits in these patients, neuropathologic studies have found no evidence of typical causes of severe cognitive impairments. This paper reviews the current findings on cognitive and functional changes in aging in schizophrenia, with a specific focus on patients with a poor lifetime functional outcome.

The present review explores the descriptive epidemiology of schizophrenia. Risk factors and correlates are divided into three groups based on whether the available evidence is consistent and strong, consistent and potentially strong, or inconsistent. The paper then considers epidemiologic studies of the course of illness, including a description of findings from the Suffolk County Mental Health Project. Given renewed attention to the need for preventive interventions for individuals at high risk for developing a psychotic illness, epidemiologic values have become more and more central to the conduct of clinical research.

Background: Psychosis is a defining feature of schizophrenia consisting of formal thought disorder, delusions, and hallucinations. Although psychosis is present in the majority of patients with schizophrenia, the prevalence, responsiveness to atypical antipsychotic drug therapy, and prediction of outcome of individual psychotic symptoms in a population of well-diagnosed patients with schizophrenia have not been conclusively established., Methods: This paper examined the prevalence, responsiveness to the atypical antipsychotic olanzapine, and relationship to outcome of individual psychotic symptoms using data from a previously reported large multicenter, double-blind clinical trial of olanzapine (mean daily dose at endpoint = 13.6 +/- 6.9 mg/day)., Results: The most frequently reported psychotic symptoms at baseline were delusions (65%), conceptual disorganization (50%), and hallucinations (52%), and the majority of patients (68%) experienced from one to three symptoms. Additionally, with olanzapine treatment there were significant improvements (p < .001) in baseline to endpoint Positive and Negative Symptom Scale (PANSS) psychotic item scores, with the largest effect sizes observed for hallucinatory behavior, unusual thought content, suspiciousness/persecution, and delusions. During the acute phase of the trial, quality of life was correlated significantly with baseline conceptual disorganization (p = .038) and unusual thought content (p = .023), and time spent in the hospital was correlated with unusual thought content (p = .005)., Conclusions: The implications of these for the clinical management of schizophrenia are discussed.

Background: Abnormalities of dopamine function in schizophrenia are suggested by the common antidopaminergic properties of antipsychotic medications. However, direct evidence of a hyperdopaminergic state in schizophrenia has been difficult to demonstrate, given the difficulty to measure dopamine transmission in the living human brain. Such evidence has recently emerged. Three studies reported an increase in dopamine transmission following acute amphetamine challenge in patients with schizophrenia compared to matched healthy control subjects, thus demonstrating a dysregulation of dopamine in schizophrenia. In all studies, a large variance was observed within the schizophrenic group in the magnitude of this finding, and clinical predictors of this effect could not be identified., Methods: In this paper, we combined previously published and newly acquired data to obtain sufficient power to address this question., Results: The most important findings derived from this extended data set are: 1) dysregulation of dopamine function revealed by the amphetamine challenge is present at onset of illness and in patients never previously exposed to neuroleptic medications; 2) this dysregulation was observed in patients experiencing an episode of illness exacerbation, but not in patients studied during a remission phase., Conclusions: A hyperdopaminergic state is present in schizophrenia during the initial episode and subsequent relapses, but not in periods of remission. This finding has important consequences for the development of new treatment strategies for the remission phase.

The genetic association strategy is currently being applied to a number of psychiatric phenotypes including disease vulnerability, personality variation and clinical response to psychotropic drugs. Association studies offer the prospect of identification of the specific alleles that confer significant effects on clinical phenotype. However, it should be noted that this strategy has additional advantages as well as unique drawbacks. In this paper, we review the basic methodology utilized in each step of a typical psychiatric genetic association study and discuss their potential benefits and pitfalls with particular emphasis on the selection of clinical phenotype, the identification of a candidate gene, the selection of a candidate variant, clinical data set design, and the statistical analysis of association data. With appropriate design and execution, it is hoped that the association strategy will prove to be as successful in psychiatry as it has proven to be in other branches of medicine.

Since bipolar disorder is inherently a longitudinal illness characterized by recurrence and cycling of mood episodes, neurobiological theories involving kindlinglike phenomena appear to possess a certain explanatory power. An approach to understanding kindlinglike phenomena at the molecular level has been made possible by advances in research on second-messenger systems in the brain. The time frame of interest has shifted from the microseconds of presynaptic events to hours, days, months, and even years in the longer duration of events beyond the synapse--through second messengers, gene regulation, and synthesis of long-acting trophic factors. These complex interlocking systems may explain how environmental stress could interact over time with genetic vulnerability to produce illness. In its two sections, this paper will review an approach to understanding two major aspects of the neurobiology of bipolar disorder: kindling phenomena and second-messenger mechanisms. We will suggest that these two fields of research together help explain the biology of recurrence.

Social phobia (or "social anxiety disorder") is a prevalent condition that has been the subject of increased scrutiny in recent years. The purpose of this paper is to review the neurobiology of social phobia. It is apparent from the extant literature that this disorder is poorly understood from a neurobiological perspective. There are nonetheless a number of clinical and preclinical observations which, at times, converge to illuminate areas worthy of further study. Included in this category are suggestive findings of central serotonergic dysregulation in social phobia, response to serotonin reuptake inhibitors in social phobia, and the role of serotonergic function in septohippocampal models of anxiety. Abnormalities in central dopaminergic function are also posited, supported to some extent by recent neuroimaging findings. There are in addition a number of animal and human behavioral models in existence that may be relevant to the study of social phobia. Included in this category are models of social dominance in wild baboons, social affiliation in the prairie vole, and behavioral inhibition to the unfamiliar in childhood. Newer technologies that are likely to play a major role in the delineation of the neural circuitry (e.g., functional magnetic resonance imaging) and heritability (e.g., molecular genetics) of social phobia are discussed. Finally, an interactive role for biology and experience in the expression of social phobia is considered.

Posttraumatic stress disorder (PTSD) is a psychiatric condition that is directly precipitated by an event that threatens a person's life or physical integrity and that invokes a response of fear, helplessness, or horror. In recent years it has become clear that only a proportion of those exposed to fear-producing events develop or sustain PTSD. Thus, it seems that an important challenge is to elucidate aberrations in the normal fear response that might precipitate trauma-related psychiatric disorder. This paper summarizes the findings from recent studies that examined the acute and longer term biological response to traumatic stress in people appearing to the emergency room immediately following trauma exposure. In the aggregate, these studies have demonstrated increased heart rate and lower cortisol levels at the time of the traumatic event in those who have PTSD at a follow-up time compared to those who do not. In contrast, certain features associated with PTSD, such as intrusive symptoms and exaggerated startle responses, are only manifest weeks after the trauma. The findings suggest that the development of PTSD may be facilitated by an atypical biological response in the immediate aftermath of a traumatic event, which in turn leads to a maladaptive psychological state.

This paper reviews the pathophysiology of panic disorder (PD), within the context of newly described "fear circuitries," which have been well characterized in preclinical models. Substantial advances in the neurosciences have made it possible for clinical neuroscientists to refine our understanding of the pathophysiology of PD and the mechanisms of currently effective treatment. These advances have in turn helped generate testable hypotheses for future neurobiological and psychopharmacologic research. Perturbation of mutual modulation ("cross talk") between key brain transmitter systems (serotonin, norepinephrine, gamma-aminobutyric acid, corticotropin-releasing factor, and others) may underlie the pathogenesis of panic-anxiety. Restoration of normal homeostasis may be an important therapeutic component of antipanic therapy and may provide information about underlying neurocircuits. Neuroimaging, an important new tool, has already begun to bridge the gap between the preclinical and clinical neurosciences through confirmation of hypothesized dysfunction of the complex human prefrontal cortex and its subcortical components. In higher species, such as humans, dysfunction of cortical inhibition or excessive cortical activation of caudal limbic structures is postulated to lead to activation of the phylogenetically conserved amygdalofugal pathways. Consistent with probable subtypes of PD, overlapping theoretical models of panic neurocircuitries are proposed, including ventilatory dysregulation, which is coupled with neurovascular instability in a critical area of the panic neurocircuitry--the amygdalohippocampus. Neuroimaging appears a critical tool in guiding further elaboration of the interaction of cortical and subcortical components of the panic neurocircuitry, whereas challenge studies appear crucial in gathering further information regarding brain stem dysfunction.

Recent attention has been focused on the involvement of serotonin (5-HT) in the pathophysiology of schizophrenia and its role in mediating antipsychotic drug effects. There are two reasons for the new emphasis: the tremendous success of the so-called "atypical" antipsychotic drugs (a common feature of which is their high affinity for specific 5-HT receptor subtypes); and the elucidation of a complex family of 5-HT receptors whose function and pharmacology is only beginning to be understood. This paper will review the evidence that pertains to the role of 5-HT in mediating antipsychotic drug effects. The interaction of dopamine and 5-HT systems will be reviewed, and the mechanisms of action of atypical antipsychotic drugs will be evaluated in this context. The impact of serotonin on neurodevelopment, and the involvement of serotonin in the psychotomimetic and psychotogenic properties of hallucinogens, will be discussed. Together, these facts will be placed into the context of changes in serotonergic function in schizophrenia.

Background: Changes in serotonin (5-HT) have been described in both Alzheimer's disease (AD) and aggressive/agitated behaviors. This paper explores a possible association between 5-HT deficits and agitation in AD, using prolactin response to d,1-fenfluramine administration as a probe for 5-HT activity., Methods: Five AD patients with agitation and 5 without agitation received a 60-mg oral dose of d,1-fenfluramine. Prolactin levels were obtained at baseline, and 2 and 3 hours following administration., Results: Change in prolactin levels from baseline to 3 hours was significantly larger among the agitated than the nonagitated Alzheimer's patients. Further, there was a positive and significant correlation between change in prolactin levels from baseline and level of agitation., Conclusions: These findings suggest an association between 5-HT responsiveness and agitation in AD.

Depersonalization remains a fascinating and obscure clinical phenomenon. In addition to earlier Jacksonian neurobiological adumbrations, and conventional psychodynamic accounts, views started to be expressed in the 1930s that depersonalization might be a vestigial form of behavior, and since the 1960s that it might be a phenomenon related to the temporal lobe. Recent advances in the neurobiology of the limbic system, and the application of Geschwind's concept of disconnection in the corticolimbic system, have opened the possibility of developing testable models. This paper includes a review of these ideas and of the clinical features of depersonalization, particularly of its emotional changes, suggesting that they are important for the neurobiological understanding of depersonalization. It also draws attention to clinical similarities between the experiential narratives produced by patients suffering from depersonalization and those with corticolimbic disconnections. On the basis of this, a new model is proposed according to which the state of increased alertness observed in depersonalization results from an activation of prefrontal attentional systems (right dorsolateral prefrontal cortex) and reciprocal inhibition of the anterior cingulate, leading to experiences of "mind emptiness" and "indifference to pain" often seen in depersonalization. On the other hand, a left-sided prefrontal mechanism would inhibit the amygdala resulting in dampened autonomic output, hypoemotionality, and lack of emotional coloring that would in turn, be reported as feelings of "unreality or detachment."

This is a review article that describes current data, issues, and controversies regarding long-term maintenance treatment of depression. The authors suggest that the issues represent a public health crisis. This paper will identify the need, from both a health-care and economic perspective, for more research on the efficacy of maintenance treatment for this pernicious and lifelong disorder. Data will be reviewed on the natural course of unipolar depression, focusing on clinical predictors that increase the risk of a relapse or recurrence. This review will include new data from the National Institute of Mental Health Collaborative Depression Study. Failing to achieve adequate maintenance treatment for unipolar recurrent major depression has psychopathological and psychosocial consequences, decreasing work productivity and the quality of a person's life. Published double-blind placebo-controlled studies on continuation treatment of major depression will be reviewed. The two competed double-blind placebo-controlled long-term maintenance studies of recurrent unipolar major depression will be discussed in detail. Despite the positive findings from research done to date, there remain many unresolved questions relating to the maintenance treatment of recurrent unipolar major depression, and the need for research in this area is critical. The paper concludes with recommendations for long-term maintenance treatment of unipolar major depression.

Background: Sleep disturbances are common in major depressive disorder. In previous open-label trials, nefazodone improved sleep continuity and increased rapid eye movement (REM) sleep, while not affecting stage 3/4 sleep or REM latency: in contrast, fluoxetine suppressed REM sleep. This study compared the objective and subjective effects of nefazodone and fluoxetine on sleep., Methods: This paper reports combined results of three identical, multisite, randomized, double-blind, 8-week, acute-phase trials comparing nefazodone (n = 64) with fluoxetine (n = 61) in outpatients with nonpsychotic major depressive disorder and insomnia. Sleep electroencephalographic (EEG) recordings were gathered at baseline and weeks 2, 4, and 8. Clinical ratings were obtained at weeks 1-4, 6, and 8., Results: Nefazodone and fluoxetine were equally effective in reducing depressive symptoms; however, nefazodone differentially and progressively increased (while fluoxetine reduced) sleep efficiency and reduced (while fluoxetine increased) the number of awakenings in a linear fashion over the 8-week trial. Fluoxetine, but not nefazodone, prolonged REM latency and suppressed REM sleep. Nefazodone significantly increased total REM sleep time. Clinical evaluations of sleep quality were significantly improved with nefazodone compared with fluoxetine., Conclusions: Nefazodone and fluoxetine were equally effective antidepressants. Nefazodone was associated with normal objective, and clinician- and patient-rated assessments of sleep when compared with fluoxetine. These differential sleep EEG effects are consistent with the notion that nefazodone and fluoxetine may have somewhat different modes and spectra of action.

Background: Dopamine affects neural information processing, cognition, and behavior; however, the mechanisms through which these three levels of function are affected have remained unspecified. We present a parallel-distributed processing model of dopamine effects on neural ensembles that accounts for effects on human performance in a selective attention task., Methods: Task performance is stimulated using principles and mechanisms that capture salient aspects of information processing in neural ensembles. Dopamine effects are simulated as a change in gain of neural assemblies in the area of release., Results: The model leads to different predictions as a function of the hypothesized location of dopamine effects. Motor system effects are simulated as a change in gain over the response layer of the model. This induces speeding of reaction times but an impairment of accuracy. Cognitive attentional effects are simulated as a change in gain over the attention layer. This induces a speeding of reaction times and an improvement of accuracy, especially at very fast reaction times and when processing of the stimulus requires selective attention., Conclusions: A computer simulation using widely accepted principles of processing in neural ensembles can account for reaction time distributions and time-accuracy curves in a selective attention task. The simulation can be used to generate predictions about the effects of dopamine agonists on performance. An empirical study evaluating these predictions is described in a companion paper.

To study the relationships between clinical and biological data that are necessary for physiopathological analysis in the field of developmental disorders, we developed a quantified grouping system, based on four developmental assessment parameters. Parallel with this clinical research, we developed electrophysiological procedures adapted to the pathology of autism. In this paper, we report the utilization of an original multivariate descriptive statistical approach (correspondence analysis followed by cluster analysis) that allowed us to identify different bioclinical profiles using these clinical and electrophysiological data conjointly. These profiles are believed to be evidence for different underlying cerebral dysfunctions. This procedure proved effective in identifying two main bioclinical dimensions in a population of 145 developmentally disordered children. These dimensions reflect the association of intellectual impairment and centroparietal electrophysiological reactivity on the one hand, and autistic behavior and temporal electrophysiological reactivity on the other. This study, performed on a large population of children using objective methods of data analysis, provides validation of numerous multidisciplinary studies of autism and other developmental disorders carried out on small samples of children.

Segregation studies have shown that Gilles de la Tourette Syndrome (GTS) is probably transmitted as an autosomal dominant gene disorder and can therefore be studied by classical linkage analysis to identify susceptibility loci. Many neurotransmitter systems have been implicated in the etiology of GTS. Most recently the alpha-1 subunit of the glycine receptor etiologically responsible for hyperekplexia has been hypothesized as the cause of the susceptibility to GTS. Because of this and the high concentration of other neuroreceptor genes at 5q33-35, it was decided to study this region and the associated gene cluster on chromosome 4p12-16 in a large British kindred multiply affected with GTS and chronic motor tics. The genotypes of the microsatellite markers at these loci were determined by polymerase chain reaction. The allele data were analyzed using both parametric and nonparametric methods. Approximate multipoint maps were constructed across the regions of interest using FASTLINK. All of the lod scores produced were negative, showing no evidence of linkage to GTS in the family studied. The multipoint maps showed good exclusion across these regions. The glycine receptor gene responsible for hyperekplexia and the other neuroreceptor genes examined in this paper are not involved in the etiology of GTS in this large pedigree.

On the basis of theories we articulated in earlier papers (Ehlers et al 1988: Arch Gen Psychiatry 45:948-952, 1993: Depression 1:285-293), we have developed an adjunctive psychosocial intervention for patients with bipolar 1 disorder. Central to this intervention is the establishment of regularity in daily routines. In this report, we present data from a controlled investigation comparing this new treatment, interpersonal and social rhythm therapy (IPSRT), with a conventional medication clinic approach. Despite comparable changes in symptomatology over a treatment period lasting up to 52 weeks, subjects assigned to IPSRT (n = 18) show significantly greater stability (p = .047) of daily routines with increasing time in treatment, while subjects assigned to the medication clinic condition (n = 20) show essentially no change in their social routines as measured by Social Rhythm Metric (SRM-Monk et al 1990: J Nerv Ment Dis 178(2):120-126) score. We conclude that IPSRT is capable of influencing lifestyle regularity in patients with bipolar 1 disorder, with the possible benefit of protection against future affective episodes.

The amplitude and suppression of the auditory P50 event-related potential may be useful for studying schizophrenia and drug abuse; however, the low reliability of the P50 suppression measure limits its value for correlation with clinical measures. Reliability can be increased either by improving measurement methods or by reducing or eliminating sources of variance in the recordings. In this paper, the effect on P50 amplitude and suppression of variation in wakeful alertness within an experimental session was examined in 20 normal subjects. The percentage of beta power in the interval immediately prior to the P50 stimuli was used as an index of alertness. P50 amplitudes or C-T ratios were estimated using peak-picking and using the singular value decomposition (SVD) method. No effects of variation of wakeful alertness were observed on any P50 amplitude or suppression measure. Comparing the peak-picking vs SVD estimates replicated our prior results showing markedly higher reliabilities with SVD. We conclude: 1) that variation within an experimental session in wakeful alertness level as indexed by the percentage of beta power does not affect P50 amplitude or suppression, and 2) the SVD method brings the reliability of the C-T ratio up to levels where its usefulness in clinical studies can be examined.

Males parolees were recruited into a laboratory study to determine the relationship between their previous criminal history (violent versus nonviolent), and behavioral and psychometric measures of impulsivity. During sessions, subjects were given two response options defined as: 1) an impulsive choice--small monetary reward after a short fixed delay; and 2) a self-control choice--a larger monetary reward after a variable longer delay. Based upon an extensive experimental literature in animals and humans related to delay of gratification, the degree of impulsivity was defined as the proportion of trials on which the subject selected the impulsive option. Our results indicated that the violent subjects selected the impulsive option significantly more often than the nonviolent parolees. The number of impulsive responses parolees emitted was significantly correlated with the number of aggressive responses reported in an earlier paper. This study provides support for the relationship between impulsivity and aggression among male parolees.

Adrenocorticotropic hormone (ACTH) is secreted by corticotrophic cells in pulsatile bursts. This paper reviews the extant literature on the phenomenon of pulsatile ACTH after addressing basic issues of hormone pulsatility in neuroendocrine systems. The following themes emerged from reviewing 51 studies measuring plasma ACTH at intervals of 20 min or less: marked inter-individual variability in the pattern of ACTH, the dependence of pulse identification on sampling frequency, the similarity in ACTH pulse amplitude and frequency across species, and the predominance of amplitude over frequency changes in ACTH pulses in altered physiological states. As the hypothalamic-pituitary-adrenocortical (HPA) axis plays a critical role in orchestrating adaptation and survival, the ability to modulate the shape of ACTH signals may prove to be an important means of transmitting complex information to ACTH responsive cells. The clinical and neurobiological significance of temporal alterations in ACTH secretion represents an area for future investigation.

The aim of the present paper was to perform a single trial analysis of event-related potentials in order to elucidate the mechanisms behind a reduced P300 amplitude occurring in unmedicated depressives (n = 11) and schizophrenics (n = 18). For this purpose, tools from linear system theory were applied to single trials in an oddball paradigm. This analysis provides estimates of the magnitude of the positive deflection occurring around the latency of P300 following target and nontarget simuli. According to the density functions of these amplitude distributions, we operationally defined "false-negative" (P300 amplitude lower than an individual threshold under target conditions) as well as "false-positive" responses (P300 amplitude higher than the threshold following nontarget stimuli). Our investigations revealed a reduction of the single-trial P300 amplitude in depression and a combination of amplitude reduction along with fewer elicited single-trial P300 waves in schizophrenics.

The aim of this paper is to study the recognition of facial expression of emotions in depressed patients with major depressive disorder (MD) and schizotypal personality disorder (STP). The pictures of sad, emotionally neutral, and happy faces followed by a masking stimulus were displayed for 80 msec on a computer screen randomly in the left or right hemifield of vision (LHF and RHF). The subjects had to respond by pressing a three position key. Multiple analysis of variance revealed that all depressed patients, relative to control subjects, made more errors in a task of recognition of facial affect. The characteristics of impairment of performance were found to be related to the nosology of depression. MD patients revealed significantly impaired recognition of negative (in LHF and in RHF) and positive (in LHF) facial emotions, as well as poorer recognition in the right hemisphere, and reduced hemispheric asymmetry. In remission, they showed statistically significant recovery of recognition function. STP patients were less impaired and showed slightly poorer recognition of sad (in RHF) and happy (in LHF) expressions. This group demonstrated significantly poor recognition of happy expressions, and more marked dysfunction of the left hemisphere. In remission, STP patients failed to improve in recognition of emotion. This suggests, that the features of emotion recognition in MD and STP groups reflect some differences in the neurophysiological mechanisms underlying the affect-related dysfunction in these groups of depressed patients.

Cellular Ca(2+)-dysregulation has been proposed as an important mechanism in certain diseases such as bipolar affective disorder (BPAD) and malignant hyperthermia. Recently it has been found that in BPAD, the plasma membrane Ca(2+)-channel blockers verapamil and nimodipine are useful substitutes in Li(+)-treatable patients. We have investigated the effects of these drugs and the antipsychotic drugs (clozapine, fluspirilene, and haloperidol) on IP3-induced Ca(2+)-release from Ca(2+)-loaded rat brain microsomes. In the presence of either the Ca(2+)-channel blockers or the neuroleptic drugs, Ca(2+)-release was blocked in a dose-dependent fashion. For the neuroleptics, the EC50 ranged from 22 microM for fluspirilene to 145 microM for haloperidol. The EC50 for nimodipine was 160 microM and 450 microM for verapamil. Carbamazapine and valproic acid, anticonvulsants recently used for treating BPAD, were relatively ineffective, as were various haloperidol metabolites. The research described in this paper establishes for the first time that antipsychotic drugs, as well as certain Ca(2+)-channel blockers, directly block the IP3-induced Ca(2+)-release in a rat brain microsome assay.