Browsing by Subject "Mood disorders"

Now showing 1 - 6 of 6
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    A randomized proof-of-mechanism trial applying the 'fast-fail' approach to evaluating κ-opioid antagonism as a treatment for anhedonia
    (Springer Nature, 2020) Krystal, Andrew D.; Pizzagalli, Diego A.; Smoski, Moria; Mathew, Sanjay J.; Nurnberger, John, Jr.; Lisanby, Sarah H.; Iosifescu, Dan; Murrough, James W.; Yang, Hongqiu; Weiner, Richard D.; Calabrese, Joseph R.; Sanacora, Gerard; Hermes, Gretchen; Keefe, Richard S. E.; Song, Allen; Goodman, Wayne; Szabo, Steven T.; Whitton, Alexis E.; Gao, Keming; Potter, William Z.; Psychiatry, School of Medicine
    The National Institute of Mental Health (NIMH) 'fast-fail' approach seeks to improve too-often-misleading early-phase drug development methods by incorporating biomarker-based proof-of-mechanism (POM) testing in phase 2a. This first comprehensive application of the fast-fail approach evaluated the potential of κ-opioid receptor (KOR) antagonism for treating anhedonia with a POM study determining whether robust target engagement favorably impacts the brain circuitry hypothesized to mediate clinical effects. Here we report the results from a multicenter, 8-week, double-blind, placebo-controlled, randomized trial in patients with anhedonia and a mood or anxiety disorder (selective KOR antagonist (JNJ-67953964, 10 mg; n = 45) and placebo (n = 44)). JNJ-67953964 significantly increased functional magnetic resonance imaging (fMRI) ventral striatum activation during reward anticipation (primary outcome) as compared to placebo (baseline-adjusted mean: JNJ-67953964, 0.72 (s.d. = 0.67); placebo, 0.33 (s.d. = 0.68); F(1,86) = 5.58, P < 0.01; effect size = 0.58 (95% confidence interval, 0.13-0.99)). JNJ-67953964, generally well tolerated, was not associated with any serious adverse events. This study supports proceeding with assessment of the clinical impact of target engagement and serves as a model for implementing the 'fast-fail' approach.
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    Elevated tph2 mRNA expression in a rat model of chronic anxiety
    (Wiley, 2012-04) Donner, Nina C.; Johnson, Philip L.; Fitz, Stephanie D.; Kellen, Karen E.; Shekhar, Anantha; Lowry, Christopher A.; Psychiatry, School of Medicine
    BACKGROUND: Allelic variations in TPH2, the gene encoding tryptophan hydroxylase 2, the rate-limiting enzyme for brain serotonin (5-HT) biosynthesis, may be genetic predictors of panic disorder and panic responses to panicogenic challenges in healthy volunteers. To test the hypothesis that tph2 mRNA is altered in chronic anxiety states, we measured tph2 expression in an established rat model of panic disorder. METHODS: We implanted 16 adult, male rats with bilateral guide cannulae and then primed them with daily injections of the corticotropin-releasing factor (CRF) receptor agonist, urocortin 1 (UCN1, 6 fmoles/100 nl per side, n = 8) or vehicle (n = 8) into the basolateral amygdaloid complex (BL) for 5 consecutive days. Anxiety-like behavior was assessed, 24 hr prior to and 48 hr following priming, in the social interaction (SI) test. A third group (n = 7) served as undisturbed home cage controls. All rats were killed 3 days after the last intra-BL injection to analyze tph2 and slc6a4 (gene encoding the serotonin transporter, SERT) mRNA expression in the dorsal raphe nucleus (DR), the main source of serotonergic projections to anxiety-related brain regions, using in situ hybridization histochemistry. RESULTS: UCN1 priming increased anxiety-related behavior in the SI test compared to vehicle-injected controls and elevated tph2, but not slc6a4, mRNA expression in DR subregions, including the ventrolateral DR/ventrolateral periaqueductal gray (DRVL/VLPAG), a subregion previously implicated in control of panic-related physiologic responses. Tph2 mRNA expression in the DRVL/VLPAG was correlated with increased anxiety-related behavior. CONCLUSION: Our data support the hypothesis that chronic anxiety states are associated with dysregulated tph2 expression.
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    Implementation and staff understanding of shared decision-making in the context of recovery-oriented care across US Veterans Health Administration (VHA) inpatient mental healthcare units: a mixed-methods evaluation
    (BMJ, 2022-05-30) Eliacin, Johanne; Carter, Jessica; Bass, Emily; Flanagan, Mindy; Salyers, Michelle P.; McGuire, Alan; Psychiatry, School of Medicine
    Objectives: To examine the understanding and practice of shared decision-making (SDM) within the context of recovery-oriented care across Veterans Health Administration (VHA) inpatient mental healthcare units. Design: VHA inpatient mental health units were scored on the Recovery-Oriented Acute Inpatient Scale (RAIN). Scores on the RAIN item for medication SDM were used to rank each site from lowest to highest. The top 7 and bottom 8 sites (n=15) were selected for additional analyses using a mixed-methods approach, involving qualitative interviews, observation notes and quantitative data. Setting: 34 VHA inpatient mental health units located in every geographical region of the USA. Participants: 55 treatment team members. Results: Our results identified an overarching theme of 'power-sharing' that describes participants' conceptualisation and practice of medication decision-making. Three levels of power sharing emerged from both interview and observational data: (1) No power sharing: patients are excluded from treatment decisions; (2) Limited power sharing: patients are informed of treatment decisions but have limited influence on the decision-making process; and (3) Shared-power: patients and providers work collaboratively and contribute to medication decisions. Comparing interview to observational data, only observational data indicating those themes differentiate top from bottom scoring sites on the RAIN SDM item scores. All but one top scoring sites indicated shared power medication decision processes, whereas bottom sites reflected mostly no power sharing. Additionally, our findings highlight three key factors that facilitate the implementation of SDM: inclusion of veteran in treatment teams, patient education and respect for patient autonomy. Conclusions: Implementation of SDM appears feasible in acute inpatient mental health units. Although most participants were well informed about SDM, that knowledge did not always translate into practice, which supports the need for ongoing implementation support for SDM. Additional contextual factors underscore the value of patients' self-determination as a guiding principle for SDM, highlighting the role of a supporting, empowering and autonomy-generating environment.
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    Patients with Mood Disorders Require Higher Doses of Buprenorphine for Management of Opioid Use Disorder But Have No Increased Risk of Neonatal Abstinence Syndrome
    (Metrodora, 2021) Tonismae, Tiffany; McDowell, Misty; Torres, Loraine; Slaven, James E.; Quinney, Sara K.; Schubert, Frank; Pell Abernathy, Mary; Obstetrics and Gynecology, School of Medicine
    Objective: This study compared differences in buprenorphine doses needed to treat opioid use disorder in pregnant women with and without mood disorders and to compare the development of neonatal abstinence syndrome in infants delivered to mothers treated with buprenorphine in patients with history of mood disorders versus those without mood disorder. Methods: This retrospective cohort study included women with opioid use disorder prescribed buprenorphine who had at least one outpatient visit at with the Indiana University Department of Maternal Fetal Medicine during pregnancy and delivered within the Indiana University Health system. Charts were reviewed for maternal demographics, medical history and medication use, and neonatal outcomes. Cases included those patients with history of mood disorder including depression, anxiety, or post-traumatic stress disorder based on initial appointment intake forms. Starting and maximum doses of buprenorphine during pregnancy were recorded. Outcomes were compared using Student’s t-tests and Analysis of Variance models for continuous variables and chi-square tests for categorical variables. All analytic assumptions were verified, with non-parametric tests being performed where necessary. Results: A total of 266 women were treated with opioids, of which 171 were diagnosed with a mood disorder: 148 depression, 130 anxiety, and 19 post-traumatic stress disorder. Over 40% of the patients had a history of dual diagnoses. Patients with a history of depression or anxiety required a higher dose of buprenorphine during pregnancy (p=0.0217, p=0.0165) compared to those without a history of mood disorder. There was no significant difference in the doses in patients with post-traumatic stress disorder versus controls. In those with a diagnosis of mood disorder, there was no difference in buprenorphine dose between women on medication versus those not on medication for depression, anxiety, and Post Traumatic Stress Disorder. There was no statistical difference between patients with or without mood disorder and the development of neonatal abstinence syndrome. For those that developed neonatal abstinence syndrome, infants whose mothers had anxiety or post-traumatic stress disorder required 2-6 extra days of morphine treatment compared to those infants of mothers without mood disorder (p=0.0088, p=0.0291), no difference seen for depression or a combination of mood disorders. Development of neonatal abstinence syndrome or length of treatment did not vary if the mother was on medication for treatment of her mood disorder. Conclusion: Pregnant women with a mood disorder require higher doses of buprenorphine compared to patients without a mood disorder. In women with mood disorders, there was no difference in buprenorphine dose in women treated with medication compared to those not taking medication for mood disorders. While, there was no difference in the incidence of neonatal abstinence syndrome in infants whose mothers also had a mood disorder, infants born of women with anxiety or post-traumatic stress disorder had longer stays at the Neonatal Intensive Care Unit as they needed 2-6 extra days of morphine treatment. These findings may help guide provider counseling of these women in discussion of post-delivery expectations.
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    Precision medicine for mood disorders: objective assessment, risk prediction, pharmacogenomics, and repurposed drugs
    (Springer Nature, 2021-07) Le-Niculescu, H.; Roseberry, K.; Gill, S.S.; Levey, D.F.; Phalen, P.L.; Mullen, J.; Williams, A.; Bhairo, S.; Voegtline, T.; Davis, H.; Shekhar, A.; Kurian, S.M.; Niculescu, A.B.; Psychiatry, School of Medicine
    Mood disorders (depression, bipolar disorders) are prevalent and disabling. They are also highly co-morbid with other psychiatric disorders. Currently there are no objective measures, such as blood tests, used in clinical practice, and available treatments do not work in everybody. The development of blood tests, as well as matching of patients with existing and new treatments, in a precise, personalized and preventive fashion, would make a significant difference at an individual and societal level. Early pilot studies by us to discover blood biomarkers for mood state were promising [1], and validated by others [2]. Recent work by us has identified blood gene expression biomarkers that track suicidality, a tragic behavioral outcome of mood disorders, using powerful longitudinal within-subject designs, validated them in suicide completers, and tested them in independent cohorts for ability to assess state (suicidal ideation), and ability to predict trait (future hospitalizations for suicidality) [3-6]. These studies showed good reproducibility with subsequent independent genetic studies [7]. More recently, we have conducted such studies also for pain [8], for stress disorders [9], and for memory/Alzheimer's Disease [10]. We endeavored to use a similar comprehensive approach to identify more definitive biomarkers for mood disorders, that are transdiagnostic, by studying mood in psychiatric disorders patients. First, we used a longitudinal within-subject design and whole-genome gene expression approach to discover biomarkers which track mood state in subjects who had diametric changes in mood state from low to high, from visit to visit, as measured by a simple visual analog scale that we had previously developed (SMS-7). Second, we prioritized these biomarkers using a convergent functional genomics (CFG) approach encompassing in a comprehensive fashion prior published evidence in the field. Third, we validated the biomarkers in an independent cohort of subjects with clinically severe depression (as measured by Hamilton Depression Scale, (HAMD)) and with clinically severe mania (as measured by the Young Mania Rating Scale (YMRS)). Adding the scores from the first three steps into an overall convergent functional evidence (CFE) score, we ended up with 26 top candidate blood gene expression biomarkers that had a CFE score as good as or better than SLC6A4, an empirical finding which we used as a de facto positive control and cutoff. Notably, there was among them an enrichment in genes involved in circadian mechanisms. We further analyzed the biological pathways and networks for the top candidate biomarkers, showing that circadian, neurotrophic, and cell differentiation functions are involved, along with serotonergic and glutamatergic signaling, supporting a view of mood as reflecting energy, activity and growth. Fourth, we tested in independent cohorts of psychiatric patients the ability of each of these 26 top candidate biomarkers to assess state (mood (SMS-7), depression (HAMD), mania (YMRS)), and to predict clinical course (future hospitalizations for depression, future hospitalizations for mania). We conducted our analyses across all patients, as well as personalized by gender and diagnosis, showing increased accuracy with the personalized approach, particularly in women. Again, using SLC6A4 as the cutoff, twelve top biomarkers had the strongest overall evidence for tracking and predicting depression after all four steps: NRG1, DOCK10, GLS, PRPS1, TMEM161B, GLO1, FANCF, HNRNPDL, CD47, OLFM1, SMAD7, and SLC6A4. Of them, six had the strongest overall evidence for tracking and predicting both depression and mania, hence bipolar mood disorders. There were also two biomarkers (RLP3 and SLC6A4) with the strongest overall evidence for mania. These panels of biomarkers have practical implications for distinguishing between depression and bipolar disorder. Next, we evaluated the evidence for our top biomarkers being targets of existing psychiatric drugs, which permits matching patients to medications in a targeted fashion, and the measuring of response to treatment. We also used the biomarker signatures to bioinformatically identify new/repurposed candidate drugs. Top drugs of interest as potential new antidepressants were pindolol, ciprofibrate, pioglitazone and adiphenine, as well as the natural compounds asiaticoside and chlorogenic acid. The last 3 had also been identified by our previous suicidality studies. Finally, we provide an example of how a report to doctors would look for a patient with depression, based on the panel of top biomarkers (12 for depression and bipolar, one for mania), with an objective depression score, risk for future depression, and risk for bipolar switching, as well as personalized lists of targeted prioritized existing psychiatric medications and new potential medications. Overall, our studies provide objective assessments, targeted therapeutics, and monitoring of response to treatment, that enable precision medicine for mood disorders.
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    The Structure of Mood and Anxiety Symptoms in the Perinatal Period
    (Elsevier, 2023) Miller, Michelle L.; O’Hara, Michael W.; Psychiatry, School of Medicine
    Background: The perinatal period is increasingly recognized as a vulnerable time for the development and exacerbation of psychiatric symptoms. Research has often focused on perinatal depression, with much less information on perinatal anxiety. This study examined the psychometric structure of all internalizing (anxiety and mood disorder symptoms) in the perinatal period. Methods: Participants were primarily community adults receiving prenatal care from an academic medical center (N = 246). Participants completed a structured clinical interview using the Interview for Mood and Anxiety Symptoms (IMAS) during pregnancy (28-32 weeks gestation) and the postpartum (6-8 weeks). Clinical interviews dimensionally assessed all current anxiety, mood, and obsessive-compulsive symptoms as well as lifetime psychiatric diagnoses. Results: Confirmatory factor analyses identified three latent factors onto which psychiatric symptoms loaded: Distress (depression, generalized anxiety, irritability, and panic symptoms), Fear (social anxiety, agoraphobia, specific phobia, and obsessive-compulsive symptoms), and Bipolar (mania and obsessive-compulsive symptoms) in both pregnancy and the postpartum. The fit statistics of the models indicated adequate to good fit in both models. Limitations: The IMAS is validated against the DSM-IV-TR rather than the DSM-5 and assessments of psychiatric symptoms were focused only on the current pregnancy. Conclusions: A three-factor model consisting of Distress, Fear and Bipolar latent factors was the best-fitting model in pregnancy and the postpartum period and showed stability across time. The structure of internalizing symptoms has important implications for future perinatal research and can be utilized to guide treatment by highlighting which psychiatric symptoms may be most similar during the perinatal period.