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Background: Genetically-mediated alterations in serotonergic transmission have been implicated in both the pathogenesis of alcoholism and suicidal behavior. Thus, the identification of vulnerability genes could uncover pathophysiological links for both syndromes. A significant association between suicide attempts and the 5-HTT promoter polymorphisms (5-HTTLPR) S-allele has been reported in a sample of French alcohol-dependent subjects, and this paper evaluates this phenomenon in a German sample. Methods: One hundred and sixty-three patients meeting DSM-IV criteria for alcohol dependence and 117 healthy controls were investigated. Blood samples were taken to genotype the 5-HTTLPR by using polymerase chain reaction (PCR) of lymphocyte DNA. Results: 5-HTTLPR-S alleles were seen more frequently in suicidal compared to nonsuicidal alcohol-dependent subjects. Furthermore, significant effects from suicide attempts on the number of S-alleles were found. Conclusions: The results are consistent with an association between the 5-HTTLPR-S-allele and suicide attempts in alcohol-dependent subjects.

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.

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.

Alcoholism, or Substance Dependence on alcohol, is a chronic relapsing disorder characterized by loss of control over intake (compulsive use) and the emergence of a negative emotional state during abstinence. Stress long has been considered a key element in the etiology of alcohol dependence, yet the exact mechanisms by which stress exacerbates and interacts with alcohol dependence have remained elusive. Recent work on the brain neurotransmitter corticotropin-releasing factor (CRF) [see footnote on nomenclature] has provided new insights into the stress-alcohol dependence interaction. Two papers in this issue of Biological Psychiatry (1, 2) provide an exciting molecular mechanism for this interaction that may have heuristic value for future translational advances. CRF is a 41 amino acid polypeptide with a wide distribution throughout the brain but high concentrations of cell bodies in the paraventricular nucleus of the hypothalamus, the basal forebrain (notably the amygdala and bed nucleus of the stria terminalis) and the brainstem. Central administration of CRF mimics the behavioral response to activation and stress in rodents, and administration of competitive CRF receptor antagonists generally have anti-stress effects (3). Two major CRF receptors have been identified, with CRF1 receptor activation associated with increased stress responsiveness and CRF2 receptor activation associated with decreases in feeding and decreased stress responsiveness, although there is some controversy in this area depending on the location of the CRF2 receptors in question. In the current issue of Biological Psychiatry, Sommer et al. (1) studied rats using an animal model of alcohol dependence and showed that CRF and expression of the crh1 transcript within the amygdala are upregulated in postdependent animals. Animals trained to self-administer alcohol in a two-bottle, free-choice procedure and exposed to intermittent ethanol vapors to induce dependence showed a doubling of ethanol intake and increased sensitivity to stress which was reversed by a CRF receptor antagonist. CRF mRNA was increased in the central nucleus of the amygdala, and crh1 transcript expression was increased in the basolateral amygdala, with a concomitant decrease in crh2 transcript expression in the basolateral amygdala. These new results fit well with a burgeoning dataset implicating an increase in extrahypothalamic CRF function with the excessive drinking associated with alcohol dependence in animal models. Rats with either a genetic predisposition for anxiety-like behavior and excessive drinking, or with a history of dependence, show decreases in drinking with administration of CRF1 antagonists administered systemically (4, 5). CRF antagonists also block stress-induced reinstatement to alcohol and other drugs of abuse (6). These effects have been localized to the region of the central nucleus of the amygdala; local injection of a CRF1/CRF2 antagonist produced similar effects (7). A CRF2 agonist microinjected into the central nucleus of the amygdala also had a similar effect, consistent with the opposing actions on crh1 and crh2 gene transcripts in the present Sommer results. Thus, it appears that not only is there increased expression of CRF neuropeptide activity in the amygdala in dependent rats, but also an increase in CRF1 receptor activity and a concomitant decrease in CRF2 receptor activity. Another innovative aspect of the Sommer results is that these molecular and behavioral effects persist into protracted abstinence, supporting the data from earlier pharmacological studies (8). Altogether, these results demonstrate numerous targets for treatment of alcohol dependence and open a new vista for addiction treatment in general. In Blomeyer et al. (2) in the current issue, an ongoing cohort from the Mannheim Study of Children at Risk were genotyped for two alleles of the CRF1 receptor. Results showed that individuals homozygous for the C allele of one single nucleotide polymorphism of the CRF1 receptor (rs1876831) drank higher maximum amounts of alcohol per occasion and had greater lifetime rates of heavy drinking but only in relation to negative life events. No similar gene × environment interactions were observed for the other crh1 allele (rs242938). These results are consistent with the observation that the genetically selected Marchigian-Sardinian alcohol preferring (msP) rat line has high alcohol preference with increased behavioral responsivity to stress and an innate upregulation of the crh1 transcript in several brain regions. Both the single nucleotide polymorphism observed in Marchigian rats and the one in the human study were in non-coding regions of the gene that can potentially influence transcription, with the former in a promoter region and the latter in an intron. Together these results suggest the exciting possibility that certain single nucleotide polymorphisms in the human population may predict vulnerability to certain subtypes of excessive drinking syndromes and, perhaps somewhat more mundane but equally provocative, may predict responsiveness to the use of CRF receptor antagonists for the treatment of alcoholism. Of course, as the authors noted, some caution must be considered given the relatively small sample size for a genetic association study. Replication of this association with attention to defined phenotypes will be an important future pursuit. Finally, the two present studies have provided molecular insight into a hypothesized conceptual framework for addiction that, in a sense, is reorienting neurobiology of addiction field. Addiction, and alcoholism in particular, has been hypothesized to reflect a break with homeostasis that represents a chronic change in reward set point that results in the emergence of a negative emotional state during abstinence. Continued drug taking to “self-medicate” the elevation in reward set point produces short-term relief but drives the set point further from homeostasis. Such a physiological change represents a classic allostatic mechanism (9) and has been hypothesized to be driven by not only decreases in reward neurotransmission (e.g., the action of opioid peptides or dopamine), but also by recruitment of brain stress systems such as CRF, neuropeptide Y, and norepinephrine (10). Most remarkable about the two studies in this issue of Biological Psychiatry is that a molecular target has been identified supporting the dark (stress) side of this conceptual framework that can be influenced by both the genetic makeup of the organism (“being born that way”) and by excessive drug taking (environmental insult) resulting in a possible gene × environment interaction. The implications of the CRF story for the treatment, diagnosis, and prevention of alcoholism are profound.

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.

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."

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.

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.

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 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.

It is well established that sleep patterns are altered in psychiatric disorders and represent a very common presenting complaint. Even though sleep disturbance is often a key feature of many psychiatric conditions, its most prominent role has been in mood disorders. The clinical implications of disordered sleep in mood disorders represent the focus for this paper. Specifically, the following questions will be discussed: (1) How sensitive and specific are the sleep findings in depressive disorders? (2) What are the characteristics of sleep in depression and subtypes of depression? (3) Are sleep changes in depression episodic (state-like) or persistent (trait-like)? As we point to specific characteristics of sleep in subtypes, it is important to note that more sophisticated analyses of sleep measures provide an opportunity to pinpoint changes between delusional/nondelusional depression or endogenous/nonendogenous depression. Furthermore, differences among subtypes will be best understood if we realize that both age and gender affect sleep measures in a consistent manner. Therefore, for example, there is a more robust separation between patients and controls in older individuals than in younger individuals.

The prolactin (PRL) response to 0.5 mg of intravenous haloperidol (HPL) IV may be a measure of tuberoinfundibular dopaminergic activity. Our earlier reports, using multidiagnostic strategies in schizophrenia, suggested that psychoses characterized by the absence of affective syndromes (Keks et al 1990) and the presence of thought disorder and passivity delusions (Keks et al 1992) are linked to blunted PRL responses. In this paper we evaluated the relationships between basal and HPL-stimulated PRL concentrations, and a number of potentially relevant symptom measures. Basal PRL was lower in patients without a depressive syndrome and suicidal ideation. Stimulated PRL was lower in patients without neurovegetative symptoms (versus patients with neurovegetative symptoms and controls), with depression (versus patients with no depression and controls) and those with disorder of associations (versus patients without association disturbance and controls). These findings can be interpreted as indicating a link between endocrine measures of dopaminergic function and a subtype of schizophrenic psychosis characterized by the presence of thinking disturbance in the absence of depression.

A large body of literature has emerged concerning the role of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) in the regulation of alcohol intake and the development of alcoholism. Despite the wealth of information, the functional significance of this neurotransmitter remains to be fully elucidated. This paper, part one of a two-part review, summarizes the available clinical research along two lines: the effects of alcohol on serotonergic functioning and the effects of pharmacological manipulation of serotonergic functioning on alcohol intake in normal (nonalcohol dependent) and alcohol-dependent individuals. It is concluded that considerable evidence exists to support the notion that some alcoholic individuals may have lowered central serotonin neurotransmission.

This paper describes the process of developing a new rating scale for acute neuroleptic-induced akathisia. Previously reported clinical characteristics of akathisia were used to construct the initial version of the scale. This was administered to 100 consecutively admitted psychiatric patients treated with neuroleptic medication. The scale was then subjected to a reliability analysis, and the number of items reduced. A factor analysis of the ratings supported the decision to rate subjective and objective items separately. The new version of the scale (The Prince Henry Hospital Akathisia Rating Scale) was further standardized in its administration. A preliminary examination of its construct validity was performed by calculating the correlations with the ratings on the analogue and global scales, as well as those of depression, anxiety, and hyperactivity. The new scale was administered to 50 new subjects to examine its interrater reliability and concurrent validity with respect to the Barnes Akathisia Rating Scale.

This paper reviews the clinical and experimental literature on patients with multiple adverse responses to chemicals (Multiple Chemical Sensitivity Syndrome-MCS) and develops a model for MCS based on olfactory-limbic system dysfunction that overlaps in part with Post's kindling model for affective disorders. MCS encompasses a broad range of chronic polysymptomatic conditions and complaints whose triggers are reported to include low levels of common indoor and outdoor environmental chemicals, such as pesticides and solvents. Other investigators have found evidence of increased prevalence of depression, anxiety, and somatization disorders in MCS patients and have concluded that their psychiatric conditions account for the clinical picture. However, none of these studies has presented any data on the effects of chemicals on symptoms or on objective measures of nervous system function. Synthesis of the MCS literature with large bodies of research in neurotoxicology, occupational medicine, and biological psychiatry, suggests that the phenomenology of MCS patients overlaps that of affective spectrum disorders and that both involve dysfunction of the limbic pathways. Animal studies demonstrate that intermittent repeated low level environmental chemical exposures, including pesticides, cause limbic kindling. Kindling (full or partial) is one central nervous system mechanism that could amplify reactivity to low levels of inhaled and ingested chemicals and initiate persistent affective, cognitive, and somatic symptomatology in both occupational and nonoccupational settings. As in animal studies, inescapable and novel stressors could cross-sensitize with chemical exposures in some individuals to generate adverse responses on a neurochemical basis. The olfactory-limbic model raises testable neurobiological hypotheses that could increase understanding of the multifactorial etiology of MCS and of certain overlapping affective spectrum disorders.

As is clear from the pages of this journal, biological psychiatrists remain fascinated by the phenomenon of dexamethasone (DEX) resistance and the hypercortisolism of various neuropsychiatric disorders. The mere existence of the endocrine abnormalities attests to the biological reality of these disorders. Furthermore, progress continues in using the occurrence of these endocrine defects as both diagnostic and prognostic markers of disease subtypes. Progress has also been made in understanding the mechanisms underlying the endocrine defects. The adrenocortical axis is vastly complex, involving multiple hypothalamic-releasing factors under CNS control, shifting pituitary and adrenal sensitivies to hormonal signals, and feedback regulation at all three levels. What defects within this system produce DEX resistance and hypercortisolism? In this paper, we review data suggesting that the endocrine problems is, at least in part, neural in nature. Drawing upon a rodent literature, we will also suggest some models by which this can occur. The hypercortisolism found in cases of affective disorders, anorexia nervosa, Alzheimer's disease, among the very aged or the chronically stressed, is not a uniform phenomenon. Basal cortisol concentrations can be elevated in all or part of the circadian cycle. Resistance to glucocorticoid (GC) feedback inhibition (as typically demonstrated by DEX resistance) can occur; the resistance can be complete, or occur as early escape from DEX suppression. Finally, elevated basal cortisol concentrations and DEX resistance can occur independently of each other. Until the end of this review, we will conveniently refer to these variants of adrenocortical hyperactivity as "hypercortisolism." In addition, rather than using the term "hypercortisolism" for the rat, we will use "hyperadrenocorticism" (as they secrete corticosterone, rather than cortisol).

Investigators have long sought self-report measures of personality that index genetic risk for schizophrenia. The Schizotypal Personality Questionnaire (SPQ, Raine, 1991) is a self-report measure that assesses the nine major features of schizotypal personality disorder as defined by the DSM. In the current investigation, the SPQ, modified to include validity scales, was administered to 122 non-psychotic first-degree biological relatives of schizophrenia inpatients, as well as to 75 non-psychiatric controls. The relatives endorsed more characteristics of schizotypy on all three factors of the SPQ: Social-Interpersonal (p , .002, Glass9 d 5 .59), Cognitive-Perceptual (p , .02, Glass9 d 5 .46), and Disorganized (p , .05, Glass9 d 5 .34). Social interpersonal deficits, reflected in the overall score and in subscale scores, best differentiated the relatives of schizophrenia patients from healthy controls, indicating that it may be the most important feature associated with genetic vulnerability. A principal components analysis was conducted that yielded three factors, correlating very highly with the three factor solution previously reported. Together, these data demonstrate that a multidimensional paper-and-pencil measure can identify and characterize the long documented schizotypal features in the relatives of schizophrenia patients. Thus, schizotypal characteristics revealed by this method appear to be useful for the further investigation and delineation of the schizophrenia spectrum and for broadening the heritable phenotype of schizophrenia.

s mOL PSYCHIATRY 1996:39:500-666 581 We addressed this issue by comparing stabilized DSM·III-R diagnosed adult schizophrenics and bipolar patients on several clinical and neuropsychological measures. Clinical state was assessed using the Positive andNegativeSyndrome Scale (PANSS), which generates threesymptom ratings: positive symptoms, negative symptoms and general psychopathology. Neuropsychological measures included the Wisconsin Card Sort Test (WeST), Trail Making B (TMB). Verbal Fluency. and Califomia Verbal Learning Test, Twenty-three schizophrenic adults (mean age 34.2) were compared to 13 adult bipolar patients. all adrnined in u manic episode (mean age 33.7), Patients groups were similar for number of prior hospitalizations and [Q. Testing was completed just prior to discharge. when patients wereconsidered most stable. Clinically, manic patients were comparable to schizophrenics on overall PANSS ratings and in general psychopathology, Manics. however. had significantly higher positive symptoms ratings whereas schizophrenics had signiflcantlymore negative symptoms. With respect to ncuropsychologlcal test performance. manics and schizophrenics were similar and both groups were highly impaired compared to established norms, Overall. these findings suggest that on tasks lhought to measure temporal and frontal lobe functions. hospitalized manic patientsdlsplay defleits as severe as those characterizing schlzophrenle patients. Clinically. schizophrenics maybe distinguishable from manics only in terms of negalive symptoms; in all other areas, manic patients appear to closely resemble schizophrenic patients. 279. ORIENTING RESPONSE IN c;;:rHT700UDl:I\TJ 1\ A ND • , . N-A _~. A~""''' .u,L,jl'.lrt. M lVlAI 1 : NEUROPSYCHOLOGICAL TESTING D.B. Schnur, S. Smith. A. Smith, D. McKay, M. Obuchowski. A. Stewart, & P. Win Mt, Sinai School of Medicine. New York, NY 10029 Orienting response (OR)dysfunction has beenussociated wilh prefrontal and temporal cortex disturbances. Thisstudyaims10expand on previous evidence drawn primarily from schizophrenic populations using electrodermal measures. Relations Were examined between skin conductance and fingerpulseamplitude reactivity (SCR. FPAR) on the onehand.and tests of executive ami memory function on the other. in schizophrenic andmanic patients. SCRand FPARto neutral tones and to an attentional lask were measured in 22 schizophrenic and 8 manic patients. Neuropsychological measures included the percentage of persevcratlve errors 011 the Wisconsin Card Sorting Test (WeST) and total recoil over the 5 learning trials of the California Verbal Learning Test (CVLT), to assess executive and memory functions respectively, As there were no differences between diagnostic groups on any autonomic or neuropsychological measures. patlem groups were combined for subsequent analysis. Percentage of'pcrsevcmtlvc errorson theWeST Was signiflenntly greater among SCR·OR nonresponders to neutral tones and among FPAR nonresponders to targeted tones in the nttentlonal task (Mann-Whitney ~269. p=O.04) andsignificantly correlated withthe frequency of FPAR to nontargeted tones in theaucntlonal task(Spearman Rho» S. p=O.Ol). CVLT was unrelated to any psychophysiological measure. It was concluded tlmt reduced autonomic reactivity to neutral and cognhlvely vulllill ~ljilluli may be; USSOCiUlCd with impaired performance on the WCST but not on theCVLT. These relations lire supportive of the view that frontal lobe disturbance may contribute to OR dysfunction in schizophrenic and manic patients. 280, EFFECTS OF AMPHETAMINE ON COGNITIVE IMPAIRMENT IN SCHIZOTYPAL PERSONALITY DISORDER R. Kirrane, R. Trestrnan, V. Mitropoulou, B. Comblatt, & L. Siever Mt. Sinlli & Bronx VA Medical Centers, New York. NY Cognitive impairment has been described in schizophrenia and schizotypal personality disorder (SPO) lind may be related 10 reduced dopamincrgic activhy in the prefrontal cortex. Amphetamine is a dopamine enhancing agent which has been shown to improve lhe cognitive dysfunction associated with schizophrenia. and which. by reversing frontal hypodopamlnergia, might improve cognitive [unction, specifi. cally executive function in SPD patients, We tested the effects of amphetamine on executive function as measured by the Wisconsin Card Sort Tll.~k (WeST)pcrseverutlve errors in 9 SPD (DSM·II J) patients one hourafteradministradon of d-amphetarnlnc 30mgand placebo. We also assessed sustnlned attention performance by theContinuous Performance Task(Identical Pairs version. measure: in d' units; thehigherthe number the better the performance) in a similarly diagnosed sample of 7 SPD patients. Word list learning performance (based on Rey's auditory learning task: measure: words learned) was also measured as well as a pen and paper visuospatial working memory task (measure: in em error in position memory). Change in psychotic symptoms was assessed using the Positive 4InU Negative Symptom Scale (PANNS). Controlling for placebo performance patients. particularly those who made more perseverative errors, demonstrated amphetamine-associated improvement on WeST performance by commhting less pcrseverativc errorson amphetamine (11.4::8.4) compared to placebo (15.5± 13.6; F[1,7]=9.34. p

There is now substantial evidence that both genetic and environmental factors play a role in the etiology of schizophrenia; however, little is known about the relationships between these factors and known markers for schizophrenia. In this paper we apply the familial/sporadic subtyping method as a first step towards examining the contribution of familial (approximated to genetic in this study) and environmental factors to relevant neurobiological markers in schizophrenia. Specifically, we compare cerebral ventricular size and neuropsycho[ogical function in schizophrenic patients with and without a first-degree relative with schizophrenia. Family history was ascertained by interview with the patient and a family member and a review of the medical record in 48 schizophrenic inpatients diagnosed by SADS/RDC and DSM-III-R criteria. Seven patients had a first-degree relative with schizophrenia. Neuropsychological functions were measured on the Wechsler Adult Intelligence Scale-Revised (full scale IQ, verbal IQ, and performance IQ); Trail Making Test Part B; Reaction Time (choice); Wisconsin Card Sorting Test (WCST); and the Controlled Oral Word Association Test. IQ, Trails B, and WCST scores were standardized to acoount for differences in age, sex, and education levels. Ventricle-brain ratios (VBRs) were calculated from CT scans. Patients with positive (FHpos) and negative (FHneg) family histories did not differ on the severity of either positive or negative symptomatology. Our results showed that a negative family history was associated with increased VBR (means -FHpos: 0.06; FHneg: 0.09; p = 0.06); these findings are consistent with several other reports. Of the neuropsychological indicators, only scores on Trails B differed significantly in the FHpos and FHneg groups; positive family history was associated with worse functioning (FHpos: 62.7; FHneg: 84.1; Mann-Whitney U: p = 0.01). These data suggest that nonfamilial factors contribute to ventricular enlargement while familial factors contribute to frontal lobe deficits in schizophrenia. This might reflect the presence of ventricular enlargement and frontal lobe neuropsychological dysfunction on separate pathogenetic pathways in schizophrenia. The results support the utility of the familial/sporadic approach in studying the pathogenetic heterogeneity of schizophrenia.

To the Editor, in the abstract to their paper, Katz et al. (1993) comment that oxaprotiline significantly resembled amitriptyline and that levoprotiline significantly resembled placebo in antidepressant potential, ! take issue with the authors on their phraseology. Statistical tests are constructed to test significance of differences (among other things) and not of resemblances. What Katz et al. actually found was that oxaprotiline did not differ significantly from amitriptyline and that levoprotiline did not differ significantly from placebo. There's no splitting of hairs hero--the issue is an important one, with bearing on the power of the applied test, which is in turn dependant on (for example) sample size. Thus, if 4 of 8 depressed patients respond to placebo while 7 of 8 respond to fiuoxetine, statistically the drug groups do not differ. This is not to say that fiuoxetine significantly resembles placebo in antidepressant potential for, if the sa:,~o proportions are maintained and if 40 of 80 depressed patients respond to placebo while 70 of 80 respond to fluoxetine, the 2 drugs will indeed differ stat.:stically. It is convenient to use phrases like "significantly resembles"

To the Editor: The report of Yassa et al (1991) is one of only two systematic studies of the Pisa syndrome that have appeared very recently, the other being that of Suzuki et al (1990). Prior to these studies, there were only a few case reports of this phenomenon. Ekbom et al (1972) coined the term "Pisa syndrome" to describe the presentation of three patients who developed a postural abnormality consisting of leaning to one side (lateral torso flexion), usually accompanied by slight posterior rotation of the torso, while being treated with neuroleptics. Following Pilette (1987), Yassa et al (1991) employed the descriptive terhn "pleurothotonus" as synonymous with the Pisa synd~orae irl the title of their paper. Pilette (1987) had pointed out that the term "pleurothotonus" predated that of "Pisa syndrome," and stated that this particular postural abnormality is at least as common as opisthotonus even though it is mentioned less frequently in recent textbooks. Strictly speaking, Pisa syndrome designates an entity more specific than pleurothotonus. Pleurothotonus delineates an anatomic deviation that could be observed prior to the advent of neuroleptic compounds. As with opisthotonus, it was, in the past, often considered to be a typical presentation of conversion hysteria. Pleurothotonus, also called "tetanus laterali~," designates a physical finding that could be related to any ,,~ a number of potential etiologies of dystonic phenomena (see DeSilva et al 1973). It is, therefore, not quite synonymous with Pisa syndrome, which in the original report implicated neuroleptic treatment in the etiology of the clinical findings. When Ekbom et al (1972) stated that they had "christened this peculiar body pos ture . . , after the well-known Italian structure," they were designating a "new dystonic syndrome associated with butyrophenone therapy." Therefore, the appropriate synonym for the Pisa syndrome would be "neuroleptic-induced pleurothotonus," or simply "drug-induced pleurothotonus."

This paper reports the phenomenon of dependence to a somatostatin octapeptide analog used for the treatment of acromegaly and severe headache. The mechanism of this dependence is still unknown, but could be based on the interaction of the somatostatin analog with opioid receptors. Analgesia may be at least partially supported by the opioid modulation of pain transmission, but also by general "appetitive" behavioral activation due to the effect of somatostatin on its receptors.

Topographic mapping of brain electrical activity is a popular, powerful, and potentially misleading technique. The map lies at the end of a long chain of physiological, technical, electronic, and mathematical processes and is vulnerable to artifact, error, and distortion at many points. Close attention must be paid to data collection parameters, subject cooperation, minimization of artifact, limitations of resolutions, selection, and transformation of parameters for display, and map generation strategy to yield an accurate, physiologically interpretable map. Review of the data at each step of analysis, from the paper electroencephalogram (EEG) to sets of maps on video display, may be necessary for optimum understanding. Development of more sophisticated qualitative and quantitative concepts of “normal” physiology is needed. These improvements in electrophys-iological data analysis demand, rather than obviate, sophistication on the part of the user.

Tardive dystonia (Keegan and Rajput 1973) is a persistent dystonia of late onset induced by antipsychotics, a few reports of which are available in the literature (Burke et al. 1982; Gimenez-Roldan et al. 1985; Saxena 1986). Tardive dystonia can be considered as a type of tardive dyskinesia, as they are both persistent movement disorders that follow chronic antipsychotic use. Even though primary affective disorders are particularly susceptible to tardive dyskinesia (Rosenbaum et al. 1977), literature in this area is scanty. As we know more about the biochemical abnormalities of affective illness than of schizophrenia, a study of the association between tardive dyskinesia and affective illness may help us to understand its etiopathogenesis. Rosenbaum et al. (1977) make brief reference to the (depressive) state specificity of tardive dyskinesia and Cutler et al. (198 1) devoted a paper to the theme. The latter also report alleviation of dyskinesia during mania. The opposite phenomenon, i.e., dyskinesia becoming less severe during depressive episodes, has been described by Keshavan and Goswami (1983). We report herewith a case of bipolar disorder with tardive dystonia where the dystonic symptoms alternated with mania.

Goldstein L, and Wiet S (1979): Some quantitated hemispheric EEG correlates of psychopathology. Paper presented at Symposium of the International Convention of Psychologists. Lesieur HR, and Custer RL (1984): Pathological gambling: Roots, phases, and treatment. Ann Am Acad Pol Soc Sci 474:146--156. Tarter RE, McBride H, Buonpane N, and Schneider DU (1977): Differentiation of alcoholics: Childhood history of minimal brain dysfunction, family history and drinking pattern. Arch Gen Psychiatry 34:761-768. Von Knotting L, Perris C, Goldstein L, Kewali D, Monakhov K, Vacca L (1983): Intercorrelations between different computer-based measures of the EEG alpha amplitude and its variability over time and their validity in differentiating healthy volunteers from depressed patients. Adv Biol Psychiatry 13:172-181. Wood D, Wender PH, Reimherr FW (1983): The prevalence of attention deficit disorder, residual type, or minimal brain dysfunction, in a population of male alcoholic patients. Am J Psychiatry 140:95-98.

Auditory brainstem evoked response (BAER) and spontaneous electroencephalogram (EEG) were measured in 124 adult male drug abusers. We examined the relationships among psychiatric diagnoses, paper and pencil measures of aggression and hostility, and electrophysiological features. Subjects meeting criteria for antisocial personality disorder (ASP), as defined by DSM-III, were not significantly different from non-ASP subjects for either BAER or spontaneous EEG measures. The more overtly aggressive subjects had significant delays in BAER latency. Aggressive subjects also had more delta activity and less alpha activity in the spontaneous EEG, as have been observed in "psychopaths" and "criminals." Although ASP and aggression are related, these data indicate that aggressiveness may be a separate, albeit overlapping, trait. As both early aggression and a diagnosis of ASP are predictors of later drug use, the findings that only aggression was associated with EEG slowing and brainstem delays may indicate that ASP and aggression make independent contributions to vulnerability to the development of drug abuse.

This paper describes the application of Gaussian mixture distributions to biological marker research in psychiatry. Mixtures of univariate and multivariate normal distributions can be used to determine if diagnostically similar psychiatric patients belong to biologically distinct subpopulations. The resulting biological subtypes may be important in understanding the etiology of psychiatric disorders. The general model and estimation procedure are described (EM algorithm; Dempster, Laird and Rubin 1977). The method is illustrated using two examples of biological data: (1) red cell membranes and monoamine oxidase activity data in normal individuals having no family history of psychiatric illness, the first-degree relatives of bipolar depressed patients and a heterogeneous patient population; and (2) smooth pursuit eye movements that classify relatives of schizophrenics, nonschizophrenics and normal controls into biologically distinct populations.

This paper describes the morphology of abnormal behavior of rhesus monkeys which had experienced a certain degree of social isolation. Analysis of the morphology of the behavior starts from the hypothesis that abnormal activities should preferably be interpreted as distortions of normal behavior. The results indicate that all abnormal activities seemed to be symptoms of one social deprivation syndrome, because all activities could tentatively be interpreted as more or less idiosyncratically distorted, often self-directed forms of normally social behavior. The results also illustrate that abnormal behavior patterns can be considered at different levels of integration which should be clearly distinguished in comparative studies. Similarities to the behavior of human mental patients suggest that social deprivation is a prominent factor in a wide variety of mental diseases.

The neurophysiological basis of behavior and psychiatric disorders is for the most part unknown. However, over the years dysfunction of the dopaminergic system and, specifically, the basal ganglia have been implicated in many complex behaviors and psychiatric disorders. Evidence is presented in support of a basal ganglia role in sensory gating in the CNS and suggests a possible mechanism by which basal ganglia dysfunction may result in complex behavioral disturbances. Using schizophrenia as an example, this paper suggests that such disorders may to a certain extent represent a complex dysfunction of sensory filtering mechanisms in the brain. The suggestion is that the basal ganglia, acting as an active sensory information gating station, maintain the normal flow of afferent information to both ascending and descending structures. When this gating system is dysfunctional, unmodulated afferent information leads to inappropriate behavioral responses.

This paper attempts to make a limited number of points: First, there are enough data indicating a probable genetic propensity in alcoholism to justify prospective studies. Second, such studies are a logical way to attempt to differentiate between factors which predispose an individual towards alcoholism and those biological and psychological changes which result from many years of heavy drinking. Third, this type of approach can be used in biological, psychological, or sociological spheres. Because this type of research is relatively expensive and time-consuming, we have attempted to gather information on as many relevant factors as possible, making our final decision about which specific factors are to be tested through a balance of how much sense they make, how easy they are to test, and how well they combine into a test battery. Our present study will not answer questions definitively but will help point us towards those investigations in the future which are most likely to pay off. Other investigators are encouraged to use a similar approach.

This paper concerns assessment of the full range of risks associated with prolonged use of antipsychotic medication. It is generally accepted that the most common side effects of drug therapy involve motor problems. Movement disorders arise because antipsychotics, in a substantial proportion of patients, disrupt the basal ganglia. The basal ganglia, however, are involved in much more than simply motor control. Specifically, this neural system has been implicated in sensory reactivity, attention, memory, and cognition. It follows from this that antipsychotic drugs, in addition to causing motor problems, might also disrupt complex psychological processes.

This paper reports the results of an investigation of voluntary control of lip, jaw, and tongue movements in schizophrenic patients with and without tardive dyskinesia. The aims of the study were to determine if voluntary orofacial motor control is disrupted in schizophrenia and to evaluate the relationship between voluntary motor control deficits and selected neurological and behavioral variables. Twenty-two schizophrenic patients and 13 normal control subjects were studied. Of the patients, 11 had moderate to severe TD. Analyses were made of performance on pursuit tracking tasks to evaluate differences between TD and non-TD patients and between medicated and currently unmedicated patients. The results indicated significant group differences in voluntary orofacial motor control. The finding that many non-TD patients exhibited voluntary motor dyscontrol suggests that this may represent a disorder independent of the involuntary dyskinesia. The findings indicated that the level of neuroleptic and/or antiparkinsonian medication was unrelated to the degree of voluntary motor control impairment. The results are discussed in terms of probable neurophysiological mechanisms underlying the motor control deficits in schizophrenia.

This paper describes the use of serial neuroendocrine challenge studies in the assessment of depressive disorder, specifically the dexamethasone suppression test (DST) and thyrotropin-releasing hormone (TRH) stimulation test. The combined use of these challenge tests revealed high sensitivity (67%) and high predictive value for the identification of endogenous depression in contrast to schizophrenia (p less than 0.025) or nondepressed patients (p less than 0.005). Further, normalization or persistence of dysregulation of these tests was correlated with clinical outcome at 6 months. Normalization of the DST occurred in 26 of 32 patients (82%) and was significantly correlated with the timing of symptomatic improvement (p less than 0.01). Five of six patients (84%) who never normalized the DST suffered an early relapse in contrast to 4 of 26 patients who did normalize (p less than 0.005). Unlike the DST, normalization of the blunted thyrotropin (TSH) response to TRH injection was not significantly correlated with the timing of symptomatic improvement. Only 8 of 19 patients (42%) ever normalized the TSH response. However, none of these 8 normalized patients suffered relapse within 6 months in contrast to 7 of 11 patients (64%) who did not normalize (p less than 0.025). Thus, failure of normalization of either the DST or TRH test was associated with a group of patients at high risk for early relapse. In this study, the use of prophylactic antidepressant medications did not avert relapse in 9 of 11 relapsed patients who had persistent neuroendocrine dysregulation.

Szabadi et al. claimed that speech pause time--the silent interval between phonations--was significantly elongated during episodes of unipolar depressions; thus representing an objective measure of psychomotor retardation. Phonation times were said to be unchanged. To replicate and possibly expand these findings, we measured pause and phonation times among four unipolar (UP) and three bipolar (BP) endogenously depressed inpatients. Speech was recorded while patients counted from one to ten at their desired rate, and then converted to paper prints with a voice-operated electrical relay. Among all patients, pause times were substantially longer during base-line medication-free periods than at discharge. Progressive decreases occurred in conjunction with clinical improvement. These data replicated Szabadi's observation on UP patients and extended it to BP depressed patients. Of potential clinical importance, in two cases we documented decreases in pause time of more than 50% within several days after starting treatment. Speech pause times may be pragmatically useful as objective pathophysiologic markers in depression. Significant decreases occur with recovery, and early decreases during treatment may, like changes in REM sleep, be predictive of ultimate clinical response.

Principles of sound research design are too often incompletely applied in scientific investigations. Physicians may fail to evaluate journal articles for quality of research, comparability among studies, and clinical relevance. For many investigators quick publishable experiments take precedence over those with rigorous methods. Clinicians and researchers are becoming more aware of these concerns. Students should be taught the skills necessary to interpret scientific reading. Greater attention should be given to correct research design, and authors should fully explain both the procedures of a study, and its relevance. Fewer published articles and more review papers or commentaries might also stimulate better research quality.

Recent advances in knowledge about calcium's role as an intracellular regulator promise to broaden our understanding of possible pathophysiologic mechanisms in affective disorders. In this paper, we review the influence of calcium on mood, the intracellular dynamics of the calcium ion, and the possible interaction of lithium with these actions. We then discuss similarities with lithium of calcium antagonists, a class of drugs that influences calcium's action within cells, and report preliminary findings of their possible usefulness in treating mania. Finally, we hypothesize ways in which alterations in intracellular calcium ion concentration may be associated with mania and depression, and suggest methods of studying this hypothesis.

This paper reports on a relative rarity, the case of a 41-year-old male who, after receiving an original admission diagnosis of clear-cut acute mania, actually turned out to be suffering from herpes simplex encephalitis. Interestingly enough, his illness was unusually "benign" in the sense that at no time during massive cycling bipolar mood disturbances did any clinically apparent neurological signs and symptoms or other serious somatic complications or any psychopathology pointing to an acute organic brain syndrome appear. Karl Bonhoeffer's often forgotten but still relevant clinical insights on acute organic psychoses are then discussed in the light of recent research attempting to link manic states and infectious illness.

The first report of this series indicated that evoked potential (EP) characteristics previously shown to correlate with psychopathology differed between subjects with high and low intelligence test scores (IQ). This paper reports the results of an attempt to determine if these IQ-EP relationships could result from variations in clinical state, rather than from differences between groups in trait IQ. Two patient groups were selected on the basis of the shifts in their Raven Progressive Matrices scores from first test to retest: (i) increase of 17-46 percentile points; (ii) decrease of 5 to 30 points. Their somatosensory, visual, and auditory EPs were compared in several ways to determine if the EP changes on retest were correlated with the IQ changes, as predicted from the state hypothesis. The results did not confirm the predictions, suggesting that the previous findings reflected differences in trait IQ.