Showing papers in "Archives of General Psychiatry in 1994"
TL;DR: The prevalence of psychiatric disorders is greater than previously thought to be the case, and morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders.
Abstract: Background: This study presents estimates of lifetime and 12-month prevalence of 14 DSM-III-R psychiatric disorders from the National Comorbidity Survey, the first survey to administer a structured psychiatric interview to a national probability sample in the United States. Methods: The DSM-III-R psychiatric disorders among persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States were assessed with data collected by lay interviewers using a revised version of the Composite International Diagnostic Interview. Results: Nearly 50% of respondents reported at least one lifetime disorder, and close to 30% reported at least one 12-month disorder. The most common disorders were major depressive episode, alcohol dependence, social phobia, and simple phobia. More than half of all lifetime disorders occurred in the 14% of the population who had a history of three or more comorbid disorders. These highly comorbid people also included the vast majority of people with severe disorders. Less than 40% of those with a lifetime disorder had ever received professional treatment, and less than 20% of those with a recent disorder had been in treatment during the past 12 months. Consistent with previous risk factor research, it was found that women had elevated rates of affective disorders and anxiety disorders, that men had elevated rates of substance use disorders and antisocial personality disorder, and that most disorders declined with age and with higher socioeconomic status. Conclusions: The prevalence of psychiatric disorders is greater than previously thought to be the case. Furthermore, this morbidity is more highly concentrated than previously recognized in roughly one sixth of the population who have a history of three or more comorbid disorders. This suggests that the causes and consequences of high comorbidity should be the focus of research attention. The majority of people with psychiatric disorders fail to obtain professional treatment. Even among people with a lifetime history of three or more comorbid disorders, the proportion who ever obtain specialty sector mental health treatment is less than 50%. These results argue for the importance of more outreach and more research on barriers to professional help-seeking.
11,648 citations
TL;DR: These data indicate that N-methyl-D-aspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
Abstract: Background: To characterize further behavioral, cognitive, neuroendocrine, and physiological effects of subanesthetic doses of ketamine hydrochloride in healthy human subjects. Ketamine, a phencyclidine hydrochloride derivative, is a dissociative anesthetic and a noncompetitive antagonist of the N -methyl-D-aspartate subtype of excitatory amino acid receptor. Methods: Nineteen healthy subjects recruited by advertisements from the community participated in this randomized, double-blind, placebo-controlled study. Subjects completed three test days involving the 40-minute intravenous administration of placebo, ketamine hydrochloride (0.1 mg/kg), or ketamine hydrochloride (0.5 mg/kg). Behaviors associated with the positive and negative symptoms of schizophrenia were assessed by using the Brief Psychiatric Rating Scale. Changes in perception and behaviors associated with dissociative states were assessed by the Perceptual Aberration Subscale of the Wisconsin Psychosis Proneness Scale and the Clinician-Administered Dissociative States Scale. Cognitive function was assessed by using the (1) Mini-Mental State Examination; (2) tests sensitive to frontal cortical dysfunction, including a continuous performance vigilance task, a verbal fluency task, and the Wisconsin Card Sorting Test; and (3) tests of immediate and delayed recall. Plasma levels of cortisol, prolactin, homovanillic acid, and 3-methoxy-4-hydroxyphenethyleneglycol were measured. Results: Ketamine (1) produced behaviors similar to the positive and negative symptoms of schizophrenia; (2) elicited alterations in perception; (3) impaired performance on tests of vigilance, verbal fluency, and the Wisconsin Card Sorting Test; (4) evoked symptoms similar to dissociative states; and (5) preferentially disrupted delayed word recall, sparing immediate recall and postdistraction recall. Ketamine had no significant effect on the Mini-Mental State Examination at the doses studied. Ketamine also had no effect on plasma 3-methoxy-4hydroxyphenethyleneglycol levels, although it blunted a test day decline in plasma homovanillic acid levels at the higher dose. It also dose dependently increased plasma cortisol and prolactin levels. Ketamine produced small dose-dependent increases in blood pressure. Conclusions: These data indicate that N -methyl-Daspartate antagonists produce a broad range of symptoms, behaviors, and cognitive deficits that resemble aspects of endogenous psychoses, particularly schizophrenia and dissociative states.
3,166 citations
TL;DR: The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings, and should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions.
Abstract: This the Diagnostic Interview for Genetic Studies (DIGS), a clinical interview especially constructed for the assessment of major mood and psychotic disorders and their spectrum conditions The DIGS, which was developed and piloted as a collaborative effort of investigators from sites in the National Institute of Mental Health (NIMH) Genetics Initiative, has the following additional features: (1) polydiagnostic capacity; (2) a detailed assessment of the course of the illness, chronology of psychotic and mood syndromes, and comorbidity; (3) additional phenomenologic assessments of symptoms; and (4) algorithmic scoring capability The DIGS is designed to be employed by interviewers who exercise significant clinical judgment and who summarize information in narrative form as well as in ratings A two-phase test-retest (within-site, between-site) reliability study was carried out for DSM-III-R criteria—based major depression, bipolar disorder, schizophrenia, and schizoaffective disorder Reliabilities using algorithms were excellent (073 to 095), except for schizoaffective disorder, for which disagreement on estimates of duration of mood syndromes relative to psychosis reduced reliability A final best-estimate process using medical records and information from relatives as well as algorithmic diagnoses is expected to be more reliable in making these distinctions The DIGS should be useful as part of archival data gathering for genetic studies of major affective disorders, schizophrenia, and related conditions
2,024 citations
TL;DR: Verbal memory, as a primary neuropsychological deficit present early in the course of schizophrenia, implicates the left temporal-hippocampal system.
Abstract: Background: Medication and chronicity have complicated past attempts to characterize the neuropsychological performance of patients with schizophrenia. There have been inconsistencies regarding the pattern, selectivity, and sources of observed deficits. Our objective was to comprehensively examine neuropsychological function in patients with schizophrenia who had never been exposed to neuroleptic medication, and who were experiencing their first episode (FE) of psychosis. Methods: Subjects were consecutive recruitments that included 37 patients with FE schizophrenia who were never exposed to neuroleptics. These subjects were compared with 65 unmedicated, previously treated (PT) patients and 131 healthy controls. Results: The patient groups had nearly identical profiles showing generalized impairment, particularly in verbal memory and learning, attention-vigilance, and speeded visual-motor processing and attention. Verbal memory and learning accounted for most of the variance between patients and controls and removing this effect substantially attenuated all other differences. By contrast, both the FE group and PT group continued to show highly significant deficits in verbal memory and learning after controlling for attention, abstraction, and all other functions. Some functions not typically implicated in schizophrenia (spatial cognition, fine motor speed, and visual memory) were more impaired in the PT group than in the FE group. Conclusions: Verbal memory, as a primary neuropsychological deficit present early in the course of schizophrenia, implicates the left temporal-hippocampal system. Neuropsychological evaluations before treatment permit differentiation of primary deficits from changes secondary to medication or chronicity. This is essential for developing a neurobehavioral perspective on schizophrenia.
1,101 citations
TL;DR: It is possible to assess personality disorders with reasonably good reliability in different nations, languages, and cultures using a semistructured clinical interview that experienced clinicians find relevant, meaningful, and user-friendly.
Abstract: Background: One of the aims of the World Health Organization/Alcohol, Drug Abuse, and Mental Health Administration joint program on psychiatric diagnosis and classification is the development and standardization of diagnostic assessment instruments for use in clinical research worldwide. The International Personality Disorder Examination (IPDE) is a semistructured clinical interview compatible with the International Classification of Diseases, Tenth Revision , and the DMS-III-R classification systems. This is the first report of the results of a field trial to investigate the feasibility of using the IPDE to assess personality disorders worldwide. Methods: The IPDE was administered by 58 psychiatrists and clinical psychologists to 716 patients enrolled in clinical facilities at 14 participating centers in 11 countries in North America, Europe, Africa, and Asia. To determine interrater reliability, 141 of the IPDEs (20%) were independently rated by a silent observer. To determine temporal stability, 243 patients (34%) were reexamined after an average interval of 6 months. Results: The IPDE proved acceptable to clinicians and demonstrated an interrater reliability and temporal stability roughly similar to instruments used to diagnose the psychoses, mood, anxiety, and substance use disorders. Conclusion: It is possible to assess personality disorders with reasonably good reliability in different nations, languages, and cultures using a semistructured clinical interview that experienced clinicians find relevant, meaningful, and user-friendly.
936 citations
TL;DR: It is suggested that severe self-awareness deficits are a prevalent feature of schizophrenia, perhaps stemming from the neuropsychological dysfunction associated with the disorder, and are more common in schizophrenia than in other psychotic disorders.
Abstract: Background: The literature on insight, or selfawareness, in schizophrenia suggests that this cognitive dimension may be of nosological value. Poor insight has descriptive validity at the phenomenological and neuropsychological levels of schizophrenia and has prognostic validity in terms of the prediction of the course of illness. The lack of empirical data on the diagnostic specificity of poor insight to schizophrenia and the previous use of insight measures with questionable reliability and validity have limited this interpretation. Methods: In the present study, we assessed insight into multiple aspects of mental disorder using a measure with demonstrated reliability and validity. A sample of 412 Patients with psychotic and mood disorders coming from geographically diverse regions of the United States and one international site was studied. The main aims were to determine the prevalence of self-awareness deficits in patients in whom schizophrenia was diagnosed, to examine the relative severity of self-awareness deficits associated with schizophrenia compared with that of schizoaffective and mood disorders with and without psychosis, and to evaluate the clinical correlates of selfawareness in patients with schizophrenia. Results: The results indicated that poor insight is a Prevalent feature of schizophrenia. A variety of selfawareness deficits are more severe and pervasive in Patients with schizophrenia than in patients with schizoaffective or major depressive disorders with or without psychosis and are associated with poorer Psychosocial functioning. Conclusions: The results suggest that severe self-awareness deficits are a prevalent feature of schizophrenia, perhaps stemming from the neuropsychological dysfunction associated with the disorder, and are more common in schizophrenia than in other psychotic disorders.
878 citations
TL;DR: Although lifetime GAD is highly comorbid, the proportion of current GAD that is not accompanied by any other current diagnosis is high enough to indicate that GAD should be considered an independent disorder rather than exclusively a residual or prodrome of other disorders.
Abstract: Background Nationally representative general population data are presented on the current, 12-month, and lifetime prevalence of DSM-III-R generalized anxiety disorder (GAD) as well as on risk factors, comorbidity, and related impairments. Methods The data are from the National Comorbidity Survey, a large general population survey of persons aged 15 to 54 years in the noninstitutionalized civilian population of the United States. DSM-III-R GAD was assessed by lay interviewers using a revised version of the Composite International Diagnostic Interview. Results Generalized anxiety disorder was found to be a relatively rare current disorder with a current prevalence of 1.6% but was found to be a more frequent lifetime disorder affecting 5.1% of the US population aged 15 to 45 years. Generalized anxiety disorder was twice as common among women as among men. Multivariate logistic regression analysis showed that being older than 24 years, separated, widowed, divorced, unemployed, and a homemaker are significant correlates of GAD. Consistent with studies in treatment samples, we found that GAD was frequently associated with a wide spectrum of other mental disorders, with a lifetime comorbidity among 90.4% of the people who had a history of GAD. Conclusion Contrary to the traditional view that GAD is a mild disorder, we found that the majority of people with GAD, whether they were comorbid or not, reported substantial interference with their life, a high degree of professional help seeking, and a high use of medication because of their GAD symptoms. Although lifetime GAD is highly comorbid, the proportion of current GAD that is not accompanied by any other current diagnosis is high enough to indicate that GAD should be considered an independent disorder rather than exclusively a residual or prodrome of other disorders.
877 citations
TL;DR: The data further implicate orbitofrontal cortex, caudate nucleus, and anterior cingulate cortex in the pathophysiology of OCD and in mediating OCD symptoms.
Abstract: Background: The study was designed to determine the mediating neuroanatomy of obsessive-compulsive disorder (OCD). Methods: The short half-life tracer oxygen 15—labeled carbon dioxide was used to allow for repeated positron emission tomographic determinations of regional cerebral blood flow on each of eight patients with OCD during a resting and a provoked (symptomatic) state. Results: Individually tailored provocative stimuli were successful in provoking OCD symptoms, in comparison with paired innocuous stimuli, as measured by selfreport on OCD analogue scales ( P =.002). Omnibus subtraction images demonstrated a statistically significant increase in relative regional cerebral blood flow during the OCD symptomatic state vs the resting state in right caudate nucleus ( P P P P =.07). Conclusions: These findings are consistent with results of previous functional neuroimaging studies and contemporary neurocircuitry models of OCD. The data further implicate orbitofrontal cortex, caudate nucleus, and anterior cigulate cortex in the pathophysiology of OCD and in mediating OCD symptoms.
835 citations
TL;DR: Incentives delivered contingent on submitting cocaine-free urine specimens significantly improve treatment outcome in ambulatory cocaine-dependent patients, and only the voucher group showed significant improvement on the ASI Psychiatric scale.
Abstract: Objective: To assess whether incentives improved treatment outcome in ambulatory cocaine-dependent patients. Method: Forty cocaine-dependent adults were randomly assigned to behavioral treatment with or without an added incentive program. The behavioral treatment was based on the Community Reinforcement Approach and was provided to both groups. Subjects in the group with incentives received vouchers exchangeable for retail items contingent on submitting cocaine-free urine specimens during weeks 1 through 12 of treatment, while the group without incentives received no vouchers during that period. The two groups were treated the same during weeks 13 through 24. Results: Seventy-five percent of patients in the group with vouchers completed 24 weeks of treatment vs 40% in the group without vouchers ( P =.03). Average durations of continuous cocaine abstinence documented via urinalysis during weeks 1 through 24 of treatment were 11.7±2.0 weeks in the group with vouchers vs 6.0±1.5 weeks in the group without vouchers ( P =.03). At 24 weeks after treatment entry, the voucher group evidenced significantly greater improvement than the no-voucher group on the Drug scale of the Addiction Severity Index (ASI). and only the voucher group showed significant improvement on the ASI Psychiatric scale. Conclusions: Incentives delivered contingent on submitting cocaine-free urine specimens significantly improve treatment outcome in ambulatory cocainedependent patients.
751 citations
TL;DR: The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients and may help to understand the neurobiology of cognitive deficits in schizophrenia.
Abstract: Psychiatric researchers need specific animal models to better understand the neurobiology of schizophrenia. Prepulse inhibition (PPI), the reduction in startle produced by a prepulse stimulus, is diminished in schizophrenic patients. Theoretically, deficient PPI in schizophrenic patients reflects a loss of sensorimotor gating that may lead to sensory flooding and cognitive fragmentation. In rats, PPI is disrupted by systemic administration of dopamine agonists or by manipulations of neural circuitry linking the limbic cortex, striatum, pallidum, and pontine reticular formation. This loss of PPI in rats may be a useful model for studying the neurobiology of impaired sensorimotor gating in schizophrenic patients. We assessed the face, predictive, and construct validity of this animal model. Face validity was supported: stimulus manipulations produced parallel changes in PPI in humans and rats, and the dopamine agonist apomorphine disrupted PPI in rats, mimicking PPI deficits in schizophrenics. Predictive validity was supported: the ability of antipsychotics to restore PPI in apomorphine-treated rats correlated with clinical antipsychotic potency ( r s =.991) and D 2 -receptor affinity ( r s =.893). Antipsychotics that restore PPI in apomorphine-treated rats include "typical" antipsychotics and the "atypical" antipsychotic clozapine. Construct validity was supported: PPI was disrupted in rats when dopamine was infused into the nucleus accumbens; this effect was blocked by haloperidol. The loss of PPI in dopamine-activated rats may be a valid animal model of sensorimotor gating deficits in schizophrenic patients. This model may help us understand the neurobiology of cognitive deficits in schizophrenic patients.
737 citations
TL;DR: The data are consistent with the idea that both early and late postnatal increases of myelination occur in a key corticolimbic relay area of the human brain and underscore the importance of applying a neurodevelopmental perspective to the study of psychopathology during childhood, adolescence, and even adulthood.
Abstract: Background: A previous study demonstrated that myelination of the superior medullary lamina along the surface of the parahippocampal gyrus is occurring in human brain during adolescence. To further investigate whether postnatal increases of myelination may continue during the second decade and possibly even longer, the extent of myelination in this region has been analyzed in 164 psychiatrically normal individuals aged newborn to 76 years. Methods: Cross sections of the hippocampal formation with adjoining hippocampal gyrus were analyzed on a blinded basis using either a global rating scale or measurements of the area of myelin staining. Results: A curvilinear increase in the extent of myelination between the first and sixth decades of life ( r =.71 and r =.67, respectively) was observed. When the area of myelination was expressed relative to brain weight, there was a twofold increase between the first and second decades and an additional increase of 60% between the fourth and sixth decades. Female subjects showed a significantly greater degree of myelin staining than did male subjects during the interval of ages 6 to 29 years; however, after the third decade, there were no gender differences in the area of myelin staining. Conclusions: The increased staining of myelin during the first and second decades principally occurred in the subicular region and adjacent portions of the presubiculum. During the fourth through sixth decades, however, it extended to progressively more lateral locations along the surface of the presubiculum. The precise origin(s) of the axons showing progressive myelination is unknown; however, the axons in the subiculum may include some perforant path fibers, while those found in the presubiculum may include cingulum bundle projections. Overall, our data are consistent with the idea that both early and late postnatal increases of myelination occur in a key corticolimbic relay area of the human brain and underscore the importance of applying a neurodevelopmental perspective to the study of psychopathology during childhood, adolescence, and even adulthood.
TL;DR: Issues of personality disorder assessment in the DSM-III/DSM-III-R era are discussed, and studies of diagnostic reliability and stability are reviewed because studies can only be interpreted in the context of the limitations imposed by modest reliability.
Abstract: Many questions face researchers conducting personality disorder research. Which measure should be used? When should patients be evaluated--at initial presentation when they are still symptomatic, or after symptom resolution? Can a patient accurately describe his or her personality, or must an informant be contacted? What do you do when personality traits change during an individual's lifetime? I discuss these and other issues of personality disorder assessment in the DSM-III/DSM-III-R era, and examine the empiric literature bearing on these questions. First, I review studies of diagnostic reliability and stability, because studies of the above questions can only be interpreted in the context of the limitations imposed by modest reliability.
TL;DR: Cannabis abuse and particularly heavy abuse can be considered a stressor eliciting relapse in patients with schizophrenia and related disorders and possibly a premorbid precipitant.
Abstract: Objective: We sought to examine the relation between cannabis abuse and the symptomatic course of recent-onset schizophrenia and related disorders. Design: A prospective cohort study over a year using monthly Brief Psychiatric Rating Scale assessments. Participants: Cannabis-abusing patients (n=24) were compared with nonabusers (n=69). Eleven patients were mild and 13 were heavy cannabis-abusing patients. Results: Significantly more and earlier psychotic relapses occurred in the cannabis-abusing group (P=.03). This association became stronger when mild and heavy cannabis abuse were distinguished (P=.002). No confounding effect of other variables, eg, other street drugs, was found. In all but one patient, cannabis abuse preceded the onset of the first psychotic symptoms for at least 1 year. Conclusions: Cannabis abuse and particularly heavy abuse can be considered a stressor eliciting relapse in patients with schizophrenia and related disorders and possibly a premorbid precipitant.
TL;DR: The categorical approach corroborated Cloninger's suggestion that boys who are high in impulsivity, low in anxiety, and low in reward dependence would be more at risk for delinquent involvement and was the best predictor of the early onset of stable, highly delinquent behavior.
Abstract: Methods: Data from a large longitudinal study of boys who were between kindergarten and age 13 years were used to (1) test whether Gray's and Cloninger's personality dimensions measured in kindergarten predicted the early onset of stable, highly delinquent behavior; (2) test whether 1, 2, or 3 dimensions were needed; and (3) test the predictive value of a categorical approach. Results: The impulsivity dimension was the best predictor of the early onset of stable, highly delinquent behavior. Anxiety and reward dependence made significant but weaker contributions. The categorical approach corroborated Cloninger's suggestion that boys who are high in impulsivity, low in anxiety, and low in reward dependence would be more at risk for delinquent involvement. Boys who were high in impulsivity and low in anxiety but high in reward dependence were much less at risk for delinquency. Differences in antisocial behavior among extreme kindergarten personality groups were stable from ages 11 to 13 years. Conclusions: The behavioral activating system appears to be the major dimension underlying the propensity toward early onset of antisocial behavior, but both the behavioral inhibition system and the need for social rewards play important roles. The behavioral style (personality) that results from the interplay of these systems is clearly in place by the kindergarten year. Preventive efforts should target preschool children with at-risk behavior profiles. However, longitudinal-experimental studies with at least yearly assessments between birth and school-entry age are needed to understand the extent to which the behavioral styles are antecedent to preschool disruptive behavior disorders.
TL;DR: Findings give plausibility to the proposition that early prenatal nutrition can have a gender-specific effect on the risk of schizophrenia.
Abstract: We tested the hypothesis that first-trimester exposure to acute food deprivation is a risk factor for schizophrenia. A sharp and time-limited decline in the food intake of the Dutch population following a Nazi blockade in 1944 to 1945 created a unique if tragic natural experiment to test this hypothesis in three regions of Holland (west, north, and south). In the west, or famine region, birth cohorts exposed to severe food deprivation (an average daily ration under 4200 kJ) during the first trimester showed a substantial increase in hospitalized schizophrenia for women but not for men. Relative risks for women were 2.17 for "broad" and 2.56 for "restricted" schizophrenia. Moderate food deprivation during the first trimester (average daily ration under 6300 kJ) was not associated with increased risk of schizophrenia in the famine region. In the north and south regions, numbers were smaller and there was no exposure to severe famine. Birth cohorts exposed to moderate food deprivation during the first trimester showed a trend toward increased risk of schizophrenia for women. These findings give plausibility to the proposition that early prenatal nutrition can have a gender-specific effect on the risk of schizophrenia.
TL;DR: Major mood disturbances associated with anabolic-androgenic steroids may represent an important public health problem for athletes using steroids and sometimes for the victims of their irritability and aggression.
Abstract: Background: We sought to expand on preliminary findings suggesting that anabolic-androgenic steroids produce psychiatric effects in some athletes who use them. Methods: We compared 88 athletes who were using steroids with 68 nonusers, using the Structured Clinical Interview for DSM-III-R to diagnose psychiatric syndromes occurring in association with steroid use (if applicable) and in the absence of steroid use. Demographic, medical, and laboratory measures were also performed. Results: Steroid users displayed more frequent gynecomastia, decreased mean testicular length, and higher cholesterol—high-density lipoprotein ratios than nonusers. Most strikingly, 23% of steroid users reported major mood syndromes—mania, hypomania, or major depression—in association with steroid use. Steroid users displayed mood disorders during steroid exposure significantly more frequently than in the absence of steroid exposure ( P P Conclusion: Major mood disturbances associated with anabolic-androgenic steroids may represent an important public health problem for athletes using steroids and sometimes for the victims of their irritability and aggression.
TL;DR: The results of this study suggest that OCD patients with a comorbid chronic tic disorder constitute a clinically meaningful subtype of OCD that might require conjoint serotonin-uptake inhibitor/neuroleptic therapy for effective symptom reduction.
Abstract: Background: To determine the efficacy of adding haloperidol to the treatment of patients with obsessive-compulsive disorder (OCD), with or without a comorbid chronic tic disorder, who were refractory to adequate treatment with the serotonin-uptake inhibitor fluvoxamine alone. It was hypothesized that OCD patients with a concurrent chronic tic disorder would preferentially respond to this treatment. Methods: Sixty-two patients with a primary DSM-III-R diagnosis of OCD received placebo fluvoxamine for 1 week, followed by 8 weeks of active fluvoxamine. Thirty-four of these patients were refractory to fluvoxamine and were randomized in a double-blind fashion to 4 weeks of treatment with either haloperidol (n=17) or placebo (n=17) added to ongoing fluvoxamine treatment. The placebo-treated group included five women and 12 men, six inpatients and 11 outpatients, and eight patients with a comorbid chronic tic disorder. The haloperidol-treated group consisted of two women and 15 men, three inpatients and 14 outpatients, and seven patients with a comorbid chronic tic disorder. All 34 patients completed the entire study. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the Clinical Global Impression scale were the principal measures of treatment outcome. Results: Haloperidol addition was significantly better than placebo in reducing the severity of obsessive-complusive symptoms as measured by the Y-BOCS. Eleven of 17 patients responded to the haloperidol, compared with none of 17 patients given placebo. Eight of eight patients with comorbid chronic tic disorders, such as Tourette's disorder, responded to double-blind haloperidol addition to ongoing fluvoxamine treatment. Haloperidol addition was of little benefit in treating OCD patients without tics. Fluvoxamine blood levels were not related to treatment response. Conclusions: The results of this study suggest that OCD patients with a comorbid chronic tic disorder constitute a clinically meaningful subtype of OCD that might require conjoint serotonin-uptake inhibitor/neuroleptic therapy for effective symptom reduction.
TL;DR: A low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence in alcoholic, impulsive and nonimpulsive offenders.
Abstract: Background: There is an extensive literature describing a central serotonin deficit in alcoholic, impulsive, violent offenders and fire setters In the present study, we investigated biochemical concomitants of impulsivity and aggressiveness, and the physiological consequences of reduced central serotonin turnover Methods: Forty-three impulsive and 15 nonimpulsive alcoholic offenders and 21 healthy volunteers were studied in the forensic psychiatry ward of a university psychiatric department The subjects underwent lumbar punctures and oral glucose and aspartame challenges, and their diurnal activity rhythm was measured with physical activity monitors Discriminant function analyses were used to investigate psychophysiological and biochemical concomitants of aggressive and impulsive behaviors Results: Alcoholic, impulsive offenders with antisocial personality disorder had low mean cerebrospinal fluid (CSF) 5-hydroxyindoleaceticacid (5-HIAA) and corticotropin levels and high mean CSF testosterone concentrations Compared with healthy volunteers, they showed increased physical activity during the daytime Alcoholic, impulsive offenders with intermittent explosive disorder had a low mean CSF 5-HIAA concentration and blood glucose nadir after an oral glucose challenge, and desychronized diuranalactivityrhythm Healthy volunteers had mean CSF 5-HIAA concentrations that were intermediate between those of alcoholic, impulsive and nonimpulsive offenders Alcoholic, nonimpulsive offenders had a significantly higher mean CSF 5-HIAA concentration than all the other groups, including healthy volunteers In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence Conclusions: In the present sample, a low CSF 5-HIAA concentration was primarily associated with impulsivity and high CSF testosterone concentration, with aggressiveness or interpersonal violence
TL;DR: These findings suggest that the antidepressant effects of uptake and MAO inhibitors emerge when serotonergic activity increases, and extracellular 5-HT concentration is dramatically augmented by the same doses in the vicinity of cell bodies ofserotonergic neurons, in the midbrain raphe nuclei.
Abstract: Preclinical evidence indicates that repeated treatment with antidepressant drugs (serotonin [5-HT] reuptake or monoamine oxidase [MAO] inhibitors) potentiates the ascending brain serotonergic pathways. 1,2 Also, clinical data show that the inhibition of 5-HT synthesis results in a marked worsening of patients recovering from depression who are treated with these drugs. 3-5 These findings suggest that the antidepressant effects of uptake and MAO inhibitors emerge when serotonergic activity increases. Using intracerebral microdialysis in the awake, freely moving rat, a single treatment with 5-HT uptake blockers, such as clomipramine 6 or fluvoxamine, 7 was reported to cause little or no increase of 5-HT concentration in frontal cortex at doses comparable with or higher than those used clinically. In contrast, extracellular 5-HT concentration is dramatically augmented by the same doses in the vicinity of cell bodies of serotonergic neurons, in the midbrain raphe nuclei, a preferential increase also observed after a single treatment
TL;DR: The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS alpha 2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems.
Abstract: Background: To determine whether elevations of plasma norepinephrine (NE) in major depression represent increased sympathetic nervous system (SNS) activity and to assess the effects of desipramine hydrochloride on sympathetic function. Methods: SNS activity was assessed in depressed patients and controls by an isotope-dilution, plasma NE Kinetic technique using mathematical modeling and compartmental analysis. This approach provided estimates of the rate of NE appearance into an extravascular compartment, which is the site of endogenous NE release from SNS nerves, the corresponding rate of NE appearance into plasma, and the rate of NE clearance from plasma. Results: Norepinephrine appearance into the extravascular and vascular compartments was significantly elevated in 17 depressed patients compared with that in 36 controls. The rate of NE clearance from plasma was similar in both groups. This is compatible with increased SNS activity in major depression. Desipramine, given for 2 days, significantly reduced the concentration of NE in plasma of patients and controls by markedly suppressing the rates of extravascular and vascular NE appearance, compatible with a short-term reduction in SNS activity. Desipramine prolonged the rate of NE clearance from plasma, consistent with a blockade of NE re-uptake into SNS nerve terminals. The initial suppression of SNS activity by desipramine was reversed by long-term (28 days) treatment of patients, with extravascular and vascular NE appearance rates returning to approximately basal levels. An associated rise in plasma NE concentrations compared with the baseline was attributable to a progressive reduction in plasma NE clearance. Conclusion: Sympathetic nervous system activity is elevated in major depression and is suppressed by short-term desipramine administration. The demonstration of SNS reactivation occurring with prolonged desipramine treatment is compatible with the theory that long-term treatment desensitizes CNS α2-adrenergic receptors and emphasizes the value of examining the temporal course of responses to pharmacological challenges of neuroendocrine systems. Previously reported elevations of plasma NE during prolonged administration of tricyclic antidepressants are probably the result of a reduction in plasma NE clearance, not an increase in SNS activity.
TL;DR: It is suggested that neuropsychological impairment in schizophrenia is unrelated to current age, age at onset, or duration of illness, and that the encephalopathy associated with schizophrenia is essentially nonprogressive and produces a pattern of deficits that is different from that seen in progressive cortical dementias.
Abstract: Background: We sought to determine whether neuropsychological impairment in schizophrenia is related to current age, age at onset, or duration of illness, and whether the pattern of such impairment can be distinguished from that caused by progressive dementias of Alzheimer's type. We administered a comprehensive neuropsychological test battery to a normal control group (n=38), a group of ambulatory patients with Alzheimer's disease (n=42), and three ambulatory schizophrenic groups: early onset—young (n=85), early onset—old (n=35), and late onset (n=22). Tests were grouped and analyzed according to eight major ability areas, and published procedures were used to remove the expected effects of normal aging. Results: The three schizophrenic groups were found to be neuropsychologically similar to one another and different from normal controls and patients with Alzheimer's disease. There were no significant differences among the schizophrenic groups in level or pattern of neuropsychological functioning. Patients with Alzheimer's disease demonstrated less efficient learning and particularly more rapid forgetting than did the other groups. Conclusions: These findings suggest that neuropsychological impairment in schizophrenia is unrelated to current age, age at onset, or duration of illness. The study further suggests that the encephalopathy associated with schizophrenia is essentially nonprogressive and produces a pattern of deficits that is different from that seen in progressive cortical dementias.
TL;DR: A delayed emergence of the effects of cognitive-behavioral relapse prevention is suggested, which may reflect the subjects' implementation of the generalizable coping skills conveyed through that treatment.
Abstract: Background: Neither the durability of brief ambulatory treatments for cocaine dependence nor the relative ability of psychotherapy vs pharmacotherapy to effect lasting change has been evaluated in well-controlled randomized trials. Methods: We conducted a 1-year naturalistic follow-up of 121 ambulatory cocaine abusers who underwent psychotherapy (cognitive-behavioral relapse prevention or clinical management) and pharmacotherapy (desipramine hydrochloride or placebo) in a 2X2 design. Subjects were interviewed 1, 3, 6, or 12 months after the termination of a 12-week course of outpatient treatment. Eighty percent (n=97) of the subjects who were randomized to treatment were followed up at least once. Results: First, the effects of study treatments appeared durable over the follow-up; as for the full sample, measures of cocaine use indicated either improvement or no change over posttreatment levels. Second, abstinence during treatment was strongly associated with less cocaine use during follow-up. Third, random effects regression models indicated significant psychotherapy-by-time effects, suggesting a delayed improved response during follow-up for patients who received cognitive-behavioral relapse prevention compared with supportive clinical management. Conclusions: Our findings suggest a delayed emergence of the effects of cognitive-behavioral relapse prevention, which may reflect the subjects' implementation of the generalizable coping skills conveyed through that treatment. Moreover, these data underline the importance of conducting follow-up studies of substance abusers and other groups because delayed effects may occur after the cessation of short-term treatments.
TL;DR: In some individuals, a genetic variant of the TPH gene may influence 5-HIAA concentration in the cerebrospinal fluid and predisposition to suicidal behavior.
Abstract: Background: To examine whether the tryptophan hydroxylase (TPH) gene, which codes for the rate-limiting enzyme in the biosynthesis of serotonin, may be a factor influencing serotonin turnover and behaviors controlled by serotonin. Methods: Using a polymerase chain reaction—based method, TPH genotype was determined in DNA samples from 56 impulsive and 14 nonimpulsive, alcoholic, violent offenders and 20 healthy volunteers. Results: In the behaviorally extreme impulsive group, we observed a significant association between TPH genotype and cerebrospinal fluid 5-hydroxyindoleacetic acid (5-HIAA) concentration. No association of TPH genotype with impulsive behavior was detected. The polymorphism was also associated with a history of suicide attempts in all violent offenders, independent of impulsivity status and cerebrospinal fluid 5-HIAA concentration. Conclusion: In some individuals, a genetic variant of the TPH gene may influence 5-HIAA concentration in the cerebrospinal fluid and predisposition to suicidal behavior.
TL;DR: The hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion is supported, consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
Abstract: Methods: A double-blind placebo-controlled cross-over study in which plasma tryptophan was manipulated by administration of a tryptophan-deficient amino acid mixture. In the placebo condition, all subjects received a nutritionally balanced amino acid mixture that contained tryptophan. To further standardize baseline amino acids, each subject was provided with a low-protein diet the day before amino acid challenges. Subjects were euthymic, healthy men aged 18 to 30 years with either a multigenerational family history of affective illness or no family history of psychiatric illness in the present or in the two previous generations. Each subject was screened with a structured clinical interview to rule out a personal history of psychiatric illness. Results: Plasma tryptophan was reduced by 89% 5 hours after the administration of the tryptophan-deficient amino acid mixture. Six of 20 subjects with a family history of affective illness and none of 19 subjects without a family history of psychiatric illness showed a lowering of mood of 10 or more points on the Profile of Mood States depression scale ( P =.012, Fisher's Exact Test) 5 hours after tryptophan depletion. No significant mood changes were observed following the control treatment (balanced amino acid mixture) in either group. Conclusions: Our data support the hypothesis that subjects with no prior depressive episodes but with a multigenerational family history of major affective disorder show a greater reduction in mood after tryptophan depletion. They are also consistent with theories that implicate deficient serotonergic function as one possible etiological factor in major depressive disorders.
TL;DR: These findings underscore the significance of heterogeneity among cocaine abusers and the need to develop specialized treatments for clinically distinct subgroups of cocaine abusers.
Abstract: Background: At present, there is no consensus regarding effective treatment for cocaine abuse or the most productive roles for the two major forms of treatment, pharmacotherapy and psychotherapy. We conducted the first randomized clinical trial evaluating psychotherapy and pharmacotherapy, alone and in combination, as treatment for ambulatory cocaine abusers. Methods: One hundred thirty-nine subjects were assigned to one of four conditions offered over a 12-week abstinence initiation trial: relapse prevention plus desipramine hydrochloride, clinical management plus desipramine, relapse prevention plus placebo, and clinical management plus placebo. All treatments were manual-guided, delivered by experienced therapists, and monitored to promote the integrity of both forms of treatment. Results: First, although all groups showed significant improvement, significant main effects for medication or psychotherapy, or their combination, were not found for treatment retention, reduction in cocaine use, or other outcomes at 12 weeks. Second, baseline severity of cocaine use interacted differently with psychotherapy and pharmacotherapy: higher-severity patients had significantly better outcome when treated with relapse prevention than with clinical management, while desipramine was associated with improved abstinence initiation among lower-severity subjects. Third, desipramine was significantly more effective than placebo in reducing cocaine use over 6, but not 12, weeks of treatment. Fourth, depressed subjects had greater reduction in cocaine use than nondepressed subjects and had better response to relapse prevention than to clinical management. Conclusion: These findings underscore the significance of heterogeneity among cocaine abusers and the need to develop specialized treatments for clinically distinct subgroups of cocaine abusers.
TL;DR: Clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans and may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.
Abstract: Background: Validation of animal models of hallucinogenic drugs' subjective effects requires human data. Previous human studies used varied groups of subjects and assessment methods. Rating scales for hallucinogen effects emphasized psychodynamic principles or the drugs' dysphoric properties. We describe the subjective effects of graded doses of N,N-dimethyltryptamine (DMT), an endogenous hallucinogen and drug of abuse, in a group of experienced hallucinogen users. We also present preliminary data from a new rating scale for these effects. Methods: Twelve highly motivated volunteers received two doses (0.04 and 0.4 mg/kg) of intravenous (IV) dimethyltryptamine fumarate "nonblind," before entering a doubleblind, saline placebo-controlled, randomized study using four doses of IV DMT. Subjects were carefully interviewed after resolution of drug effects, providing thorough and systematic descriptions of DMT's effects. They also were administered a new instrument, the Hallucinogen Rating Scale (HRS). The HRS was drafted from interviews obtained from an independent sample of 19 experienced DMT users, and modified during early stages of the study. Results: Psychological effects of IV DMT began almost immediately after administration, peaked at 90 to 120 seconds, and were almost completely resolved by 30 minutes. This time course paralleled DMT blood levels previously described. Hallucinogenic effects were seen after 0.2 and 0.4 mg/kg of dimethyltryptamine fumarate, and included a rapidly moving, brightly colored visual display of images. Auditory effects were less common. "Loss of control," associated with a brief, but overwhelming "rush," led to a dissociated state, where euphoria alternated or coexisted with anxiety. These effects completly replaced subjects' previously ongoing mental experience and were more vivid and compelling than dreams or waking awareness. Lower doses, 0.1 and 0.05 mg/kg, were primarily affective and somaesthetic, while 0.1 mg/kg elicited the least desirable effects. Clustering of HRS items, using either a clinical, mental status method or principal components factor analysis provided better resolution of dose effects than did the biological variables described previously. Conclusions: These clinical and preliminary quantitative data provide bases for further psychopharmacologic characterization of DMT's properties in humans. They also may be used to compare the effects of other agents affecting relevant brain receptors in volunteer and psychiatric populations.
TL;DR: The hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder is supported.
Abstract: Objective: To determine whether schizophrenics and their nonschizophrenic siblings have a similar pattern of neuropsychological deficit when compared with normal controls. Design and Participants: Fifteen probands with schizophrenia, 16 of their nonschizophrenic siblings, and 31 unrelated, demographically balanced, normal individuals underwent evaluation with a comprehensive neuropsychological test battery. All subjects were screened for history of head injury, neurologic illness, major medical conditions, substance use, and axis I psychiatric disorders other than schizophrenia. Probands underwent evaluation twice: once at intake when half had never received neuroleptic medication and the other half had received none for a minimum of 2 weeks, and again at the 2- to 4-week follow-up, after stabilization with neuroleptic medications. Results: Both schizophrenics and their nonschizophrenic siblings were impaired neuropsychologically compared with normal controls, with the nonschizophrenic siblings' performance intermediate between that of the schizophrenic siblings and the normal controls on all measures of functioning. The shapes of the deficit profiles of schizophrenic patients and their siblings were similar; in patients, verbal memory, abstraction, attention, and language functions were significantly more affected compared with spatial abilities, spatial memory, and sensorymotor functions, with a nonsignificant trend in the same direction in siblings. Cognitive functioning in patients was found to be stable across changes in medication status and clinical state. Four fifths of patients obtained more deviant scores than their nonschizophrenic siblings. Among the sibling group, those with probable and certain diagnoses of schizotypal personality disorder were more impaired compared with those without schizophrenia-spectrum symptoms. Conclusion: These results support the hypothesis that impaired information processing aggregates in the family members of schizophrenics and may serve as an indicator of genetic vulnerability to the disorder. Further work is needed to establish whether particular areas of functioning are selectively impaired in relatives and to determine whether the performance deficits are mediated by structural and/or metabolic disturbances in specific brain regions.
TL;DR: This study and its confirmation of previous results in the Copenhagen Study speak for a syndrome that can be reliably recognized in which genetic factors play a significant etiologic role: observed familial clustering in schizophrenia is an expression of shared genetic factors.
Abstract: Background: Our previous investigation of the prevalence of mental illness among the biological and adoptive relatives of schizophrenic adoptees in Copenhagen, Denmark, showed a significant concentration of chronic schizophrenia (5.6%) and what Bleuler called "latent schizophrenia" (14.8%) in the biological relatives of chronic schizophrenic adoptees, indicating the operation of heritable factors in the liability for schizophrenic illness. Methods: We now report the results of a replication of that study in the rest of Denmark (the "Provincial Sample"). Results: In this sample, the corresponding prevalences were 4.7% and 8.2%. In the combined "National Sample" of adoptees with chronic schizophrenia, that disorder was found exclusively in their biological relatives and its prevalence overall was 10 times greater than that in the biological relatives of controls. Conclusions: This study and its confirmation of previous results in the Copenhagen Study speak for a syndrome that can be reliably recognized in which genetic factors play a significant etiologic role. These findings provide important and necessary support for the assumption often made in family studies: observed familial clustering in schizophrenia is an expression of shared genetic factors.
TL;DR: This is the first study to show that birth complications in combination with early child rejection predispose to violent crime, and it is suggested that prenatal, perinatal, and early postnatal health care interventions could significantly reduce violence.
Abstract: Background: This study tests the biosocial interaction hypothesis that birth complications when combined with early maternal rejection of the infant predispose to adult violent crime. Methods: This hypothesis was tested using a cohort of 4269 consecutive live male births on whom measures of birth complications (age 0), early maternal rejection (age 1 year), and violent crime (age 18 years) were collected. Results: A significant interaction (P Conclusions: To our knowledge, this is the first study to show that birth complications in combination with early child rejection predispose to violent crime. The findings illustrate the critical importance of integrating biological with social measures to fully understand how violence develops and also suggest that prenatal, perinatal, and early postnatal health care interventions could significantly reduce violence.
TL;DR: Although on long-term follow-up, dysthymic disorder and MDD are associated with similar rates of certain outcomes, there exist sufficient differences to warrant diagnosis of each disorder.
Abstract: Objectives: To characterize the clinical presentation, course, and outcome of childhood-onset dysthymic disorder and assess the predictive validity of this diagnosis. Design: As part of a longitudinal prospective study, school-age, clinically referred youngsters (n=55) whose first depression was dysthymic disorder and a comparison group of youngsters (n=60) whose first affective episode was major depressive disorder (MDD) were repeatedly examined during a 3- to 12-year interval. The diagnoses were based on DSM-III criteria. Results: Dysthymic disorder was associated with earlier age at onset than MDD, similarly frequent symptoms of affective dysregulation, but low rates of anhedonia and neurovegetative symptoms and greater overall risk of any subsequent affective disorder. The affective disorders that dysthymic children developed, including first-episode MDD (76%) and bipolar disorder (13%), far outnumbered nonaffective conditions. After the first episode of MDD, the clinical course of the initially dysthymic youths was similar to the course of the comparison patients with regard to rates of recurrent major depression, bipolar disorder, and certain nonaffective disorders. Conclusions: Childhood-onset dysthymic disorder is an early marker of recurrent affective illness. Although on long-term follow-up, dysthymic disorder and MDD are associated with similar rates of certain outcomes, there exist sufficient differences to warrant diagnosis of each disorder. Dysthymic children who have subsequent mood disorders are most likely first to have an episode of MDD, and that episode appears to be the "gateway" to recurrent affective illness. The interval between the onset of dysthymia and the first major depression provides a window of opportunity for intervention and possible prevention of later episodes.