The impact of childhood trauma exposure on social functioning in schizophrenia: the moderated mediation role of oxytocin and oxytocin receptor gene polymorphisms.

BACKGROUND: Childhood trauma has been linked to increased risk of schizophrenia and social dysfunction, and oxytocin and its receptor gene have been implicated in regulating social behavior. This study investigated the potential role of oxytocin and oxytocin receptor gene (OXTR) in mediating the effects of childhood trauma on social functioning in schizophrenia. METHODS: The study consisted of 382 patients with schizophrenia and 178 healthy controls who were assessed using the Taiwanese version of the Childhood Trauma Questionnaire (CTQ-SF), the Social Functioning Scale (SFS), and plasma oxytocin levels. DNA was extracted to genotype the OXTR and ten single-nucleotide polymorphisms (SNPs; rs2254298, rs237885, rs237887, rs237899, rs53576, rs9840864, rs13316193, rs7632287, rs1042778, and rs237895) were selected. RESULTS: Patients with schizophrenia showed higher CTQ-SF scores (t = 12.549, p < 0.001), lower SFS scores (t = -46.951, p < 0.001), and lower plasma oxytocin levels (t = -5.448, p < 0.001) compared to healthy controls. The study also found significant differences in OXTR SNPs between both groups, with risk alleles being more prevalent in patients with schizophrenia (t = 2.734, p = 0.006). Results indicated a significant moderated mediation effect, with oxytocin and the OXTR SNPs partially mediating the relationship between childhood trauma exposure and social functioning in patients with schizophrenia (index of mediation = 0.038, 95% CI [0.033-0.044]). CONCLUSIONS: The findings suggest that oxytocin and its receptor gene may be promising targets for interventions aimed at improving social functioning in patients with a history of childhood trauma and schizophrenia. However, further research is needed to fully understand these effects and the potential of oxytocin-based interventions in this population.

Retina as a potential biomarker in schizophrenia spectrum disorders: a systematic review and meta-analysis of optical coherence tomography and electroretinography.

INTRODUCTION: Abnormal findings on optical coherence tomography (OCT) and electroretinography (ERG) have been reported in participants with schizophrenia spectrum disorders (SSDs). This study aims to reveal the pooled standard mean difference (SMD) in retinal parameters on OCT and ERG among participants with SSDs and healthy controls and their association with demographic characteristics, clinical symptoms, smoking, diabetes mellitus, and hypertension. METHODS: Using PubMed, Scopus, Web of Science, and PSYNDEX, we searched the literature from inception to March 31, 2023, using specific search terms. This study was registered with PROSPERO (CRD4202235795) and conducted according to PRISMA 2020. RESULTS: We included 65 studies in the systematic review and 44 in the meta-analysis. Participants with SSDs showed thinning of the peripapillary retinal nerve fiber layer (pRNFL), macular ganglion cell layer- inner plexiform cell layer, and retinal thickness in all other segments of the macula. A meta-analysis of studies that excluded SSD participants with diabetes and hypertension showed no change in results, except for pRNFL inferior and nasal thickness. Furthermore, a significant difference was found in the pooled SMD of pRNFL temporal thickness between the left and right eyes. Meta-regression analysis revealed an association between retinal thinning and duration of illness, positive and negative symptoms. In OCT angiography, no differences were found in the foveal avascular zone and superficial layer foveal vessel density between SSD participants and controls. In flash ERG, the meta-analysis showed reduced amplitude of both a- and b-waves under photopic and scotopic conditions in SSD participants. Furthermore, the latency of photopic a-wave was significantly shorter in SSD participants in comparison with HCs. DISCUSSION: Considering the prior report of retinal thinning in unaffected first-degree relatives and the results of the meta-analysis, the findings suggest that retinal changes in SSDs have both trait and state aspects. Future longitudinal multimodal retinal imaging studies are needed to clarify the pathophysiological mechanisms of these changes and to clarify their utility in individual patient monitoring efforts.

Retinal layers and associated clinical factors in schizophrenia spectrum disorders: a systematic review and meta-analysis.

INTRODUCTION: The retina shares structural and functional similarities with the brain. Furthermore, structural changes in the retina have been observed in patients with schizophrenia spectrum disorders (SSDs). This systematic review and meta-analysis investigated retinal abnormalities and their association with clinical factors for SSD. METHODS: Studies related to retinal layers in SSD patients were retrieved from PubMed, Scopus, Web of Science, Cochrane Controlled Register of Trials, International Clinical Trials Registry Platform, and PSYNDEX databases from inception to March 31, 2021. We screened and assessed the eligibility of the identified studies. EZR ver.1.54 and the metafor package in R were used for the meta-analysis and a random-effects or fixed-effects model was used to report standardized mean differences (SMDs). RESULTS: Twenty-three studies (2079 eyes of patients and 1571 eyes of controls) were included in the systematic review and meta-analysis. The average peripapillary retinal nerve fiber layer (pRNFL) thickness, average macular thickness (MT), and macular ganglion cell layer-inner plexiform layer (GCL-IPL) thickness were significantly lower in patients than in controls (n = 14, 6, and 3, respectively; SMD = -0.33, -0.49, and -0.43, respectively). Patients also had significantly reduced macular volume (MV) compared to controls (n = 7; SMD = -0.53). The optic cup volume (OCV) was significantly larger in patients than in controls (n = 3; SMD = 0.28). The meta-regression analysis indicated an association between several clinical factors, such as duration of illness and the effect size of the pRNFL, macular GCL-IPL, MT, and MV. CONCLUSION: Thinning of the pRNFL, macular GCL-IPL, MT, and MV and enlargement of the OCV in SSD were observed. Retinal abnormalities may be applicable as state/trait markers in SSDs. The accumulated evidence was mainly cross-sectional and requires verification by longitudinal studies to characterize the relationship between OCT findings and clinical factors.

Long-Term Treatment With Long-Acting Injectable Antipsychotic in Schizophrenia Patients With and Without Dopamine Supersensitivity Psychosis: A 6-Year Retrospective Comparative Study.

BACKGROUND: Dopamine supersensitivity psychosis (DSP) is an unstable psychotic state in patients with schizophrenia due to an upregulation of dopamine D2 receptors induced by antipsychotic medication. Long-acting antipsychotic injectable (LAI) could be advantageous for controlling the dopamine supersensitivity state, but it is not known if long-term treatment with LAI might ultimately lead to development or exacerbation of DSP. METHODS: The present study included 58 patients who had been treated with LAI for at least 3 years, with medical records for the 3 years before its introduction. Those records were used to classify patients as having DSP (n = 30, DSP group) or not (n = 28, non-DSP group). The effects of LAI treatments on the clinical course during the 3 years after the LAI introduction were compared between the 2 groups. RESULTS: Both groups demonstrated significant decreases in antipsychotic dosage (combined LAI and oral antipsychotics) and a significant improvement measured by clinical global impression-improvement. These indicators did not differ between them, suggesting similar efficacy of LAI for both groups. On average, the DSP group was treated with a higher dose of antipsychotics (1004.8 mg) before the LAI introduction compared with the non-DSP group but reduced them to within the standard dose range (662.0 mg) after the introduction of LAI. CONCLUSIONS: Our results indicated the effectiveness of LAI treatment for at least 3 years for patients with DSP, suggesting that this treatment strategy is unlikely to worsen DSP. The efficacy might be explained by the large decrease in the total antipsychotic dose with the introduction of LAI.

A preliminary genetic association study of GAD1 and GABAB receptor genes in patients with treatment-resistant schizophrenia.

BACKGROUND: GABAergic system dysfunction has been implicated in the etiology of schizophrenia and of cognitive impairments in particular. Patients with treatment-resistant schizophrenia (TRS) generally suffer from profound cognitive impairments in addition to severe positive symptoms, suggesting that GABA system dysfunction could be involved more closely in patients with TRS. METHODS AND RESULTS: In the present study, exome sequencing was conducted on fourteen TRS patients, whereby four SNPs were identified on GAD1, GABBR1 and GABBR2 genes. An association study for five SNPs including these 4 SNPs and rs3749034 on GAD1 as then performed among 357 patients with TRS, 682 non-TRS patients and 508 healthy controls (HC). The results revealed no significant differences in allelic and/or genetic distributions for any of the five SNPs. However, several subanalyses in comparisons between schizophrenia and HC groups, as well as between the three groups, showed nominal-level significance for rs3749034 on GAD1 and rs10985765/rs3750344 on GABBR2. In particular, in comparisons of female subjects, rigorous analysis for rs3749034 showed a statistical difference between the schizophrenia and HC groups and between the TRS and HC groups. CONCLUSIONS: Several positive results in subanalyses suggested that genetic vulnerability in the GABA system to schizophrenia or TRS could be affected by sex or sampling area, and overall, that rs3749034 on GAD1 and rs10985765 on GABBR2 could be related to TRS. In the present study, only a few SNPs were examined; it is possible that other important genetic variants in other regions of GABA-related genes were not captured in this preliminary study.

Genetic risks of schizophrenia identified in a matched case-control study.

It has been suggested that dopaminergic neurotransmission plays important roles for the psychotic symptoms and probably etiology of schizophrenia. In our recent preliminary study, we demonstrated that the specific allele combinations of dopamine-related functional single nucleotide polymorphisms (SNPs), rs10770141, rs4680, and rs1800497 could indicate risks for schizophrenia. The present validation study involved a total of 2542 individuals who were age- and sex-matched in a propensity score matching analysis, and the results supported the statistical significances of the proposed genetic risks described in our previous reports. The estimated odds ratios were 1.24 (95% CI 1.06-1.45, p < 0.001) for rs4680, 1.73 (95% CI 1.47-2.02, p < 0.0001) for rs1800497, and 1.79 (95% CI 1.35-2.36, p < 0.0001) for rs10770141. A significant relationship was also revealed among these three polymorphisms and schizophrenia, with corresponding coefficients (p < 0.0001). In this study, we also present a new scoring model for the identification of individuals with the disease risks. Using the cut-off value of 2, our model exhibited sensitivity for almost two-thirds of all of the schizophrenia patients: odds ratio 1.87, 95% CI 1.59-2.19, p < 0.0001. In conclusion, we identified significant associations of dopamine-related genetic combinations with schizophrenia. These findings suggest that some types of dopaminergic neurotransmission play important roles for development of schizophrenia, and this type of approach may also be applicable for other multifactorial diseases, providing a potent new risk predictor.

First-episode psychosis in treatment-resistant schizophrenia: a cross-sectional study of a long-term follow-up cohort.

BACKGROUND: Approximately one-third of schizophrenia patients eventually develop treatment-resistant schizophrenia (TRS). Although the time course of TRS development varies from patient to patient, the details of these variations have not been clarified. The present study compared the duration of time required to achieve control of the first-episode psychosis (FEP) between patients who went on to develop TRS and those who did not, in order to determine whether a bifurcation point exists for the transition to TRS. METHODS: The present study included 271 schizophrenia patients. Based on the clinical assessment, each patient was assigned to a TRS (n = 79) or Non-TRS group (n = 182). Clinical factors relating to FEP treatment such as the duration of initial hospital admission and the degree of improvement were retrospectively identified. RESULTS: There was no significant difference in the duration of initial hospital admission (defined as the time from treatment introduction to successful discharge) between the two groups (mean of 87.9 days for TRS vs. 53.3 days for Non-TRS). The degree of improvement during initial hospital admission of the TRS group was significantly lower than that of the Non-TRS group (Global Assessment of Functioning (GAF) of 50 points for TRS vs. 61 points for Non-TRS). Approximately half of the TRS patients showed an acute onset pattern and longer hospital admission (mean 169 days) for their FEP. The other half of TRS patients needed no hospital admission, indicating an insidious onset pattern with no clear psychotic episode and treatment introduction without hospital admission. CONCLUSIONS: Future TRS patients can have difficulty in improvement during their FEP. There appear to be two distinct patterns for the development of TRS. One pattern is characterized by refractory positive symptoms and a longer period to control the first psychosis; the other shows latent or insidious onset and poor response to the initial treatment.

Antipsychotic-Induced Dopamine Supersensitivity Psychosis: Pharmacology, Criteria, and Therapy.

The first-line treatment for psychotic disorders remains antipsychotic drugs with receptor antagonist properties at D2-like dopamine receptors. However, long-term administration of antipsychotics can upregulate D2 receptors and produce receptor supersensitivity manifested by behavioral supersensitivity to dopamine stimulation in animals, and movement disorders and supersensitivity psychosis (SP) in patients. Antipsychotic-induced SP was first described as the emergence of psychotic symptoms with tardive dyskinesia (TD) and a fall in prolactin levels following drug discontinuation. In the era of first-generation antipsychotics, 4 clinical features characterized drug-induced SP: rapid relapse after drug discontinuation/dose reduction/switch of antipsychotics, tolerance to previously observed therapeutic effects, co-occurring TD, and psychotic exacerbation by life stressors. We review 3 recent studies on the prevalence rates of SP, and the link to treatment resistance and psychotic relapse in the era of second-generation antipsychotics (risperidone, paliperidone, perospirone, and long-acting injectable risperidone, olanzapine, quetiapine, and aripiprazole). These studies show that the prevalence rates of SP remain high in schizophrenia (30%) and higher (70%) in treatment-resistant schizophrenia. We then present neurobehavioral findings on antipsychotic-induced supersensitivity to dopamine from animal studies. Next, we propose criteria for SP, which describe psychotic symptoms and co-occurring movement disorders more precisely. Detection of mild/borderline drug-induced movement disorders permits early recognition of overblockade of D2 receptors, responsible for SP and TD. Finally, we describe 3 antipsychotic withdrawal syndromes, similar to those seen with other CNS drugs, and we propose approaches to treat, potentially prevent, or temporarily manage SP.

Altered serum level of matrix metalloproteinase-9 and its association with decision-making in eating disorders.

AIM: The aims of this study were to determine whether the serum levels of precursor brain-derived neurotrophic factor (proBDNF), mature BDNF (mBDNF), and matrix metalloproteinase-9 (MMP-9) are altered in patients with eating disorders (ED), including anorexia nervosa (AN) and bulimia nervosa (BN), and to explore whether those levels are associated with decision-making abilities. METHODS: Nineteen women with AN, 28 women with BN, and 22 age-matched healthy control women (HC) were enrolled in the current study. All participants had their decision-making abilities assessed using the Iowa Gambling Task (IGT). Their eating-related pathophysiology and depressive/anxiety symptoms were also evaluated. RESULTS: The MMP-9 level in AN was significantly lower than that in either BN or HC, but the serum levels of proBDNF and mBDNF did not differ among the three groups. Investigation of the serum levels of proBDNF and MMP-9 in patients with ED and controls revealed a significant correlation between them. In the BN, there were positive correlations between mBDNF level and IGT performance and also between MMP-9 level and IGT performance, but these correlations did not occur in AN. The MMP-9 level was positively associated with the Symptom Scale, one of the subscales of the Bulimic Investigatory Test, Edinburgh, only in AN. CONCLUSION: These results suggest that the serum level of MMP-9 plays a role in the pathophysiology of AN, and both the serum levels of mBDNF and MMP-9 may be associated with decision-making abilities in patients with BN.

Genetic and molecular risk factors within the newly identified primate-specific exon of the SAP97/DLG1 gene in the 3q29 schizophrenia-associated locus.

The synapse-associated protein 97/discs, large homolog 1 of Drosophila (DLG1) gene encodes synaptic scaffold PDZ proteins interacting with ionotropic glutamate receptors including the N-methyl-D-aspartate type glutamate receptor (NMDAR) that is presumed to be hypoactive in brains of patients with schizophrenia. The DLG1 gene resides in the chromosomal position 3q29, the microdeletion of which confers a 40-fold increase in the risk for schizophrenia. In the present study, we performed genetic association analyses for DLG1 gene using a Japanese cohort with 1808 schizophrenia patients and 2170 controls. We detected an association which remained significant after multiple comparison testing between schizophrenia and the single nucleotide polymorphism (SNP) rs3915512 that is located within the newly identified primate-specific exon (exon 3b) of the DLG1 gene and constitutes the exonic splicing enhancer sequence. When stratified by onset age, although it did not survive multiple comparisons, the association was observed in non-early onset schizophrenia, whose onset-age selectivity is consistent with our recent postmortem study demonstrating a decrease in the expression of the DLG1 variant in early-onset schizophrenia. Although the present study did not demonstrate the previously reported association of the SNP rs9843659 by itself, a meta-analysis revealed a significant association between DLG1 gene and schizophrenia. These findings provide a valuable clue for molecular mechanisms on how genetic variations in the primate-specific exon of the gene in the schizophrenia-associated 3q29 locus affect its regulation in the glutamate system and lead to the disease onset around a specific stage of brain development.

Repetitive Transcranial Magnetic Stimulation Changes Cerebral Oxygenation on the Left Dorsolateral Prefrontal Cortex in Bulimia Nervosa: A Near-Infrared Spectroscopy Pilot Study.

Previous studies showed that food craving in eating disorders can be weakened with high-frequency repetitive transcranial magnetic stimulation (rTMS) on the left dorsolateral prefrontal cortex (DLPFC). The aims of this study were to assess cerebral oxygenation change induced with rTMS and to assess the short-term impact of rTMS on food craving and other bulimic symptoms in patients with bulimia nervosa (BN). Eight women diagnosed with BN according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria participated in this study. We measured haemoglobin concentration changes in the DLPFC with near-infrared spectroscopy during cognitive tasks measuring self-regulatory control in response to food photo stimuli, both at baseline and after a single session of rTMS. Subjective ratings for food cravings demonstrated significant reduction. A significant decrease in cerebral oxygenation of the left DLPFC was also observed after a single session of rTMS. Measurement with NIRS after rTMS intervention may be applicable for discussing the mechanisms underlying rTMS modulation in patients with BN.

Increased serum levels of serine enantiomers in patients with depression.

OBJECTIVE: Glutamatergic neurotransmission via the N-methyl-d-aspartate (NMDA) receptor is integral to the pathophysiology of depression. This study was performed to examine whether amino acids related to NMDA receptor neurotransmission are altered in the serum of patients with depression. METHOD: We measured the serum levels of d-serine, l-serine, glycine, glutamate and glutamine in patients with depression (n=70), and age-matched healthy subjects (n=78). RESULTS: Serum levels of d-serine and l-serine in patients with depression were significantly higher than those of healthy controls (p<0.001). In contrast, serum levels of glycine, glutamate and glutamine did not differ between the two groups. Interestingly, the ratio of l-serine to glycine in patients was significantly higher than that of healthy controls (p<0.001). CONCLUSION: This study suggests that serine enantiomers may be peripheral biomarkers for depression, and that abnormality in the d-serine-l-serine-glycine cycle plays a role in the pathophysiology of depression.

Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

It is widely accepted that malfunction of the N-methyl-D-aspartate (NMDA)-type glutamate receptor may be involved in the pathophysiology of schizophrenia. Several recent microRNA (miRNA) studies have demonstrated that the expression of the glutamate system-related miR-132 and miR-212 is changed in postmortem schizophrenic brains. Here we attempted to obtain further insight into the relationships among schizophrenia, the NMDA receptor, the molecular cascades controlled by these miRNAs and commonly predicted target genes of the two miRNAs. We focused on the H2AFZ (encoding H2A histone family, member Z) gene, whose expression was shown in our screening study to be modified by a schizophrenomimetic NMDA antagonist, phencyclidine. By performing polymerase chain reaction with fluorescent signal detention using the TaqMan system, we examined four tag single nucleotide polymorphisms (SNPs; SNP01-04) located around and within the H2AFZ gene for their genetic association with schizophrenia. The subjects were a Japanese cohort (2,012 patients with schizophrenia and 2,170 control subjects). We did not detect any significant genetic association of these SNPs with schizophrenia in this cohort. However, we observed a significant association of SNP02 (rs2276939) in the male patients with schizophrenia (allelic P = 0.003, genotypic P = 0.008). A haplotype analysis revealed that haplotypes consisting of SNP02-SNP03 (rs10014424)-SNP04 (rs6854536) also showed a significant association in the male patients with schizophrenia (P = 0.018). These associations remained significant even after correction for multiple testing. The present findings suggest that the H2AFZ gene may be a susceptibility factor in male subjects with schizophrenia, and that modification of the H2AFZ signaling pathway warrants further study in terms of the pathophysiology of schizophrenia.

Erratum to: Association study of H2AFZ with schizophrenia in a Japanese case-control sample.

Table 1 contains several errors as originally published. Table 1 should read as follows; the corrected values are shown in italics.

Sequencing and expression analyses of the synaptic lipid raft adapter gene PAG1 in schizophrenia.

Disruption of synaptic networks has been advocated in the pathogenesis of psychiatric diseases like schizophrenia. The majority of synaptic proteins involved in neuronal communications are localized in lipid rafts. These rafts form the platform for coordinating neuronal signal transduction, by clustering interacting partners. The PAG1 protein is a transmembrane adaptor protein in the lipid raft signaling cluster that regulates Src family kinases (SFKs), a convergent point for multiple pathways regulating N-methyl-D-aspartate (NMDA) receptors. Reports of de novo missense mutations in PAG1 and SFK mediated reductions in tyrosine phosphorylation of NMDA receptor subunit proteins in schizophrenia patients, point to a putative role in schizophrenia pathogenesis. To evaluate this, we resequenced the entire coding region of PAG1 in Japanese schizophrenia patients (n = 1,140) and controls (n = 1,140). We identified eight missense variants, of which four were previously unreported. Case-control genetic association analysis of these variants in a larger cohort (n = 4,182) showed neither a statistically significant association of the individual variants with schizophrenia, nor any increased burden of the rare alleles in the patient group. Expression levels of PAG1 in post-mortem brain samples from schizophrenia patients and controls also showed no significant differences. To assess the precise role of PAG1 in schizophrenia, future studies with larger sample sizes are needed.

Alterations of Dopamine D2 Receptors and Related Receptor-Interacting Proteins in Schizophrenia: The Pivotal Position of Dopamine Supersensitivity Psychosis in Treatment-Resistant Schizophrenia.

Although the dopamine D2 receptor (DRD2) has been a main target of antipsychotic pharmacotherapy for the treatment of schizophrenia, the standard treatment does not offer sufficient relief of symptoms to 20%-30% of patients suffering from this disorder. Moreover, over 80% of patients experience relapsed psychotic episodes within five years following treatment initiation. These data strongly suggest that the continuous blockade of DRD2 by antipsychotic(s) could eventually fail to control the psychosis in some point during long-term treatment, even if such treatment has successfully provided symptomatic improvement for the first-episode psychosis, or stability for the subsequent chronic stage. Dopamine supersensitivity psychosis (DSP) is historically known as a by-product of antipsychotic treatment in the manner of tardive dyskinesia or transient rebound psychosis. Numerous data in psychopharmacological studies suggest that the up-regulation of DRD2, caused by antipsychotic(s), is likely the mechanism underlying the development of the dopamine supersensitivity state. However, regardless of evolving notions of dopamine signaling, particularly dopamine release, signal transduction, and receptor recycling, most of this research has been conducted and discussed from the standpoint of disease etiology or action mechanism of the antipsychotic, not of DSP. Hence, the mechanism of the DRD2 up-regulation or mechanism evoking clinical DSP, both of which are caused by pharmacotherapy, remains unknown. Once patients experience a DSP episode, they become increasingly difficult to treat. Light was recently shed on a new aspect of DSP as a treatment-resistant factor. Clarification of the detailed mechanism of DSP is therefore crucial, and a preventive treatment strategy for DSP or treatment-resistant schizophrenia is urgently needed.

A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists.

STUDY OBJECTIVES: Although novel hypnotics have recently emerged, there are currently no data comparing the clinical potency of benzodiazepine receptor agonists (BZRAs) and novel hypnotics, or the effectiveness of different methods of switching between them. This study examined how novel hypnotics might help reduce BZRA use in real-world practice. METHODS: 289 patients with psychiatric disorders who took BZRAs for over 1 year before switching to either of 2 dual-orexin receptor antagonists (DORAs; suvorexant [SUV] or lemborexant [LEM]) or a melatonin receptor agonist (ramelteon [RMT]) were enrolled. We collected data on BZRAs at baseline and 3 months after commencement of SUV/LEM/RMT. RESULTS: Significant reductions in BZRAs were observed for all 3 agents: -4.10, -2.80, and -1.65 mg in diazepam-equivalent doses in the SUV, LEM, and RMT groups, respectively. Dose reduction was significantly greater in the DORA than the RMT group (F = 15.053, P < .001). Within the DORA group, dose reduction was significantly greater in patients taking SUV than those taking LEM (F = 4.337, P = .043). The switching success rate did not differ among the switching methods for any of the hypnotics. CONCLUSIONS: The reduction rate of BZRAs achieved by the switch fell into their equivalent-potency range estimated from clinical trials. The results suggest that DORAs can replace approximately 1 tablet of a BZRA. The difference in dose reduction between DORAs and RMT reflected the greater sleeping potency of the DORAs, whereas that between SUV and LEM might have reflected patient backgrounds: patients taking LEM may have been more strongly dependent on BZRAs. CITATION: Tachibana M, Kanahara N, Oda Y, Hasegawa T, Kimura A, Iyo M. A retrospective clinical practice study comparing the usefulness of dual-orexin receptor antagonists and a melatonin receptor agonist in patients switching from long-term benzodiazepine receptor agonists. J Clin Sleep Med. 2024;20(4):603-613.

Optimal extent of dopamine D2 receptor occupancy by antipsychotics for treatment of dopamine supersensitivity psychosis and late-onset psychosis.

Several studies have proposed an optimal dopamine D2 receptor occupancy by antipsychotics (OOc) to establish optimal pharmacological treatment of schizophrenia. However, there are limitations to the use of the OOc, especially in application to patients with treatment-resistant schizophrenia, including dopamine supersensitivity psychosis (DSP) or late-onset psychosis (LOP). It has been suggested that D2 receptor density is up-regulated by chronic treatment of antipsychotics in DSP, whereas it may be low in LOP owing to age-related reduction. In estimation of the proposed OOc, these alterations have not been taken into account, which may be one of the factors contributing to the limited application of this index. We here hypothesize that there is an optimal range in the number of D2 receptors available for dopamine binding to elicit adequate neurotransmission in the treatment of patients with schizophrenia. We then estimated the OOc under the assumption that the range is constant while D2 density is variable. The results showed that the OOc and plasma level of antipsychotics increase with an increase in the D2 density but decrease with a decrease in the D2 density. That is, if the range of OOc is 65% to 78% in a standard D2 density, it becomes 82% to 89% under 2-fold up-regulated density and 42% to 63% under a 40% reduced density. The results also indicated that the reduction of the plasma antipsychotic level is greater during a given time period in patients with higher D2 density, as they need a higher antipsychotic dose to achieve the raised OOc, which would account for the clinical features of DSP, for example, acute exacerbation after a discontinuation of antipsychotics. On the other hand, in patients with lower D2 density, only a lower antipsychotic dose will achieve the OOc, and a small increase in the dose will result in a greater increase in occupancy and induce extrapyramidal adverse effects more easily. Furthermore, the reduction of the plasma antipsychotic level during the time period is smaller, which prolongs extrapyramidal adverse effects after discontinuation of antipsychotics in LOP. We also attempted to develop a strategy for the prevention and treatment of patients with DSP or LOP by focusing on D2 density.