Pharmacogenomic Clinical Support Tools for the Treatment of Depression.

OBJECTIVE: In this review, the authors update the 2018 position statement of the American Psychiatric Association Council of Research Workgroup on Biomarkers and Novel Treatments on pharmacogenomic (PGx) tools for treatment selection in depression. METHODS: The literature was reviewed for new clinical trials and meta-analyses, published from 2017 to 2022, of studies using PGx tools for treatment selection in depression. The blinding and control conditions, as well as primary and secondary outcomes and post hoc analyses, were summarized. RESULTS: Eleven new clinical trials and five meta-analyses were identified; all studies had primary outcome measures related to speed or efficacy of treatment response. Three trials (27%) demonstrated efficacy on the primary outcome measure with statistical significance; the three studies used different PGx tools; one study was open-label and the other two were small single-blind trials. Five trials (45%) did not detect efficacy with statistical significance on either primary or secondary outcome measures. Only one trial (9%) used adverse events as a primary outcome measure. All studies had significant limitations; for example, none adopted a fully blinded study design, only two studies attempted to blind the treating clinician, and none incorporated measures to estimate the effectiveness of the blinds or the influence of lack of blinding on the study results. CONCLUSIONS: The addition of these new data do not alter the recommendations of the 2018 report, or the advice of the U.S. Food and Drug Administration, that the evidence does not support the use of currently available combinatorial PGx tools for treatment selection in major depressive disorder. Priority efforts for future studies and the development and testing of effective tools include fully blinded study designs, inclusion of promising genetic variants not currently included in any commercially available tests, and investigation of other uses of pharmacogenomics, such as estimating the likelihood of rare adverse drug effects, rather than increasing the speed or magnitude of drug response.

Cerebellar transcranial magnetic stimulation in psychotic disorders: intermittent, continuous, and sham theta-burst stimulation on time perception and symptom severity.

Background: The cerebellum contributes to the precise timing of non-motor and motor functions, and cerebellum abnormalities have been implicated in psychosis pathophysiology. In this study, we explored the effects of cerebellar theta burst stimulation (TBS), an efficient transcranial magnetic stimulation protocol, on temporal discrimination and self-reported mood and psychotic symptoms. Methods: We conducted a case-crossover study in which patients with psychosis (schizophrenias, schizoaffective disorders, or bipolar disorders with psychotic features) were assigned to three sessions of TBS to the cerebellar vermis: one session each of intermittent (iTBS), continuous (cTBS), and sham TBS. Of 28 enrolled patients, 26 underwent at least one TBS session, and 20 completed all three. Before and immediately following TBS, participants rated their mood and psychotic symptoms and performed a time interval discrimination task (IDT). We hypothesized that cerebellar iTBS and cTBS would modulate these measures in opposing directions, with iTBS being adaptive and cTBS maladaptive. Results: Reaction time (RT) in the IDT decreased significantly after iTBS vs. Sham (LS-mean difference = -73.3, p = 0.0001, Cohen's d = 1.62), after iTBS vs. cTBS (LS-mean difference = -137.6, p < 0.0001, d = 2.03), and after Sham vs. cTBS (LS-mean difference = -64.4, p < 0.0001, d = 1.33). We found no effect on IDT accuracy. We did not observe any effects on symptom severity after correcting for multiple comparisons. Conclusion: We observed a frequency-dependent dissociation between the effects of iTBS vs. cTBS to the cerebellar midline on the reaction time of interval discrimination in patients with psychosis. iTBS showed improved (adaptive) while cTBS led to worsening (maladaptive) speed of response. These results demonstrate behavioral target engagement in a cognitive dimension of relevance to patients with psychosis and generate testable hypotheses about the potential therapeutic role of cerebellar iTBS in this clinical population. Clinical Trial Registration: clinicaltrials.gov, identifier NCT02642029.

Should Medical Insurance Review Serve the Patient's Best Interests? Examples and Considerations Illustrated by Behavioral Health Cases.

ABSTRACT: Physician medical directors working for health care insurance companies conduct utilization reviews, participate in quality-of-care reviews, and adjudicate appeals. As a result, they have access to substantial and important clinical information. The medical director may have both current and historical information that can assist the treatment team in providing care. Sharing this information with a patient's current health care provider(s) is problematic due to concerns about patient privacy and the insurer's goal of not assuming legal liability for patient care. While this paper considers legal issues, it predominantly addresses the ethical responsibilities of medical directors who have valuable information unavailable to or unrecognized by the treatment team. Although it is important to consider sharing general medical information, this paper emphasizes the sharing of behavioral health information, which can be highly sensitive but also pertinent to psychiatric and other medical treatment choices. We suggest that clinical information should flow from insurer to provider when the insurer has information that will benefit the patient or prove crucial to optimal care rather than just flow from provider to insurer for the purposes of claims payments. To support and secure that flow, the paper outlines procedures for determining the need to share information, the means of providing that information, ways to separate liability, and processes for protecting privacy.

Disease-specific differences in gene expression, mitochondrial function and mitochondria-endoplasmic reticulum interactions in iPSC-derived cerebral organoids and cortical neurons in schizophrenia and bipolar disorder.

We compared transcriptomic profiles of cerebral organoids differentiated from induced pluripotent stem cells of eight schizophrenia and eight bipolar disorder patients to identify genes that were differentially expressed in cerebral organoids between two disorders. Gene ontology analysis showed relative up-regulation in schizophrenia organoids of genes related to response to cytokines, antigen binding and clathrin-coated vesicles, while showing up-regulation in bipolar disorder of genes involved in calcium binding. Gene set enrichment analysis revealed enrichment in schizophrenia of genes involved in mitochondrial and oxidative phosphorylation while showing enrichment in bipolar disorder of genes involved in long term potentiation and neuro-transporters. We compared mitochondrial function in cerebral organoids from schizophrenia and bipolar disorder subjects and found that while schizophrenia organoids showed deficits in basal oxygen consumption rate and ATP production when compared to healthy control organoids, while bipolar disorder organoids did not show these deficits. Gene ontology analyses also revealed enrichment in bipolar disorder of genes in ion binding and regulation of transport. Experiments examining the interaction between mitochondria and endoplasmic reticulum in cortical neurons from bipolar disorder subjects showed a significantly lower number of contact sites between mitochondria and endoplasmic reticulum when compared to cortical neurons from schizophrenia patients. These results point to disease-specific deficits in mitochondrial respiration in schizophrenia and in mitochondrial-endoplasmic reticulum interactions in bipolar disorder. Supplementary Information: The online version contains supplementary material available at 10.1007/s44192-023-00031-8.

Survey of quality and clarity of methods and results reporting in 1 year of intervention studies published in high-impact medical and psychiatric journals.

OBJECTIVE: We assessed how well articles in major medical and psychiatric journals followed best reporting practices in presenting results of intervention studies. METHOD: Standardised data collection was used to review studies in high-impact and widely read medical (JAMA, Lancet and New England Journal of Medicine) and psychiatric (American Journal of Psychiatry, JAMA Psychiatry, Journal of Clinical Psychiatry and Lancet Psychiatry) journals, published between 1 September 2018 and 31 August 2019. Two team members independently reviewed each article. MEASURES: The primary outcome measure was proportion of papers reporting consensus elements required to understand and evaluate the results of the intervention. The secondary outcome measure was comparison of complete and accessible reporting in the major medical versus the major psychiatric journals. RESULTS: One hundred twenty-seven articles were identified for inclusion. At least 90% of articles in both medical and psychiatric journals included sample size, statistical significance, randomisation method, elements of study flow, and age, sex, and illness severity by randomisation group. Selected elements less frequently reported by either journal type were confidence intervals in the abstract, reported in 93% (95% CI 84% to 97%) of medical journal articles and 58% (95% CI 45% to 69%) of psychiatric journal articles, and sample size method (93%, 95% CI 84% to 97% medical; 69%, 95% CI 57% to 80% psychiatric), race and ethnicity by randomisation group (51%, 95% CI 40% to 63% medical; 73%, 95% CI 60% to 83% psychiatric), and adverse events (94%; 95% CI 86% to 98% medical; 80%, 95% CI 68% to 88% psychiatric) in the main text. CIs were included less often in psychiatric than medical journals (p<0.004 abstract, p=0.04 main text, after multiple-testing correction). CONCLUSIONS: Recommendations include standard inclusion of a table specifying the outcome(s) designated as primary, and the sample size, effect size(s), CI(s) and p value(s) corresponding to the primary test(s) for efficacy.

Clinical phenotypes of five patients with psychotic disorders carrying rare schizophrenia-associated loss-of-function variants.

The Schizophrenia Exome Meta-Analysis (SCHEMA) consortium identified 10 genes in which loss-of-function (LoF) variants are highly associated with schizophrenia (SZ). In a well-characterized sample of 988 patients with psychotic disorders, we investigated whether patients bearing a SCHEMA variant presented with unusual or unique signs, symptoms, or course of illness. We identified 5 patients who carried a LoF variant in a SCHEMA gene, each in a different gene. None of the patients with a SCHEMA variant had unique symptoms. However, compared to the average of patients in the sample, all of the patients with a SCHEMA variant had earlier onset of any mental illness and more hospitalizations. Also, among SCHEMA carriers, 80 % were treated with clozapine, 60 % with ECT, all with either clozapine or ECT and 40 % with both clozapine and ECT, compared to only 2 % treated with clozapine and 18 % treated with ECT in the comparison group of patients without SCHEMA variants. All 5 patients with a SCHEMA variant had polysubstance abuse, and all had attempted suicide. Fewer than half had such presentations in the group without SCHEMA variants. In this small sample, SCHEMA variants appear to be associated with earlier onset, less favorable response to standard first-line treatments, and more severe illness, but not unique presentations of illness.

Diagnostic terms psychiatrists prefer to use for common psychotic and personality disorders.

OBJECTIVE: There are ongoing discussions on updating various standard psychiatric terms, including schizophrenia, which can be confusing, and personality disorders, which can be pejorative. To contribute to this process, suggestions and recommendations on terminology were sought from academic psychiatrists with substantial clinical experience. METHODS: In an online survey, 263 psychiatrists were asked how often they used alternative instead of standard terms for the diagnosis or symptom description of psychotic disorders and DSM Cluster B personality disorders. They were also asked what specific terms they preferred to use. Reasons for their views and choices were obtained. RESULTS: 125 clinicians (48%) responded. Only a minority of clinicians (31%) tended to use the term schizophrenia often, preferring to say psychosis or to refer to thinking and perceptual problems. Even lower proportions of clinicians (7-14%) often use the terms for Cluster B personality disorder subtypes: antisocial, narcissistic, histrionic, and borderline. Alternatives suggested for these disorders included discussing emotional dysregulation, traits of sensitivity and reactivity, and relational difficulties. Reasons cited for choosing alternative terms were to avoid miscommunication (71% of responders) and to avoid offending the patient (78% of responders). CONCLUSIONS: There are practical alternatives to standard psychiatric terminology that may improve communication with patients and be more respectful choices, as well. The suggestions of the psychiatrists responding to this survey might be of immediate value to others in their practices and might be worthy of consideration by those writing the next versions of the standard manuals, both the DSM and the ICD.

Nicotinamide riboside and caffeine partially restore diminished NAD availability but not altered energy metabolism in Alzheimer's disease.

The redox co-factor nicotinamide adenine dinucleotide (NAD) declines with age, and NAD deficits are specifically associated with dysfunctional energy metabolism in late-onset Alzheimer's disease (LOAD). Nicotinamide riboside (NR), a dietary NAD precursor, has been suggested to ameliorate the aging process or neurodegeneration. We assessed whether NR with or without caffeine, which increases nicotinamide mononucleotide transferase subtype 2 (NMNAT2), an essential enzyme in NAD production, modulates bioenergetic functions in LOAD. In LOAD patients-and young or old control individuals-derived dermal fibroblasts as well as in induced pluripotent stem cell-differentiated neural progenitors and astrocytes, NR and caffeine cell type-specifically increased the NAD pool, transiently enhanced mitochondrial respiration or glycolysis and altered the expression of genes in the NAD synthesis or consumption pathways. However, continued treatment led to reversed bioenergetic effects. Importantly, NR and caffeine did not alter the characteristics of a previously documented inherent LOAD-associated bioenergetic phenotype. Thus, although NR and caffeine can partially restore diminished NAD availability, increasing NAD alone may not be sufficient to boost or restore energy metabolism in brain aging or alter aberrant energy management in LOAD. Nicotinamide riboside might still be of value in combination with other agents in preventive or therapeutic intervention strategies to address the aging process or age-associated dementia.

Auditory hallucinations across the psychosis spectrum: Evidence of dysconnectivity involving cerebellar and temporal lobe regions.

BACKGROUND: Auditory hallucinations (AH) are typically associated with schizophrenia (SZ), but they are also prevalent in bipolar disorder (BD). Despite the large body of research on the neural correlates of AH in SZ, the pathophysiology underlying AH remains unclear. Few studies have examined the neural substrates associated with propensity for AH in BD. Investigating AH across the psychosis spectrum has the potential to inform about the neural signature associated with the trait of AH, irrespective of psychiatric diagnosis. METHODS: We compared resting state functional magnetic resonance imaging data in psychosis patients with (n = 90 AH; 68 SZ, 22 BD) and without (n = 55 NAH; 16 SZ, 39 BD) lifetime AH. We performed region of interest (ROI)-to-ROI functional connectivity (FC) analysis using 91 cortical, 15 subcortical, and 26 cerebellar atlas-defined regions. The primary aim was to identify FC differences between patients with and without lifetime AH. We secondarily examined differences between AH and NAH within each diagnosis. RESULTS: Compared to the NAH group, patients with AH showed higher FC between cerebellum and frontal (left precentral gyrus), temporal [right middle temporal gyrus (MTG), left inferior temporal gyrus (ITG), left temporal fusiform gyrus)], parietal (bilateral superior parietal lobules), and subcortical (left accumbens, left palldium) brain areas. AH also showed lower FC between temporal lobe regions (between right ITG and right MTG and bilateral superior temporal gyri) relative to NAH. CONCLUSIONS: Our findings suggest that dysconnectivity involving the cerebellum and temporal lobe regions may be common neurofunctional elements associated with AH propensity across the psychosis spectrum. We also found dysconnectivity patterns that were unique to lifetime AH within SZ or bipolar psychosis, suggesting both common and distinct mechanisms underlying AH pathophysiology in these disorders.

SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes.

During somatic reprogramming, cellular energy metabolism fundamentally switches from predominantly mitochondrial oxidative phosphorylation toward glycolysis. This metabolic reprogramming, also called the Warburg effect, is critical for the induction of pluripotency, but its molecular mechanisms remain poorly defined. Notably, SIRT2 is consistently downregulated during the reprogramming process and regulates glycolytic switch. Here, we report that downregulation of SIRT2 increases acetylation of mitogen-activated protein kinase (MAPK) kinase-1 (MEK1) at Lys175, resulting in activation of extracellular signal-regulated kinases (ERKs) and subsequent activation of the pro-fission factor dynamin-related protein 1 (DRP1). In parallel, downregulation of SIRT2 hyperacetylates the serine/threonine protein kinase AKT1 at Lys20 in a non-canonical way, activating DRP1 and metabolic reprogramming. Together, our study identified two axes, SIRT2-MEK1-ERK-DRP1 and SIRT2-AKT1-DRP1, that critically link mitochondrial dynamics and oxidative phosphorylation to the somatic reprogramming process. These upstream signals, together with SIRT2's role in glycolytic switching, may underlie the Warburg effect observed in human somatic cell reprogramming.

Hypothesis and Theory: Characterizing Abnormalities of Energy Metabolism Using a Cellular Platform as a Personalized Medicine Approach for Alzheimer's Disease.

Sporadic or late-onset Alzheimer's disease (LOAD) is characterized by slowly progressive deterioration and death of CNS neurons. There are currently no substantially disease-modifying therapies. LOAD pathology is closely related to changes with age and include, among others, accumulation of toxic molecules and altered metabolic, microvascular, biochemical and inflammatory processes. In addition, there is growing evidence that cellular energy deficits play a critical role in aging and LOAD pathophysiology. However, the exact mechanisms and causal relationships are largely unknown. In our studies we tested the hypothesis that altered bioenergetic and metabolic cell functions are key elements in LOAD, using a cellular platform consisting of skin fibroblasts derived from LOAD patients and AD-unaffected control individuals and therefrom generated induced pluripotent stem cells that are differentiated to brain-like cells to study LOAD pathogenic processes in context of age, disease, genetic background, cell development, and cell type. This model has revealed that LOAD cells exhibit a multitude of bioenergetic and metabolic alterations, providing evidence for an innate inefficient cellular energy management in LOAD as a prerequisite for the development of neurodegenerative disease with age. We propose that this cellular platform could ultimately be used as a conceptual basis for a personalized medicine tool to predict altered aging and risk for development of dementia, and to test or implement customized therapeutic or disease-preventive intervention strategies.

Alternative Diagnostic Models of the Psychotic Disorders: Evidence-Based Choices.

Standard diagnostic systems, the predominantly categorical DSM-5 and ICD-11, have limitations in validity, utility, and predictive and descriptive power. For psychotic disorders, these issues were partly addressed in current versions, but additional modifications are thought to be needed. Changes should be evidence based. We reviewed categorical, modified-categorical, and continuum-based models versus factor-based models of psychosis. Factors are clusters of symptoms or single prominent aspects of illness. Consistent evidence from studies of the genetics, pathobiology, and clinical presentation of psychotic disorders all support an underlying structure of factors, not categories, as best characterizing psychoses. Factors are not only the best fit but also comprehensive, as they can encompass any key feature of illness, including symptoms and course, as well as determinants of risk or response. Factors are inherently dimensional, even multidimensional, as are the psychoses themselves, and they provide the detail needed for either grouping or distinguishing patients for treatment decisions. The tools for making factor-based diagnoses are available, reliable, and concordant with actual practices used for clinical assessments. If needed, factors can be employed to create categories similar to those in current use. In addition, they can be used to define unique groupings of patients relevant to specific treatments or studies of the psychoses. Lastly, factor-based classifications are concordant with other comprehensive approaches to psychiatric nosology, including personalized (precision treatment) models and hierarchical models, both of which are currently being explored. Factors might be considered as the right primary structural choice for future versions of standard diagnostic systems, both DSM and ICD.

Brain cells derived from Alzheimer's disease patients have multiple specific innate abnormalities in energy metabolism.

Altered energy metabolism has been implicated both in aging and the pathogenesis of late-onset Alzheimer's disease (LOAD). However, it is unclear which anomalies are acquired phenotypes and which are inherent and predispose to disease. We report that neural progenitor cells and astrocytes differentiated from LOAD patient-derived induced pluripotent stem cells exhibit multiple inter-related bioenergetic alterations including: changes in energy production by mitochondrial respiration versus glycolysis, as a consequence of alterations in bioenergetic substrate processing and transfer of reducing agents, reduced levels of NAD/NADH, diminished glucose uptake and response rates to insulin (INS)/IGF-1 signaling, decreased INS receptor and glucose transporter 1 densities, and changes in the metabolic transcriptome. Our data confirm that LOAD is a "multi-hit" disorder and provide evidence for innate inefficient cellular energy management in LOAD that likely predisposes to neurodegenerative disease with age. These processes may guide the development and testing of diagnostic procedures or therapeutic agents.

Clinical Features of Psychotic Disorders: Comparing Categorical and Dimensional Models.

Objective: Despite research demonstrating the value of dimensional approaches, standard systems for classifying psychotic disorders rely primarily on categorization of patients into distinct diagnoses. We present the first study comparing analyses of dimensional features, categories, and standard diagnoses, all derived from the same sample. Methods: Using symptom ratings from 934 patients hospitalized for psychosis, we examined dimensional models, fit using factor analysis, categorical models, fit to factor-based scores from the dimensional model, and their correspondence with DSM-defined diagnoses. We compared the ability of each model to discriminate patients' assignment to medication regimen as a clinical validator. Results: Dimensional modeling identified four factors (manic, depressive, negative symptoms, and positive symptoms), which corresponded to factors in prior studies and appeared robust to statistical approach. Scores based on these factors overlapped substantially among DSM diagnoses. Patients assigned to clusters had less overlap in factor-based scores. However, categorical models were sensitive to statistical approach. The addition of DSM diagnoses, but not cluster assignments, improved the fits of models with dimensional scores alone as the clinical predictors for some medication classes. Conclusions: The results highlight the variability of symptom presentation within DSM-defined diagnostic categories, the utility of symptom dimensions or factors, and a potential lack of robustness of data-driven categorical approaches. Findings support initiatives to develop updated diagnostic systems that complement categorical classification of psychotic illness with factors representing dimensional ratings of symptoms.

Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia.

The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)-which are known to be affected in schizophrenia (SCZ) when matured-from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-L-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.