Enhanced Adoption of Measurement-Based Care in a Psychiatry Outpatient Clinic After High-Reliability Process Changes.

OBJECTIVE: This study examined the impact of high-reliability changes to how measurement-based care questionnaires were administered to patients on rates of questionnaire completion. METHODS: Medical record data were abstracted from 44,305 adult outpatient return visits to a psychiatry outpatient clinic within two 10-month periods (before and after process changes were implemented). Linear mixed models tested the change in questionnaire completion rates and the interaction effects between time and age, sex, and race. RESULTS: Patient completion of questionnaires increased by 79% after process changes. Women were more likely to complete questionnaires regardless of the process. After process changes, older patients and White patients were more likely to complete questionnaires. CONCLUSIONS: High-reliability process changes to measurement-based care questionnaire administration were associated with higher questionnaire completion rates. Racial, age, and sex disparities in questionnaire completion rates were notable and deserve attention in future measurement-based care implementation efforts.

National Network of Depression Centers' Recommendations on Harmonizing Clinical Documentation of Electroconvulsive Therapy.

ABSTRACT: Electroconvulsive therapy (ECT) is a highly therapeutic and cost-effective treatment for severe and/or treatment-resistant major depression. However, because of the varied clinical practices, there is a great deal of heterogeneity in how ECT is delivered and documented. This represents both an opportunity to study how differences in implementation influence clinical outcomes and a challenge for carrying out coordinated quality improvement and research efforts across multiple ECT centers. The National Network of Depression Centers, a consortium of 26+ US academic medical centers of excellence providing care for patients with mood disorders, formed a task group with the goals of promoting best clinical practices for the delivery of ECT and to facilitate large-scale, multisite quality improvement and research to advance more effective and safe use of this treatment modality. The National Network of Depression Centers Task Group on ECT set out to define best practices for harmonizing the clinical documentation of ECT across treatment centers to promote clinical interoperability and facilitate a nationwide collaboration that would enable multisite quality improvement and longitudinal research in real-world settings. This article reports on the work of this effort. It focuses on the use of ECT for major depressive disorder, which accounts for the majority of ECT referrals in most countries. However, most of the recommendations on clinical documentation proposed herein will be applicable to the use of ECT for any of its indications.

Going Virtual During a Pandemic: An Academic Psychiatry Department's Experience with Telepsychiatry.

Background: The novel coronavirus pandemic (COVID-19) led healthcare providers, including mental health providers, across the U.S. to swiftly shift to telemedicine. Objectives: This shift gave our Department of Psychiatry a chance to better understand key challenges and opportunities vis-à-vis virtual mental healthcare. We aimed to obtain provider feedback on the use of telepsychiatry and to learn from the provider perspective about patient experiences with video visits. This information will be used to inform the telemedicine strategy at a systems level within our psychiatry department, our academic health system, as well as the field of telemedicine as a whole. Design and Sample: A 22-item online questionnaire comprising 16 quantitative and six qualitative items was distributed to providers currently using video visits to provide care. Results: A total of 89 mental health providers completed the questionnaire. Outcomes demonstrated that while providers perceive challenges associated with virtual care (e.g., fatigue, technology-related issues, and age-related concerns), they also recognize a number of benefits to themselves and their patients (e.g., convenience and increased access). Overall, provider satisfaction, comfort, and willingness to use telepsychiatry was high. Conclusions: The vast majority of providers adapted quickly to the use of virtual platforms; many endorse advantages that suggest virtual care will continue to be a modality they provide in the future, post-COVID-19. It will be important to continue to evaluate aspects of virtual care that may limit clinical assessments and to optimize use to improve access, convenience, and cost-efficiency of mental healthcare delivery.

Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior.

The fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Implementing Measurement-Based Care in Various Practice Settings.

Measurement-based care (MBC) is recognized as a valuable component to maximize quality in psychiatric care; however, actual use of MBC by practitioners is poor. A host of implementation barriers have been noted, and are likely significant contributors to this poor adoption. Many of these barriers are related to work-flow issues that can be managed or mitigated by appropriate infrastructure considerations. This article offers an overview of the continuum of infrastructures to support MBC in clinical practice, delineating the tradeoffs between these infrastructures, and then identifying specific experience-based strategies for addressing several major patient-, provider-, and organization-level barriers to MBC implementation.

Development of the National Network of Depression Centers Mood Outcomes Program: A Multisite Platform for Measurement-Based Care.

OBJECTIVES: Mood disorders are among the most burdensome public health concerns. The National Network of Depression Centers (NNDC) is a nonprofit consortium of 26 leading clinical and academic member centers in the United States providing care for patients with mood disorders, including depression and bipolar disorder. The NNDC has established a measurement-based care program called the Mood Outcomes Program whereby participating sites follow a standard protocol to electronically collect patient-reported outcome assessments on depression, anxiety, and suicidal ideation in routine clinical care. This article describes the approaches taken to develop and implement the program. METHODS: Since 2015, eight pilot sites have implemented the program and followed more than 10,000 patients. This pilot study presents descriptive statistics based on the first 24-month period of data collection. RESULTS: In this sample, 58.6% of patients with bipolar disorder (N=849) and 57.5% of patients with unipolar depression (N=3,998) remained symptomatic at follow-up. Lifetime rates of planned or actual suicide attempts were high, ranging from 27.6% for patients with unipolar mood disorders to 33.5% for patients with bipolar disorder. Men, unmarried individuals, and those with comorbid anxiety had a poorer longitudinal course. This initial snapshot of clinical burden is consistent with public health data indicating that mood disorders are severely debilitating. CONCLUSIONS: This study demonstrates the potential of the Mood Outcomes Program to create a nationwide "learning health system" for mood disorders. This goal will be further realized as the program expands in reach and scope across additional NNDC sites.

The Michigan Child Collaborative Care Program: Building a Telepsychiatry Consultation Service.

This column describes the establishment of the Michigan Child Collaborative Care (MC3), a statewide telepsychiatry consultation program that provides support to primary care providers (PCPs) in meeting the mental health needs of youths and perinatal women. The MC3 program provides cost-effective, timely, remote consultation to primary care providers in an effort to address the lack of access and scarcity of resources in child, adolescent, and perinatal psychiatry. Data from 10,445 service requests are summarized. Common diagnoses included attention-deficit hyperactivity disorder, mood disorders, anxiety disorders, and autistic spectrum disorders, with many cases (58%) deemed moderate to severe. Co-occurring psychological trauma was suspected in 9% of service requests. Partnerships, stakeholder roles, PCP engagement, and workflow integration are highlighted as keys to the program's success.

Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder.

Obsessive-compulsive disorder is a severe psychiatric disorder linked to abnormalities in glutamate signaling and the cortico-striatal circuit. We sequenced coding and regulatory elements for 608 genes potentially involved in obsessive-compulsive disorder in human, dog, and mouse. Using a new method that prioritizes likely functional variants, we compared 592 cases to 560 controls and found four strongly associated genes, validated in a larger cohort. NRXN1 and HTR2A are enriched for coding variants altering postsynaptic protein-binding domains. CTTNBP2 (synapse maintenance) and REEP3 (vesicle trafficking) are enriched for regulatory variants, of which at least six (35%) alter transcription factor-DNA binding in neuroblastoma cells. NRXN1 achieves genome-wide significance (p = 6.37 × 10-11) when we include 33,370 population-matched controls. Our findings suggest synaptic adhesion as a key component in compulsive behaviors, and show that targeted sequencing plus functional annotation can identify potentially causative variants, even when genomic data are limited.Obsessive-compulsive disorder (OCD) is a neuropsychiatric disorder with symptoms including intrusive thoughts and time-consuming repetitive behaviors. Here Noh and colleagues identify genes enriched for functional variants associated with increased risk of OCD.

Partnerships with Primary Care for the Treatment of Preschoolers.

This article reviews mental health access issues relevant to preschool children and data on this population obtained through the Michigan Child Collaborative Care Program (MC3). The MC3 program provides telephonic consultation to primary care physicians (PCPs) in 40 counties in Michigan and video telepsychiatric consultation to patients and families. Attention-deficit/hyperactivity disorder and disruptive behavioral disorders are frequent initial presenting diagnoses, but autism spectrum disorders, parent-child relational issues, trauma, and posttraumatic stress disorder should also be considered. Collaborative care programs provide promising ways to promote access to child psychiatric services when these services are distant to local PCP offices.

The regulation of corticosteroid receptors in response to chronic social defeat.

Our previous studies demonstrated that chronic social defeat (CSD) up-regulated expression of the serotonin transporter (SERT) and norepinephrine transporter (NET) in the brain, which was mediated by corticosteroid receptors. In the present study we first analyzed the alterations of corticosteroid receptors in different brain regions after the CSD paradigm. The results showed that CSD significantly reduced glucocorticoid receptor (GR) protein levels in the CA1 and dentate gyrus of the hippocampus, as well as in central and basolateral nuclei of the amygdala, which was accompanied by the translocation of GR from cytoplasm to nuclei. CSD also markedly reduced GR mRNA levels and MR immunoreactivity in the CA1, CA3 and dentate gyrus areas of the hippocampus. Conversely, CSD pronouncedly enhanced GR mRNA and protein levels in the dorsal raphe nucleus and locus coeruleus relative to the control. As an extension of our previous studies, in situ hybridization and immunohistochemical staining demonstrated that CSD regimen caused a notable increase of SERT mRNA levels in the dorsal raphe nucleus and increased SERT immunoreactivities in CA1 and CA3 of the hippocampus, as well as those in the basolateral nuclei of the amygdala. Likewise, CSD regimen resulted in an evident enhancement of NET immunoreactivity in the CA1 of the hippocampus and in the basolateral nuclei of the amygdala. Our current findings suggest that GR expressional alterations in response to CSD are complex and brain region-specific, which may correspond to their different functions in these regions.

Outcomes of a Character Strengths-Based Intervention on Self-Esteem and Self-Efficacy of Psychiatrically Hospitalized Youths.

OBJECTIVE: Mental health treatment approaches based on character strengths can be used to complement the traditional focus on functional impairment. The study tested use of a character strengths-based intervention to enhance the self-esteem and self-efficacy of psychiatrically hospitalized youths. METHODS: Eighty-one hospitalized adolescents were randomly assigned to intervention or comparison groups. The intervention used the Values in Action Inventory of Strengths for Youth to discover character strengths and incorporate them into coping skills. Self-efficacy and self-esteem were measured at baseline, postintervention, two weeks, and three months. RESULTS: Self-esteem and self-efficacy initially increased in both groups, but only the intervention group showed sustained improvement. The intervention was associated with increased self-efficacy at two weeks and increased self-efficacy and self-esteem at three months. CONCLUSIONS: A brief, easily administered character strengths-based intervention may be an adjunctive tool in the treatment of psychiatrically hospitalized youths.

In situ hybridization freeze-assisted punches (IFAP): technique for liquid-based tissue extraction from thin slide-mounted sections for DNA methylation analysis.

In situ hybridization-assisted punches (IFAP) are a low-cost method for extracting tissue from frozen slide-mounted sections as thin as 12 µm. The method synergizes well with standard histological workflows and uses in situ hybridization to target corresponding slide-mounted cryosections that contain the region of interest. Liquid beads of M-1 embedding matrix are applied and snap frozen, binding the matrix to the underlying tissue. Bead-tissue complexes are removed and DNA extracted using a high-salt method. IFAP-extracted DNA is suitable for downstream DNA methylation analysis.

Maternal separation alters serotonergic and HPA axis gene expression independent of separation duration in mice.

Adverse early life experiences (aELEs), such as child abuse, neglect, or trauma, increase lifetime vulnerability for mental illness. In this study, aELEs were modeled in c57bl/6 mice using the maternal separation (MS) paradigm, in which pups were separated for 180 min/day (MS180), 15 min/day (MS15), or left undisturbed (AFR) from postnatal day 2-14. As adults, pups that experienced MS15 or MS180 demonstrated decreases in tryptophan hydroxylase 2 and serotonin transporter mRNA in the dorsal raphe dorsalis and ventralis, and increases in glucocorticoid receptor mRNA in the dentate gyrus of the hippocampus. To investigate factors underlying shared expression between MS conditions, dam on-nest time and DNA methylation at the TPH2 promoter and 5' UTR were assessed. Post-reunion on-nest time increased as a function of separation duration, potentially serving as a mitigating factor underlying similar expression between MS conditions. TPH2 DNA methylation remained unchanged, suggesting changes in TPH2 mRNA are not mediated by changes in DNA methylation of this region. The shared pattern of expression between MS15 and MS180 conditions suggests a species- or strain- specific response to MS unique to c57bl/6 mice.

Maternal behavior and offspring resiliency to maternal separation in C57Bl/6 mice.

Adverse early life experience, such as childhood abuse, neglect, and trauma, increases lifetime risk for mental illness. To investigate underlying mechanisms, the maternal separation (MS) paradigm was developed and validated as an animal model of early adversity in rats, reliably effecting long-term changes to anxiety, gene expression, and stress response. However, across-species validation of core findings in mice has met with limited success. To re-visit parameters governing the effectiveness of MS in mice, this study investigated the effect of MS on maternal care, offspring behavior, and offspring stress-induced corticosterone response in the c57bl/6 mouse strain. The results from this study suggest that: (i) levels of maternal care increase as a function of separation duration immediately after daily MS, but long-term care remains unchanged; and (ii) c57bl/6 mice are resilient to MS, exhibiting subtle decreases in anxiety and unchanged stress-induced corticosterone response as adults, irrespective of separation duration.

ISH-guided freeze-matrix assisted punches: technique for extracting punches from thin slide-mounted tissues for DNA methylation analysis.

Dissection of discrete brain regions for molecular analysis is complicated by trade-offs between accuracy, flexibility, and costs. We developed a flexible and cost-effective method, in situ hybridization (ISH) guided freeze-matrix assisted punches (IFAP), for extracting nanogram quantities of DNA from slide-mounted sections as thin as 12 µm. Using ISH to localize regions of interest, tissue is targeted by applying a small bead of M-1 embedding matrix onto cryosections, snap-freezing, and collecting the beads for nucleic acid purification. The method quantitatively recovers RNA and DNA usable for PCR and DNA methylation analysis.

Regulation of corticoid and serotonin receptor brain system following early life exposure of glucocorticoids: long term implications for the neurobiology of mood.

Potent glucocorticoids (GC) administered early in life have improved premature infant survival dramatically. However, these agents may increase the risk for physical, neurological and behavior alterations. Anxiety, depression and attention difficulties are commonly described in adolescent and young adult survivors of prematurity. In the present study we administered vehicle, dexamethasone, or hydrocortisone to Sprague-Dawley rat pups on postnatal days 5 and 6, mimicking a short term clinical protocol commonly used in human infants. Two systems that are implicated in the regulation of stress and behavior were assessed: the limbic-hypothalamic-pituitary-adrenal axis [LHPA; glucocorticoid and mineralocorticoid receptors within] and the Serotonin (5-HT) system. We found that as adults, male Sprague-Dawley pups treated with GC showed agent specific altered growth, anxiety-related behavior, changes in corticoid response to novelty and gene expression changes within LHPA and 5-HT-related circuitry. The data suggest that prolonged GC-receptor stimulation during the early neonatal period can contribute to the development of individual differences in stress response and anxiety-related behavior later in life.

Stress coping stimulates hippocampal neurogenesis in adult monkeys.

Coping with intermittent social stress is an essential aspect of living in complex social environments. Coping tends to counteract the deleterious effects of stress and is thought to induce neuroadaptations in corticolimbic brain systems. Here we test this hypothesis in adult squirrel monkey males exposed to intermittent social separations and new pair formations. These manipulations simulate conditions that typically occur in male social associations because of competition for limited access to residency in mixed-sex groups. As evidence of coping, we previously confirmed that cortisol levels initially increase and then are restored to prestress levels within several days of each separation and new pair formation. Follow-up studies with exogenous cortisol further established that feedback regulation of the hypothalamic-pituitary-adrenal axis is not impaired. Now we report that exposure to intermittent social separations and new pair formations increased hippocampal neurogenesis in squirrel monkey males. Hippocampal neurogenesis in rodents contributes to spatial learning performance, and in monkeys we found that spatial learning was enhanced in conditions that increased hippocampal neurogenesis. Corresponding changes were discerned in the expression of genes involved in survival and integration of adult-born granule cells into hippocampal neural circuits. These findings support recent indications that stress coping stimulates hippocampal neurogenesis in adult rodents. Psychotherapies designed to promote stress coping potentially have similar effects in humans with major depression.

Stress-induced changes in corticosteroid receptor expression in primate hippocampus and prefrontal cortex.

Neurobiological studies of stress often focus on the hippocampus where cortisol binds with different affinities to two types of corticosteroid receptors, i.e., mineralocorticoid receptor (MR) and glucocorticoid receptor (GR). The hippocampus is involved in learning and memory, and regulates the neuroendocrine stress response, but other brain regions also play a role, especially prefrontal cortex. Here, we examine MR and GR expression in adult squirrel monkey prefrontal cortex and hippocampus after exposure to social stress in infancy or adulthood. In situ hybridization histochemistry with (35)S-labeled squirrel monkey riboprobes and quantitative film autoradiography were used to measure the relative distributions of MR and GR mRNA. Distinct cortical cell layer-specific patterns of MR expression differed from GR expression in three prefrontal regions. The relative distributions of MR and GR also differed in hippocampal Cornu Ammonis (CA) regions. In monkeys exposed to adult social stress compared to the no-stress control, GR expression was diminished in hippocampal CA1 (P=0.021), whereas MR was diminished in cell layer III of ventrolateral prefrontal cortex (P=0.049). In contrast, exposure to early life stress diminished GR but not MR expression in cell layers I and II of dorsolateral prefrontal cortex (P's<0.048). Similar reductions likewise occurred in ventrolateral prefrontal cortex, but the effects of early life stress on GR expression in this region were marginally not significant (P=0.053). These results provide new information on regional differences and the long-term effects of stress on MR and GR distributions in corticolimbic regions that control cognitive and neuroendocrine functions.

Regulation of tryptophan hydroxylase-2 gene expression by a bipartite RE-1 silencer of transcription/neuron restrictive silencing factor (REST/NRSF) binding motif.

Tryptophan hydroxylase-2 (TPH2) is the rate-limiting enzyme in raphe serotonin biosynthesis, and polymorphisms of TPH2 are implicated in vulnerability to psychiatric disorders. Dynamic transcription regulation of TPH2 may underlie differences in vulnerability. We identified a transcription element in the TPH2 promoter that resembles the binding motif for RE-1 silencer of transcription (REST; also known as NRSF) transcription factor. REST limits tissue expression of non-neuronal genes through a canonical 21-bp motif called the NRSE (neuron-restrictive silencing element). The NRSE in TPH2 is a novel bipartite variant interrupted by a 6-base insertion. We confirmed that this bipartite NRSE permits transcriptional repression by REST identical to canonical NRSE in rat C6-glioma cells. Synthetic permutations of the motif revealed considerable flexibility in the juxtaposition of the two halves of bipartite NRSE. Computational analysis revealed many bipartite NRSE variants conserved between mouse and human genomes. A subgroup of these was found to bind REST by chromatin immunoprecipitation. Messenger RNAs for TPH2 and potassium channel H6, another gene with a bipartite NRSE, were up-regulated by dominant-negative REST in C6-glioma cells. These findings, which indicate that TPH2 expression is part of the developmental program regulated by REST and suggest that many previously unrecognized genes may be regulated by REST through the novel motif, have implications for the mechanism of REST action.