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.

Weight gain as a predictor of frontal and temporal lobe volume loss in bipolar disorder: A prospective MRI study.

OBJECTIVES: A sizable fraction of people with bipolar I disorder (BDI) experience a deteriorating clinical course with increasingly frequent mood episodes and chronic disability. This is believed to result from neurobiological illness progression, or neuroprogression. Excessive weight gain predicts neuroprogression across multiple brain illnesses, but no prospective studies have investigated this in BDI. The objective of this study was to determine whether BDI patients who experienced clinically significant weight gain (CSWG; gaining ≥7% of baseline weight) over 12 months had greater 12-month brain volume loss in frontal and temporal regions important to BDI. METHODS: In 55 early-stage BDI patients we measured (i) rates of CSWG, (ii) the number of days with mood symptoms, using NIMH LifeCharts, and (iii) baseline and 12-month brain volumes, using 3T MRI. We quantified brain volumes using the longitudinal processing stream in FreeSurfer v6.0. We used general linear models for repeated measures to investigate whether CSWG predicted volume loss, adjusting for potentially confounding clinical and treatment variables. RESULTS: After correction for multiple comparisons, CSWG in patients predicted greater volume loss in the left orbitofrontal cortex (effect size [ES; Cohen's d] = -1.01, P = 0.002), left cingulate gyrus (ES = -1.31, P < 0.001), and left middle temporal gyrus (ES = -0.96, P = 0.004). Middle temporal volume loss predicted more days with depression (ß = -0.406, P = 0.010). CONCLUSIONS: These are the first prospective data on weight gain and neuroprogression in BDI. CSWG predicted neuroprogression, and neuroprogression predicted a worse clinical illness course. Trials of weight loss interventions are needed to confirm the causal direction of the weight gain-neuroprogression relationship, and to determine whether weight loss is a disease-modifying treatment.

Efficacy, Safety, and Durability of Repeated Ketamine Infusions for Comorbid Posttraumatic Stress Disorder and Treatment-Resistant Depression.

OBJECTIVE: The present study examined the efficacy, safety, and durability of repeated ketamine infusions for the treatment of comorbid posttraumatic stress disorder (PTSD) and treatment-resistant depression (TRD) in a sample of veterans. METHODS: Individuals with comorbid DSM-5-defined PTSD and DSM-IV-defined major depressive disorder (N = 15) received 6 intravenous ketamine infusions (0.5 mg/kg) on a Monday-Wednesday-Friday schedule over a 12-day period from May 2015 to June 2016. Data from outcome measures were collected before and 24 hours after each infusion and weekly for 8 weeks following the final infusion. RESULTS: Continuous measures of symptom change were significant for both disorders and were associated with large effect sizes (mean decrease in PTSD Checklist for DSM-5 score = 33.3 points [95% CI, 23.0-43.5 points], P < .0005, sample size-adjusted Cohen d [d'] = 2.17; mean decrease in Montgomery-Asberg Depression Rating Scale score = 26.6 points [95% CI, 23.0-30.2 points], P < .0005, d' = 4.64). The remission rate for PTSD was 80.0%, and the response rate for TRD was 93.3%. Participants in remission from PTSD after the infusion series (n = 12) had a median time to relapse of 41 days. Similarly, participants whose depression symptoms responded to the infusion series (n = 14) had a median time to relapse of 20 days. Repeated ketamine infusions were associated with transient increases in dissociative symptoms. No participant reported worsening of PTSD symptoms over the study duration. CONCLUSIONS: This study, the first open-label study of repeated ketamine infusions in a comorbid population, found rapid and sustained improvement in PTSD and depression symptoms. This report suggests that repeated ketamine treatments are safe and may represent an efficacious treatment for individuals with comorbid PTSD and TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02577250.

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.

The 10-Item Substance Use Disorder Outcome Scale: Psychometric evaluation.

The current study describes the psychometric properties of a scale (entitled "Substance Use Disorder Outcome Scale-10 items" or 10-Item Substance Use Disorder Outcome Scale) designed for longitudinal studies. Sixteen male veterans attending a substance use disorder recovery clinic were studied over a 2-year period. The attending nurse and physician conducted four, 10-Item Substance Use Disorder Outcome Scale scale ratings, each encompassing a 6-month period, for each participant. Analyses involved scale descriptive results, Cronbach alpha scores, effects of deleting the item on Cronbach alpha scores for the remaining items, and item-to-scale correlations across the four periods, plus three exploratory studies. Scale scores showed skewness p ≤ 1.0 and Cronbach alphas of 0.89 to 0.93. Six of 10 items correlated with total scale scores at 3 or 4 rating periods at p ≤ 0.005. Two items showed p ≤ 0.005 correlations only in the first two periods, and two items showed p ≤ 0.005 correlations only in the last two periods. Exploratory analyses revealed some item convergence over time plus non-significant associations with long-standing demographic and clinical variables. Desirable 10-Item Substance Use Disorder Outcome Scale psychometric properties included normal distribution, excellent Cronbach alphas, and high item-to-score correlations, all of which persisted over time.

Methadone maintenance dose/weight ratio, long QTc, and EKG screening.

BACKGROUND AND OBJECTIVES: Electrocardiogram (EKG) monitoring during methadone maintenance treatment (MMT) has been recommended to prevent potentially fatal prolonged computed QT intervals (QTc). However, risk indicators for obtaining EKGs do not exist. This study assessed 23 variables that might help identify prolonged QTc during MMT. METHODS: EKGs concurrent with methadone serum levels were obtained from 69 veterans during a 5-year study, encompassing 302.8 person-years. Two cardiologists hand-measured QT intervals, selecting each patient's longest QTc. QTc categories included: normal duration <440 ms; borderline duration of 440-469 ms; and abnormal duration ≥470 ms. QTc's were compared with seven methadone parameters and 16 bio-psycho-social variables using two QTc cut-offs (440 and 470 ms). RESULTS: Among the 69 patients, 19 had normal QTc's, 28 had borderline QTc's, and 22 had abnormal QTc's. Methadone dose/weight was moderately correlated with QTc, and independently associated with longer QTc at both 440 and 470 cut-offs. DISCUSSION AND CONCLUSION: Dose/weight ≥.49 is useful for screening EKGs for QTc's ≥440 cut-off. Dose/weight ≥.65 produces high-yield abnormal QTc's ≥470 cut-off. SCIENTIFIC SIGNIFICANCE: Methadone dose/weight provides moderately reliable thresholds for making routine screening decisions and urgent clinical decisions to obtain an EKG for prolonged QTc. (Am J Addict 2016;25:499-507).

Regulation of growth and prostatic marker expression by activin A in an androgen-sensitive prostate cancer cell line LNCAP.

Activin A, a homodimer of the betaA subunit of inhibin, is a member of the TGF-beta family. It is a multifunctional molecule regulating the growth, differentiation, and survival of a variety of cells. Treatment with activin A to an androgen-sensitive human prostatic cancer cell line LNCaP resulted in growth and morphological change and those were accompanied by up-regulation of prostatic differentiation markers prostate-specific antigen (PSA) and prostatic acid phosphatase (PAP). In addition, the expression of androgen receptor was also enhanced by activin treatment. These results suggest that activin has significant influence on LNCaP cells.

Activins and activin receptors in cell growth.

Activin and inhibin, members of transforming growth factor-beta (TGFbeta) superfamily, have diverse and widespread effects within living organisms at many stages during growth and development. From the initial isolation of these growth factors based on their effects of FSH secretion, the study of these factors, as well as of the activin-binding protein follistatin, has progressed from the localization of the expression of the inhibin alpha subunit, activin betaA and betaB subunits, and activin receptors in the tissues of various organisms to the examination of activin and inhibin as autocrine and paracrine agents in cell proliferation and differentiation. The inhibitory effects on cell growth and differentiation that have been observed upon treatment of cells with activin suggest that further understanding of the bioactivity of this molecule and its characterization on a molecular level may aid in a more complete understanding of cell growth and differentiation. This minireview discusses the roles of activin, inhibin, and follistatin in the arenas of cell proliferation, differentiation, and embryogenesis, as well as the roles of these molecules in cancerous cells.

p53 is involved in the inhibition of cell proliferation mediated by activin A in cultured human prostate cancer LNCaP cells.

Activin A in a concentration ranging from 0.7 to 75 ng/ml specifically inhibited cell growth of an androgen-sensitive human prostate cancer line, LNCaP, but had no effects on two androgen-insensitive human prostate cancer lines, PC3 and DU-145. This activin-mediated inhibition of cell growth in LNCaP cells results from a decrease of cell proliferation and an increase of apoptosis. Northern blot analysis of mRNA expression encoding human p53 in untreated and activin-treated LNCaP cells resulted in upregulation of p53 gene expression. We conclude that autocrine inhibition of cell growth in LNCaP cells by activin is in part related to the expression of the p53 gene.

Overexpression of activin A inhibits growth, induces apoptosis, and suppresses tumorigenicity in an androgen-sensitive human prostate cancer cell line LNCaP.

The effects of overexpression of activin A in the androgen-sensitive human prostate cancer cell line LNCaP were studied. A full-length cDNA of activin beta A coding region was inserted into a eukaryotic expression vector and transfected into the LNCaP cells. Overexpression of activin BA significantly inhibited growth of this cell line. An increased death rate was also noted in these activin-overproducing cells, which was believed to be due to apoptosis as manifested by morphological change, DNA laddering, and FAGS analysis. The expression of bcl-2 was suppressed and the expression of c-myc was stimulated in these cells. In addition, the efficiency of soft agar colony formation and the tumorigenicity in the nude mice were suppressed for the activin producing LNCaP cells.

Activin A inhibits growth and hexamethylene bisacetamide-induced differentiation in human retinoblastoma Y-79 cells.

Activin regulates the growth and differentiation of a variety of cells and is a member of the transforming growth factor-beta (TGF-beta) family. Previously, we found that the retinoblastoma cell line Y-79 expresses both activins and activin receptors, suggesting that activin may have an autocrine function in these cells. In this study, the effects of exogeneous activin A on cultured Y-79 cells were examined. The results demonstrate that activin A inhibits hexamethylene bisacetamide (HMBA) -induced Y-79 cell differentiation in both serum-containing and serum-free medium. Activin A also inhibits Y-79 cell growth in serum-containing medium but not in serum-free medium.

Activin and activin receptors in a rat osteogenic-sarcoma cell-line, umr-106.

We have localized immunocytochemically activin-A-like reactivity in UMR-106 osteogenic cells with a characterized, specific antiserum against synthetic fragment of subunits of activin-A, a member of transforming growth factor B (TGFB) superfamily. No staining was seen when the activin BA-subunit antisera were replaced by immunoneutralized sera, antiserum dilution buffer, or normal rabbit serum. Using in situ hybridization and the reverse transcription polymerase chain reaction (RT-PCR), we have observed the expression of the BA-subunit of activin and activin receptors II & IIB, DNA sequencing data show that the RT-PCR product corresponds to the predicted fragments of activin-A and activin receptors, respectively. In addition, exogenously administered activin inhibited cell growth in cultured UMR-106 cells. Our findings have shown that (a) activin-A was localized immunohistochemically to UMR-106 cells, (b) expression of activin-A and its receptors are detected by in situ hybridization and RT-PCR in UMR-106 cells, and (c) activin may have an inhibitory autocrine function in the proliferation of these cells.

Expression of activins and activin receptor messenger-rnas in lncap cells, a human prostatic adenocarcinoma cell-line.

An androgen-responsive human prostatic cell line, LNCaP, was examined for the expression of mRNAs encoding the inhibin/activin subunits and activin receptors as determined by reverse transcription polymerase chain reaction (RT-PCR) and hybridization. Messenger RNA of the beta A- and beta B-subunits of inhibin/activin and activin receptors I, II, and IIB were expressed in these cells. The specificity of the RT-PCR products was confirmed by DNA sequencing. However, the expression of the alpha subunit of inhibin was not observed. In addition, activin proteins were localized immunocytochemically in the cytoplasm of LNCaP cells. The expression of both activins and activin receptors in LNCaP cells suggests that activin may have an autocrine function in these cells. Since activin acts as a modulator of cell proliferation and differentiation in many biological systems and inhibin possesses antagonistic actions to those of activin, it is proposed that the proliferation of LNCaP cells may be associated with an imbalance between the expression of activins and inhibins.