Virtual twins for model-informed precision dosing of clozapine in patients with treatment-resistant schizophrenia.

Model-informed precision dosing using virtual twins (MIPD-VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD-VT approach (Simcyp version 21), we predicted the steady-state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment-resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD-VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2 ) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady-state clozapine concentrations were overpredicted two to four-fold. This work supports the application of a high virtualization MIPD-VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug-drug interactions, particularly with fluvoxamine augmentation.

SETD1A variant-associated psychosis: A systematic review of the clinical literature and description of two new cases.

OBJECTIVE: SETD1A encodes a histone methyltransferase involved in various cell cycle regulatory processes. Loss-of-function SETD1A variants have been associated with numerous neurodevelopmental phenotypes, including intellectual disability and schizophrenia. While the association between rare coding variants in SETD1A and schizophrenia has achieved genome-wide significance by rare variant burden testing, only a few studies have described the psychiatric phenomenology of such individuals in detail. This systematic review and case report aims to characterize the neurodevelopmental and psychiatric phenotypes of SETD1A variant-associated schizophrenia. METHODS: A PubMed search was completed in July 2022 and updated in May 2023. Only studies that reported individuals with a SETD1A variant as well as a primary psychotic disorder were ultimately included. Additionally, another two previously unpublished cases of SETD1A variant-associated psychosis from our own sequencing cohort are described. RESULTS: The search yielded 32 articles. While 15 articles met inclusion criteria, only five provided case descriptions. In total, phenotypic information was available for 11 individuals, in addition to our own two unpublished cases. Our findings suggest that although individuals with SETD1A variant-associated schizophrenia may share a number of common features, phenotypic variability nonetheless exists. Moreover, although such individuals may exhibit numerous other neurodevelopmental features suggestive of the syndrome, their psychiatric presentations appear to be similar to those of general schizophrenia populations. CONCLUSIONS: Loss-of-function SETD1A variants may underlie the development of psychosis in a small percentage of individuals with schizophrenia. Identifying such individuals may become increasingly important, given the potential for advances in precision medicine treatment approaches.

Patient Pain and Satisfaction With 10, 30, and 70 mL Transcervical Foley Balloons for Cervical Ripening During Induction of Labor.

Objective To assess patient pain and satisfaction and time to delivery following transcervical Foley catheter balloon inflation to 10, 30, or 70 mL with simultaneous administration of oxytocin. Methods We performed a randomized prospective study with 30 or 70 mL transcervical Foley balloon catheters in combination with oxytocin during labor induction at term. A 10 mL group was included as a sham control group. Time to delivery was measured, and a patient questionnaire was administered at the time the catheter was expelled to determine patient pain and satisfaction. Results In 120 enrolled patients, there was a non-significant trend toward reduced time to delivery in the large Foley balloon group (10 mL: 30:45 ± 38:53, 30 mL: 26:41 ± 20:53, and 70 mL 22:40 ± 15:35, hh:mm, P = 0.412). The pain score at the time the balloon was expelled was significantly higher in the 70 ml group compared to the 10 ml and 30 ml groups (P = 0.004 and P = 0.034, respectively). We found no other differences in patient satisfaction or pain scores at the time of placement of the Foley catheter for the three groups. Conclusion Small gains in time to delivery should be balanced against patient experiences, and expectations of pain during the ripening process should be addressed at the time of Foley insertion.

Deep Brain Stimulator (DBS) Artifact in the EEG of a Pediatric Patient.

We report the first case of deep brain stimulator (DBS) artifact in the EEG of a pediatric patient. Our case is a 7-year-old male with bilateral globus pallidus interna (GPi) DBS for whom the EEG recorded a rhythmic 7.5 Hz theta activity on EEG related to DBS artifact. This artifact was also appreciated as a monochromatic invariable frequency band over 7.5 Hz on density spectral array (DSA). This rhythmic artifact may mimic an ictal pattern and should be recognized as artifact in order to avoid unnecessary treatment with anti-seizure medications (ASM).

A 1p31.3 deletion encompassing the nuclear factor 1A gene presenting as possible temporal lobe epilepsy in association with schizoaffective disorder.

Chromosome 1p32-p31 deletion syndrome, which is characterized by a variety of neurodevelopmental abnormalities, is thought to occur as a result of nuclear factor 1A (NFIA) haploinsufficiency. We present a case of a right-handed 40-year-old female with a 1p31.3 deletion, who exhibited numerous common features of this syndrome, in addition to treatment resistant schizoaffective disorder and possible temporal lobe epilepsy, making her presentation unique. While neither psychosis nor temporal lobe epilepsy has been described in this syndrome previously, these conditions likely occurred in our patient as a result of NFIA haploinsufficiency.

Subjective cognitive functioning, depressive symptoms, and objective cognitive functioning in people with treatment-resistant psychosis.

Introduction: Relationships between subjective cognitive functioning (SCF), objective cognitive functioning (OCF), and depressive symptoms are poorly understood in treatment-resistant psychosis (TRP). This study (a) compares SCF in TRP using positively and negatively worded scales, (b) assess these scales' accuracy, and (c) explores the association between these scales and depressive symptoms. We hypothesised that both SCF scales would be highly correlated, minimally associated with OCF, and similarly associated with depressive symptoms. Methods: Archival clinical data from 52 TRP inpatients was utilised. OCF composite scores were derived from a broad neuropsychological battery. SCF was assessed using the norm-referenced PROMIS 2.0 Cognitive Abilities (positively worded) and Concerns (negatively worded) subscales. A depressive symptom score was derived from the Positive and Negative Syndrome Scale. Results: SCF ratings were higher in patients than OCF. There was a small but significant correlation between PROMIS subscales (r = .30). Neither PROMIS subscale was associated with OCF (r = -.11, r = .01). Depressive symptoms were correlated with the positively (r = -.29) but not negatively worded scale (r = -.13). Conclusion: Individuals with TRP inaccurately rate their cognitive functioning and tend to overestimate their ability. Positively and negatively worded SCF scales associate variably with depressive symptoms, indicating they may not be used interchangeably in TRP.

Whole-genome sequencing analysis of clozapine-induced myocarditis.

One of the concerns limiting the use of clozapine in schizophrenia treatment is the risk of rare but potentially fatal myocarditis. Our previous genome-wide association study and human leucocyte antigen analyses identified putative loci associated with clozapine-induced myocarditis. However, the contribution of DNA variation in cytochrome P450 genes, copy number variants and rare deleterious variants have not been investigated. We explored these unexplored classes of DNA variation using whole-genome sequencing data from 25 cases with clozapine-induced myocarditis and 25 demographically-matched clozapine-tolerant control subjects. We identified 15 genes based on rare variant gene-burden analysis (MLLT6, CADPS, TACC2, L3MBTL4, NPY, SLC25A21, PARVB, GPR179, ACAD9, NOL8, C5orf33, FAM127A, AFDN, SLC6A11, PXDN) nominally associated (p < 0.05) with clozapine-induced myocarditis. Of these genes, 13 were expressed in human myocardial tissue. Although independent replication of these findings is required, our study provides preliminary insights into the potential role of rare genetic variants in susceptibility to clozapine-induced myocarditis.

Sleep Abnormalities in the Synaptopathies-SYNGAP1-Related Intellectual Disability and Phelan-McDermid Syndrome.

Neurodevelopmental disorders are frequently associated with sleep disturbances. One class of neurodevelopmental disorders, the genetic synaptopathies, is caused by mutations in genes encoding proteins found at the synapse. Mutations in these genes cause derangement of synapse development and function. We utilized a validated sleep instrument, Children's Sleep Habits Questionnaire (CSHQ) to examine the nature of sleep abnormalities occurring in individuals with two synaptopathies-Phelan-McDermid syndrome (PMD) (N = 47, male = 23, female = 24, age 1-46 years) and SYNGAP1-related intellectual disability (SYNGAP1-ID) (N = 64, male = 31, female = 33, age 1-64 years), when compared with unaffected siblings (N = 61, male = 25, female = 36, age 1-17 years). We found that both PMD and SYNGAP1-ID have significant sleep abnormalities with SYNGAP1-ID having greater severity of sleep disturbance than PMD. In addition, sleep disturbances were more severe for PMD in individuals 11 years and older compared with those less than 11 years old. Individuals with either disorder were more likely to use sleep aids than unaffected siblings. In conclusion, sleep disturbances are a significant phenotype in the synaptopathies PMD and SYNGAP1-ID. Improved sleep is a viable endpoint for future clinical trials for these neurodevelopmental disorders.

A novel description of converting a gastric plication to sleeve gastrectomy for weight loss: A case report.

INTRODUCTION: Bariatric surgery is a rapidly growing field with trends and standards of care changing more rapidly than most. Gastric plication was once an exciting novel procedure which showed promise, however it has fallen out of favor for other procedures such as the sleeve gastrectomy. Existing literature on the surgical conversion of a gastric plication to a sleeve gastrectomy does not provide specific details on the operative technique of this rarely encountered operation. CASE REPORT: In this case report we describe a morbidly obese female who presented weight gain after laparoscopic gastric plication and gastric banding. We provide the operative technique involved in conversion to a laparoscopic sleeve gastrectomy. CONCLUSION: This case provides specific operative technique with detailed media for the conversion of gastric plication to LSG.

Polysomnographic predictors of abnormal brainstem imaging in children.

STUDY OBJECTIVES: Evaluation of elevated central apnea-hypopnea index (CAHI) or prolonged central apneas in pediatric patients typically includes neuroimaging with a focus on brainstem pathology. There is little evidence guiding thresholds of polysomnographic variables that accurately predict abnormal neuroimaging. We sought to evaluate whether additional polysomnographic variables may help predict brainstem pathology. METHODS: A 10-year retrospective review of patients ages 1-18 years who received a brain magnetic resonance imaging (MRI) for an indication of central sleep apnea diagnosed via polysomnography was performed. Demographics, medical history, polysomnogram variables, and MRI results were compared. RESULTS: This study included 65 patients (69.2% male). The median age was 5.8 years (interquartile range, 3.0-8.3). Most patients had negative (normal or nonsignificant) MRIs (n = 45, 69.2%); 20 (30.8%) had abnormal MRIs. Of the patients with abnormal MRIs, 13 (20.0%) had abnormalities unrelated to the brainstem. Seven patients (10.8%) were found to have brainstem pathology and had a median CAHI of 10.8 events/h (interquartile range, 6.5-21.9), and three of seven (42.9%) had hypoventilation and were more likely to have developmental delay, abnormal neurological examinations, and reflux. Other patients (n = 58) had a median CAHI of 5.6 events/h (interquartile range, 3.1-9.1), and seven (12.1%) had hypoventilation. Area under the curve and receiver operating characteristic curves showed a CAHI ≥ 9.5 events/h and ≥ 6.4% of total sleep time with end-tidal CO2 ≥ 50 mm Hg predicted abnormal brainstem imaging. Prolonged central apneas did not predict abnormal brainstem imaging. CONCLUSIONS: Most patients with central sleep apnea do not have MRIs implicating structurally abnormal brainstems. Utilizing a cutoff of CAHI of ≥ 9.5 events/h, ≥ 6.4% total sleep time with end-tidal CO2 ≥ 50 mm Hg and/or frank hypoventilation, and additional clinical history may optimize MRI utilization in patients with central sleep apnea.

Review and Consensus on Pharmacogenomic Testing in Psychiatry.

The implementation of pharmacogenomic (PGx) testing in psychiatry remains modest, in part due to divergent perceptions of the quality and completeness of the evidence base and diverse perspectives on the clinical utility of PGx testing among psychiatrists and other healthcare providers. Recognizing the current lack of consensus within the field, the International Society of Psychiatric Genetics assembled a group of experts to conduct a narrative synthesis of the PGx literature, prescribing guidelines, and product labels related to psychotropic medications as well as the key considerations and limitations related to the use of PGx testing in psychiatry. The group concluded that to inform medication selection and dosing of several commonly-used antidepressant and antipsychotic medications, current published evidence, prescribing guidelines, and product labels support the use of PGx testing for 2 cytochrome P450 genes (CYP2D6, CYP2C19). In addition, the evidence supports testing for human leukocyte antigen genes when using the mood stabilizers carbamazepine (HLA-A and HLA-B), oxcarbazepine (HLA-B), and phenytoin (CYP2C9, HLA-B). For valproate, screening for variants in certain genes (POLG, OTC, CSP1) is recommended when a mitochondrial disorder or a urea cycle disorder is suspected. Although barriers to implementing PGx testing remain to be fully resolved, the current trajectory of discovery and innovation in the field suggests these barriers will be overcome and testing will become an important tool in psychiatry.

First Whole Transcriptome RNAseq on CHD8 Haploinsufficient Patient and Meta-Analyses Across Cellular Models Uncovers Likely Key Pathophysiological Target Genes.

In 2019, we confirmed that the haploinsufficiency of CHD8 does indeed cause the novel syndromic neurodevelopmental disease we first discovered a dozen years before. Here, we report the first whole transcriptome RNAseq gene expression profiling for a patient with this new syndrome, as a preliminary exploration of potential pathophysiological mechanisms. We compared our patient transcriptome profile with that of all publicly available RNAseq datasets from human cellular models including neuronal progenitor cells, neurons and organoids. We compared differential gene expression profiles overall and conducted phenotype-informed data filtration based on the characteristic syndrome presentation. We found that concordance among differential gene expression profiles was poor across all datasets. Nevertheless, remarkably, we show that the patient blood differential gene expression profile most resembled that of the neuronal cell model, a finding that encourages further transcriptome profiling using patient blood samples. In addition, our custom phenotype-informed analyses yielded important, differentially expressed syndrome pathophysiology target genes. Finally, we note that genes dysregulated due to CHD8 heterozygous deletion are linked to known neurological as well as oncological pathways.

Treatment-resistant psychotic symptoms and early-onset dementia: A case report of the 3q29 deletion syndrome.

The 3q29 deletion is a rare copy number variant associated with neurodevelopmental and psychiatric disorders, including a >40-fold increased risk for schizophrenia. Current understanding of the clinical phenotype is derived primarily from published cases of patients in childhood or early adolescence. Symptoms include mild to moderate learning disability, developmental delay, facial dysmorphism, microcephaly, ocular disorders, and gastrointestinal abnormalities. There is, however, a lack of detailed longitudinal case studies describing 3q29 deletion syndrome in adults with psychosis. In this case report, we describe the lifetime clinical portrait of a 57-year-old woman with 3q29 deletion syndrome, treatment-resistant psychotic symptoms, multiple medical comorbidities, and a previously unreported co-occurrence of early-onset dementia.

Clinical and biochemical footprints of inherited metabolic diseases. III. Psychiatric presentations.

Psychiatric symptoms are common manifestations in many inborn errors of metabolism (IEMs), ranging from attention deficit, anxiety and mood and behavioral disorders to psychosis. Furthermore, IEMs represent a significant percentage of all autism cases. We reviewed and updated the list of metabolic disorders known to be associated with various psychiatric manifestations and found more than 100 relevant IEMs. This represents the third of a series of articles attempting to create and maintain a comprehensive list of clinical and metabolic differential diagnoses according to organ system involvement.

Metastatic Brain Choriocarcinoma in a Postmenopausal Woman: A Case Report.

BACKGROUND Choriocarcinoma is the most aggressive form of gestational trophoblastic disease and usually occurs in women of childbearing age, most commonly within 1 year after an abnormal pregnancy. Postmenopausal choriocarcinoma is exceptionally rare and few cases have been described in the literature. CASE REPORT We present the case of a 66-year-old woman who presented to the Emergency Department with sudden onset of left upper- and lower-extremity weakness. She was found to have a brain mass, which was excised by neurosurgery and found to be a choriocarcinoma. She was then started on standard first-line therapy of EMACO, but was subsequently lost to follow-up. CONCLUSIONS Postmenopausal choriocarcinoma is rare and there are few case reports in the literature. It is a rare but possibly under-diagnosed metastatic disease in women. At present, a postmenopausal woman without a clear primary tumor should have a pregnancy test performed to rule out choriocarcinoma, as it is readily responsive to therapy.

Pediatric polysomnography-A review of indications, technical aspects, and interpretation.

Polysomnography is an elaborate diagnostic test composed of numerous data-collecting sensors working concomitantly to aid in the evaluation of varied sleep disorders in all age groups. Polysomnography is the study of choice for the assessment of pediatric sleep-disordered breathing, including obstructive sleep apnea syndrome, central apnea, and hypoventilation disorders, and is used to help determine treatment efficacy. Beyond the purview of snoring and breathing pauses, polysomnography can elucidate the etiology of hypersomnolence, when associated with a multiple sleep latency test, and abnormal movements or events, whether nocturnal seizure or complex parasomnia, when a thorough patient history cannot provide clear answers. This review will highlight the multitudinous indications for pediatric polysomnography and detail its technical aspects by describing the multiple neurophysiologic and respiratory parametric sources. Knowledge of these technical aspects will provide the practitioner with a thoughtful means to understand the limitations and interpretation of polysomnography.

Preliminary examination of the validity of the NIH toolbox cognition battery in treatment-resistant psychosis.

Objective: Prior research has suggested that treatment-resistant psychosis (TRP) may be a categorically distinct subtype from treatment-responsive psychotic disorders. However, relatively few studies have investigated the cognitive profile of individuals with TRP. Moreover, no prior studies have investigated the effectiveness of using the NIH Toolbox Cognition Battery (NTCB) for assessing cognition among psychiatric inpatients despite its promising efficiency and practicality in such settings. The current study aimed to investigate the validity of the NTCB and the associated cognitive profile of inpatients with TRP.Methods: Participants (N = 38) were administered the NTCB and a neuropsychological test battery. The Positive and Negative Syndrome Scale and the Routine Assessment of Patient Progress measured psychosis symptomatology and daily functioning, respectively.Results: Results showed deficits relative to normative values in fluid cognitive abilities using the NTCB, as predicted. There was strong convergent validity and adequate divergent validity between the NTCB subtests and corresponding neuropsychological measures, though no NTCB subtest correlated with performance on the Wisconsin Card Sorting Task. NTCB performance correlated with positive and disorganized symptoms of psychosis as well as daily functioning.Conclusions: Taken together, the NTCB appears to be a relatively strong tool for cognitive screening among psychiatric inpatients and may be used to identify which patients might benefit from further neuropsychological evaluation.