Using ecological momentary assessments of negative affect and craving during residential opioid use disorder treatment to predict patients' relapse to substance use.

BACKGROUND: Negative affect (NA) and craving are often independently examined as precipitators of relapse among individuals with substance use disorders, including opioid use disorder (OUD). Recent ecological momentary assessment (EMA) research has revealed that NA and craving frequently co-occur within individuals. Yet we know little about the general patterns of, and variability in, within-person associations between NA and craving, as well as whether the nature and degree of within-person NA-craving coupling predicts post-treatment time-to-relapse. METHODS: Seventy-three patients (77 % male, Mage = 30.10, Range = 19-61) in residential treatment for OUD took part in a 12-day, 4× daily smartphone-based EMA study. Linear mixed-effects models tested within-person, day-level associations between self-reported NA and craving during treatment. The study used Person-specific slopes (i.e., average within-person NA-craving coupling for each participant) estimated from the mixed-effects model in survival analyses with Cox proportional hazards regression models to determine if between-person differences in the within-person coupling predicted post-treatment time-to-relapse (operationalized as the return to problematic use of any substance except tobacco), and whether this prediction was similar across patients' average levels of NA and craving intensity. The study monitored relapse through a combination of hair samples and reports from patients or alternative contacts via a voice response system twice a month for up to 120 days or more following discharge. RESULTS: Among the 61 participants with time-to-relapse data, those with stronger positive within-person NA-craving coupling on average during residential OUD treatment had a lower hazard of relapsing (slower time to relapse) post-treatment than participants with weaker NA-craving slopes. The significant association held after controlling for interindividual differences in age, sex, and average levels of NA and craving intensity. Average NA and craving intensity did not moderate the association between NA-craving coupling and time-to-relapse. CONCLUSIONS: Interindividual differences in average within-person, day-level NA-craving coupling during residential treatment predict OUD patients' post-treatment time-to-relapse.

Prefrontal cortical response to natural rewards and self-reported anhedonia are associated with greater craving among recently withdrawn patients in residential treatment for opioid use disorder.

Both anhedonia and craving are common among patients with opioid use disorder (OUD), and are associated with vulnerability to relapse. Although these constructs are theoretically linked relatively few studies have examined them together. In the current study, recently withdrawn patients (N = 71) in residential treatment for prescription OUD underwent a cue reactivity paradigm while being monitored with functional near-infrared spectroscopy (fNIRS). Patients also self-reported symptoms of anhedonia via the Snaith-Hamilton Pleasure Scale (SHAPS), while smartphone-based ecological momentary assessments (EMA) were used to measure craving levels. On average, lower right prefrontal cortex (PFC) activity in response to positive social stimuli was associated with higher craving (ß = - 2.87; S.E. = 1.23; p = 0.02). Self-reported anhedonia moderated the association between PFC activity and craving (ß = - 1.02; S.E. = 0.48; p = 0.04), such that patients with two or more anhedonic symptoms had a significant and stronger negative association between PFC activation to hedonically positive images and craving, compared to patients with fewer than two anhedonic symptoms, among whom the association was not significant. This finding provides evidence that higher levels of anhedonia among patients in residential treatment for OUD are associated with a stronger link between lower PFC response to positive social experiences and higher levels of craving, potentially increasing overall vulnerability to relapse.

Affect Modulated Startle Response in Anorexia Nervosa, Restricting Type: Implications for Theory and Practice.

OBJECTIVE: Individuals with anorexia nervosa (AN), restricting type demonstrate unique emotional responses to hedonically positive stimuli beyond eating disorder (ED)-related stimuli. The goal of this study was to evaluate differences in responses to five types of emotionally positive stimuli among acutely ill anorexia nervosa (IAN), restricting type patients, weight-recovered anorexia patients (WRAN), and healthy controls (HCs) using affect modulated startle response (AMSR) as an objective measure. METHOD: A total of 28 participants were recruited (n=28). Fourteen participants were recruited as IAN using the Diagnostic and Statistical Manual of Mental Disorders-V (DSM-V) criteria, seven were WRAN, and seven were HC females. All participants were female and aged between 8 and 18 years. The participants viewed images depicting negative, neutral, standardized, and non-eating disorder (ED)-related positive stimuli. Additionally, four categories of ED-related stimuli (high-calorie food, body image, success, and parent-child relationships) were presented to all participants during a standard AMSR paradigm. RESULTS:  No significant between-group differences were found for any of the four ED stimulus categories; all groups showed an inhibited startle response to the four ED-related categories. In contrast, IAN and WRAN showed reduced hedonic responses to standardized positive stimuli relative to HC-replicating previous results. Reduced hedonic response to the standardized (non-ED) positive stimuli was highly correlated with self-reported social anxiety, low self-esteem, body dissatisfaction, asceticism, interpersonal problems, and ineffectiveness. CONCLUSION: AN patients had a reduced hedonic response to some non-ED-related positive stimuli, which correlated with several anxiety-related traits. In contrast, their early automatic responses to high-calorie food, normal weight models, images of success, and positive parent-child relationships did not differ from HC, suggesting these stimuli are either being evaluated as highly interesting or hedonically positive.

Dose titration with the glucagon-like peptide-1 agonist, liraglutide, reduces cue- and drug-induced heroin seeking in high drug-taking rats.

Opioid use disorder (OUD), like other substance use disorders (SUDs), is widely understood to be a disorder of persistent relapse. Despite the use of three FDA-approved medications for OUD, typically in conjunction with behavioral treatments, relapse rates remain unacceptably high. Whereas medication assisted therapy (MAT) reduces the risk of opioid overdose mortality, the benefits of MAT are negated when people discontinue the medications. Currently approved medications present barriers to efficient use, including daily visits to a treatment center or work restrictions. With spiking increases in opioid relapse and death, it is imperative to identify new treatments that can reduce the risk of relapse. Recent evidence suggests that glucagon-like peptide-1 receptor agonists (GLP-1RAs), currently FDA-approved to treat obesity and type two diabetes, may be promising candidates to reduce relapse. GLP-1RAs have been shown to reduce relapse in rats, whether elicited by cues, drug, and/or stress. However, GLP-1RAs also can cause gastrointestinal malaise, and therefore, in humans, the medication typically is titrated up to full dose when initiating treatment. Here, we used a rodent model to test whether cue- and drug-induced heroin seeking can be reduced by the GLP-1RA, liraglutide, when the dose is titrated across the abstinence period and prior to test. The results show this titration regimen is effective in reducing both cue-induced heroin seeking and drug-induced reinstatement of heroin seeking, particularly in rats with a history of high drug-taking. Importantly, this treatment regimen had no effect on either circulating glucose or insulin. GLP-1RAs, then, appear strong candidates for the non-opioid prevention of relapse to opioids.

Reregulation of cortisol levels and sleep in patients with prescription opioid use disorder during long-term residential treatment.

OBJECTIVE: Research has demonstrated that hypothalamic-pituitary-adrenal (HPA) axis function and sleep patterns are dysregulated in patients diagnosed with opioid use disorder (OUD). It is unclear whether and/or when cortisol and sleep might re-regulate over time, and, whether re-regulation is associated with abstinence following discharge from residential treatment. The current study evaluated changes in sleep and basal cortisol levels in prescription OUD patients in residential treatment, and the association between these measures and treatment outcome following discharge. METHOD: As part of a larger study, 55 participants with prescription OUD provided two days of salivary cortisol samples and 12 consecutive nights of sleep actigraphy between days 19-30 of residential treatment (Time Point 1; TP1). Thirteen of the original 55 participants remained in residence and repeated the measures between days 60-72 (Time Point 2; TP2). Thirty-seven healthy controls (HC) provided baseline measures (TP1) of salivary cortisol and sleep. Treatment outcome data, abstinence vs relapse, were established at 120 days following discharge. RESULTS: Prescription OUD patients had higher cortisol levels and lower total sleep time (TST) than HC at TP1. At TP2, TST and cortisol levels no longer differed from HCs in the subgroup of patients who remained abstinent following discharge after TP2. Individuals whose cortisol and TST did not change from TP1 to TP2 were more likely to relapse following discharge from residential treatment. CONCLUSION: Re-regulation of TST and cortisol levels while in residential treatment was associated with better treatment outcome following discharge for prescription OUD patients.

Effectiveness and Utility of Mobile Device Assessment of Subjective Craving during Residential Opioid Dependence Treatment.

Background: Craving is a dynamic state that is both theoretically and empirically linked to relapse in addiction. Static measures cannot adequately capture the dynamic nature of craving, and research has shown that these measures are limited in their capacity to link craving to treatment outcomes. Methods: The current study reports on assessments of craving collected 4x-day across 12 days from 73 patients in residential treatment for opioid dependence. Analyses investigated whether the within-person assessments yielded expected across- and within-day variability, whether levels of craving changed across and within days, and, finally, whether individual differences in craving variability predicted post-residential treatment relapse. Results: Preliminary analyses found acceptable levels of data entry compliance and reliability. Consistent with expectations, craving varied both between (46%) and within persons, with most within-person variance (over 40%) existing within days. Other patterns that emerged indicated that, on average, craving declined across the 12-days of assessment, and was generally strongest at mid-day. Analyses also found that patients' person-level craving variability predicted post-treatment relapse, above and beyond their mean levels of craving. Conclusion: Analyses support the reliability, sensitivity, and potential utility of the 4x-day, 12-day assessment protocol for measuring craving during residential treatment.

Daily meaningfulness among patients with opioid use disorder: Examining the role of social experiences during residential treatment and links with post-treatment relapse.

BACKGROUND: A sense of meaningfulness is an important initial indicator of the successful treatment of addiction, and supports the larger recovery process. Most studies address meaningfulness as a static trait, and do not assess the extent to which meaningfulness might vary within an individual, or how it may vary in response to daily life events such as social experiences. METHODS: Ecological momentary assessment (EMA) was used to: 1) examine the amount of within-person variability in meaningfulness among patients in residential treatment for prescription opioid use disorder; 2) determine whether that variability was related to positive or negative social experiences on a daily basis; and 3) assess whether those day-to-day relationships were related to relapse at four months post-treatment. Participants (N = 73, 77% male, Mage = 30.10, Range = 19-61) completed smartphone-based assessments four times per day for 12 days. Associations among social experiences, meaningfulness, and relapse were examined using multilevel modeling. RESULTS: Between-person variability accounted for 52% (95% CI = 0.35, 0.67) of variance in end-of-day meaningfulness. End-of-day meaningfulness was higher on days when participants reported more positive social experiences (ß = 1.17, SE = 0.33, p < .05, ΔR2 = 0.041). On average, participants who relapsed within four months post-residential treatment exhibited greater within-day reactivity to negative social experiences (ß = -1.89, SE = 0.88, p < .05, ΔR2 = 0.024) during treatment than participants who remained abstinent. CONCLUSION: Individual differences in maintaining meaningfulness day by day when faced with negative social experiences may contribute to the risk of relapse in the early months following residential treatment.

Daily associations among craving, affect, and social interactions in the lives of patients during residential opioid use disorder treatment.

OBJECTIVE: This study captured the interrelationships among craving, negative affect, and positive and negative social exchanges in the daily lives of patients in residential treatment for opioid use disorders (OUDs). METHOD: Participants were 73 patients (77% male), age 19 to 61 (Mage = 30.10, SDage = 10.13) in residential treatment for OUD. Participants completed a smartphone-based survey 4 times per day for 12 consecutive days that measured positive and negative social exchanges (Test of Negative Social Exchange), negative affect (PA-NA scales), and craving (frequency and intensity). Within-person, day-level associations among daily positive and negative social exchanges, negative affect, and craving were examined using multilevel modeling. RESULTS: Daily negative social exchanges (M = 1.44, SD = 2.27) were much less frequent than positive social exchanges (M = 6.59, SD = 4.00) during residential treatment. Whereas negative social exchanges had a direct association with same-day craving (ß = 0.08; 95% CI = 0.01, 0.16, ΔR2 = 0.01), positive social exchanges related to craving indirectly via moderation of the within-person negative affect-craving link (ß = -0.01; 95% CI = -0.01, -0.001, ΔR2 = 0.002). Positive social exchanges decoupled the same-day linkage between negative affect and craving on days when individuals had at least four more positive social exchanges than usual. CONCLUSIONS: These results indicate that both negative affect and negative social exchanges are uniquely related to craving on a daily basis, and that extra positive social interactions can reduce the intraindividual coupling of negative affect and craving during residential treatment for OUD. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Examining the time-varying association of negative affect and covariates with craving during treatment for prescription opioid dependence with two types of mixed models.

Opioid use disorders are chronic and relapse is common. Both negative affect and craving have been suggested antecedents of relapse and have been shown to demonstrate within- and between-person variability, as well as association with each other. The present study extends previous research by examining the covariation of negative affect and craving both within-day and at the person-level during 12 days of treatment among opioid-dependent patients. Ecological momentary assessment (EMA) data were collected from 73 participants starting between 10 and 14 days after admission to an inpatient treatment facility. These data were analyzed using multivariate multilevel models and time-varying effect models. Results demonstrated strong association between negative affect and craving. Within-day, negative affect and craving were most associated in the early afternoon. At the person-level, association between negative affect and craving declined during the first week of data collection. Following this initial decline in association, negative affect and craving increasingly covaried during days 8-12 of data collection. To our knowledge, this is the first study to report a lagged increase in the association between negative affect and craving among patients during inpatient treatment for opioid dependence. Implications for research and treatment providers are discussed.

Daily sleep quality affects drug craving, partially through indirect associations with positive affect, in patients in treatment for nonmedical use of prescription drugs.

OBJECTIVE: Sleep disturbance has been identified as a risk factor for relapse in addiction to a range of substances. The relationship between sleep quality and treatment outcome has received relatively little attention in research on nonmedical use of prescription drugs (NMUPD). This study examined the within-person association between sleep quality and craving in medically detoxified patients in residence for the treatment of NMUPD. METHOD: Participants (n=68) provided daily reports of their sleep quality, negative affect (NA), positive affect (PA), and craving for an average of 9.36 (SD=2.99) days. Within-person associations of sleep quality and craving were examined using multilevel modeling. Within-person mediation analyses were used to evaluate the mediating roles of NA and PA in the relationship between sleep quality and craving. RESULTS: Greater cravings were observed on days of lower than usual sleep quality (γ10=-0.10, p=0.003). Thirty-one percent of the overall association between sleep quality and craving was explained by PA, such that poorer sleep quality was associated with lower PA and, in turn, lower PA was associated with greater craving. No evidence emerged for an indirect association between sleep quality and craving through NA. CONCLUSIONS: Daily fluctuations in sleep quality were associated with fluctuations in craving, an association partially explained by the association between sleep quality and daily PA. These data encourage further research on the relationship between sleep, affect, and craving in NMUPD patients, as well as in patients with other substance use disorders.

Ecological momentary assessment of affect and craving in patients in treatment for prescription opioid dependence.

Low positive affect (PA) is likely to contribute to risk of relapse; however, it has received relatively little attention in clinical research. This study examined the associations among positive affect, negative affect (NA), and craving in medically withdrawn patients using ecological momentary assessment (EMA). Participants (n=73) provided reports of their PA, NA, and craving 4 times a day for an average of 10.47 (SD=3.80) days. Person- and day-level associations between PA, NA, and craving were examined using multilevel models. A significant interaction emerged between person- and day-level PA such that PA on the day level was negatively associated with craving for individuals experiencing low mean PA throughout the study. No significant interaction emerged between person- and day-level NA. The main effects for both person- and day-level NA were significant. Individuals experiencing high NA throughout the study experienced higher craving overall and on days when NA was higher than usual, craving was also higher. Results suggest that high person- and day-level NA may directly contribute to the risk for relapse via increased craving, whereas low day- level PA may contribute to risk for relapse among individuals exhibiting low person-level PA via increased craving on days with lower than average levels of PA for those individuals. Given that there is a paucity of research relating low PA to craving, continued investigation into how and when low PA creates risk for relapse is warranted.

Possible evidence for re-regulation of HPA axis and brain reward systems over time in treatment in prescription opioid-dependent patients.

OBJECTIVES: There is growing evidence for a neuroadaptive model underlying vulnerability to relapse in opioid dependence. The purpose of this study was to evaluate clinical measures hypothesized to mirror elements of allostatic dysregulation in patients dependent on prescription opioids at 2 time points after withdrawal, compared with healthy control participants. METHODS: Recently withdrawn (n = 7) prescription opioid-dependent patients were compared with the patients in supervised residential care for 2 to 3 months (extended care; n = 7) and healthy controls (n = 7) using drug cue reactivity, affect-modulated startle response tasks, salivary cortisol, and 8 days of sleep actigraphy. Prefrontal cortex was monitored with functional near-infrared spectroscopy during the cue reactivity task. RESULTS: Startle response results indicated reduced hedonic response to natural rewards among patients recently withdrawn from opioids relative to extended care patients. The recently withdrawn patients showed increased activation to pill stimuli in right dorsolateral prefrontal cortex relative to extended care patients. Cortisol levels were elevated among recently withdrawn patients and intermediate for extended care relative to healthy controls. Actigraphy indicated disturbed sleep between recently withdrawn patients and extended care patients; extended care patients were similar to controls. Dorsolateral prefrontal cortex activation to drug and natural reward cues, startle responses to natural reward cues, day-time cortisol levels, time in bed, and total time spent sleeping were all correlated with the number of days since last drug use (ie, time in supervised residential treatment). CONCLUSIONS: These results suggest possible re-regulation of dysregulated hypothalamic-pituitary-adrenal axis and brain reward systems in prescription opioid-dependent patients over the drug-free period in residential treatment.

Biochemical correlates of neuropsychiatric illness in maple syrup urine disease.

Maple syrup urine disease (MSUD) is an inherited disorder of branched chain amino acid metabolism presenting with neonatal encephalopathy, episodic metabolic decompensation, and chronic amino acid imbalances. Dietary management enables survival and reduces risk of acute crises. Liver transplantation has emerged as an effective way to eliminate acute decompensation risk. Psychiatric illness is a reported MSUD complication, but has not been well characterized and remains poorly understood. We report the prevalence and characteristics of neuropsychiatric problems among 37 classical MSUD patients (ages 5-35 years, 26 on dietary therapy, 11 after liver transplantation) and explore their underlying mechanisms. Compared with 26 age-matched controls, MSUD patients were at higher risk for disorders of cognition, attention, and mood. Using quantitative proton magnetic resonance spectroscopy, we found lower brain glutamate, N-acetylaspartate (NAA), and creatine concentrations in MSUD patients, which correlated with specific neuropsychiatric outcomes. Asymptomatic neonatal course and stringent longitudinal biochemical control proved fundamental to optimizing long-term mental health. Neuropsychiatric morbidity and neurochemistry were similar among transplanted and nontransplanted MSUD patients. In conclusion, amino acid dysregulation results in aberrant neural networks with neurochemical deficiencies that persist after transplant and correlate with neuropsychiatric morbidities. These findings may provide insight into general mechanisms of psychiatric illness.

High prevalence of personality disorders among healthy volunteers for research: implications for control group bias.

Individuals who volunteer as control subjects for clinical studies are regularly screened for Axis I diagnoses, but seldom screened for Axis II disorders. This study examined the relative rates of Axis II diagnoses among 341 volunteers passing an initial telephone screen for entry into biological research studies. Axis I and II diagnoses by DSM-IV were assigned by best estimate after structured clinical interview, and subjects were categorized into one of three groups based on their diagnostic profiles: (1) volunteers without lifetime Axis I or II diagnoses ("healthy controls"), (2) personality-disordered volunteers without any history of Axis I pathology, and (3) personality-disordered volunteers with past (but not current) Axis I pathology. The results revealed a high prevalence of personality disorders (44.4%) among these volunteers. Several clinically relevant self-report inventories were used to demonstrate important characterological differences between the three comparison groups. Although inventory results demonstrated multiple differences between all three groups, most scales revealed differences between healthy controls and the two personality-disordered groups (with or without lifetime Axis I diagnoses), suggesting that most of the variance was accounted for by the presence or absence of an Axis II disorder, not a past Axis I disorder. These results suggest that personality-disordered volunteers may bias a control group due to the infrequent screening for Axis II disorders among volunteers for medical and psychiatric research. Implications are discussed for routine Axis II screening of volunteers for research with specific diagnostic instruments.

Filicidal mothers and the impact of psychosis on maternal filicide.

The objective of this study was to examine a sample (n = 55) of filicidal mothers to compare those with and without psychotic symptoms at the time of the filicide. Clinical data were gathered through retrospective chart review of filicidal women referred for criminal responsibility/competence to stand trial evaluations from 1974 to 1996 at Michigan's Center for Forensic Psychiatry. Most (52.7%) women had psychotic symptoms at the time of filicide. Women with psychosis were more likely than those without to have a history of substance abuse; to have past and ongoing psychiatric treatment; and to be older, unemployed, more educated, and divorced or separated. They were less likely to be first time mothers or to have had prior contact with Children's Protective Services. The psychotic mothers more often confessed, attempted suicide at the time of the filicide, used weapons, killed multiple children, and expressed homicidal thoughts and/or concerns about their children to psychiatrists and family before the filicide. Psychotic women were as likely as nonpsychotic women to have used alcohol or illegal drugs at the time of the filicide.