FHN Subjects Research Articles

208. Predictors of Cannabis-Induced Psychosis

Abstract Background: The endocannabinoid system (ECS) has been implicated in the pathophysiology of psychosis and epidemiological studies demonstrate an association between exposure to exogenous cannabinoids and acute as well as delayed psychosis outcomes. Family history of psychosis represents a nonmodifiable risk factor for psychosis, while cannabis exposure is a modifiable one. Individuals with a family history of psychosis (FHP) are at a greater risk for a psychotic disorder such as schizophrenia, psychosis associated with cannabis use, and enhanced sensitivity to the acute psychotomimetic effects of THC. In fact, it has been suggested that enhanced sensitivity to cannabis’ psychotomimetic effects may be a marker of familial risk for psychosis. Methods: Data will be presented from ongoing studies systematically examining the ECS in FHP individuals compared to those without a family history of psychosis (FHN) using a multidimensional approach. Cannabinoid 1 receptor (CB1R) availability was measured using the reversible ligand [11C]OMAR and High Resolution Research Tomography PET. The acute response to delta-9-tetrahydrocannabinol (THC) was measured in randomized, placebo-controlled, double-blind, acute pharmacological challenge study designed to examine the effects of intravenous THC on a wide range of subjective, cognitive, and electrophysiological biomarkers of psychosis. FHP and FHN subjects were matched on a number of relevant variables such as age, education, BMI, cannabis use histories, other substance exposure, and so on. Results: Data will be presented demonstrating that compared to FHN, FHP have (A) ↓ CB1R availability ([11C]OMAR VT)), (B) ↑ THC-induced psychotomimetic effects (Positive And Negative Syndrome Scale [PANSS] positive subscale), and (C) ↑ THC-induced cortical noise (Lempel-Ziev complexity scores) compared to FHN. Conclusion: These data are the very first to examine the confluence of the endocannabinoid and exogenous cannabinoid hypotheses in the risk for psychosis. Preliminary data suggest that a family history of psychosis is associated with lower CB1R availability and altered response to THC, a pattern of effects similar to that observed in individuals with a psychotic disorder. Future studies should aim to develop a stratification of the risk of exposure to cannabinoids in individuals with a family history of psychosis and inform public health policies. This is particularly important given that cannabis exposure is the main modifiable risk factor for psychosis.

A family history of Type 1 alcoholism differentiates alcohol consumption in high cortisol responders to stress

BackgroundThe differentiation between high and low cortisol responders to stress is of interest in determining the risk factors which may, along with genetic vulnerability, influence alcohol intake. Study 1: MethodsThirty-two healthy volunteers, family history positive to alcoholism (FHP, n=16) and family history negative (FHN, n=16) attended two laboratory sessions during which alcohol or placebo was offered. ResultsThere were no differences in consumption of alcohol or placebo between FHP and FHN subjects. Study 2: MethodsFifty-eight healthy social drinkers, FHP (n=27) and FHN (n=31) attended two laboratory sessions. They were administered either alcohol or placebo in both sessions they attended. All subjects underwent either a stress task (the Trier Social Stress Test, TSST) or a stress-free period, at two separate occasions, before being offered beverage. After the salivary cortisol analysis, subjects in each group were divided into high (HCR) or low (LCR) cortisol responders. ResultsAfter stress, subjects who were FHP-HCR consumed more alcohol than FHN-HCR. There were no differences in the placebo intake between FHP and FHN subjects regardless of their cortisol response. ConclusionsThis result indicates that stress promotes alcohol consumption only in subjects with a family history of Type 1 alcoholism who show an increase in cortisol response to stress. This behaviour is similar to that previously observed in alcohol dependent individuals after stress and thus could represent an endophenotype posing a risk for future development of alcohol use disorders.

S15 * ALCOHOL DEPENDENCE AND NEUROENDOCRINOLOGY - NEW FINDINGS AND PERSPECTIVES

S15 * ALCOHOL DEPENDENCE AND NEUROENDOCRINOLOGY - NEW FINDINGS AND PERSPECTIVES

Family history of alcoholism interacts with alcohol to affect brain regions involved in behavioral inhibition

Impulsive behavior is associated with both alcohol use disorders and a family history of alcoholism (FHA). One operational definition of impulsive behavior is the stop-signal task (SST) which measures the time needed to stop a ballistic hand movement. Employ functional magnetic resonance imaging (fMRI) to study right frontal responses to stop signals in heavy drinking subjects with and without FHA, and as a function of alcohol exposure. Twenty-two family history-positive (FHP; age = 22.7 years, SD = 1.9) and 18 family history-negative (FHN; age = 23.7, SD = 1.8) subjects performed the SST in fMRI in two randomized visits: once during intravenous infusion of alcohol, clamped at a steady-state breath alcohol (BrAC) concentration of 60 mg/dL, and once during infusion of placebo saline. An independent reference group (n = 13, age = 23.7, SD = 1.8) was used to identify a priori right prefrontal regions activated by successful inhibition (Inh) trials, relative to "Go" trials that carried no need for inhibition [Inh > Go]. FHA interacted with alcohol exposure in right prefrontal cortex, where alcohol reduced [Inh > Go] activation in FHN subjects but not in FHP subjects. Within this right frontal cortical region, stop-signal reaction time also correlated negatively with [Inh > Go] activation, suggesting that the [Inh > Go] activity was related to inhibitory behavior. The results are consistent with the low level of response theory (Schuckit, J Stud Alcohol 55:149-158, 1980; Quinn and Fromme, Alcohol Clin Exp Res 35:1759-1770, 2011), with FHP being less sensitive to alcohol's effects.

Effects of memantine on event-related potential, oscillations, and complexity in individuals with and without family histories of alcoholism.

Enhanced N-methyl-D-aspartate (NMDA) receptor function associated with a positive family history of alcoholism (FHP) has been hypothesized to contribute to the heritable risk for alcoholism. The objective of this study was to evaluate the relationship of alcoholism family history, NMDA receptor function, and cortical information processing by testing acute effects of the NMDA receptor antagonist memantine on event-related potential (ERP). Twenty-two healthy FHP and 20 healthy family history-negative (FHN; no alcoholic relatives) subjects were administered placebo or 40 mg of memantine under double-blind counterbalanced conditions on two separate occasions. Electroencephalogram data were collected from eight channels with eyes open during an auditory oddball discrimination task. We evaluated P3b amplitude, total theta, alpha activity, and fractal dimension from ERP trials. FHP and FHN subjects did not differ in P3b amplitude. A significant Group × Drug interaction was observed in theta, alpha activity, and fractal dimension at the parietal and occipital sites. FHP individuals exhibited significantly higher fractal dimension and lower theta and alpha activity after placebo relative to FHN subjects. Following memantine administration, theta activity decreased in both groups but more markedly for FHN individuals. Alpha activity decreased for FHN subjects and increased for FHP individuals, whereas the fractal dimension decreased for FHP subjects and increased for FHN subjects after memantine. A plausible interpretation of these results is that FHP individuals may have altered NMDA receptor function compared with FHN individuals. These findings provide additional evidence of differences in the regulation of NMDA receptor function between FHP and FHN individuals.

Family history of alcohol dependence and antidepressant response to an N-methyl-D-aspartate antagonist in bipolar depression.

Both ketamine and ethanol are N-methyl-d-aspartate (NMDA) receptor antagonists. Ketamine has rapid antidepressant properties in major depressive disorder (MDD) as well as bipolar depression. In individuals with MDD, a positive family history of alcohol dependence (FHP) was associated with greater improvement in depressive symptoms after ketamine administration compared to individuals whose family history of alcohol dependence was negative (FHN). This study investigated whether FHP influences ketamine's antidepressant and perceptual effects in individuals with bipolar depression. A post hoc analysis was conducted on 33 subjects with DSM-IV bipolar disorder (BD) type I or II depression pooled from two previously published studies. All subjects had undergone a double-blind, randomized, crossover trial of a single intravenous infusion of ketamine (0.5 mg/kg) combined with lithium or valproate therapy. Subjects were rated at baseline; at 40, 80, 120, and 230 min; and at days 1, 2, 3, 7, 10, and 14 post-infusion. The primary outcome measure was Montgomery-Åsberg Depression Rating Scale (MADRS) scores. Patients were categorized as FHP when they reported at least one first-degree relative with alcohol dependence. Measures of psychosis, dissociation, and dysphoria were also collected. After ketamine infusion, subjects with FHP showed significantly greater improvement on MADRS scores than FHN subjects. In addition, patients with FHP had attenuated psychotomimetic and dissociative scores compared to FHN patients. FHP appears to predict a more sustained antidepressant response to ketamine in individuals with BD. Family history of alcoholism may be an important consideration in the development of glutamatergic-based therapies for depression.

Memantine, an NMDA receptor antagonist, differentially influences Go/No-Go performance and fMRI activity in individuals with and without a family history of alcoholism

Individuals with a family history of alcoholism (family history positive [FHP]) show higher alcoholism rates and are more impulsive than those without such a family history (family history negative [FHN]), possibly due to altered N-methyl-D-aspartate (NMDA) receptor function. We investigated whether memantine, an NMDA receptor antagonist, differentially influences impulsivity measures and Go/No-Go behavior and fMRI activity in matched FHP and FHN individuals. On separate days, participants received a single dose of 40 mg memantine or identical-appearing placebo. No group performance differences were observed on placebo for Go correct hit or No-Go false alarm reaction time on the Go/No-Go task. During fMRI, right cingulate activation differed for FHP vs. FHN subjects during No-Go correct rejects. Memantine had attenuated effects in FHP vs. FHN subjects: For No-Go false alarms, memantine was associated with limited reduction in subcortical, cingulate, and temporal regions in FHP subjects and reduced activity in fronto-striatal-parietal networks in FHN subjects. For No-Go correct rejects, memantine (relative to placebo) reduced activity in left cingulate and caudate in FHP but not FHN subjects. Lower sensitivity to the effects of memantine in FHP subjects is consistent with greater NMDA receptor function in this group.

Ethanol and Pain Sensitivity: Effects in Healthy Subjects Using an Acute Pain Paradigm

The primary objective of this study was to determine whether healthy subjects without a history of heavy alcohol use or a family history of alcoholism exhibit a concentration-dependent analgesic effect of ethanol. In a preliminary fashion, we also compared this sample to a group of subjects with a strong positive family history for alcoholism (FHP) to test the secondary hypothesis that FHP individuals will be more sensitive to the analgesic effects of alcohol compared to healthy subjects who are negative for a family history of alcoholism (FHN). Forty-one healthy FHN subjects and 19 FHP subjects participated. Test days included an ethanol high concentration (breathalyzer = 0.100 g/dl), ethanol low concentration (breathalyzer = 0.040 g/dl) or placebo. The infusion of ethanol was via computerized pump to achieve a steady-state ("clamp") ethanol concentration. Noxious electrical stimulation and pain assessments were performed prior to start of placebo/ethanol infusion and at the 60-min infusion mark. The applied current was progressively increased until the pain was reported as 5 or higher on an 11-point Verbal Numeric Scale (VNS). Outcome variables included measures of pain threshold and tolerance and Visual Analog Scales of mood states. Among FHN subjects there was a significant ethanol concentration effect on pain tolerance (F = 3.0, p = 0.05). The average change in pain stimuli required to reach a VNS of 5 or greater were (-2.4, -1.0, and 2.2 mAmps respectively) for high concentration, low concentration, and placebo. There were no ethanol concentration related differences in pain threshold. The analgesic effect of ethanol was not correlated with changes in mood states, suggesting an independent analgesic effect of the drug. A comparison of FHP to FHN subjects produced no differences on pain responses. The findings support the hypothesis that in healthy subjects intravenous ethanol administration has a concentration effect on pain tolerance but not on pain threshold. Additional studies are planned to further elucidate the mechanisms of ethanol's analgesic effects.

Rates of ethanol metabolism decrease in sons of alcoholics following a priming dose of ethanol

Rapid changes in rates of ethanol metabolism in response to acute ethanol administration have been observed in animals and humans. To examine whether this phenomenon might vary by risk for alcoholism, 23 young men with a positive family history of alcoholism (family history positive [FHP]) were compared to 15 young men without a family history of alcoholism (family history negative [FHN]). Rates of ethanol metabolism were measured in all subjects first after an initial ethanol dose (0.85 g/kg) and then, several hours later, a second dose (0.3 g/kg), and the two rates were compared. The two groups of subjects were similar in their histories of ethanol consumption. FHP subjects demonstrated faster initial rates of ethanol metabolism, 148 ± 36 mg/kg/h, compared to FHN subjects, 124 ± 18 mg/kg/h, P = .01. However, FHN subjects increased their rate of metabolism by 10 ± 27% compared to a decrease of −15 ± 24% in FHP subjects, P = .007. Fifty-two percent of the FHP and none of the FHN subjects exhibited a decline in metabolic rate of 20% or more, P = .0008. Since a significant proportion of FHP subjects exhibited a decrease in the second rate of ethanol metabolism, these preliminary data might help to partly explain why FHP individuals differ in their sensitivity to ethanol and are more likely to develop alcohol dependence.

Hormonal Responses to Psychological Stress and Family History of Alcoholism

The present study was designed to determine whether stress hormones and subjective responses to a psychological stressor were different in nonalcoholic offspring from families with a history of alcohol dependence (family history positive, FHP) than in nonalcoholic offspring without a family history of alcohol dependence (family history negative, FHN). Forty-five healthy subjects (17 FHP, 28 FHN), between the ages of 18 and 29 years, completed the Trier Social Stress Test (TSST). The TSST consisted of 5 min of public speaking followed by 5 min of mental arithmetic. Three baseline and five post-TSST blood samples were drawn. Pre- and post-TSST self-report measures of anxiety were obtained. Cortisol, adrenocorticotropin (ACTH), and prolactin significantly increased in response to the TSST in the entire study sample (F(1,187)=70.22, p<0.001, F(1,143)=33, p<0.001, and F(1,134)=14.37, p<0.001, respectively). Cortisol responses were influenced by an interaction between racial composition and family history of alcoholism (F(1,57)=4.50, p=0.038). Among Caucasian subjects, FHP subjects had greater cortisol response to the TSST compared to FHN subjects (F(1,57)=4.45, p=0.039). No family history effect was identified in African-American subjects. Adrenocorticotropin responses did not differ between FHP and FHN subjects. Adrenocorticotropin response was positively associated with baseline ACTH levels in FHN subjects (t=5.02, p=or<0.001), but not in FHP subjects. Prolactin responses did not differ between FHP and FHN subjects. Anxiety response scores (post-TSST scores minus pre-TSST scores) were higher in FHP subjects compared with FHN subjects (z=-2.67, p=0.007). In addition, anxiety response scores were positively associated with cortisol response levels to the TSST in FHN subjects (t=4.52, p<0.001). In contrast, anxiety responses were negatively associated with cortisol responses in FHP subjects (t=-2.30, p=0.024). Our findings are consistent with theories that greater reactivity to stress is associated with greater risks for alcoholism. Furthermore, the findings suggest that the association between the hypothalamic-pituitary-adrenal axis hormonal response and the subjective perception of stress might be deranged in offspring of alcoholics.

Confirmation That Offspring From Families With Alcohol‐Dependent Individuals Have Greater Hypothalamic‐Pituitary‐Adrenal Axis Activation Induced by Naloxone Compared With Offspring Without a Family History of Alcohol Dependence

This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence. Sixty-four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty-seven subjects were offspring from families with alcohol dependence and were designated as family history-positive subjects (FHP). Thirty-seven subjects were biological offspring of non-alcohol-dependent parents and were designated as family history-negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 microg/kg) in double-blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min. No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects. These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.

Confirmation That Offspring From Families With Alcohol-Dependent Individuals Have Greater Hypothalamic-Pituitary-Adrenal Axis Activation Induced by Naloxone Compared With Offspring Without a Family History of Alcohol Dependence

Background: This study was designed to confirm our previous findings that nonalcoholic offspring from families with alcohol-dependent individuals have greater hypothalamic-pituitary-adrenal axis activation induced by opioid blockade compared with nonalcoholic subjects without a family history of alcohol dependence. Methods: Sixty-four nonalcoholic subjects aged 18 to 25 years were enrolled in the protocol. Twenty-seven subjects were offspring from families with alcohol dependence and were designated as family history–positive subjects (FHP). Thirty-seven subjects were biological offspring of non–alcohol-dependent parents and were designated as family history–negative subjects (FHN). Subjects received naloxone hydrochloride (0, 50, 125, 375, and 500 μg/kg) in double-blind, randomized order; adrenocorticotropin (ACTH) and cortisol were monitored over 120 min. Results: No hormone differences at baseline or during placebo administration were identified between FHP and FHN subjects. FHP subjects had greater ACTH and cortisol response to opioid receptor blockade induced by naloxone hydrochloride compared with FHN subjects. Conclusions: These observations confirm previous findings that differences in ACTH and cortisol dynamics between FHP and FHN subjects can be unmasked by opioid receptor blockade.

Comorbidity of cocaine abuse and schizophrenia: An examination of clinical functioning across an acute episode

Ascertaining th~ impact of cocaine abuse on schizophrenic (Sz) illness will be informative for the further understanding of the psychopharmacoiogy, neumpsychology and neumbiology of the illness because cocaine has a powerful effect on brain dopamine neurons. This present study examined the clinical functioning and neuroleptic response in cocaine ahusing schizophrenic inpatients (n= 15) over the course of an acute psychiatric admission. Nonsubstance abusing schizophrenic inpatients (n=l 5)served as the control group. Diagnoses of substance abuse and schizophrenia was assessed with the SCIDP using DSM.III-R criteria. Additionally, all substance abusing patients were required to have positive urine toxicology screens for cocaine to be entered into the study. To assess patients' severity of illness and medication response all patients were examined with the SAPS, SANS and BPRS at medication free presentation in the Emergency Room, and again at Day 7 and Day 28 of their hospitalization. Results revealed that the substance abusing Sz patients demonstrated significant elevations in positive symptoms and decreased severity of negatire symptoms at baseline. This process reversed itself at retesting Day 28. These results are discussed in terms of the effect of cocaine intoxica. tion and withdrawal on functioning and neuroleptic response in schizophrenia. '14, T3, FTI, cortisol and glucose were similar between groups. Baseline PRL was lower in Flip subjects, p.-.03. Though mean 8maxTSH values were similar between groups FHP (10.1 ± 6.0 mU/L) vs. FHN (10.9 ± 4.0 mU/L), Flip subjects clustered in the lower end of the distribution, group effect p...06, Wilcoxon, one-tailed. 8maxPRL was not different between groups. FI-lP subjects whose father's alcoholism began after age 25 years (n-I 2)had significantly reduced 8maxTSH values compared to FHN subjects, p-.02, Wilcoxon. PRL responses were not different. FilP subjects, father early-onset did not differ in TSH or PRL response compared to FHN subjects. These findings support the hypothesis that a reduced TRHinduced TSH response is a risk marker for alcoholism and suggest that the marker may segregate based on subtype of alcoholism.

Sensation seeking, stress reactivity, and alcohol dampening discriminate the density of a family history of alcoholism.

Data collected from 95 nonalcoholic men who had either a multigenerational (MFH), unigenerational (UFH), or negative family history (FHN) of alcoholism were subjected to a discriminant function analysis to determine how well a set of variables differentiated between the family history groups. The data-set comprised personality measures (sensation seeking scales, neuroticism, and extroversion), measures of cardiovascular reactivity to unavoidable shock, and measures of the cardiovascular reactivity-dampening effects of alcohol. The discriminant analyses correctly classified 62% of all subjects, 75% of MFH subjects, 47% of UFH subjects, and 63% of FHN subjects. A canonical discriminant function analysis revealed one significant dimension (canonical variable) that differentiated between family history groups. The high density (MFH) family group scored positively on this dimension, while the UFH and FHN groups had negative mean scores on this variable. A MFH of alcoholism was characterized by a pattern of increased sensitivity to the cardiovascular reactivity-dampening effect of alcohol, cardiovascular hyperreactivity to unavoidable shock when sober, and the personality characteristic of experience seeking, which is associated with a desire for novel and unconventional experiences.

Differences and similarities in development of drinking behavior between alcoholic offspring of alcoholics and alcoholic offspring of non-alcoholics

Self-reported initial, early, and long-term drinking behaviors, experiences, and consequences were obtained from male alcoholics completing inpatient treatment. Subjects were recruited and selected on the basis that they met DSM-III criteria for diagnosis of alcohol dependency and that their biological fathers were alcoholic (FHP; Family History Positive) or that they had no biological family history of alcoholism (FHN; Family History Negative). Results indicated that FHP subjects rated their initial taste of beer higher than FHN subjects, that FHP subjects began tasting and subsequently regularly drinking alcohol at an earlier age than FHN subjects and that there was significantly shorter elapsed time between initiating regular drinking and developing alcoholic-symptomatic problems in living among FHP alcoholics than FHN alcoholics. Although there were a few other significant differences, the drinking-behavioral histories of the two groups were remarkably similar and parallel. Taken together, results suggest that familial risk factors primarily influence the rate at which alcoholic drinking and alcoholism develop, rather than the form or pattern of alcoholic drinking.

Family History of Alcoholism in Males: Absence of Distinguishing Features for Treatment Matching

One variable for subtyping the alcoholic population that could influence treatment-matching efforts is family history of alcoholism. This study compared two groups of male patients undergoing rehabilitation for alcohol dependence (39 family history positive [FHP] versus 36 family history negative [FHN]) on a number of salient dimensions for which specific targeted intervention components might be implemented. The FHP were similar to FHN subjects on all variables except that FHP had significantly fewer years of education than did FHN. Several possible explanations to account for these findings are discussed.

Event-related brain potentials in individuals at high and low risk for developing alcoholism: failure to replicate.

Event-related brain potentials (ERPs) were used to compare young men having a positive paternal family history for alcoholism (FHP) with carefully matched control subjects having no family history for alcoholism (FHN). The P300 ERP component was obtained from all subjects (n = 10/group) with a complex auditory paradigm before and on two occasions after they received a placebo drink which they were told might contain alcohol. The procedures employed replicated those of a previous study in which FHP subjects showed diminished P300 potentials compared to FHN subjects under the placebo as well as ethanol consumption conditions--a finding which raised the possibility that the P300 ERP component might be a biological marker for subjects at high risk to develop alcoholism. No differences between the family history groups were obtained for the P300 or any other ERP component using the replication procedures. Both groups demonstrated a decrease in P300 amplitude across trial blocks in a similar fashion suggesting that habituation effects may have diminished the ERP response.