Precision psychiatry and Research Domain Criteria: Implications for clinical trials and future practice.

Psychiatric disorders are associated with significant social and economic burdens, many of which are related to issues with current diagnosis and treatments. The coronavirus (COVID-19) pandemic is estimated to have increased the prevalence and burden of major depressive and anxiety disorders, indicating an urgent need to strengthen mental health systems globally. To date, current approaches adopted in drug discovery and development for psychiatric disorders have been relatively unsuccessful. Precision psychiatry aims to tailor healthcare more closely to the needs of individual patients and, when informed by neuroscience, can offer the opportunity to improve the accuracy of disease classification, treatment decisions, and prevention efforts. In this review, we highlight the growing global interest in precision psychiatry and the potential for the National Institute of Health-devised Research Domain Criteria (RDoC) to facilitate the implementation of transdiagnostic and improved treatment approaches. The need for current psychiatric nosology to evolve with recent scientific advancements and increase awareness in emerging investigators/clinicians of the value of this approach is essential. Finally, we examine current challenges and future opportunities of adopting the RDoC-associated translational and transdiagnostic approaches in clinical studies, acknowledging that the strength of RDoC is that they form a dynamic framework of guiding principles that is intended to evolve continuously with scientific developments into the future. A collaborative approach that recruits expertise from multiple disciplines, while also considering the patient perspective, is needed to pave the way for precision psychiatry that can improve the prognosis and quality of life of psychiatric patients.

Revisiting the seven pillars of RDoC.

BACKGROUND: In 2013, a few years after the launch of the National Institute of Mental Health's Research Domain Criteria (RDoC) initiative, Cuthbert and Insel published a paper titled "Toward the future of psychiatric diagnosis: the seven pillars of RDoC." The RDoC project is a translational research effort to encourage new ways of studying psychopathology through a focus on disruptions in normal functions (such as reward learning or attention) that are defined jointly by observable behavior and neurobiological measures. The paper outlined the principles of the RDoC research framework, including emphases on research that acquires data from multiple measurement classes to foster integrative analyses, adopts dimensional approaches, and employs novel methods for ascertaining participants and identifying valid subgroups. DISCUSSION: To mark the first decade of the RDoC initiative, we revisit the seven pillars and highlight new research findings and updates to the framework that are related to each. This reappraisal emphasizes the flexible nature of the RDoC framework and its application in diverse areas of research, new findings related to the importance of developmental trajectories within and across neurobehavioral domains, and the value of computational approaches for clarifying complex multivariate relations among behavioral and neurobiological systems. CONCLUSION: The seven pillars of RDoC have provided a foundation that has helped to guide a surge of new studies that have examined neurobehavioral domains related to mental disorders, in the service of informing future psychiatric nosology. Building on this footing, future areas of emphasis for the RDoC project will include studying central-peripheral interactions, developing novel approaches to phenotyping for genomic studies, and identifying new targets for clinical trial research to facilitate progress in precision psychiatry.

The role of constraint in the development of nicotine, marijuana, and alcohol dependence in young adulthood.

The personality-related construct of behavioral disinhibition is hypothesized to confer a generalized risk for alcohol and drug dependence. On average, rates of substance use and scores on measures of disinhibition peak in adolescence and decline as people mature into adulthood. The present study investigated this developmental change by evaluating the relationship between disinhibition and substance use disorders using a longitudinal study of 2,608 twins assessed at ages 17, 24, and 29. These ages include the period of highest risk for substance use disorders (ages 17-24) as well as when substance dependence symptoms typically decline (ages 24-29). Disinhibition was measured with the Multidimensional Personality Questionnaire higher-order scale of Constraint, as well as its constituent facet scales of Harm Avoidance, Control, and Traditionalism. Constraint's relationship with substance dependence was statistically significant but small and largely genetic, with the genetic relationship declining from adolescence into adulthood. However, this result appeared to be almost entirely driven by Traditionalism, a propensity to hold traditional moral and social values, and not an obvious component of behavioral disinhibition. The results suggest that personality measures of Control and Harm Avoidance play only a small role in the development of substance dependence during late adolescence, and previous findings linking personality measures of disinhibition and substance use may be driven significantly by social and moral values than deficits in impulse control.

Premorbid risk factors for major depressive disorder: are they associated with early onset and recurrent course?

Premorbid risk for major depressive disorder (MDD) and predictors of an earlier onset and recurrent course were examined in two studies in a large, community-based sample of parents and offspring, prospectively assessed from late childhood into adulthood. In Study 1 (N = 2,764 offspring and their parents), parental psychiatric status, offspring personality at age 11, and age 11 offspring internalizing and externalizing symptoms predicted the subsequent development of MDD, as did poor quality parent-child relationships, poor academic functioning, early pubertal development, and childhood maltreatment by age 11. Parental MDD and adult antisocial behavior, offspring negative emotionality and disconstraint, externalizing symptoms, and childhood maltreatment predicted an earlier onset of MDD, after accounting for course; lower positive emotionality, trait anxiety, and childhood maltreatment predicted recurrent MDD, after accounting for age of onset. In Study 2 (N = 7,146), we examined molecular genetic risk for MDD by extending recent reports of associations with glutamatergic system genes. We failed to confirm associations with MDD using either individual single nucleotide polymorphism based tests or gene-based analyses. Overall, results speak to the pervasiveness of risk for MDD, as well as specific risk for early onset MDD; risk for recurrent MDD appears to be largely a function of its often earlier onset.

The structure of common mental disorders in incarcerated offenders.

BACKGROUND: Dimensional models of mental disorders in community-based epidemiological samples have consistently demonstrated correlated externalizing and internalizing factors underlying common mood, anxiety, and substance use disorders. However, such analyses tend to exclude populations such as prisoners and psychiatric inpatients. As these samples have been shown to have a much higher prevalence of mental disorders and comorbidity than community samples, whether the internalizing-externalizing structure of psychopathology will replicate in such samples is unknown. OBJECTIVES: The current study examined the consistency of this structure in a representative sample of 1837 prisoners through structural equation modeling of 10 common mental disorders along with a record-based index of antisocial behavior. METHOD: Diagnoses were determined by administration of the Composite International Diagnostic Interview 2.1. Data were analyzed via tetrachoric correlations using the weighted least squares estimator in exploratory and confirmatory factor analyses. RESULTS: Results revealed that a two-factor solution, entailing correlated internalizing and externalizing factors, displayed the best fit to the data. CONCLUSIONS: This study provides additional support for characterizing common psychopathology in terms of internalizing and externalizing factors.

Studying fine-grained elements of psychopathology to advance mental health science.

Given the now well-recognized limitations of traditional classification systems for research, this editorial proposes to advance mental health science by focusing research efforts on studying fine-grained elements of mental health and illness such as symptoms, mechanisms, and processes. Our own perspectives are informed by three approaches in particular that have gained traction over the last decade: the Hierarchical Taxonomy of Psychopathology, the network or systems approach, and the National Institute of Mental Health Research Domain Criteria. Drawing on these and other perspectives as well as the diverse views of the author teams that contributed to this Special Section, we summarize the state of the field and propose an ambitious plan for the way ahead. Specifically, we propose that embracing pluralistic, multimethod, and multisystem approaches offers a way forward. This will require strategies to reduce research waste and much stronger channels for communication to identify confluence, discoveries, and dead ends within and between disciplines. We are optimistic this will lead to a better understanding of the mechanisms underpinning psychopathology and ultimately to more effective interventions. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Innovative Technologies in CNS Trials: Promises and Pitfalls for Recruitment, Retention, and Representativeness.

Objective: Recruitment of a sufficiently large and representative patient sample and its retention during central nervous system (CNS) trials presents major challenges for study sponsors. Technological advances are reshaping clinical trial operations to meet these challenges, and the COVID-19 pandemic further accelerated this development. Method of Research: The International Society for CNS Clinical Trials and Methodology (ISCTM; www.isctm.org) Innovative Technologies for CNS Trials Working Group surveyed the state of technological innovations for improved recruitment and retention and assessed their promises and pitfalls. Results: Online advertisement and electronic patient registries can enhance recruitment, but challenges with sample representativeness, conversion rates from eligible prescreening to enrolled patients, data privacy and security, and patient identification remain hurdles for optimal use of these technologies. Electronic medical records (EMR) mining with artificial intelligence (AI)/machine learning (ML) methods is promising but awaits translation into trials. During the study treatment phase, technological innovations increasingly support participant retention, including adherence with the investigational treatment. Digital tools for adherence and retention support take many forms, including patient-centric communication channels between researchers and participants, real-time study reminders, and digital behavioral interventions to increase study compliance. However, such tools add technical complexities to trials, and their impact on the generalizability of results are largely unknown. Conclusion: Overall, the group found a scarcity of systematic data directly assessing the impact of technological innovations on study recruitment and retention in CNS trials, even for strategies with already high adoption, such as online recruitment. Given the added complexity and costs associated with most technological innovations, such data is needed to fully harness technologies for CNS trials and drive further adoption.

Examining the overlap between bipolar disorder, nonaffective psychosis, and common mental disorders using latent class analysis.

BACKGROUND: While dimensional models of psychopathology have delineated two broad factors underlying common mental disorders--internalizing and externalizing--it is unclear where bipolar disorder and nonaffective psychoses fit in relation to this structure and to each other. Given their low prevalence rates in the general population, these disorders generally tend to be excluded from such models. The current study used the person-centered approach of latent class analysis (LCA) to evaluate this question. SAMPLING AND METHODS: LCA of diagnostic data from an epidemiological sample, the National Comorbidity Survey (n = 5,877), was undertaken. Diagnoses utilized in analyses included mania, nonaffective psychoses, specific phobia, social phobia, agoraphobia, panic disorder, major depression, dysthymia, generalized anxiety disorder, post-traumatic stress disorder, alcohol dependence, drug dependence, and conduct disorder. RESULTS: Results indicated that a 5-class LCA model optimally fit the data. Four of the classes mirrored those found in dimensional models--a class with few disorders, and 3 others with primarily fear, distress, and externalizing disorders. However, the fifth class--which is not evident in dimensional models--was unique in that it was the only one in which individuals demonstrated significant probabilities of both manic episodes and nonaffective psychoses in addition to markedly high levels of internalizing and externalizing disorders. CONCLUSION: This finding has important implications for nosological classification of psychopathology.

An evaluation of Internet searches as a marker of trends in population mental health in the US.

The absence of continuous, real-time mental health assessment has made it challenging to quantify the impacts of the COVID-19 pandemic on population mental health. We examined publicly available, anonymized, aggregated data on weekly trends in Google searches related to anxiety, depression, and suicidal ideation from 2018 to 2020 in the US. We correlated these trends with (1) emergency department (ED) visits for mental health problems and suicide attempts, and (2) surveys of self-reported symptoms of anxiety, depression, and mental health care use. Search queries related to anxiety, depression, and suicidal ideation decreased sharply around March 2020, returning to pre-pandemic levels by summer 2020. Searches related to depression were correlated with the proportion of individuals reporting receiving therapy (r = 0.73), taking medication (r = 0.62) and having unmet mental healthcare needs (r = 0.57) on US Census Household Pulse Survey and modestly correlated with rates of ED visits for mental health conditions. Results were similar when considering instead searches for anxiety. Searches for suicidal ideation did not correlate with external variables. These results suggest aggregated data on Internet searches can provide timely and continuous insights into population mental health and complement other existing tools in this domain.

Patterns of comorbidity among mental disorders: a person-centered approach.

OBJECTIVE: Comorbidity poses a major challenge to conventional methods of diagnostic classification. Although dimensional models of psychopathology have shed some light on this issue, the reason for interrelationships among dimensions is unclear. The current study employed an alternative approach to characterizing patterns of comorbidity among common mental disorders by modeling them instead as clusters by using latent class analysis (LCA). METHOD: Latent class analyses of Diagnostic and Statistical Manual of Mental Disorders diagnoses from two nationally representative epidemiological samples--the National Comorbidity Survey and National Comorbidity Survey--Replication datasets--were undertaken. RESULTS: Within each dataset, LCA yielded 5 latent classes exhibiting distinctive profiles of diagnostic comorbidity: a fear class (all phobias and panic disorder), a distress class (depression, generalized anxiety disorder, dysthymia), an externalizing class (alcohol and drug dependence, conduct disorder), a multimorbid class (highly elevated rates of all disorders), and a few-disorders class (very low probability of all disorders). Whereas some disorders were relatively specific to certain classes, others (major depression, posttraumatic stress disorder, social phobia) appeared to be evident across all classes. Profiles for the five classes were highly similar across the two samples. When bipolar I disorder was added to the LCA models, in both samples, it occurred almost exclusively in the multimorbid class. CONCLUSIONS: Comorbidity among mental disorders in the general population appears to occur in a finite number of distinct patterns. This finding has important implications for efforts to refine existing diagnostic classification schemes, as well as for research directed at elucidating the etiology of mental disorders.

Pressure-Induced Interlamellar Stromal Keratitis After Small-Incision Lenticule Extraction Procedure: A Case Report.

PURPOSE: To report a case of pressure-induced interlamellar stromal keratitis (PISK) after small-incision lenticule extraction (SMILE) for the correction of myopic astigmatism in the United States. METHODS: We report the case of a 27-year-old man who underwent uneventful SMILE surgery and presented with pressure-induced stromal keratitis. Anterior and posterior segment examination, uncorrected distance visual acuity, refraction, intraocular pressure, and pachymetry values are reported from this time period. RESULTS: Three weeks postoperatively, examination revealed new-onset central corneal haze and edema in both eyes, more significant in the right eye. The patient was given a presumptive diagnosis of diffuse lamellar keratitis. Intensive corticosteroid treatment was administered, causing a significant decline in uncorrected distance visual acuity OD from 20/25 to 20/250 and OS from 20/20 to 20/60, with a significant myopic shift of -3.0 D and -1.0 D, respectively. In our case, pachymetry measurements revealed 78 µm OD and 43 µm OS of additional corneal thickness. Pressure readings were 25 mm Hg OD and 19 mm Hg OS, respectively. He was diagnosed with PISK, and after 4 days of steroid discontinuation and Brimonidine-Timolol administration, his symptoms had improved with resolution of corneal edema. CONCLUSIONS: Clinicians should be aware that PISK is a potential complication of SMILE. Postoperative intraocular pressure measurements are an important aspect of the management of postcorneal refractive surgery patients because the differentiation of PISK from diffuse lamellar keratitis, as well as the early detection and treatment of PISK, can avoid severe complications.

Myopic regression and recurrent Salzmann nodule degeneration after laser in situ keratomileusis in Ehlers Danlos Syndrome.

PURPOSE: We describe the first case of Ehlers Danlos Syndrome (EDS) reported in the English language ophthalmic literature to have undergone Laser In Situ Keratomileusis (LASIK) surgery. OBSERVATIONS: We review our patient's specific postoperative complications of myopic regression, Salzmann nodular degeneration, and dry eye syndrome, as well as the risks and consequences of performing LASIK on patients with this collagen disorder. CONCLUSIONS AND IMPORTANCE: Refractive errors may prompt EDS patients to seek laser vision correction, placing them at increased risk for complications such as myopic regression, keratectasia, and dry eye syndrome. Aberrant wound healing and collagen dysfunction may have influenced our patient's myopic regression and Salzmann nodule degeneration post-LASIK. Currently, EDS is considered a relative contraindication in LASIK due to a presumed higher risk of postoperative keratectasia; however, we believe it is possible that not all forms of EDS need to be an absolute contraindication to LASIK. More research is warranted to determine preoperative risk stratification for laser vision surgery in each subtype of EDS.

Human allograft refractive lenticular implantation for high hyperopiccorrection.

Hyperopia is a common form of refractive error in the United States. Many refractive errors can be treated with refractive surgery methods such as laser in-situ keratomileusis and photorefractive keratectomy; however, in patients with large degrees of hyperopia (≥+5.0 diopters [D]), these surgical methods are limited because of higher rates of refractive regression. Lenticule Intrastromal Keratoplasty (LIKE) is a surgical procedure that can be used to correct refractive errors in patients with high hyperopia. The authors describe the first intrastromal implantation of an allograft lenticule performed for the primary correction of hyperopia in the United States, and demonstrate that LIKE is potentially an effective procedure for the correction of high hyperopia. Mechanisms for achieving the intended refractive correction and the complications our patient experienced, including epithelial ingrowth and flap necrosis, are discussed.

Delayed-Onset Transient Light Sensitivity Syndrome after Corneal Collagen Cross-Linking: A Case Series.

In this case series, we report a potentially novel association of corneal collagen crosslinking (CCL) with the development of photophobia symptoms in a series of patients at a tertiary ophthalmology clinic and describe their clinical course. Photosensitivity is a rare and seemingly unpredictable complication of refractive surgery but can present as a disabling, bilateral ocular pain that requires immediate treatment. This complication, termed transient light-sensitivity syndrome (TLSS), can have a substantially delayed presentation after ocular procedures and is associated with inflammation of structures in the anterior chamber that can be imperceptible on slit-lamp examination. Traditionally, exposure to high-energy femtosecond lasers is hypothesized to create stromal gas bubbles powering postoperative inflammatory reactions. TLSS-like symptoms after CCL may be due to a secondary inflammatory response involving activated keratocytes and cytokine release. However, free radical damage from the interaction of riboflavin and ultraviolet in CCL may also drive this inflammatory process.

Comparison of FDA-Reported Visual and Refractive Outcomes of the Toric ICL Lens, SMILE, and Topography-Guided LASIK for the Correction of Myopia and Myopic Astigmatism.

PURPOSE: To compare U.S. Food and Drug Administration (FDA)-reported visual and refractive outcomes following surgical correction of myopia and myopic astigmatism using the Visian Toric Implantable Collamer Lens (STAAR Surgical, Monrovia, CA) (Toric ICL), small incision lenticule extraction (SMILE), and topography-guided laser in situ keratomileusis (TG-LASIK). METHODS: FDA summary of safety and effectiveness data (SSED) were analyzed for each of the three platforms. Primary outcomes measured were efficacy, safety, stability, and accuracy of refractive correction. Stratified mean refractive spherical equivalent (MRSE) data were assessed. RESULTS: One hundred twenty-four Toric ICL patients (210 eyes), 357 SMILE patients (357 eyes), and 212 TG-LASIK patients (249 eyes) were included. SMILE eyes had a significant improvement in postoperative uncorrected distance visual acuity with respect to preoperative corrected distance visual acuity from 3 to 12 months (P < .001), whereas TG-LASIK had no further improvement from 3 to 12 months (P = .79). For preoperative MRSE greater than 10.00 diopters (D), there was a significant difference in the percentage of eyes achieving postoperative MSRE within ±0.50 D between Toric ICL (66%) and SMILE (100%) (P < .001). SMILE was consistently more accurate than Toric ICL for cylinder within ±0.25 D (P < .001), ±0.50 D (P < .001), and ±1.00 D (P = .0014). CONCLUSIONS: All three platforms analyzed in this study had excellent efficacy, safety, stability, and accuracy. Stratified analysis revealed that SMILE may be comparable to Toric ICL for patients with high myopia or myopic astigmatism, and SMILE may have a longer visual recovery compared to TG-LASIK than previously indicated. [J Refract Surg. 2019;35(11):699-706.].

Biological Staining and Culturing in Infectious Keratitis: Controversy in Clinical Utility.

Infectious keratitis causes significant, financial burden and is only increasing in frequency with contact lens use. Despite this, no retrospective studies, prospective studies, or clinical trials have evaluated the diagnostic validity of clinical guidelines in cases of infectious keratitis. Currently, standard of care recommends that corneal samples be obtained for staining and culturing in select patients showing evidence of corneal ulceration. Ideally, diagnostic information from corneal sampling is thought to help guide therapeutic interventions, prevent disease progression, reduce antibiotic resistance, and decrease overall expenditures for the management and treatment of infectious keratitis. However, current staining and culturing methods are limited by poor sensitivity in non-bacterial cases (i.e. fungal, viral) and lengthy turnaround times, and these methods do not frequently change clinical decision making. Newer fluoroquinolones and broad-spectrum antibiotics resolve the vast majority of cases of infectious keratitis, rendering cultures less essential for management. We studied the clinical utility of obtaining corneal samples for culturing and staining and the need for future research to establish superior diagnostic guidelines for their use in infectious keratitis.

Polymerase Chain Reaction and Its Application in the Diagnosis of Infectious Keratitis.

PCR involves a repeating cycle of replication to amplify small segments of deoxyribonucleic acid (DNA). A novel application of this technique is microbial identification in infectious keratitis, one of the leading causes of blindness in the world. PCR is more sensitive than biological stains and culture, which are considered the current gold standards for diagnosing infectious keratitis. The diagnosis and treatment of infectious keratitis cost the United States millions of dollars in health expenditure. PCR may help offset that cost by allowing for individualized disease management and screening for multiple antibiotic-resistant genes. While beneficial, PCR demonstrates lower specificity rates compared to culture and stain, indicating its shortcomings; this can be overcome by performing PCR after narrowing the pool of potential microorganisms. This article examines the clinical utility of PCR in cases of infectious keratitis by evaluating its reliability, validity, associated costs, and indications.

Persistent Corneal Epithelial Defects: A Review Article.

Persistent corneal epithelial defects (PEDs or PCEDs) result from the failure of rapid re-epithelialization and closure within 10-14 days after a corneal injury, even with standard supportive treatment. Disruptions in the protective epithelial and stromal layers of the cornea can render the eye susceptible to infection, stromal ulceration, perforation, scarring, and significant vision loss. Although several therapies exist and an increasing number of novel approaches are emerging, treatment of PEDs can still be quite challenging. It is important to treat the underlying causative condition, which may include an infection, limbal stem cell deficiency, or diabetes, in order to facilitate wound healing. Standard treatments, such as bandage contact lenses (BCLs) and artificial tears (ATs), aim to provide barrier protection to the epithelial layer. Recently-developed medical treatments can target the re-epithelialization process by facilitating access to growth factors and anti-inflammatory agents, and novel surgical techniques can provide re-innervation to the cornea. PEDs should be treated within 7-10 days to avoid secondary complications. These interventions, along with a step-wise approach to management, can be useful in patients with PEDs that are refractory to standard medical treatment. In this review, we discuss the epidemiology, etiology, diagnosis, current and novel management, and prognosis of persistent epithelial defects.

Formulation of a measurement model for the boldness construct of psychopathy.

We describe efforts to formulate a quantitative measurement model for boldness, a construct that has been intensively discussed and investigated in the psychopathy literature in recent years. Although the Fearless Dominance factor of the Psychopathic Personality Inventory (PPI-FD) has served as a major referent for studying this dispositional construct, boldness was not explicitly targeted in developing the PPI, creating the need for a formal measurement model for this construct. Using an exploratory approach to test construction and multiple waves of data collection and analysis involving 1,791 participants, we created nine unidimensional scales (comprising a total of 130 items) for assessing correlated but thematically distinct facets of boldness, and characterized their higher-order structure. Overall scores on this new Boldness Inventory correlated highly with PPI-FD (positively) and dispositional fear (negatively), and negligibly with disinhibitory proclivities, in validation samples consisting of undergraduates (N = 767) and male prisoners (N = 326). The structural model of this new inventory, encompassing a general factor on which all facet scales loaded and two subordinate factors defined by residual variances of certain scales, effectively accommodated the constituent scales of PPI-FD. The model development work reported here establishes a valuable foundation for further, more fine-grained investigation of boldness as it relates to psychopathy and other clinical conditions as well as to adaptive functioning and performance. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Diagnosis and Management of Pseudoguttata: A Literature Review.

Corneal pseudoguttata (PG), also known as pseudoguttae or secondary guttata, is a transient, reversible endothelial edema commonly associated with anterior segment pathology. While considered rare, PG presents on slit-lamp examination more commonly than originally thought. We have clinically observed PG after refractive surgeries, in association with infectious keratitis, and following medication use. PG presents as dark lesions on slit-lamp exam with specular illumination, similar to primary corneal guttata. PG is distinct from guttata because PG resolves over time and does not involve Descemet's membrane. Other ocular findings that may be confused with guttata include endothelial blebs (EB) and endothelial denudation (ED). EB are possibly a type of PG that present after contact lens use or hypoxia. ED is a distinct entity that is characterized by loss of endothelial cells without involvement of Descemet's membrane. Confocal microscopy may be useful in differentiating these four endothelial lesions, with differences in border definition and the presence of hyperreflective areas two main distinctions. PG presents as a hyporeflective, elevated shape without clear borders on confocal microscopy. PG, EB, and ED can resolve with time without the need for surgical intervention, unlike corneal guttata. Treatment of the underlying condition will lead to resolution of both PG and EB.