Mary R. Lee

Effects of adjunctive intranasal oxytocin on olfactory identification and clinical symptoms in schizophrenia: Results from a randomized double blind placebo controlled pilot study

BACKGROUND Deficits in olfactory identification have been widely reported in patients with schizophrenia (SZ) and are associated with negative symptomatology. Adjunctive oxytocin delivered intranasally has been shown to improve some aspects of social cognition as well as positive and negative symptoms in patients with schizophrenia. Given the intranasal delivery route of oxytocin to olfactory pathways and that olfactory abnormalities are a potential endophenotype in SZ, we investigated the effect of intranasal oxytocin on olfactory identification as well as positive and negative symptoms in people with schizophrenia. METHODS Individuals with schizophrenia or schizoaffective disorder (n=28; 16 outpatients, 12 inpatients) were randomized to receive adjunctive intranasal oxytocin 20 IU BID or placebo for 3 weeks. RESULTS All 28 participants completed the clinical trial. Odor identification performance significantly improved on the University of Pennsylvania Smell Identification Test (UPSIT) total score and subscore for pleasant smells. UPSIT score (F=5.20, df=1,23, p=0.032) and subscore for pleasant smells (F=4.56, df=1,23, p=0.044), in patients treated with oxytocin were compared to placebo from baseline to endpoint. Global symptomatology as well as positive and negative symptoms were not improved by intranasal oxytocin. In fact, global symptoms, not positive or negative symptoms, improved in the placebo group. Secondary analysis shows that intranasal oxytocin improved negative symptoms in the small group of inpatients. Intranasal oxytocin was well tolerated during the three week trial. CONCLUSION Adjunctive intranasal oxytocin may improve olfactory identification, particularly in items of positive valence. Larger studies are needed to determine the effects of oxytocin on negative symptoms in SZ. (NCT00884897; http://www.clinicaltrials.gov).

Complexity of oxytocin's effects in a chronic cocaine dependent population

Behavioral and neuroplastic changes occurring in the development of addiction parallel those that occur in social bonding. This has led to speculation that drugs of abuse co-opt systems that subserve social attachment to shift attachment to drugs of abuse. Oxytocin, a neuropeptide that is important in social bonding, has been shown in rodents to decrease psychostimulant self-administration, locomotor activity, and conditioned place preference, it is unclear what role it may play in human drug addiction. In this double-blind, placebo-controlled crossover study, 23 cocaine-dependent inpatients in court-ordered treatment completed 4 task sessions measuring desire to use cocaine, cue-induced craving, monetary reward decisions and social cognition. Before each session, subjects administered 24 IU of intranasal oxytocin or placebo. Oxytocin increased desire to use cocaine and cue-induced excitability with no effect on cue-induced desire to use. Oxytocin also removed the effect of state anger on several measures of cue reactivity. Response to monetary reward increased under oxytocin and measures of social cognition worsened. The significant increase in the desire for drug and monetary reward as well as the significant decrease in measures of social cognition was small but warrant further study of the effect of oxytocin׳s effect in cocaine dependent subjects. The effect of oxytocin to modulate the relationship between state anger and cue reactivity should be explored further for potential therapeutic use of oxytocin in cocaine dependent patients. These findings are discussed in light of the human and rodent oxytocin literature.

Gender differences in neural–behavioral response to self-observation during a novel fMRI social stress task

UNLABELLED The neural correlates of response to psychosocial stress and gender differences therein are difficult to model experimentally as this type of stressor is difficult to induce in a brain imaging environment. The Trier Social Stress Test (TSST), a behavioral paradigm that reliably induces moderate levels of stress was thus modified for the MRI environment. To determine the neurobehavioral basis of gender differences in response to observing oneself under social evaluative stress, 26 subjects (14 females) performed the TSST while being videotaped. During fMRI scanning, subjects were shown alternating video clips of two CONDITIONS SELF or a same-sex OTHER performing the TSST. Subjects rated their stress level immediately after the video clips. GENDER differences in the [SELF-OTHER] contrast were analyzed. There was a GENDER×CONDITION interaction such that only women reported increased subjective stress during video feedback of their TSST session. A whole brain analysis (SELF vs. OTHER) showed activation in the bilateral insula, inferior, middle and superior frontal gyri. Greater recruitment was seen among males in some of these same areas in the context of significantly lower stress ratings. Activation of areas involved in inhibitory control and sensory awareness might contribute to the significantly lower stress ratings in males. Understanding these gender differences is relevant to disorders of stress and self-concept.

Exogenous ghrelin administration increases alcohol self-administration and modulates brain functional activity in heavy-drinking alcohol-dependent individuals

Preclinical evidence suggests that ghrelin, a peptide synthesized by endocrine cells of the stomach and a key component of the gut–brain axis, is involved in alcohol seeking as it modulates both central reward and stress pathways. However, whether and how ghrelin administration may impact alcohol intake in humans is not clear. For, we believe, the first time, this was investigated in the present randomized, crossover, double-blind, placebo-controlled, human laboratory study. Participants were non-treatment-seeking alcohol-dependent heavy-drinking individuals. A 10-min loading dose of intravenous ghrelin/placebo (3 mcg kg−1) followed by a continuous ghrelin/placebo infusion (16.9 ng/kg/min) was administered. During a progressive-ratio alcohol self-administration experiment, participants could press a button to receive intravenous alcohol using the Computerized Alcohol Infusion System. In another experiment, brain functional magnetic resonance imaging was conducted while participants performed a task to gain points for alcohol, food or no reward. Results showed that intravenous ghrelin, compared to placebo, significantly increased the number of alcohol infusions self-administered (percent change: 24.97±10.65, P=0.04, Cohen’s d=0.74). Participants were also significantly faster to initiate alcohol self-administration when they received ghrelin, compared to placebo (P=0.03). The relationships between breath alcohol concentration and subjective effects of alcohol were also moderated by ghrelin administration. Neuroimaging data showed that ghrelin increased the alcohol-related signal in the amygdala (P=0.01) and modulated the food-related signal in the medial orbitofrontal cortex (P=0.01) and nucleus accumbens (P=0.08). These data indicate that ghrelin signaling affects alcohol seeking in humans and should be further investigated as a promising target for developing novel medications for alcohol use disorder.

Relationship of plasma oxytocin levels to baseline symptoms and symptom changes during three weeks of daily oxytocin administration in people with schizophrenia

Several clinical studies have found an inverse relationship between clinical symptoms and peripheral oxytocin (OT) levels in people with schizophrenia. As oxytocin is a putative treatment for schizophrenia, the effect of repeated dosing of OT on OT levels, clinical symptoms and the relationship between the two is of interest. In a, randomized, double blind, parallel group 3 week study (N=28) with daily administration of intranasal OT (20 IU twice daily) or placebo (PBO), we examined the effect of OT administration on the correlation between the change in peripheral OT levels and change in clinical symptoms in patients with schizophrenia. At baseline, there were no significant treatment group differences in OT levels. There were no significant associations between baseline OT levels and any symptom measures. After 3 weeks of OT/PBO dosing, there was no significant difference in the magnitude of change in OT levels between the two treatment groups. Correlations between changes in peripheral OT levels and changes in the BPRS total and negative symptom scores were not different between treatment groups. Larger studies are needed to examine the effect of exogenous OT on peripheral OT levels and the relationship between the latter and clinical symptoms. Clinical Trials.gov=NCT00884897.

Management of Alcohol Use Disorder in Patients Requiring Liver Transplant

A woman with alcohol use disorder presents with jaundice, enlargement of the abdomen, severe fatigue, and malaise. “Ms.W”isa48-year-olddivorcedCaucasianwomanwith a history of alcohol use disorder who presents to the emergency department with complaints of increasing fatigue, shortness of breath, and increased abdominal girth. On initial evaluation, she is awake and alert, with a blood pressure of 95/65 mmHg and a pulse of 105 bpm. She reports daily alcohol drinking, usually one to two bottles of wine per day. She also reports a history of depression dating back to her late teens and early 20s, before her alcohol use began, and again shortly after her divorce several years ago. On physical examination, she appears jaundiced with a distended abdomen and pedal

Neuroendocrine response to GABA-B receptor agonism in alcohol-dependent individuals: Results from a combined outpatient and human laboratory experiment

&NA; Gamma‐aminobutyric acid (GABA), the main inhibitory neurotransmitter in the nervous system, plays an important role in biobehavioral processes that regulate alcohol seeking, food intake, and stress response. The metabotropic GABA‐B receptor has been investigated as a potential therapeutic target for alcohol use disorder, by using orthosteric agonists (e.g., baclofen) and positive allosteric modulators. Whether and how pharmacological manipulation of the GABA‐B receptor, in combination with alcohol intake, may affect feeding‐ and stress‐related neuroendocrine pathways remains unknown. In the present randomized, double‐blind, placebo‐controlled study, thirty‐four alcohol‐dependent individuals received baclofen (30 mg/day) or placebo in a naturalistic outpatient setting for one week, and then performed a controlled laboratory experiment which included alcohol cue‐reactivity, fixed‐dose priming, and self‐administration procedures. Blood samples were collected, and the following neuroendocrine markers were measured: ghrelin, leptin, amylin, glucagon‐like peptide‐1 (GLP‐1), insulin, prolactin, thyroid‐stimulating hormone, growth hormone, cortisol, and adrenocorticotropic hormone (ACTH). During the outpatient phase, baclofen significantly increased blood concentrations of acyl‐ghrelin (p = 0.01), leptin (p = 0.01), amylin (p = 0.004), and GLP‐1 (p = 0.02). Significant drug × time‐point interaction effects for amylin (p = 0.001) and insulin (p = 0.03), and trend‐level interaction effects for GLP‐1 (p = 0.06) and ACTH (p = 0.10) were found during the laboratory experiment. Baclofen, compared to placebo, had no effect on alcohol drinking in this study (ps ≥ 0.05). Together with previous studies, these findings shed light on the role of the GABAergic system and GABA‐B receptors in the shared neurobiology of alcohol‐, feeding‐, and stress‐related behaviors. HighlightsBaclofen administration in an outpatient setting increased blood ghrelin, leptin, amylin, and GLP‐1 concentrations.Baclofen altered the pattern of change in blood amylin, insulin, GLP‐1, and ACTH concentrations during a human lab experiment.GABA‐B receptors mediate the neuroendocrine correlates of alcohol‐, feeding‐, and stress‐related behaviors.

Pharmacological manipulation of the ghrelin system and alcohol hangover symptoms in heavy drinking individuals: Is there a link?

ABSTRACT Ghrelin, an orexigenic peptide synthesized in the stomach, is a key player in the gut‐brain axis. In addition to its role in regulating food intake and energy homeostasis, ghrelin has been shown to modulate alcohol‐related behaviors. Alcohol consumption frequently results in hangover, an underexplored phenomenon with considerable medical, psychological, and socioeconomic consequences. While the pathophysiology of hangover is not clear, contributions of mechanisms such as alcohol‐induced metabolic/endocrine changes, inflammatory/immune response, oxidative stress, and gut dysbiosis have been reported. Interestingly, these mechanisms considerably overlap with ghrelins physiological functions. Here, we investigated whether pharmacological manipulation of the ghrelin system may affect alcohol hangover symptoms. Data were obtained from two placebo‐controlled laboratory studies. The first study tested the effects of intravenous (IV) ghrelin and consisted of two experiments: a progressive‐ratio IV alcohol self‐administration (IV‐ASA) and a fixed‐dose IV alcohol clamp. The second study tested the effects of an oral ghrelin receptor inverse agonist (PF‐5190457) and included a fixed‐dose oral alcohol administration experiment. Alcohol hangover data were collected the morning after each alcohol administration experiment using the Acute Hangover Scale (AHS). IV ghrelin, compared to placebo, significantly reduced alcohol hangover after IV‐ASA (p = 0.04) and alcohol clamp (p = 0.04); PF‐5190457 had no significant effect on AHS scores. Females reported significantly higher hangover symptoms than males following the IV‐ASA experiment (p = 0.04), but no gender × drug condition (ghrelin vs. placebo) effect was found. AHS total scores were positively correlated with peak subjective responses, including ‘stimulation’ (p = 0.08), ‘sedation’ (p = 0.009), ‘feel high’ (p = 0.05), and ‘feel intoxicated’ (p = 0.03) during the IV‐ASA. IV ghrelin blunted the positive association between alcohol sedation and hangover as shown by trend‐level drug × sedation effect (p = 0.08). This is the first study showing that exogenous ghrelin administration, but not ghrelin receptor inverse agonism, affects hangover symptoms. Future research should investigate the potential mechanism(s) underlying this effect. HighlightsGhrelin, an orexigenic peptide primarily synthesized in the stomach, modulates alcohol‐related behaviors.There is considerable overlap between the pathways underlying both ghrelins function and alcohol hangover pathophysiology.Ghrelin administration significantly reduced the severity of alcohol hangover following intravenous alcohol administration.Ghrelin receptor inverse agonism had no effect on the severity of alcohol hangover following oral alcohol administration.Ghrelins effect on alcohol hangover may be mediated through oxidative, inflammatory, metabolic, and/or endocrine pathways.

Identifying and Characterizing Subpopulations of Heavy Alcohol Drinkers Via a Sucrose Preference Test: A Sweet Road to a Better Phenotypic Characterization?

Aims Sweet preference in individuals with alcohol use disorder (AUD) has been associated with family history of AUD and personality traits. Therefore, testing sweet preference may help identify subpopulations of AUD individuals. Short summary Sweet preference has been associated with family history of AUD and personality traits. We compared heavy drinkers based on their sweet liker status and using two cutoffs. Our findings support the role of sweet preference in heavy drinkers and point to the importance of how sweet likers are defined. Methods This study aimed at describing and comparing heavy drinkers based on their sweet liker status, through demographic, neuroendocrine, inflammatory, behavioral and drinking characteristics. Participants rated the pleasantness and intensity of sucrose solutions (0.05, 0.10, 0.21, 0.42 and 0.83 M). Two cutoffs were used to identify likers versus dislikers: Grouping A likers preferred 0.83 M and Grouping B likers preferred 0.83 or 0.42 M; the rest were dislikers. Results Sweet likers were 36% (n = 20) using Grouping A and 58.2% (n = 32) using Grouping B. Grouping B, but not Grouping A, sweet likers had higher BMI (P = 0.01). In Grouping B, sweet likers had higher plasma leptin and insulin concentrations and higher insulin resistance (Ps < 0.05). C-reactive protein concentrations were higher in sweet likers in Grouping A (P = 0.0015) and at a trend level in Grouping B (P = 0.07). Grouping A sweet likers had higher alcohol craving (P = 0.0004). Sweet likers preferred spirits compared to nonspirits (wine and beer) across both grouping (Ps < 0.05). Conclusions These results provide further support for the role of sweet liking phenotype in identifying subpopulations of AUD individuals. These findings also point to the importance of how sweet likers are defined, therefore highlighting the need for further research.