The combination of donepezil and cognitive training for improving treatment outcomes for alcohol use disorder: Design of a randomized controlled trial.

BACKGROUND: The development of alcohol use disorder (AUD) is a major concern in public health, and cognitive impairments caused by alcohol are involved in this process. Emerging neurobiological evidence suggests that donepezil, an anticholinesterase agent, may improve AUD treatment outcomes by enhancing neurocognitive functioning. Previous research has also suggested that cognitive remediation therapy (CRT) could potentially improve cognitive function and AUD treatment outcomes. We present the rationale and design of a trial to evaluate the combination of donepezil and cognitive remediation therapy (donepezil + CRT) as an intervention for AUD. METHODS: We propose a 13-week, randomized, double-blind, placebo-controlled, between-subjects trial comparing 4 groups (donepezil + CRT vs. donepezil alone vs. CRT alone vs. placebos) as an intervention for AUD. The main goal of the study is to evaluate if donepezil + CRT is superior to placebo in reducing heavy drinking days and improving neurocognitive functioning. A total of 160 patients (4 groups, 40 per each group) with AUD between the ages of 18-80 years will be recruited at Yale University and the VA Connecticut Healthcare System. Primary outcome measures include 1) heavy drinking by Timeline Follow Back (TLFB) over 13 weeks and 2) global neurocognitive functioning by a global index of neurocognitive function score at 7 and 13 weeks. DISCUSSION: This protocol paper describes the rationale and proposed methods for the randomized controlled trial for improving AUD treatment outcomes. This project has significant clinical potential to help patients suffering from AUD by improving their cognition and reducing alcohol consumption. TRIAL REGISTRATION: NCT05042102.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p<0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p<0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Progesterone Attenuates the Stress Response in Individuals with Alcohol Dependence and Post-Traumatic Stress Disorder - A Pilot Study.

OBJECTIVE: Evidence from laboratory studies suggests that progesterone may be effective in reducing stress and craving, and may improve cognitive performance in smokers and individuals with cocaine dependence. The objective of this study was to examine if progesterone would attenuate stress-induced craving, anxiety, affect and physiological measures, as well as improve stress-induced cognitive performance (processing speed and selective attention) in individuals diagnosed with alcohol use disorder (AUD) and post traumatic stress disorder (PTSD). METHODS: This laboratory study included (n = 13) participants who were diagnosed with current AUD and PTSD who were randomly assigned to recive either progesterone (200mg bid) or placebo in identical looking capsules for 3 days. On the fourth day they completed a laboratory session. In the morning of the test session, they received the last dose of medication and completed the rest of the laboratory procedures. The procedures included presentation in random order of personalized trauma and neutral scripts with relaxation in between. Main outcomes included measure of craving, anxiety, affect and cognitive performance. RESULTS: Consistent with other research, trauma scripts produced significantly greater increases in craving, anxiety and negative affect when compared with neutral scripts. Progesterone significantly reduced stress-induced symptoms of craving, anxiety, fear, anger and sadness but had no effect on positive emotions (joy, relaxation). Progesterone was effective in ameliorating stress-induced decreases in cognitive performance. CONCLUSIONS: The findings from this study demonstrate that progesterone can be effective in reducing stress-induced craving, anxiety and negative affect in a laboratory setting in individuals with comorbid AUD and PTSD. Interestingly, progesterone also improved cognitive performance. These findings require replication in a larger clinical trial and may have implications for treatment among individuals with AUD and PTSD.This study was registered as NCT02187224, at www.clinicaltrials.gov.

Altered corollary discharge in the auditory cortex could reflect louder inner voice experience in patients with verbal hallucinations, a pilot fMRI study.

INTRODUCTION: Wide range of evidence associates auditory verbal hallucinations (AVH) with frontotemporal corollary discharge deficit. AVH likely reflect altered experiences of the inner voice and are phenomenologically diverse. The aspects of hallucinations (and related inner voice experiences) that could be explained by this deficit remain unclear. To address this important subject, we examined the temporal cortex activity during two tasks with and without corollary discharge. METHODS: We carried out an event-related BOLD fMRI study to examine temporal cortex activity in seven patients and eight healthy controls during two tasks with and without corollary discharge: reading aloud and hearing, respectively. Data were denoised by removing independent components related to head movement and subsequently processed using finite impulse response basis function to address hemodynamic response variations. To mitigate the small sample size, final analyses were carried out using permutation-based analysis of variance. RESULTS: There was a significant group interaction in the Read relative to Hear condition during the early post-stimulus stage in the left Heschl's Gyrus (p < 0.01, corrected for multiple comparisons, at peak voxel [-72,53,41]). This effect was driven by a higher activity in the Read relative to the Hear condition in the same area in the patients (p < 0.02, corrected). CONCLUSIONS: Our results are consistent with prior literature indicating abnormal frontotemporal disconnection in participants with hallucinations. The functional repercussions of this deficit were limited to the primary auditory cortex in early post-stimulus stage, which suggests louder experience of the inner voice in patients and could account for the loudness of their hallucinations.

Keeping the inner voice inside the head, a pilot fMRI study.

INTRODUCTION: The inner voice is experienced during thinking in words (inner speech) and silent reading and evokes brain activity that is highly similar to that associated with external voices. Yet while the inner voice is experienced in internal space (inside the head), external voices (one's own and those of others) are experienced in external space. In this paper, we investigate the neural basis of this differential spatial localization. METHODS: We used fMRI to examine the difference in brain activity between reading silently and reading aloud. As the task involved reading aloud, data were first denoised by removing independent components related to head movement. They were subsequently processed using finite impulse response basis function to address the variations of the hemodynamic response. Final analyses were carried out using permutation-based statistics, which is appropriate for small samples. These analyses produce spatiotemporal maps of brain activity. RESULTS: Reading silently relative to reading aloud was associated with activity of the "where" auditory pathway (Inferior parietal lobule and middle temporal gyrus), and delayed activity of the primary auditory cortex. CONCLUSIONS: These pilot data suggest that internal space localization of the inner voice depends on the same neural resources as that for external space localization of external voices-the "where" auditory pathway. We discuss the implications of these findings on the possible mechanisms of abnormal experiences of the inner voice as is the case in verbal hallucinations.

Alcohol Craving and Psychiatric Disorders Among Current Drinkers.

BACKGROUND AND OBJECTIVES: Previous research has shown that alcohol craving is associated with psychiatric comorbidities. However, no population studies have examined the odds of psychiatric disorders in cravers and noncravers. The purpose of this study was to investigate current prevalence rates and odds ratios of psychiatric disorders among alcohol drinkers with and without alcohol craving in a population-based sample. We also compared four craving groups (cravers with and without alcohol use disorder [AUD], noncravers with and without AUD) for psychiatric comorbidities. METHODS: The study data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC). A subset of the NESARC sample (N = 22 000) who reported alcohol use during the past 12 months was included. Prevalence rates of psychiatric disorders were compared among current drinkers with alcohol craving (N = 900) and without alcohol craving (N = 21 500). RESULTS: Cravers had higher prevalence rates of current psychiatric disorders than noncravers. Even after adjustment for other psychiatric disorders including AUD, cravers had significantly higher odds of any substance use disorder (adjusted odds ratio [AOR], 9.01), any mood disorder (AOR, 1.78), any anxiety disorder (AOR, 1.86), and any personality disorder (AOR, 1.92) than noncravers. Interestingly, cravers without AUD had even higher rates of any anxiety disorder and any personality disorder than noncravers with AUD. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: Alcohol craving is associated with a higher prevalence of various psychiatric disorders. These findings suggest that alcohol craving may be related to transdiagnostic features that are present across various psychiatric disorders. (Am J Addict 2021;30:34-42).

Donepezil and cognitive remediation therapy to augment treatment of alcohol use disorder related mild cognitive impairment (AUD-MCI): An open label pilot study with historical controls.

Background: Pharmacological and psychosocial interventions have only modest efficacy for Alcohol Use Disorder (AUD), and continued alcohol use has brain effects on neurocognition, which place heavy drinkers at increased risk of early onset dementia. The most common neurocognitive deficits are in the domains of executive function and memory, and these deficits may impact AUD treatment outcomes. AUD related Mild Cognitive Impairment (AUD-MCI) is a diagnosis in DSM-V and ICD-10. Donepezil, a cholinesterase inhibitor, is currently FDA approved for treatment of dementia, and recent preclinical research suggests anticholinesterase agents may treat alcoholism. Another approach to cognitive recovery is Cognitive Remediation Therapy (CRT). Recent research supports CRT efficacy in schizophrenia and related disorders, and some research suggests that CRT could improve neurocognition in substance abuse disorders (SUDs). This is the first report of an open-label clinical trial that combined donepezil with CRT to improve neurocognitive and clinical outcomes in the early phase of AUD recovery. Methods: Eleven older male US Veterans with AUD-MCI as determined by Level II neurocognitive criteria and who had recently relapsed participated in an open-label trial of 13 weeks of donepezil combined with CRT. They were compared with matched historical control samples on neurocognitive and clinical outcomes. Results: Participants had excellent adherence to donepezil and CRT. Neurocognitive improvements were highly significant on a composite score of learning and memory and executive function measures (p < .0001) and was significantly better than historical matched controls (p < .001). On a Clinical Global Impression scale, 90.9% of participants had a good clinical recovery compared with 59.5% of historical matched controls (p <.052). Conclusions: AUD-MCI has not received much research attention but is of considerable public health importance. Findings in this open-label trial of donepezil + CRT should encourage further investigation into the clinical benefit of this combined treatment for AUD-MCI.

Zonisamide as an Adjunctive Treatment to Cognitive Processing Therapy for Veterans With Posttraumatic Stress Disorder and Comorbid Alcohol Use Disorder: A Pilot Study.

BACKGROUND AND OBJECTIVES: There are high rates of comorbid alcohol use disorder (AUD) among those who have posttraumatic stress disorder (PTSD). Ideally, treatment for comorbidity should address both disorders simultaneously. Zonisamide, an anticonvulsant, may be effective in decreasing alcohol use and may attenuate symptoms of PTSD. Treatment strategies can include medication in combination with a proven evidence-based psychotherapy designed to treat PTSD, such as cognitive processing therapy (CPT). METHODS: This 12-week pilot study was designed to test feasibility, acceptability, and preliminary efficacy of zonisamide (400 mg) as an adjunct to CPT for veterans with PTSD and comorbid AUD. Veterans (n = 24) with PTSD and current alcohol dependence were randomized in a 3:1 ratio to receive zonisamide or placebo in a double-blind fashion. All subjects received CPT enhanced to include sessions addressing drinking behavior. RESULTS: Subjects overall reported a significant decrease in drinking outcomes, craving, and symptoms of PTSD. Zonisamide was well-tolerated and easily administered with CPT, which was also well-tolerated. Exploratory analysis of comparison of groups suggests there was no advantage of zonisamide vs placebo in drinking or PTSD outcomes. There was a numeric but nonsignificant higher rate of abstinence with zonisamide (50%) vs placebo (33%). CONCLUSION AND SCIENTIFIC SIGNIFICANCE: The interpretation of the results is limited by the pilot nature of this study. The combination of psychosocial treatment with medication management mimics real-world treatment. In order to isolate the individual contributions of medication vs psychotherapy a much larger study would need to be conducted. (Am J Addict 2020;29:515-524).

Methadone-Related Delirium: Prevalence, Causes, and Outcomes.

Goals consist of determining 5-year prevalence and recurrence of methadone-related delirium (MRD), along with causes, treatments, and outcomes. Sample comprised 81 patients in methadone maintenance treatment. Criteria for MRD encompassed delirium with high methadone serum levels plus alleviation of delirium upon lowering methadone serum levels. MRD occurred in 14 cases who had 25 episodes. MRD precipitants included physician prescribing (i.e., excessive methadone or medications slowing methadone metabolism), drug misuse, and renal-fluid alterations. Social affiliation (housing with family, intimate partner) reduced MRD; employment increased MRD. Recovery occurred in 23/25 episodes of MRD; two episodes progressed to dementia. Obtaining serum methadone levels fostered prompt recognition.

Targeting neuroinflammation with minocycline in heavy drinkers.

RATIONALE: Alcohol has both acute and chronic effects on neuroimmune signaling, including triggering pro-inflammatory cytokine release by microglia. Minocycline, a second-generation tetracycline antibiotic, inhibits microglial activation and reduces neuroinflammation in preclinical studies. In mice, minocycline also reduces ethanol intake, attenuates ethanol-induced conditioned place preference, and inhibits ethanol-induced microglial activation and pro-inflammatory cytokine release. OBJECTIVE: Here, for the first time, we tested the effects of minocycline on subjective response to ethanol and acute ethanol-induced inflammation in humans. METHODS: Forty-eight heavy drinkers participated in a double-blind, placebo-controlled trial in which they were randomized to receive placebo, 100 mg, or 200 mg of minocycline for 10 days. Each subject then underwent two experimental sessions in which they were given a fixed dose of intravenous ethanol using a "clamp" procedure (100 mg%) or placebo (normal saline) on days 8 and 10 of treatment. RESULTS: Minocycline was well tolerated, but there was no effect of either dose of minocycline on subjective response to ethanol or ethanol-induced craving; minocycline effects on cognitive function seem to interact with age. Minocycline treatment did not alter serum cytokine levels at baseline or during ethanol-exposure, although certain baseline cytokine levels predict sedative response to ethanol. CONCLUSION: These findings indicate that a short-term treatment with minocycline may not alter ethanol-related inflammation or subjective response to ethanol in humans. Further research is needed to identify pharmacological agents with robust effects on ethanol-induced inflammation to determine whether neuroimmune modulation represents a viable treatment strategy for alcohol use disorder.

A Pilot Randomized, Placebo-Controlled Trial of Glycine for Treatment of Schizophrenia and Alcohol Dependence.

Objectives: The hypofunctioning of N-methyl-D-aspartate (NMDA) receptors are thought to play an important role in the pathophysiology of schizophrenia. The augmentation of the glutamatergic system through the NMDA receptor may attenuate alcohol craving and use. This study was designed to evaluate the efficacy of glycine, an agonist of the glycine B co-agonist site of the NMDA receptor on alcohol consumption and cravings as well as on negative symptoms in schizophrenia. Methods: Participants (N = 20) were given 0.8 g/kg glycine or matching placebo (provided in bottles with mixed in solution) each week for the duration of the 12-week trial. Primary outcome measures included drinking, craving for alcohol, and symptoms of schizophrenia. Cognitive functioning (attention, concentration, and memory) was also evaluated. Results: Glycine showed no benefit over placebo in the reduction of heavy drinking days or craving for alcohol over a 12-week treatment period. Nor was there an effect on negative symptoms of schizophrenia or on cognitive functioning. Conclusions: Although our study showed no beneficial effect of glycine over placebo, our results are consistent with the largest trial of glycine treatment in schizophrenia. Diagnosed schizophrenia and alcohol dependence might be more difficult to treat because of more severe psychopathology. This is the first study to date to examine an innovative treatment approach with an amino acid, glycine, as potentially acting on both alcohol intake and negative symptoms of schizophrenia.

Alcohol withdrawal hallucinations in the general population, an epidemiological study.

Hallucinations are sometimes encountered in the course of alcohol withdrawal; however, both the factors predisposing to alcohol withdrawal hallucinations (AWH) and the implications of AWH with respect to the mechanisms of hallucinations remain unclear. To clarify these issues, we used data from the National Epidemiologic Survey on Alcohol and Related Conditions (NESARC) to investigate the demographic correlates, alcohol-use clinical patterns, and psychiatric comorbidities in two groups: drinkers with and without a history of AWH. We estimated the odds ratios for studied factors and used logistic regression analyses to compare the two groups. We found that over 2% of drinkers reported AWH (758 of a sample of 34,533 subjects). Alcohol tolerance and withdrawal seizures were highly associated with AWH, and exposure to alcohol during brain development was associated with a 10-fold increase in AWH compared to exposure during adulthood. African Americans, Native Americans, and unmarried subjects, as well as subjects with lower levels of education and lower levels of income were more likely to experience AWH. Furthermore, those with a history of AWH had higher odds ratios for most psychiatric illnesses than those without such history-yet of anxiety disorders, only panic was associated with AWH. These associations suggest that higher levels of education and of standard of living could protect against AWH; while social isolation, hypervigilance, exposure to alcohol during brain development, and long and severe exposure to alcohol could predispose to AWH.

Long QTc During Methadone Maintenance: Contributors and Interventions Over 4 Years.

Our goal consisted of describing the 4-year prevalence, contributors, and interventions for long QTc's in methadone maintenance treatment. Cardiologists' diagnosis of long QTc defined case-ness in 62 patients. Long QTc categories, drawn from epidemiological reports, encompassed 440 to 469 (borderline), 470 to 499 (moderate), and 500+ milliseconds (severe). Data collection included electrocardiograms, demographic characteristics, contributors to long QTc, and interventions-plus-outcomes (defined by resolution of long QTc). Of 62 patients, 21 had 39 long QTc episodes-a 4-year case prevalence of 34%, and an annual episode incidence of 15.7 per 100. Contributing factors identified in 36 of 39 episodes consisted of medication management (n = 19), illicit drug use (n = 11), and other factors (n = 6). Long QTc reverted to normal in 38 of 39 episodes. Of 21 patients, 12 (57%) experienced one or two recurrences. Methadone maintenance treatment physicians normalized most episodes as outpatients, often in collaboration with patients' primary care physicians. One fifth of episodes required hospitalization and other specialty care. Lack of timely QTc normalization may have accounted for one sudden death.

Effect of Antidepressant Switching vs Augmentation on Remission Among Patients With Major Depressive Disorder Unresponsive to Antidepressant Treatment: The VAST-D Randomized Clinical Trial.

IMPORTANCE: Less than one-third of patients with major depressive disorder (MDD) achieve remission with their first antidepressant. OBJECTIVE: To determine the relative effectiveness and safety of 3 common alternate treatments for MDD. DESIGN, SETTING, AND PARTICIPANTS: From December 2012 to May 2015, 1522 patients at 35 US Veterans Health Administration medical centers who were diagnosed with nonpsychotic MDD, unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration, participated in the study. Patients were randomly assigned (1:1:1) to 1 of 3 treatments and evaluated for up to 36 weeks. INTERVENTIONS: Switch to a different antidepressant, bupropion (switch group, n = 511); augment current treatment with bupropion (augment-bupropion group, n = 506); or augment with an atypical antipsychotic, aripiprazole (augment-aripiprazole group, n = 505) for 12 weeks (acute treatment phase) and up to 36 weeks for longer-term follow-up (continuation phase). MAIN OUTCOMES AND MEASURES: The primary outcome was remission during the acute treatment phase (16-item Quick Inventory of Depressive Symptomatology-Clinician Rated [QIDS-C16] score ≤5 at 2 consecutive visits). Secondary outcomes included response (≥50% reduction in QIDS-C16 score or improvement on the Clinical Global Impression Improvement scale), relapse, and adverse effects. RESULTS: Among 1522 randomized patients (mean age, 54.4 years; men, 1296 [85.2%]), 1137 (74.7%) completed the acute treatment phase. Remission rates at 12 weeks were 22.3% (n = 114) for the switch group, 26.9% (n = 136)for the augment-bupropion group, and 28.9% (n = 146) for the augment-aripiprazole group. The augment-aripiprazole group exceeded the switch group in remission (relative risk [RR], 1.30 [95% CI, 1.05-1.60]; P = .02), but other remission comparisons were not significant. Response was greater for the augment-aripiprazole group (74.3%) than for either the switch group (62.4%; RR, 1.19 [95% CI, 1.09-1.29]) or the augment-bupropion group (65.6%; RR, 1.13 [95% CI, 1.04-1.23]). No significant treatment differences were observed for relapse. Anxiety was more frequent in the 2 bupropion groups (24.3% in the switch group [n = 124] vs 16.6% in the augment-aripiprazole group [n = 84]; and 22.5% in augment-bupropion group [n = 114]). Adverse effects more frequent in the augment-aripiprazole group included somnolence, akathisia, and weight gain. CONCLUSIONS AND RELEVANCE: Among a predominantly male population with major depressive disorder unresponsive to antidepressant treatment, augmentation with aripiprazole resulted in a statistically significant but only modestly increased likelihood of remission during 12 weeks of treatment compared with switching to bupropion monotherapy. Given the small effect size and adverse effects associated with aripiprazole, further analysis including cost-effectiveness is needed to understand the net utility of this approach. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01421342.