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Background: Depression is common in caregivers of children with asthma and is associated with poor outcomes in their child. No prior studies have longitudinally examined caregiver depression remission as a predictor of improvement in child asthma control., Objective: This 2-site study examined whether the proportion of time a caregiver was in depression remission predicted subsequent child asthma control at exit., Method: Caregivers (n = 205) with current major depressive disorder and their children, ages 7 to 17, with persistent asthma were observed every 4 weeks for 52 weeks. Caregiver depressive symptoms were measured using the 17-item Hamilton Rating Scale for Depression (HRSD). Child asthma was assessed with the (Childhood) Asthma Control Test (cACT/ACT) and spirometry, and depression with the Children's Depression Inventory (CDI). Linear regression analyses were conducted with change in cACT/ACT, CDI, and forced expiratory volume in 1 second (FEV 1 )% predicted as outcomes and proportion of time the caregiver was in remission (HRSD score ≤ 7) as the predictor. Multilevel mediation analyses examined the role of child depressive symptoms and asthma controller medication adherence., Results: Children were, on average, 54.1% female and 11 years old. Caregiver proportion of time in HRSD-assessed remission of depression was a significant predictor of improvement in cACT/ACT, CDI, and FEV 1 % predicted. Child CDI score, but not medication adherence, mediated the relationship between caregiver HRSD scores and child asthma control scores., Conclusions: Improvement in caregiver depression positively influences child asthma outcomes partially through improvement in child depressive symptom severity. Caregiver depression screening and treatment might lead to improvement in child asthma outcomes., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Pediatric asthma is associated with increased health services utilization, missed school days, and diminished quality of life. Children with asthma also report more frequent depressive and anxiety symptoms than children without asthma, which may further worsen asthma outcomes., Objective: The current study investigated the relationship between depressive and anxiety symptoms and 4 asthma outcomes (asthma control, asthma severity, lung function, and asthma-related quality of life) in children (N = 205) with moderate to severe persistent asthma., Methods: The data were analyzed using a canonical correlation analysis, a multivariate framework that allows examination of all variables of interest in the same model., Results: We found a statistically significant relationship between symptoms of depression and anxiety and asthma outcomes (1 - Λ = .372; P < .001). A large effect size suggests that 37.2% of variance is shared between depression and anxiety symptoms and 4 asthma outcomes (particularly asthma control and asthma-related quality of life) in the overall sample. Among girls (vs. boys), asthma control (measured by the Asthma Control Test) emerged as a stronger contributor to asthma outcomes compared with boys., Conclusions: These results suggest that psychiatric symptoms, especially anxiety, are associated with poor asthma-related quality of life, and more negative perception of asthma control in girls compared with boys (with no observed sex difference in physiological lung function). Clinicians should consider incorporating questions about psychiatric symptoms as part of routine asthma management, and focus patient education on unique differences in which boys and girls perceive their asthma symptoms., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Bipolar disorder is associated with high rates of alcohol use disorder. However, little is known about the treatment of this dual diagnosis population. Previous studies suggest that ondansetron decreases alcohol use, particularly in people with specific single nucleotide polymorphism (SNP) alleles. A 12-week, randomized, double-blind, placebo-controlled trial of ondansetron was conducted in 70 outpatients with bipolar spectrum disorders and early onset alcohol use disorder. Outcome measures included alcohol use, assessed with the Timeline Followback method, Penn Alcohol Craving Scale (PACS), Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self-report, and Young Mania Rating Scale. SNPs rs1042173, rs1176713 and rs1150226 were explored as predictors of response. Participants had a mean age of 44.9 ± 9.4 years, were mostly men (60.0%), and African American (51.4%). Mean ondansetron exit dose was 3.23 ± 2.64 mg. No significant between-group differences in alcohol use measures were observed. However, a significant reduction in HRSD scores was observed (p = 0.045). Inclusion of SNPs increased effect sizes for some alcohol-related outcomes and the HRSD. Ondansetron was well tolerated. This proof-of-concept study is the first report on ondansetron in bipolar people with bipolar disorders and alcohol use disorder. Alcohol use did not demonstrate a significant between-group difference. However, the findings suggest that ondansetron may be associated with reduction in depressive symptom severity in persons with bipolar illnesses and alcohol use disorder. A larger trial is needed to examine the effects of ondansetron on bipolar depression., (Copyright © 2020. Published by Elsevier B.V.)

Preclinical and clinical research indicates that excess corticosteroid is associated with adverse effects on the hippocampus. Animal model data suggest that N-methyl-D-aspartate (NMDA) receptor antagonists may block corticosteroid effect on the hippocampus. This translational clinical trial investigated the effect of memantine vs. placebo on hippocampal subfield volume in humans receiving chronic corticosteroid therapy. Men and women (N = 46) receiving chronic prescription corticosteroid therapy were randomized to memantine or placebo in a double-blind, crossover design (two 24-week treatment periods, separated by a 4-week washout) for 52 weeks. Structural magnetic resonance imaging was obtained at baseline and after each treatment. Data were analyzed using repeated measures analysis of variance. Mean corticosteroid dose was 7.69 ± 6.41 mg/day and mean duration 4.90 ± 5.61 years. Controlling for baseline volumes, the left DG/CA3 region was significantly larger following memantine than placebo (p = .011). The findings suggest that an NMDA receptor antagonist attenuates corticosteroid effect in the same hippocampal subfields in humans as in animal models. This finding has both mechanistic and clinical implications. Attenuation of the effect of corticosteroids on the human DG/CA3 region implicates the NMDA receptor in human hippocampal volume losses with corticosteroids. In addition, by suggesting a drug class that may, at least in part, block the effects of corticosteroids on the human DG/CA3 subfield, these results may have clinical relevance for people receiving prescription corticosteroids, as well as to those with cortisol elevations due to medical or psychiatric conditions.

Purpose/background: Glucocorticoids are a class of hormones that include naturally occurring cortisol and corticosterone, as well as prescription drugs commonly used to manage inflammatory, autoimmune, and allergic conditions. Adverse effects, including neuropsychiatric symptoms, are common. The hippocampus appears to be especially sensitive to the effects of glucocorticoids. However, to our knowledge, no studies to date have examined hippocampal subfields in humans receiving glucocorticoids. We examined patients on chronic glucocorticoid regimens to determine relationships between dose and duration of treatment, and hippocampal subfields, and related regions volumes., Methods/procedures: The study included adult men and women receiving at least 5 mg daily of prednisone equivalents for at least 6 months. Volumes of brain regions were measured via magnetic resonance imaging. A multivariate general linear model was used for analysis, with brain volumes as dependent variables and age, sex, and cumulative corticosteroid exposure, as predictors., Findings/results: The study population consisted of 81 adult outpatients (43 male) on corticosteroids (mean dose, 7.88 mg; mean duration, 76.75 months). Cumulative glucocorticoid exposure was negatively associated with left and right hippocampal dentate gyrus/CA3 volume. In subsequent subgroup analysis, this association held true for the age group older than the median age of 46 years but not for the younger age group., Implications/conclusions: This finding is consistent with previous studies showing detrimental effects of elevated glucocorticoids on the hippocampus but further suggests that the dentate gyrus and CA3 regions are particularly vulnerable to those effects, which is consistent with animal models of chronic stress but has not been previously demonstrated in humans.

Background: Past studies suggest that brexpiprazole is an effective adjunctive treatment for major depressive disorder and schizophrenia; however, no studies have examined brexpiprazole for bipolar depression. In this study, we examined the effects of brexpiprazole on mood, cognition, and quality of life in outpatients with bipolar depression., Methods: Twenty-one adults with bipolar disorder (most recent episode depressed) and scoring at least a 25 on the Montgomery-Åsberg Depression Rating Scale (MADRS) were recruited. Brexpiprazole was titrated up to 4 mg/day over the 8-week period. Depressive symptoms were measured using MADRS and Inventory of Depressive Symptomatology Self-report (IDS-SR 30 ). Manic symptoms were measured using Young Mania Rating Scale, quality of life with the Quality of Life in Bipolar Disorder (QOLBD), and cognition with Rey Auditory Verbal Learning Test, Stroop Color Word Test, and Trail Making Test., Results: MADRS and IDS-SR 30 scores decreased from baseline at weeks 4 and 8. YMRS and cognitive scores did not change significantly. QOLBD scores increased from baseline to week 8., Limitations: A limitation to this study is the open-label design., Conclusion: To our knowledge, this is the first study to examine the effects of brexpiprazole on bipolar depression. We found a significant reduction in depressive symptoms and an increase in quality of life., (Copyright © 2019. Published by Elsevier B.V.)

In animals, stress and corticosteroid excess are associated with decreases in memory performance and hippocampal volume that may be prevented with agents that decrease glutamate release. Humans also demonstrate changes in memory and hippocampus with corticosteroids. In this report the effects of glutamate-release inhibitor lamotrigine on hippocampal structure and memory were examined in people receiving medically needed prescription corticosteroid therapy. A total of 54 outpatient adults (n = 28 women) receiving chronic (≥ 6 months) oral corticosteroid therapy were randomized to lamotrigine or placebo for 48 weeks. Declarative memory was assessed using the Rey Auditory Verbal Learning Test (RAVLT); structural magnetic resonance imaging (MRI) as well as single-voxel proton MR spectroscopy ( 1 HMRS) focused on hippocampus were obtained at baseline and week 48. Utilizing a mixed-model approach, structural and biochemical data were examined by separate ANOVAs, and memory was assessed with a multi-level longitudinal model. RAVLT total scores demonstrated significantly better declarative memory performance with lamotrigine than placebo (p = 0.047). Hippocampal subfield volumes were not significantly different between the treatment groups. In summary, lamotrigine was associated with less decline in declarative memory performance than placebo in corticosteroid-treated patients. Findings suggest that, in humans as well as in animal models, glutamate release inhibitors may attenuate some of the effects on the human memory associated with corticosteroids., (Copyright © 2018. Published by Elsevier B.V.)

Background: Alcohol use disorder is a major societal and individual burden that exacerbates health outcomes, decreases quality of life, and negatively affects U.S. healthcare spending. Although pharmacological treatments are available for alcohol use disorder, many of them are limited by small effect sizes and used infrequently. Citicoline is a widely available over-the-counter supplement with a favorable side effect profile. It acts through cholinergic pathways and phospholipid metabolism. The current report examines the effect of oral citicoline on alcohol use, craving, depressive symptoms, and cognitive outcomes in individuals with alcohol use disorder., Methods: A 12-week, randomized, double-blind, parallel-group, placebo-controlled, pilot study of citicoline (titrated to 2,000 mg/d) in 62 adults (age 18 to 75) with alcohol use disorder was conducted. Alcohol use, such as number of drinking days, amount used, and number of heavy drinking days, was assessed using the Timeline Followback method and liver enzymes, while alcohol craving was measured using the Penn Alcohol Craving Scale. A neurocognitive battery (e.g., Rey Auditory Verbal Learning Test) and depressive symptoms scale (e.g., Inventory of Depressive Symptomatology Self-Report) scores were also collected. Data were analyzed using a random regression analysis., Results: The primary outcome analysis was conducted in the intent-to-treat sample and consisted of 55 participants (78.2% men and 21.8% women, mean age of 46.47 ± 9.15 years). In the assessment period, the drinking days, on average, represented 77% of the assessed days. Significant between-group differences were not observed on alcohol use, craving, and cognitive or depressive symptom measures. Citicoline was well tolerated., Conclusions: This proof-of-concept study observed that citicoline was well tolerated, but was not associated with a reduction in alcohol use or other outcomes, as compared to placebo. The favorable effects reported with citicoline for cocaine use, cognitive disorders, and other conditions do not appear to extend to alcohol use disorder., (© 2018 by the Research Society on Alcoholism.)

Background: Depression is common in asthma and is associated with poor outcomes. However, antidepressant therapy in depressed patients with asthma has been the topic of little research., Objective: This study examined the impact of antidepressant treatment with escitalopram versus placebo on the Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self Report (IDS-SR), Asthma Control Questionnaire (ACQ), and oral corticosteroid use in patients with asthma and major depressive disorder (MDD)., Methods: Single-site 12-week, randomized, double-blind, placebo-controlled, parallel-group trial of escitalopram (10 mg/d) was conducted in 139 outpatients with asthma and MDD. Randomization was stratified by oral corticosteroid use (≥3 bursts in past 12 months, yes or no) and baseline depressive symptom severity (HRSD score ≥ 20) (higher severity, n = 42) versus less than 3 bursts, HRSD score less than 20, or both (lower severity, n = 97). The primary data analysis was conducted using hierarchical linear modeling Version 7.01 on the higher and lower severity samples and post hoc was conducted on the combined sample., Results: Among the higher severity completers (n = 21), a significant reduction in the ACQ score (P = .04) and oral corticosteroid use (P = .04) was observed with escitalopram. In the combined sample, no significant differences were observed, but a trend toward greater reduction in the IDS-SR score was observed with escitalopram (P = .07). Side effects were comparable across groups., Conclusions: The findings suggest that patients with more severe asthma and depression symptomatology may have a positive response, in terms of both asthma and depressive symptom reduction, to antidepressant treatment., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The effects of the glucocorticoid and progesterone receptor agonist megestrol on declarative memory, and the ability of phenytoin to block these effects, were assessed., Methods: Healthy volunteers received each medication combination (placebo and megestrol, phenytoin and megestrol, and placebo and placebo) using a randomized, crossover design. The Rey Auditory Verbal Learning Test assessed declarative memory., Results: Megestrol was associated with a significant reduction in declarative memory (p = 0.0008), which was attenuated by phenytoin, and was associated with significant cortisol suppression compared to placebo (p < 0.001)., Conclusion: Changes in memory and cortisol suppression were found in healthy volunteers given megestrol., (© 2018 S. Karger AG, Basel.)

Purpose/background: In animal models, levels of the neurosteroid pregnenolone increase after tetrahydrocannabinol (THC) administration and pregnenolone appears to attenuate the brain effects of THC. Given these interactions between pregnenolone and THC, we evaluated baseline neurosteroid levels in participants with a history of a cannabis use disorders (CUDs)., Methods/procedures: Bipolar depressed participants were enrolled in a randomized placebo-controlled clinical trial to evaluate the efficacy of add-on pregnenolone for depression and before receiving pregnenolone or placebo. Baseline serum levels of neurosteroids (pregnenolone, allopregnanolone, pregnanolone, and androsterone) were analyzed in 53 participants with highly sensitive and specific gas chromatography/mass spectrometry. Current, active substance use disorders, or a positive baseline urine drug screen, were exclusionary. Participants were classified by past cannabis abuse or dependence diagnosis using the structured clinical interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Data were analyzed by independent t tests for separate neurosteroids., Findings/results: Participants with a history of CUD had higher serum pregnanolone, lower allopregnanolone, a higher pregnanolone to allopregnanolone ratio, and a lower pregnenolone to pregnanolone ratio compared with those without a history of cannabis use. Similar findings were not observed based on a history of other substance use disorders with the exception of lower allopregnanolone in those with opioid use disorders. Notably, the majority of those with an opioid use disorder also had a CUD (75%)., Implications/conclusions: These findings potentially suggest either enduring changes in neurosteroids in people with past CUDs or represent a vulnerability marker for a CUD.

Objective: Although drug dependence is common in patients with bipolar disorder, minimal data are available on the treatment of drug dependence in this patient population. The authors previously reported a decreased risk of relapse to cocaine use in a pilot study of citicoline in patients with bipolar disorder and cocaine dependence. The primary aim of the present study was to determine whether citicoline reduces cocaine use in outpatients with bipolar I disorder and current cocaine dependence and active cocaine use., Method: A total of 130 outpatients with bipolar I disorder (depressed or mixed mood state) and cocaine dependence received citicoline or placebo add-on therapy for 12 weeks. Results of thrice-weekly urine drug screens were analyzed using a generalized linear mixed model that was fitted to the binary outcome of cocaine-positive screens at each measurement occasion for 12 weeks. Mood was assessed with the Inventory of Depressive Symptomatology-Self Report, the Hamilton Depression Rating Scale, and the Young Mania Rating Scale., Results: In the intent-to-treat sample (N=61 in both groups), significant treatment group and group-by-time effects were observed, whether or not missing urine screens were imputed as cocaine positive. The group effect was greatest early in the study and tended to decline with time. No between-group differences in mood symptoms or side effects were observed., Conclusions: Citicoline was well tolerated for treatment of cocaine dependence in patients with bipolar disorder. Cocaine use was significantly reduced with citicoline initially, although treatment effects diminished over time, suggesting the need for augmentation strategies to optimize long-term benefit.

In animal models, corticosterone elevations are associated with hippocampal changes that can be prevented with phenytoin. In humans, Cushing's syndrome and long-term prescription corticosteroid use are associated with a reduction in the hippocampal volume. However, little is known about the effects of short-term corticosteroid administration on the hippocampus. The current report examines changes in the hippocampal volume during a brief hydrocortisone exposure and whether volumetric changes can be blocked by phenytoin. A randomized, double-blind, placebo-controlled, within-subject crossover study was conducted in healthy adults (n=17). Participants received hydrocortisone (160 mg/day)/placebo, phenytoin/placebo, both medications together, or placebo/placebo, with 21-day washouts between the conditions. Structural MRI scans and cortisol levels were obtained following each medication condition. No significant difference in the total brain volume was observed with hydrocortisone. However, hydrocortisone was associated with a significant 1.69% reduction in the total hippocampal volume compared with placebo. Phenytoin blocked the volume reduction associated with hydrocortisone. Reduction in hippocampal volume correlated with the change in cortisol levels (r=-0.58, P=0.03). To our knowledge, this is the first report of structural hippocampal changes with brief corticosteroid exposure. The correlation between the change in hippocampal volume and cortisol level suggests that the volume changes are related to cortisol elevation. Although the findings from this pilot study need replication, they suggest that the reductions in hippocampal volume occur even during brief exposure to corticosteroids, and that hippocampal changes can, as in animal models, be blocked by phenytoin. The results may have implications both for understanding the response of the hippocampus to stress as well as for patients receiving prescription corticosteroids.

Although bipolar disorder and substance dependence are both associated with treatment non-adherence and cognitive impairment, no studies have investigated relationships between treatment adherence and cognitive functioning in this population. As part of a clinical trial, baseline performance on two neuropsychological tests in 120 outpatients with bipolar disorder and cocaine dependence was used to examine whether cognitive functioning was associated with appointment attendance, medication adherence, and return of medication bottles. This study found that higher baseline cognitive functioning measured by the Stroop Color-Word condition predicted better treatment adherence. However, this study also reports measurement sensitivity of cognition as it relates to treatment adherence when applied to this dual diagnosis population. Poorer performance in simple visual attention tasks as assessed by the Stroop Word condition was inversely associated with some measures of adherence. Future studies are warranted that include a comprehensive neuropsychological battery and advanced medication adherence measures to confirm these findings., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Depression in bipolar disorder (BPD) is challenging to treat. Therefore, additional medication options are needed. In the current report, the effect of the neurosteroid pregnenolone on depressive symptoms in BPD was examined. Adults (n=80) with BPD, depressed mood state, were randomized to pregnenolone (titrated to 500 mg/day) or placebo, as add-on therapy, for 12 weeks. Outcome measures included the 17-item Hamilton Rating Scale for Depression (HRSD), Inventory of Depressive Symptomatology-Self-Report (IDS-SR), Hamilton Rating Scale for Anxiety (HRSA), and Young Mania Rating Scale (YMRS). Serum neurosteroid levels were assessed at baseline and week 12. Data were analyzed using a mixed model ANCOVA with a between factor of treatment assignment, a within factor (repeated) of visit, and the baseline value, as well as age and gender, as covariates. In participants with at least one postbaseline visit (n=73), a significant treatment by week interaction for the HRSD (F(5,288)=2.61, p=0.025), but not IDS-SR, was observed. Depression remission rates were greater in the pregnenolone group (61%) compared with the placebo group (37%), as assessed by the IDS-SR (χ(2)(1)=3.99, p=0.046), but not the HRSD. Large baseline-to-exit changes in neurosteroid levels were observed in the pregnenolone group but not in the placebo group. In the pregnenolone group, baseline-to-exit change in the HRSA correlated negatively with changes in allopregnanolone (r(22)=-0.43, p=0.036) and pregNANolone (r(22)=-0.48, p=0.019) levels. Pregnenolone was well tolerated. The results suggest that pregnenolone may improve depressive symptoms in patients with BPD and can be safely administered.

Background: Alcohol dependence is common in bipolar disorder (BPD) and associated with treatment nonadherence, violence, and hospitalization. Quetiapine is a standard treatment for BPD. We previously reported improvement in depressive symptoms, but not alcohol use, with quetiapine in BPD and alcohol dependence. However, mean alcohol use was low and a larger effect size on alcohol-related measures was observed in those with higher levels of alcohol consumption. In this study, efficacy of quetiapine in patients with BPD and alcohol dependence was examined in patients with higher mean baseline alcohol use than in the prior study., Methods: Ninety outpatients with bipolar I or II disorders, depressed or mixed mood state, and current alcohol dependence were randomized to 12 weeks of sustained release quetiapine (to 600 mg/d) add-on therapy or placebo. Drinking was quantified using the Timeline Follow Back method. Additional assessment tools included the Hamilton Rating Scale for Depression, Inventory of Depressive Symptomatology-Self-Report, Young Mania Rating Scale, Penn Alcohol Craving Scale, liver enzymes, and side effects. Alcohol use and mood were analyzed using a declining-effects random-regression model., Results: Baseline and demographic characteristics in the 2 groups were similar. No significant between-group differences were observed on the primary outcome measure of drinks per day or other alcohol-related or mood measures (p > 0.05). Overall side effect burden, glucose, and cholesterol were similar in the 2 groups. However, a significant weight increase was observed with quetiapine at week 6 (+2.9 lbs [SE 1.4] quetiapine vs. -2.0 lbs [SE 1.4], p = 0.03), but not at week 12. Scores on the Barnes Akathisia Scale increased significantly more (p = 0.04) with quetiapine (+0.40 [SE 0.3]) than placebo (-0.52 [SE 0.3]) at week 6 but not week 12. Retention (survival) in the study was similar in the groups., Conclusions: Findings suggest that quetiapine does not reduce alcohol consumption in patients with BPD and alcohol dependence., (Copyright © 2014 by the Research Society on Alcoholism.)

Background: In animal models, corticosteroids are associated with changes in hippocampal structure and functioning that are prevented by glutamate release inhibitors or N-methyl-D-aspartate (NMDA) receptor antagonists. Cushing's disease and prescription corticosteroid administration are also associated with memory impairment and hippocampal atrophy. Use of NMDA receptor antagonists to attenuate corticosteroid effects in humans has not been investigated. We examine the NMDA receptor antagonist memantine in patients receiving corticosteroids., Methods: Twenty outpatients receiving long-term oral corticosteroid therapy were randomized to 8 weeks of memantine (maximum dose 20 mg/day) and 8 weeks of placebo in a double-blind fashion, with a 4-week washout period between courses. Declarative memory was assessed with the Hopkins Verbal Learning Test (HVLT) and mood with the Hamilton Rating Scale for Depression and Young Mania Rating Scale. Changes in outcome measures were compared during memantine and placebo exposure., Results: Seventeen participants completed both treatment phases and were used in the analysis. Significant improvement (p < .05) in total and delayed recall on the HVLT was observed with memantine as compared with placebo. No significant changes in mood were observed., Conclusions: Memantine therapy was associated with improvement in declarative memory but not mood in patients receiving prescription corticosteroids.