Sander Markx

Objective: To examine and compare the prevalence, incidence, and specificity and positive predictive value of incidence measures in a national commercial insurance database and a state Medicaid database, for different age groups over the life span. Methods: This cross-sectional study examined the annual prevalence of schizophrenia in 2019 in two databases: a) MarketScan, a United States national commercial insurance database ( N = 16,365,997), and b) New York State Medicaid program ( N = 4,414,153). A subset of these individuals with 10 years of continuous insurance prior to 2019 (2009-2018) was used to assess incidence and to create a reference standard for incidence measure testing, including positive predictive value and specificity, by age group. Continuous enrollment was required for all years of study (45-day gap allowance per year, and one or more health care services annually to ensure opportunity to be diagnosed). Results: The prevalence of schizophrenia in 2019 was 0.13% in MarketScan, and 2.13% in Medicaid. Prevalence was highest in MarketScan among individuals aged 21-25 years. In contrast, prevalence in Medicaid increased over the lifespan, with the peak among those 56-60 years of age. The incidence of new-onset schizophrenia in 2019 was 0.07% in MarketScan and 0.19% in Medicaid and peaked in young adulthood (26-30 years of age) in both databases (0.16% and 0.40%, respectively). Positive predictive value (PPV) for the incidence measures was higher for women than men and increased with longer lookback periods prior to the first schizophrenia diagnosis in 2019. Using a one-year lookback period, the PPV for those ≤35 years of age was 79% in MarketScan and 51% in Medicaid; a ≥95% PPV was achieved with a two-year lookback in MarketScan, and a seven-year lookback period in Medicaid. PPVs were also higher in younger age groups; in Medicaid a two-year lookback period yielded a PPV of 68% for those ≤35 years, but was 94% for those ≤20 years. Specificity was high even for the total population with one year of observation prior to the first schizophrenia diagnosis in 2019, and was higher in Medicaid (92%) than in MarketScan (80%), increasing further with longer lookback periods in both databases. Conclusions: The prevalence of schizophrenia is over 10-fold higher, and the incidence two-fold higher, in the New York State Medicaid population compared to the MarketScan national commercial insurance database. Within each database, prevalence and incidence varied by sex, age, and duration of insurance. Yet despite these differences, accurate measures of incidence of new-onset schizophrenia could be constructed with high specificity and positive predictive values.

Advances in 3D neuronal cultures, such as brain spheroids and organoids, are allowing unprecedented in vitro access to some of the molecular, cellular and developmental mechanisms underlying brain diseases. However, their efficacy in recapitulating brain network properties that encode brain function remains limited, thereby precluding development of effective in vitro models of complex brain disorders like schizophrenia. Here, we develop and characterize a Modular Neuronal Network (MoNNet) approach that recapitulates specific features of neuronal ensemble dynamics, segregated local-global network activities and a hierarchical modular organization. We utilized MoNNets for quantitative in vitro modelling of schizophrenia-related network dysfunctions caused by highly penetrant mutations in SETD1A and 22q11.2 risk loci. Furthermore, we demonstrate its utility for drug discovery by performing pharmacological rescue of alterations in neuronal ensembles stability and global network synchrony. MoNNets allow in vitro modelling of brain diseases for investigating the underlying neuronal network mechanisms and systematic drug discovery.

It has become increasingly clear that the immune system can play a critical role in the pathophysiology of certain psychiatric disorders. For immune-mediated psychiatric illness, various forms of immunosuppressive therapy have been utilized. In this context, hematopoietic stem cell transplantation (HSCT) remains a theoretical consideration for treatment of patients who present with an immune-mediated psychiatric disorder. For such severe disorders, the best HSCT regimen and patient selection is yet to be defined. At the present time, HSCT should only be undertaken by an experienced team under an institutional review board-approved and monitored protocol with an outside data safety monitoring board.

We conducted blinded psychiatric assessments of 26 Amish subjects (52 ± 11 years) from four families with prevalent bipolar spectrum disorder, identified 10 potentially pathogenic alleles by exome sequencing, tested association of these alleles with clinical diagnoses in the larger Amish Study of Major Affective Disorder (ASMAD) cohort, and studied mutant potassium channels in neurons. Fourteen of 26 Amish had bipolar spectrum disorder. The only candidate allele shared among them was rs78247304, a non-synonymous variant of KCNH7 (c.1181G>A, p.Arg394His). KCNH7 c.1181G>A and nine other potentially pathogenic variants were subsequently tested within the ASMAD cohort, which consisted of 340 subjects grouped into controls subjects and affected subjects from overlapping clinical categories (bipolar 1 disorder, bipolar spectrum disorder and any major affective disorder). KCNH7 c.1181G>A had the highest enrichment among individuals with bipolar spectrum disorder (χ² = 7.3) and the strongest family-based association with bipolar 1 (P = 0.021), bipolar spectrum (P = 0.031) and any major affective disorder (P = 0.016). In vitro, the p.Arg394His substitution allowed normal expression, trafficking, assembly and localization of HERG3/Kv11.3 channels, but altered the steady-state voltage dependence and kinetics of activation in neuronal cells. Although our genome-wide statistical results do not alone prove association, cumulative evidence from multiple independent sources (parallel genome-wide study cohorts, pharmacological studies of HERG-type potassium channels, electrophysiological data) implicates neuronal HERG3/Kv11.3 potassium channels in the pathophysiology of bipolar spectrum disorder. Such a finding, if corroborated by future studies, has implications for mental health services among the Amish, as well as development of drugs that specifically target HERG3/Kv11.3.