Childhood trauma and cognitive functioning in individuals at clinical high risk (CHR) for psychosis.

Evidence suggests that early trauma may have a negative effect on cognitive functioning in individuals with psychosis, yet the relationship between childhood trauma and cognition among those at clinical high risk (CHR) for psychosis remains unexplored. Our sample consisted of 626 CHR children and 279 healthy controls who were recruited as part of the North American Prodrome Longitudinal Study 2. Childhood trauma up to the age of 16 (psychological, physical, and sexual abuse, emotional neglect, and bullying) was assessed by using the Childhood Trauma and Abuse Scale. Multiple domains of cognition were measured at baseline and at the time of psychosis conversion, using standardized assessments. In the CHR group, there was a trend for better performance in individuals who reported a history of multiple types of childhood trauma compared with those with no/one type of trauma (Cohen d = 0.16). A history of multiple trauma types was not associated with greater cognitive change in CHR converters over time. Our findings tentatively suggest there may be different mechanisms that lead to CHR states. Individuals who are at clinical high risk who have experienced multiple types of childhood trauma may have more typically developing premorbid cognitive functioning than those who reported minimal trauma do. Further research is needed to unravel the complexity of factors underlying the development of at-risk states.

Neurocognitive predictors of metacognition in individuals at clinical high risk for psychosis.

BACKGROUND: Metacognition refers to the ability to evaluate and control our cognitive processes. While studies have investigated metacognition in schizophrenia and clinical high risk for psychosis (CHR), less is known about the potential mechanisms which result in metacognitive deficits. AIMS: We aimed to investigate whether neurocognitive functions including attention, working memory, verbal learning and executive functions predicted the tendency to focus on one's thoughts (cognitive self-consciousness) and beliefs in the efficacy of one's cognitive skills (cognitive confidence). METHOD: Participants (130 CHR individuals) were recruited as part of the multi-site PREDICT study. They were assessed using the Metacognitions Questionnaire (MCQ) as well as measures of executive function (WCST), attention (N-Back), working memory (LNS) and verbal learning (AVLT). RESULTS: Cognitive competence was negatively correlated with N-Back while cognitive self-consciousness was positively correlated with N-Back and LNS. Linear regression analysis with N-Back, AVLT, LNS and WCST as predictors showed that neurocognition significantly predicted cognitive self-consciousness, with N-Back, LNS and WCST as significant predictors. The model accounted for 14% of the variance in cognitive self-consciousness. However, neurocognition did not result in a significant predictive model of cognitive competence. CONCLUSIONS: Neurocognition was associated with an increased focus on one's thoughts, but it was not associated with higher confidence in one's cognitive skills. Neurocognition accounted for less than one-sixth of the variance in metacognition, suggesting that interventions that target neurocognition are unlikely to improve metacognitive abilities.

Does hallucination perceptual modality impact psychosis risk?

OBJECTIVE: Subthreshold perceptual abnormalities are commonly used to identify individuals at clinical high risk (CHR) for developing a psychotic disorder. Predictive validity for modality-specific perceptual abnormality severity on psychosis risk is unknown. METHODS: We examined prospectively collected data from 164 individuals age 12-35 meeting criteria for CHR followed for 6-24 months or until conversion to psychosis. Using intake interview notes, baseline perceptual abnormality scores were split into auditory, visual, somatic/tactile, and olfactory/gustatory components, and auditory scores were further split into those for verbal vs non-verbal content. Relationships between perceptual abnormality characteristics and conversion were assessed with Cox proportional hazards regression and logistic regression. RESULTS: Unusual thought content and paranoia were predictive of conversion, but no modality-specific perceptual abnormality score predicted conversion status or days to conversion. However, when auditory perceptual abnormalities were further categorized as verbal vs non-verbal, the severity of verbal experiences was predictive of conversion to psychosis (P = 0.007). CONCLUSIONS: Perceptual abnormality scores failed to meaningfully predict conversion to psychosis in either direction in this CHR sample. However, verbal auditory experiences may identify a group of CHR individuals at elevated risk of conversion. Further exploration of the relationship between phenomenological aspects of perceptual abnormalities and conversion risk is warranted.

Premorbid social adjustment and association with attenuated psychotic symptoms in clinical high-risk and help-seeking youth.

BACKGROUND: Attenuated positive symptom syndrome (APSS), characterized by 'putatively prodromal' attenuated psychotic-like pathology, indicates increased risk for psychosis. Poor premorbid social adjustment predicts severity of APSS symptoms and predicts subsequent psychosis in APSS-diagnosed individuals, suggesting application for improving detection of 'true' prodromal youth who will transition to psychosis. However, these predictive associations have not been tested in controls and therefore may be independent of the APSS diagnosis, negating utility for improving prediction in APSS-diagnosed individuals. METHOD: Association between premorbid social maladjustment and severity of positive, negative, disorganized, and general APSS symptoms was tested in 156 individuals diagnosed with APSS and 76 help-seeking (non-APSS) controls enrolled in the Enhancing the Prospective Prediction of Psychosis (PREDICT) study using prediction analysis. RESULTS: Premorbid social maladjustment was associated with social anhedonia, reduced expression of emotion, restricted ideational richness, and deficits in occupational functioning, independent of the APSS diagnosis. Associations between social maladjustment and suspiciousness, unusual thought content, avolition, dysphoric mood, and impaired tolerance to normal stress were uniquely present in participants meeting APSS criteria. Social maladjustment was associated with odd behavior/appearance and diminished experience of emotions and self only in participants who did not meet APSS criteria. CONCLUSIONS: Predictive associations between poor premorbid social adjustment and attenuated psychotic-like pathology were identified, a subset of which were indicative of high risk for psychosis. This study offers a method for improving risk identification while ruling out low-risk individuals.

Substance use in individuals at clinical high risk of psychosis.

BACKGROUND: A series of research reports has indicated that the use of substances such as cannabis, alcohol and tobacco are higher in youth at clinical high risk (CHR) of developing psychosis than in controls. Little is known about the longitudinal trajectory of substance use, and findings on the relationship between substance use and later transition to psychosis in CHR individuals are mixed. METHOD: At baseline and 6- and 12-month follow-ups, 735 CHR and 278 control participants completed the Alcohol and Drug Use Scale and a cannabis use questionnaire. The longitudinal trajectory of substance use was evaluated with linear mixed models. RESULTS: CHR participants endorsed significantly higher cannabis and tobacco use severity, and lower alcohol use severity, at baseline and over a 1-year period compared with controls. CHR youth had higher lifetime prevalence and frequency of cannabis, and were significantly younger upon first use, and were more likely to use alone and during the day. Baseline substance use did not differentiate participants who later transitioned to psychosis (n = 90) from those who did not transition (n = 272). Controls had lower tobacco use than CHR participants with a prodromal progression clinical outcome and lower cannabis use than those with a psychotic clinical outcome at the 2-year assessment. CONCLUSIONS: In CHR individuals cannabis and tobacco use is higher than in controls and this pattern persists across 1 year. Evaluation of clinical outcome may provide additional information on the longitudinal impact of substance use that cannot be detected through evaluation of transition/non-transition to psychosis alone.

Alcohol confounds relationship between cannabis misuse and psychosis conversion in a high-risk sample.

OBJECTIVE: Cannabis use has been examined as a predictor of psychosis in clinical high-risk (CHR) samples, but little is known about the impact of other substances on this relationship. METHOD: Substance use was assessed in a large sample of CHR participants (N = 370, mean age = 18.3) enrolled in the multisite North American Prodrome Longitudinal Study Phase 1 project. Three hundred and forty-one participants with cannabis use data were divided into groups: No Use (NU, N = 211); Cannabis Use without impairment (CU, N = 63); Cannabis Abuse/Dependence (CA/CD, N = 67). Participants (N = 283) were followed for ≥2 years to determine psychosis conversion. RESULTS: Alcohol (45.3%) and cannabis (38.1%) were the most common substances. Cannabis use groups did not differ on baseline attenuated positive symptoms. Seventy-nine of 283 participants with cannabis and follow-up data converted to psychosis. Survival analysis revealed significant differences between conversion rates in the CA/CD group compared with the No Use (P = 0.031) and CU group (P = 0.027). CA/CD also significantly predicted psychosis in a regression analysis, but adjusting for alcohol use weakened this relationship. CONCLUSION: The cannabis misuse and psychosis association was confounded by alcohol use. Non-impairing cannabis use was not related to psychosis. Results highlight the need to control for other substance use, so as to not overstate the cannabis/psychosis connection.

Attenuated psychosis syndrome: ready for DSM-5.1?

Prodromal features of the schizophrenia syndrome have been described for a century, and work in the past two decades has produced a substantial literature based on these features to identify individuals at increased risk for developing a psychotic disorder. Sometimes conceptualized as a "risk state" and sometimes as early manifestations of a "disorder," the work has been conducted with several related but different constructs. Early in the preparation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) public comment was sought on the proposal to create a new disorder termed attenuated psychosis syndrome (APS), and a range of issues emerged that generated interesting and important controversies. In this review, these criticisms are fully discussed, the APS concept is explicated; data relating to reliability, validity, and treatment are updated; the heterogeneity of APS is considered; and alternative views of the construct are presented with an emphasis on developmental pattern with timing for primary and secondary prevention and early treatment. Areas of future research are identified, and a potential roadmap for inclusion in DSM-5.1 is traced.

Persistent negative symptoms in youth at clinical high risk for psychosis: A longitudinal study.

BACKGROUND: Severity of negative symptoms has been associated with poor functioning, cognitive deficits, and defeatist beliefs in schizophrenia patients. However, one area that remains understudied is persistent negative symptoms (PNS). Negative symptoms, including PNS, have been observed in those at clinical high-risk (CHR) for psychosis. The aim of this study was to determine if PNS were associated with functioning, neurocognition, and defeatist beliefs in a CHR sample. METHOD: CHR participants (n = 764) were recruited for the North American Prodrome Longitudinal Study. Negative symptoms were rated on the Scale of Psychosis-risk Symptoms. Generalized linear mixed models for repeated measures were used to examine changes over time between and within groups (PNS vs non-PNS). RESULTS: The PNS group (n = 67) had significant deficits in functioning at baseline, 6, 12, 18, and 24-months compared to the non-PNS group (n = 673). Functioning improved over time in the non-PNS group, while functioning in the PNS group remained relatively stable and poor over a two-year period. A consistent trend emerged demonstrating higher defeatist beliefs in the PNS group; however, this result was lost when controlling for persistent depressive symptoms. There were no significant differences between the groups on neurocognition, social cognition, and transition to psychosis. CONCLUSIONS: PNS exist in youth at CHR for psychosis, resulting in significant and persistent functional impairment, which remains when controlling for persistent depressive symptoms. PNS remain even in CHR youth who do not transition to psychosis. Thus, PNS may represent an unmet therapeutic need in CHR populations for which there are currently no effective treatments.

Longitudinal changes in social cognition in individuals at clinical high risk for psychosis: An outcome based analysis.

Social cognition deficits have been observed in individuals at clinical high risk (CHR) for psychosis. Longitudinal change in social cognition were analyzed in CHR individuals from the North American Prodrome Longitudinal Study (NAPLS2) based on outcome at 24 months. Individuals (n = 359) were classified into remission, symptomatic, prodromal progression and transition to psychosis (CHR-T) groups. Social cognition was assessed using theory of mind, emotion perception, and social perception tasks. There were no differences at baseline or 24 months between the groups on social cognition. Non-transition groups improved significantly over time on social cognition, but CHR-T did not show this effect.

The Early Psychosis Screener for Internet (EPSI)-SR: Predicting 12 month psychotic conversion using machine learning.

INTRODUCTION: A faster and more accurate self-report screener for early psychosis is needed to promote early identification and intervention. METHODS: Self-report Likert-scale survey items were administered to individuals being screened with the Structured Interview for Psychosis-risk Syndromes (SIPS) and followed at eight early psychosis clinics. An a priori analytic plan included Spectral Clustering Analysis to reduce the item pool, followed by development of Support Vector Machine (SVM) classifiers. RESULTS: The cross-validated positive predictive value (PPV) of the EPSI at the default cut-off (76.5%) exceeded that of the clinician-administered SIPS (68.5%) at separating individuals who would not convert to psychosis within 12 months from those who either would convert within 12 months or who had already experienced a first episode psychosis (FEP). When used in tandem with the SIPS on clinical high risk participants, the EPSI increased the combined PPV to 86.6%. The SVM classified as FEP/converters only 1% of individuals in non-clinical and 4% of clinical low risk populations. Sensitivity of the EPSI, however, was 51% at the default cut-off. DISCUSSION: The EPSI identifies, comparably to the SIPS but in less time and with fewer resources, individuals who are either at very high risk to develop a psychotic disorder within 12 months or who are already psychotic. At its default cut-off, EPSI misses 49% of current or future psychotic cases. The cut-off can, however, be adjusted based on purpose. The EPSI is the first validated assessment to predict 12-month psychotic conversion. An online screening system, www.eps.telesage.org, is under development.

The Early Psychosis Screener (EPS): Item development and qualitative validation.

A panel of experts assembled and analyzed a comprehensive item bank from which a highly sensitive and specific early psychosis screener could be developed. Twenty well-established assessments relating to the prodromal stage, early psychosis, and psychosis were identified. Using DSM-5 criteria, we identified the core concepts represented by each of the items in each of the assessments. These granular core concepts were converted into a uniform set of 490 self-report items using a Likert scale and a 'past 30days' time frame. Partial redundancy was allowed to assure adequate concept coverage. A panel of experts and TeleSage staff rated these items and eliminated 189 items, resulting in 301 items. The items were subjected to five rounds of cognitive interviewing with 16 individuals at clinically high risk for psychosis and 26 community mental health center patients. After each round, the expert panel iteratively reviewed, rated, revised, added, or deleted items to maximize clarity and centrality to the concept. As a result of the interviews, 36 items were revised, 52 items were added, and 205 items were deleted. By the last round of cognitive interviewing, all of the items were clearly understood by all participants. In future work, responses to the final set of 148 items and machine learning techniques will be used to quantitatively identify the subset of items that will best predict clinical high-risk status and conversion.

The Early Psychosis Screener (EPS): Quantitative validation against the SIPS using machine learning.

Machine learning techniques were used to identify highly informative early psychosis self-report items and to validate an early psychosis screener (EPS) against the Structured Interview for Psychosis-risk Syndromes (SIPS). The Prodromal Questionnaire-Brief Version (PQ-B) and 148 additional items were administered to 229 individuals being screened with the SIPS at 7 North American Prodrome Longitudinal Study sites and at Columbia University. Fifty individuals were found to have SIPS scores of 0, 1, or 2, making them clinically low risk (CLR) controls; 144 were classified as clinically high risk (CHR) (SIPS 3-5) and 35 were found to have first episode psychosis (FEP) (SIPS 6). Spectral clustering analysis, performed on 124 of the items, yielded two cohesive item groups, the first mostly related to psychosis and mania, the second mostly related to depression, anxiety, and social and general work/school functioning. Items within each group were sorted according to their usefulness in distinguishing between CLR and CHR individuals using the Minimum Redundancy Maximum Relevance procedure. A receiver operating characteristic area under the curve (AUC) analysis indicated that maximal differentiation of CLR and CHR participants was achieved with a 26-item solution (AUC=0.899±0.001). The EPS-26 outperformed the PQ-B (AUC=0.834±0.001). For screening purposes, the self-report EPS-26 appeared to differentiate individuals who are either CLR or CHR approximately as well as the clinician-administered SIPS. The EPS-26 may prove useful as a self-report screener and may lead to a decrease in the duration of untreated psychosis. A validation of the EPS-26 against actual conversion is underway.

Insights into psychosis risk from leukocyte microRNA expression.

Dysregulation of immune system functions has been implicated in schizophrenia, suggesting that immune cells may be involved in the development of the disorder. With the goal of a biomarker assay for psychosis risk, we performed small RNA sequencing on RNA isolated from circulating immune cells. We compared baseline microRNA (miRNA) expression for persons who were unaffected (n=27) or who, over a subsequent 2-year period, were at clinical high risk but did not progress to psychosis (n=37), or were at high risk and did progress to psychosis (n=30). A greedy algorithm process led to selection of five miRNAs that when summed with +1 weights distinguished progressed from nonprogressed subjects with an area under the receiver operating characteristic curve of 0.86. Of the five, miR-941 is human-specific with incompletely understood functions, but the other four are prominent in multiple immune system pathways. Three of those four are downregulated in progressed vs. nonprogressed subjects (with weight -1 in a classifier function that increases with risk); all three have also been independently reported as downregulated in monocytes from schizophrenia patients vs. unaffected subjects. Importantly, these findings passed stringent randomization tests that minimized the risk of conclusions arising by chance. Regarding miRNA-miRNA correlations over the three groups, progressed subjects were found to have much weaker miRNA orchestration than nonprogressed or unaffected subjects. If independently verified, the leukocytic miRNA biomarker assay might improve accuracy of psychosis high-risk assessments and eventually help rationalize preventative intervention decisions.

Carbon dioxide sensitivity in panic anxiety. Ventilatory and anxiogenic response to carbon dioxide in healthy subjects and patients with panic anxiety before and after alprazolam treatment.

One hypothesis that could account for the anxiogenic response to breathing air supplemented with carbon dioxide seen in panic anxiety patients is that panic patients might have abnormally high central medullary chemoreceptor sensitivity. Chemoreceptor sensitivity was assessed by using a rebreathing technique to measure the ventilatory response to CO2 in 14 medication-free patients with agoraphobia and panic attacks and 23 healthy subjects. Ventilatory response to CO2 was similar in patients and controls (mean +/- SEM, 1.58 +/- 0.16 vs 1.58 +/- 0.14 L/min/mm Hg), suggesting that abnormal chemoreceptor sensitivity does not explain the behavioral sensitivity of panic patients to CO2. Anxiety ratings increased markedly during rebreathing both in patients and controls; anxiety increases were significantly greater in patients than in healthy subjects matched for age, sex, and rebreathing duration. Alprazolam treatment in eight patients markedly attenuated anxiety increases during rebreathing. Differences in anxiogenic sensitivity to CO2 between patients and controls may be due to differences in the regulation of noradrenergic or other neuronal systems.

Situational panic attacks. Behavioral, physiologic, and biochemical characterization.

To investigate the pathophysiology of nonpharmacologically induced panic attacks, 18 drug-free agoraphobic patients and 13 matched healthy subjects underwent structured exposure to phobic situations. Heart rate, blood pressure, and plasma free 3-methoxy-4-hydroxyphenylglycol (MHPG), cortisol, growth hormone, and prolactin levels were measured before, during, and after exposure. Fifteen patients experienced situational panic attacks during exposure. Panicking patients displayed significantly greater increases in heart rate but not blood pressure or plasma free MHPG or cortisol in comparison with the healthy subjects. Growth hormone and prolactin responses tended to be smaller in the patients. If brain noradrenergic hyperactivity occurs during situational panic attacks, it may be too brief or too restricted in regional localization to affect MHPG levels in plasma. Chronically recurrent attacks may cause an adaptation of neuroendocrine mechanisms activated by anxiety or stress.

Carbon dioxide-induced anxiety. Behavioral, physiologic, and biochemical effects of carbon dioxide in patients with panic disorders and healthy subjects.

Carbon dioxide was administered for 15 minutes to patients with panic disorders (5% CO2, n = 14) and healthy subjects (5% CO2, n = 11; 7.5% CO2, n = 8). Following administration of CO2 and air placebo, changes in behavioral ratings, vital signs, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylglycol, cortisol, growth hormone, and prolactin were measured over three hours. In the healthy subjects, CO2 produced dose-related increases in anxiety, somatic symptoms, vital signs, and plasma cortisol levels. In the patients, the frequency of panic attacks (in eight of 14 patients) and the increases in anxiety and somatic symptoms induced by 5% CO2 exceeded those in the healthy subjects and were similar to those induced by 7.5% CO2 in the healthy subjects. The physiologic and biochemical measurements obtained did not elucidate the mechanisms underlying CO2-induced anxiety or the greater anxiogenic effects of CO2 seen in patients with panic disorders.

Early coadministration of clonazepam with sertraline for panic disorder.

BACKGROUND: There is debate about combining benzodiazepines with selective serotonin reuptake inhibitors in the acute treatment of panic disorder. Although this medication combination is widely used in clinical practice, there is no well-tested, optimal method of coadministering these medications for the treatment of panic disorder. The purpose of this study was to test the efficacy of early coadministration of clonazepam with sertraline in the treatment of panic disorder. METHODS: Fifty patients with panic disorder were randomized into a double-blind clinical trial. Patients received open-label sertraline for 12 weeks (target dose, 100 mg/d), and in addition were randomized to groups receiving either 0.5 mg of active clonazepam 3 times daily or placebo clonazepam for the first 4 weeks of the trial. The clonazepam dose was then tapered during 3 weeks and discontinued. RESULTS: Thirty-four (68%) of 50 patients completed the trial. Drop-out rates were similar in the sertraline/placebo vs the sertraline/clonazepam group (38% vs 25%) (P =.5). An intent-to-treat analysis (on last observation carried forward data) revealed a much greater proportion of responders in the sertraline/clonazepam compared with the sertraline/placebo group at the end of week 1 of the trial (41% vs 4%) (P =.003). There was also a significant between-group difference at the end of week 3 with 14 (63%) of 22 of the sertraline/clonazepam group responding to treatment vs 8 (32%) of 25 of the sertraline/placebo group (P =.05). This difference was not observed at other times during the trial. CONCLUSION: These data indicate that rapid stabilization of panic symptoms can be safely achieved with a sertraline/clonazepam combination, supporting the clinical utility of this type of regimen for facilitating early improvement of panic symptoms relative to sertraline alone.

Clinical and medication outcome after short-term alprazolam and behavioral group treatment in panic disorder. 2.5 year naturalistic follow-up study.

Sixty patients with agoraphobia with panic attacks or panic disorder who completed a 4-month combined drug and behavioral group treatment program and were discharged on a regimen of alprazolam were interviewed 1.7 to 4 years (mean, 2.5 years) after discharge. At follow-up (FU), 18 (30%) of the patients had discontinued alprazolam treatment, 36 (60%) continued with a lower dose, 3 (5%) received the same dose, and 3 (5%) received an increased dose compared with discharge. A lower frequency of panic attacks at admission was associated with an increased ability to discontinue alprazolam treatment. There was little evidence of tolerance to the antipanic effects of alprazolam. Panic attack frequency dropped from a mean of 4.4 attacks per week at admission to 1.2 attacks per week at discharge and remained decreased at 1.6 attacks per week at FU. Treatment gains in the program were maintained or enhanced on 11 of 14 behavioral measures at FU and were similar in the groups that were receiving and not receiving alprazolam. Patients receiving nonpharmacologic therapy in the FU period tended to have greater symptom severity, possibly due to self-selection. A lifetime diagnosis of major depression at admission was associated with higher levels of depressive and anxiety symptoms and higher alprazolam doses at FU. Episodes of major depression were common in the FU period and did not appear to be prevented by initial alprazolam and behavioral therapy or by low-dose alprazolam maintenance.(ABSTRACT TRUNCATED AT 250 WORDS)

m-Chlorophenylpiperazine effects in neuroleptic-free schizophrenic patients. Evidence implicating serotonergic systems in the positive symptoms of schizophrenia.

OBJECTIVE: This study evaluated whether alterations in serotonin function in schizophrenic patients could be demonstrated by comparing the reactivity to a serotonin partial agonist, m-chlorophenylpiperazine (MCPP) in patients and healthy subjects. This study also assessed whether stimulation of serotonin receptors influenced the symptoms of schizophrenia. DESIGN: Double-blind randomized comparison of MCPP (0.1 mg/kg, intravenously, administered over 20 minutes) and placebo effects in patients and healthy subjects. SETTING: Department of Veterans Affairs Medical Center, West Haven, Conn. PATIENTS AND HEALTHY SUBJECTS: Fifteen healthy subjects recruited by public advertisement and 12 schizophrenic inpatients who had been neuroleptic free for at least 2 weeks prior to entry into the study. MAIN OUTCOME MEASURES: The principal outcome variable was the positive symptoms of schizophrenia operationally defined as the sum of scores on the four key items for schizophrenia on the Brief Psychiatric Rating Scale and the Brief Psychiatric Rating Scale thought disorder factor. Anxiety was assessed with a clinician-rated visual analog scale and plasma hormone levels were measured. RESULTS: m-Chlorophenylpiperazine significantly increased the positive symptoms of schizophrenia in patients but not healthy subjects. Patients and healthy subjects exhibited anxiety increases of comparable magnitude following MCPP. However, patients had higher baseline levels of anxiety and exhibited more prolonged anxiogenic responses to MCPP. Anxiety elevations did not correlate with increases in the four key symptoms in patients. Patients exhibited lower baseline prolactin levels compared with healthy subjects, but the two groups did not differ in their prolactin, growth hormone, and cortisol responses to MCPP. CONCLUSIONS: Schizophrenics, the only psychotic patient group studied to date, are the first patient group to exhibit propsychotic responses to MCPP. These data provide further evidence that serotonin systems modulate positive symptoms in some schizophrenic patients.

Psychiatric disorders in relatives of probands with panic disorder and/or major depression.

BACKGROUND: Panic disorder and major depression (MDD) are both highly familial disorders that co-occur in individuals but do not cosegregate in families. Evidence concerning their familial aggregation with other psychiatric disorders, including phobias, substance abuse, and antisocial personality, has been contradictory. In part, the contradictory findings may be due to failure to account for the effects of proband comorbidity on risks in relatives. METHODS: A family study of 1047 adult first-degree relatives of 193 probands in four diagnostic groups (panic disorder without MDD, panic disorder plus MDD, early-onset MDD, and screened normal controls) was used to determine the range of psychiatric disorders associated with panic disorder and MDD and the effects of proband comorbidity on the rates of disorders in relatives. RESULTS: Compared to relatives of normal controls, relatives of probands with panic disorder or panic disorder and MDD showed significantly increased risks of panic disorder, but relatives of probands with early-onset MDD did not. After proband comorbidity was controlled for, relatives of probands with panic disorder were also at a significantly increased risk for social phobia but not for any other psychiatric disorders. Relatives of probands with early-onset MDD were at significantly increased risk for MDD, dysthymia, abuse of or dependence on alcohol and other drugs, and antisocial personality disorders but not for any other psychiatric disorders. CONCLUSIONS: We conclude that panic disorder is a specific familial entity that is not associated with a broad range of other anxiety or other psychiatric disorders, with the possible exception of social phobia. Dysthymia, substance abuse, and antisocial personality appear to be on the spectrum of early-onset MDD.