The cellular pathology of schizophrenia and the potential of antipsychotics to target underlying neuronal dysfunctions are still largely unknown. We employed glutamatergic neurons derived from induced pluripotent stem cells (iPSC) obtained from schizophrenia patients with known histories of response to clozapine and healthy controls to decipher the mechanisms of action of clozapine, spanning from molecular (transcriptomic profiling) and cellular (electrophysiology) levels to observed clinical effects in living patients. Glutamatergic neurons derived from schizophrenia patients exhibited deficits in intrinsic electrophysiological properties, synaptic function and network activity. Deficits in K+ and Na+ currents, network behavior, and glutamatergic synaptic signaling were restored by clozapine treatment, but only in neurons from clozapine-responsive patients. Moreover, neurons from clozapine-responsive patients exhibited a reciprocal dysregulation of gene expression, particularly related to glutamatergic and downstream signaling, which was reversed by clozapine treatment. Only neurons from clozapine responders showed return to normal function and transcriptomic profile. Our results underscore the importance of K+ and Na+ channels and glutamatergic synaptic signaling in the pathogenesis of schizophrenia and demonstrate that clozapine might act by normalizing perturbances in this signaling pathway. To our knowledge this is the first study to demonstrate that schizophrenia iPSC-derived neurons exhibit a response phenotype correlated with clinical response to an antipsychotic. This opens a new avenue in the search for an effective treatment agent tailored to the needs of individual patients.

ObjectivesOsteocalcin is a protein secreted by osteoblasts with a versatile endocrine role. Several domains in which it plays a role—stress response, monoamine synthesis, and cognitive functioning—are implicated also in the pathophysiology of major depressive disorder. In search of possible objective biomarkers of depression, the aim of the study was to assess the relationship between osteocalcin and depressive symptoms during the treatment of depressive episode.MethodsThe study included female inpatients with at least moderate depressive episode. In these patients, depression severity was measured using the Montgomery-Åsberg Depression Rating Scale (MADRS), and osteocalcin levels were assessed before the stabilization of antidepressive treatment and after 6 weeks. Relationships between osteocalcin levels and symptoms were analyzed with mixed-effect and linear models, taking into account age, menopausal status, and body mass index.ResultsIn 11 out of 13 enrolled inpatients, osteocalcin levels decreased during the first 6 weeks of treatment; this decrease was significant according to the mixed-effects model (t = −2.345, p = 0.019). According to the linear model, this decrease was significantly associated with reduction in depressive symptom severity (t = 2.673, p = 0.028). Osteocalcin was not associated with initial depressive symptom severity, and initial osteocalcin levels did not predict response to treatment. Limitations of the study include low sample size and inclusion of both pre- and postmenopausal women of various ages.ConclusionsThis preliminary study suggests that osteocalcin may be a candidate biomarker of antidepressive treatment response and that this topic warrants further investigation.

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Objectives:The aim of this study was to describe the practice of electroconvulsive therapy (ECT) in child and adolescent patients in the Czech Republic. Methods:We conducted a mail questionnaire survey among Czech facilities associated with the Association of Child and Adolescent Psychiatry, and university hospitals with inpatient psychiatric wards, focused on the practice of ECT between 2013 and 2017 in patients younger than 18 years.Results: Of 18 approached facilities, 13 had access to ECT, and only 6 used ECT on 16 patients. The most common diagnosis was schizophrenia or related disorders (68.75% of patients), and the most common reason for ECTwas catatonic symptoms (37.5%). The most common ECT methodology was bitemporal electrode placement with brief-pulse current (62.5%). In 2 patients, ECTwas terminated because of ineffectiveness and in 1 patient because of adverse reaction. In other patients, ECT ended after achieving a clinical effect. The most common adverse effect was transient memory impairment in a quarter of the patients. The number of pharmacological treatment attempts before ECT significantly correlated with hospitalization length. Conclusions:The utilization of ECT among children and adolescents was low. It was usually used in severe conditions after several pharmacological treatment attempts, which may indicate reluctance among providers to use this modality. A number of pharmacological attempts were associated with longer hospitalizations. In the majority of patients, ECT was effective and safe. On the other hand, the monitoring of cognitive adverse effects was insufficient and could be improved.