Synaptic loss and deficits in functional connectivity are hypothesized to contribute to symptoms associated with major depressive disorder (MDD) and post-traumatic stress disorder (PTSD). The ...synaptic vesicle glycoprotein 2A (SV2A) can be used to index the number of nerve terminals, an indirect estimate of synaptic density. Here, we used positron emission tomography (PET) with the SV2A radioligand
CUCB-J to examine synaptic density in n = 26 unmedicated individuals with MDD, PTSD, or comorbid MDD/PTSD. The severity of depressive symptoms was inversely correlated with SV2A density, and individuals with high levels of depression showing lower SV2A density compared to healthy controls (n = 21). SV2A density was also associated with aberrant network function, as measured by magnetic resonance imaging (MRI) functional connectivity. This is the first in vivo evidence linking lower synaptic density to network alterations and symptoms of depression. Our findings provide further incentive to evaluate interventions that restore synaptic connections to treat depression.
Sleep abnormalities are associated with acute and chronic use of addictive substances. Although sleep complaints associated with use and abstinence from addictive substances are widely recognized, ...familiarity with the underlying sleep abnormalities is often lacking, despite evidence that these sleep abnormalities may be recalcitrant and impede good outcomes. Substantial research has now characterized the abnormalities associated with acute and chronic use of alcohol, cannabis, cocaine, and opiates. This review summarizes this research and discusses the clinical implications of sleep abnormalities in the treatment of substance use disorders.
Despite well-known peripheral immune activation in posttraumatic stress disorder (PTSD), there are no studies of brain immunologic regulation in individuals with PTSD.
CPBR28 Positron Emission ...Tomography brain imaging of the 18-kDa translocator protein (TSPO), a microglial biomarker, was conducted in 23 individuals with PTSD and 26 healthy individuals-with or without trauma exposure. Prefrontal-limbic TSPO availability in the PTSD group was negatively associated with PTSD symptom severity and was significantly lower than in controls. Higher C-reactive protein levels were also associated with lower prefrontal-limbic TSPO availability and PTSD severity. An independent postmortem study found no differential gene expression in 22 PTSD vs. 22 controls, but showed lower relative expression of TSPO and microglia-associated genes TNFRSF14 and TSPOAP1 in a female PTSD subgroup. These findings suggest that peripheral immune activation in PTSD is associated with deficient brain microglial activation, challenging prevailing hypotheses positing neuroimmune activation as central to stress-related pathophysiology.
Attention-deficit/hyperactivity disorder (ADHD) is a common condition that often persists into adulthood, although data suggest that the current diagnostic criteria may not represent how the ...condition presents in adults. We aimed to use qualitative methods to better understand ADHD symptomatology in young adults, especially regarding attentional and emotional dysregulation.
Nine focus groups involving young adults (aged 18-35 years; N = 43; 84% female; 86% US and Canada) with diagnoses of ADHD were conducted. Participants were asked about their perceptions of the current diagnostic criteria and how their symptoms have presented and changed over time. Data were analyzed using an interpretive phenomenological analysis framework.
Most participants reported that the diagnostic criteria did not accurately capture their experiences with ADHD. They reported struggling with attention dysregulation, including hyperfocusing, and emotional dysregulation, including rejection-sensitive dysphoria. Many participants believed that their changing environments and behavioral adaptations influenced how their symptoms presented into adulthood.
Current diagnostic criteria for ADHD may not capture the range of symptoms present in young adults. More research is needed to characterize attentional and emotional dysregulation in this population.
Alcohol use disorder (AUD) is a leading cause of global disease burden. Chronic, heavy use increases the likelihood of alcohol withdrawal symptoms and associated secondary outcomes of alcohol craving ...and mood, anxiety, and sleep disturbances, which are predictive of poor treatment outcomes. The authors examined whether alcohol withdrawal symptoms moderate the efficacy of prazosin in reducing alcohol intake and associated secondary outcomes.
A 12-week, double-blind, randomized, controlled proof-of-concept trial of prazosin (16 mg/day, with a 2-week titration) was conducted in community-recruited adults with current alcohol dependence (N=100) with varying levels of alcohol withdrawal symptoms assessed at treatment entry. Primary outcomes were daily self-reported drinking days and heavy drinking days, and secondary outcomes were average drinks/day and mood, anxiety, craving, and sleep quality ratings.
Modified intent-to-treat analyses indicated a significant interaction of alcohol withdrawal symptom score by treatment by full-dose treatment period (weeks 3-12) for drinking days, heavy drinking days, and average drinks/day. By week 12, participants with high alcohol withdrawal symptoms on prazosin reported 7.07% heavy drinking days and 27.46% drinking days, while those on placebo had 35.58% heavy drinking days and 58.47% drinking days (heavy drinking days: odds ratio=0.14, 95% CI=0.058, 0.333; drinking days: odds ratio=0.265, 95% CI=0.146, 0.481). No such benefit of prazosin was observed in those reporting low or no alcohol withdrawal symptoms. Individuals with high alcohol withdrawal symptoms on prazosin compared with placebo also showed significantly improved anxiety, depression, and alcohol craving over the course of the trial.
The findings indicate that alcohol withdrawal symptoms are a significant moderator of prazosin treatment response for alcohol use outcomes and for associated symptoms of alcohol craving, anxiety, and mood symptoms. These data support further evaluation of alcohol withdrawal symptoms as a prognostic indicator of prazosin's efficacy in the treatment of AUD.
Background
Chronic alcohol use results in changes to stress biology and autonomic arousal contributing to acute alcohol withdrawal symptoms, neuroendocrine tolerance of the ...hypothalamic–pituitary–adrenal axis responses, high stress‐induced craving, and risk of alcohol relapse. Thus, stress coping and recovery from alcohol during early abstinence may be jeopardized by such stress system dysfunction. Significant preclinical evidence suggests that noradrenergic disruption may contribute to these alcohol‐related stress arousal changes and that alpha‐1 adrenergic antagonists, such as prazosin, may normalize these stress system adaptations and reduce alcohol intake. Thus, we hypothesized that prazosin would reduce stress‐induced craving and improve neuroendocrine and autonomic response to stress and alcohol cue exposure during early abstinence. We secondarily also assessed the role of lifetime anxiety disorders on these prazosin effects.
Methods
Forty inpatient treatment‐seeking alcohol‐dependent individuals were randomly assigned to receive placebo (n = 18) or 16 mg/d, T.I.D., prazosin (n = 22) in a double‐blind manner, titrated over 2 weeks. In weeks 3 to 4 after achieving full dose, patients were exposed to 3 5‐minute personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue), on 3 consecutive days in a random, counterbalanced order. Alcohol craving, anxiety, heart rate, cortisol, and adrenocorticotropic hormone (ACTH) levels were assessed at baseline, following imagery and at repeated recovery timepoints.
Results
Prazosin reduced stress cue–induced alcohol craving (p < 0.05) and stress‐ and alcohol cue–induced anxiety (p < 0.05) and increased heart rate responses in all imagery conditions (p < 0.05). Prazosin lowered basal cortisol and ACTH (p’s < 0.05) and attenuated stress cue–induced rises in cortisol (p < 0.05) versus placebo. Finally, in those without lifetime anxiety disorder, the placebo group showed stress‐ and alcohol cue–induced increases in cortisol (p’s < 0.05), while the prazosin group did not.
Conclusions
Prazosin may attenuate stress cue–induced alcohol craving and anxiety during early abstinence while improving adrenergic and stress system function, effects which are independent of a history of lifetime anxiety disorders.
Inpatient treatment‐seeking individuals with alcohol use disorder received placebo or 16 mg/d, T.I.D., prazosin and were exposed to personalized guided imagery conditions (stress cue, alcohol cue, neutral/relaxing cue) in the laboratory. Prazosin reduced stress cue‐induced alcohol craving and stress‐ and alcohol cue‐induced anxiety and normalized heart rate responses in all imagery conditions. Prazosin lowered basal cortisol and ACTH and attenuated stress cue‐induced rises in cortisol. In those without lifetime anxiety disorder, prazosin decreased stress‐ and alcohol cue‐induced increases in cortisol.
The cholinergic system is a critical mediator of cognition in animals. People who smoke cigarettes exhibit cognitive deficits, especially during quit attempts. Few studies jointly examine the ...cholinergic system and cognition in people while trying to quit smoking. We used positron emission tomography (PET) brain imaging with the β
-subunit containing nicotinic acetylcholine receptor (β
*-nAChR) partial agonist radioligand (-)-
Fflubatine and the acetylcholinesterase inhibitor physostigmine to jointly examine the cholinergic system, smoking status, and cognition. (-)-
FFlubatine scans and cognitive data were acquired from twenty people who recently stopped smoking cigarettes (aged 38 ± 11 years; 6 female, 14 male; abstinent 7 ± 1 days) and 27 people who never smoked cigarettes (aged 29 ± 8 years; 11 female, 16 male). A subset of fifteen recently abstinent smokers and 21 never smokers received a mid-scan physostigmine challenge to increase acetylcholine levels. Regional volume of distribution (V
) was estimated with equilibrium analysis at "baseline" and post-physostigmine. Participants completed a cognitive battery prior to (-)-
Fflubatine injection and physostigmine administration assessing executive function (Groton Maze Learning test), verbal learning (International Shopping List test), and working memory (One Back test). Physostigmine significantly decreased cortical (-)-
Fflubatine V
, consistent with increased cortical acetylcholine levels reducing the number of β
*-nAChR sites available for (-)-
Fflubatine binding, at comparable magnitudes across groups (p values < 0.05). A larger magnitude of physostigmine-induced decrease in (-)-
Fflubatine V
was significantly associated with worse executive function in people who recently stopped smoking (p values < 0.05). These findings underscore the role of the cholinergic system in early smoking cessation and highlight the importance of neuroscience-informed treatment strategies.
Background
Stress and depression have each been associated with relapse risk. In clinical practice, chronic alcohol use is often accompanied by poor emotional and self‐regulatory processes. Tonic and ...phasic changes in stress responsivity impact an individual's relapse risk to alcohol. A further complicating factor is the pervasive coexistence of depressive symptoms in those with Alcohol Use Disorder (AUD), where the contribution of depressive symptomatology to these processes is not well understood. Individuals with AUD (AD) (21 with and 12 without sub‐clinical depressive symptoms) and 37 social drinking controls (16 with and 21 without sub‐clinical depressive symptoms) as part of a more extensive study (Fox et al., 2019). All participants were exposed to two 5‐min personalized guided imagery conditions (stress and neutral) in a randomized and counterbalanced order across consecutive days. Alcohol craving, negative mood, Stroop performance, and plasma measures (cortisol, adrenocorticotrophic hormone, and salivary alpha‐amylase) were collected before and after imagery exposure.
Results
Elevations in autonomic response (heart rate) to imagery (stress and neutral) were observed as a function of drinking (in both depressed and non‐depressed individuals with alcohol use disorder compared with depressed and non‐depressed social drinkers). Conversely, suppressed cortisol following stress was observed as a function of depressive symptomatology across both drinking groups. Individuals with comorbid AD and depressive symptoms demonstrated attenuated Adrenocorticotropic Hormone and poor Stroop performance compared with the other groups, indicating an interactive effect between drinking and depression on pituitary and inhibitory systems.
Conclusion
Sub‐clinical depressive pathophysiology may be distinct from drinking severity and may alter relapse‐related stress adaptations during protracted abstinence from alcohol.
BACKGROUNDInvestigations of stress dysregulation in posttraumatic stress disorder (PTSD) have focused on peripheral cortisol, but none have examined cortisol in the human brain. This study used ...positron emission tomography (PET) to image 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), a cortisol-producing enzyme, as a putative brain cortisol marker in PTSD.METHODSSixteen individuals with PTSD and 17 healthy, trauma-exposed controls (TCs) underwent PET imaging with 18FAS2471907, a radioligand for 11β-HSD1.RESULTSPrefrontal-limbic 11β-HSD1 availability, estimated as 18FAS2471907 volume of distribution (VT), was significantly higher in the PTSD group compared with the TC group (β = 1.16, P = 0.0057). Lower prefrontal-limbic 11β-HSD1 availability was related to greater overall PTSD severity (R2 = 0.27, P = 0.038) in the PTSD group. 11β-HSD1 availability was not related to plasma cortisol levels (R2 = 0.026, P = 0.37). In a PTSD subset (n = 10), higher 11β-HSD1 availability was associated with higher availability of translocator protein (TSPO), a microglial marker (β = 4.40, P = 0.039).CONCLUSIONHigher brain cortisol-producing 11β-HSD1 in the PTSD group may represent a resilience-promoting neuroadaptation resulting in lower PTSD symptoms. Along with preliminary associations between 11β-HSD1 and TSPO, corroborating previous evidence of immune suppression in PTSD, these findings collectively challenge previous hypotheses of the deleterious effects of both excessive brain glucocorticoid and brain immune signaling in PTSD.FUNDINGBrain and Behavior Research Foundation Independent Investigator Grant, National Institute of Mental Health grants F30MH116607 and R01MH110674, the Veterans Affairs National Center for PTSD, the Gustavus and Louise Pfeiffer Foundation Fellowship, Clinical and Translational Science Awards grant UL1 TR000142 from the NIH National Center for Advancing Translational Science.
: Major depressive disorder (MDD) and cocaine use disorder (CUD) are prevalent and frequently co-occur. When co-occurring, the presence of one disorder typically negatively impacts the prognosis for ...the other. Given the clinical relevance, we sought to examine pharmacotherapies for co-occurring CUD and MDD. While multiple treatment options have been examined in the treatment of each condition individually, studies exploring pharmacological options for their comorbidity are fewer and not conclusive.
: For this review, the authors searched the literature in PubMed using clinical query options for therapies and keywords relating to each condition. Then, they described potentially promising pharmacologic therapeutic options based on shared mechanisms between the two conditions and/or results from individual clinical trials conducted to date.
: Medications like stimulants, dopamine (D3) receptors partial agonists or antagonists, antagonists of kappa opioid receptors, topiramate, and ketamine could be promising as there is significant overlap relating to reward deficiency models, antireward pathways, and altered glutamatergic systems. However, the available clinical literature on any one of these types of agents is mixed. Additionally, for some agents there is possible concern related to abuse potential (e.g. ketamine and stimulants).
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