Advancements in Non-Dopaminergic Treatments for Schizophrenia: A Systematic Review of Pipeline Developments.

INTRODUCTION: Conventional antipsychotic drugs that attenuate dopaminergic neural transmission are ineffective in approximately one-third of patients with schizophrenia. This necessitates the development of non-dopaminergic agents. METHODS: A systematic search was conducted for completed phase II and III trials of compounds for schizophrenia treatment using the US Clinical Trials Registry and the EU Clinical Trials Register. Compounds demonstrating significant superiority over placebo in the primary outcome measure in the latest phase II and III trials were identified. Collateral information on the included compounds was gathered through manual searches in PubMed and press releases. RESULTS: Sixteen compounds were identified; four compounds (ulotaront, xanomeline/trospium chloride, vabicaserin, and roluperidone) were investigated as monotherapy and the remaining 12 (pimavanserin, bitopertin, BI 425809, encenicline, tropisetron, pregnenolone, D-serine, estradiol, tolcapone, valacyclovir, cannabidiol, and rimonabant) were examined as add-on therapy. Compared to the placebo, ulotaront, xanomeline/trospium chloride, vabicaserin, bitopertin, estradiol, cannabidiol, rimonabant, and D-serine showed efficacy for positive symptoms; roluperidone and pimavanserin were effective for negative symptoms; and encenicline, tropisetron, pregnenolone, tolcapone, BI 425809, and valacyclovir improved cognitive function. DISCUSSION: Compounds that function differently from existing antipsychotics may offer novel symptom-specific therapeutic strategies for patients with schizophrenia.

Comparison of changes in stress coping strategies between cognitive behavioral therapy and pharmacotherapy.

Background: Coping refers to conscious responses to negative circumstances, with the intention of ameliorating these situations. Few studies have compared the differences between psychotherapy and medication treatment for coping strategies for depression. In this study, we investigated the differences in coping strategies between cognitive behavioral therapy (CBT) combined with medication (CBT group) and medication alone (pharmacotherapy group) among outpatients with depression. Methods: A prospective observational study was conducted among 50 patients with major depression (24 and 26 in the CBT and pharmacotherapy groups, respectively). Stress coping strategies (Coping Inventory for Stressful Situations [CISS]) and depression severity (Beck Depression Inventory-Second Edition [BDI-II]) were assessed at baseline and 16 weeks later. Changes in the CISS and BDI-II scores in both groups were tested using repeated analysis of variance. Inverse probability weighting with propensity score analysis was applied to address potential selection bias. Results: At 16 weeks, the CBT group exhibited increased CISS task-oriented coping, distraction, and social diversion scores, which differed from those of the pharmacotherapy group. The CBT group exhibited a significantly greater reduction in depressive symptoms than the pharmacotherapy group. Limitations: This study was not a randomized controlled trial and thus may have selection bias. Conclusion: Gaining adaptive coping skills, including task-oriented coping, distraction, and social diversion skills, by combining CBT with medication may lead to greater improvement in depression symptoms. These findings suggest that clinicians should evaluate coping strategies and facilitate the acquisition of adaptive coping strategies in patients with depression to reduce their symptoms.

Comparable Psychotropic Prescription Rates After Hospital Discharge Between Patients with COVID-19 and Those With Non-COVID-19-Related Respiratory Infection.

INTRODUCTION: Whether psychiatric symptoms after recovery from coronavirus disease 2019 (COVID-19) are specific to this illness remains unclear. METHODS: In this retrospective study, the Diagnosis Procedure Combination data and outpatient clinic data were used for patients who received inpatient treatment in Saiseikai-affiliated hospitals for COVID-19 or other respiratory tract infections (non-COVID) from 2020 to 2022. The primary outcome was new prescriptions of psychotropic drugs after discharge (i. e., prescriptions of psychotropics to patients who had not received them before or during their hospitalization). Values of interest were compared between groups using the chi-square test or Fisher's exact test. A COX proportional-hazards model was used to examine factors associated with psychotropic prescriptions after discharge in age- and sex-matched COVID-19 and non-COVID patients. RESULTS: Of 31,993 chart records, 19,613 were excluded due to a positive history with psychiatric disorders (n=2,445), prescriptions of psychotropics (n=744), and no follow-ups (n=16,424). Thus, 3,648 COVID-19 and 8,732 non-COVID patients were included (mean [range] duration of follow-up, days: 146.9 [1-727] and 239.2 [1-729], respectively). Two hundred and four (5.6%) of the 3,648 patients with COVID-19 received psychotropic prescriptions after discharge. No statistically significant differences were observed in the prescription rates of any psychotropic category between the COVID-19 and non-COVID groups. An increase in severity during hospitalization was significantly associated with more frequent psychotropic prescriptions (hazard ratio 1.83, p<0.001). DISCUSSION: The development of psychiatric symptoms should be closely observed, especially in patients who experienced increased severity during hospitalization, regardless of whether they suffered from COVID-19.

Alterations in subcortical magnetic susceptibility and disease-specific relationship with brain volume in major depressive disorder and schizophrenia.

Quantitative susceptibility mapping is a magnetic resonance imaging technique that measures brain tissues' magnetic susceptibility, including iron deposition and myelination. This study examines the relationship between subcortical volume and magnetic susceptibility and determines specific differences in these measures among patients with major depressive disorder (MDD), patients with schizophrenia, and healthy controls (HCs). This was a cross-sectional study. Sex- and age- matched patients with MDD (n = 49), patients with schizophrenia (n = 24), and HCs (n = 50) were included. Magnetic resonance imaging was conducted using quantitative susceptibility mapping and T1-weighted imaging to measure subcortical susceptibility and volume. The acquired brain measurements were compared among groups using analyses of variance and post hoc comparisons. Finally, a general linear model examined the susceptibility-volume relationship. Significant group-level differences were found in the magnetic susceptibility of the nucleus accumbens and amygdala (p = 0.045). Post-hoc analyses indicated that the magnetic susceptibility of the nucleus accumbens and amygdala for the MDD group was significantly higher than that for the HC group (p = 0.0054, p = 0.0065, respectively). However, no significant differences in subcortical volume were found between the groups. The general linear model indicated a significant interaction between group and volume for the nucleus accumbens in MDD group but not schizophrenia or HC groups. This study showed susceptibility alterations in the nucleus accumbens and amygdala in MDD patients. A significant relationship was observed between subcortical susceptibility and volume in the MDD group's nucleus accumbens, which indicated abnormalities in myelination and the dopaminergic system related to iron deposition.

Decreased short-latency afferent inhibition in individuals with mild cognitive impairment: A TMS-EEG study.

TMS combined with EEG (TMS-EEG) is a tool to characterize the neurophysiological dynamics of the cortex. Among the TMS paradigms, short-latency afferent inhibition (SAI) allows the investigation of inhibitory effects mediated by the cholinergic system. The aim of this study was to compare cholinergic function in the DLPFC between individuals with mild cognitive impairment (MCI) and healthy controls (HC) using TMS-EEG with the SAI paradigm. In this study, 30 MCI and 30 HC subjects were included. The SAI paradigm consisted of 80 single pulse TMS and 80 SAI stimulations applied to the left DLPFC. N100 components, global mean field power (GMFP) and total power were calculated. As a result, individuals with MCI showed reduced inhibitory effects on N100 components and GMFP at approximately 100 ms post-stimulation and on ß-band activity at 200 ms post-stimulation compared to HC. Individuals with MCI showed reduced SAI, suggesting impaired cholinergic function in the DLPFC compared to the HC group. We conclude that these findings underscore the clinical applicability of the TMS-EEG method as a powerful tool for assessing cholinergic function in individuals with MCI.

Aberrant heartbeat-evoked potential in schizophrenia.

Self-disturbance is considered a core feature underlying the psychopathology of schizophrenia. Interoception has an important role in the development of a sense of self, leading to increased interest in the potential contribution of abnormal interoception to self-disturbances in schizophrenia. Several neuropsychological studies have demonstrated aberrant interoception in schizophrenia. However, cortical interoceptive processing has not yet been thoroughly investigated. Thus, we sought to examine resting-state heartbeat-evoked potential (HEP) in this population. We hypothesized that patients with schizophrenia would exhibit significant alterations in HEP compared to healthy controls (HCs). In this cross-sectional electroencephalogram (EEG) study, we compared the HEPs between age- and sex-matched groups of patients with schizophrenia and HCs. A 10-min resting-state EEG with eyes closed and an electrocardiogram (ECG) were recorded and analyzed for the time window of 450 ms to 500 ms after an ECG R peak. A positive HEP shift was observed in the frontal-central regions (F [1, 82] = 7.402, p = 0.008, partial η2 = 0.009) in patients with schizophrenia (n = 61) when compared with HCs (n = 31) after adjusting for confounders such as age, sex, and heart rate. A cluster-based correction analysis revealed that the HEP around the right frontal area (Fp2, F4, and F8) showed the most significant group differences (F [1, 82] = 10.079, p = 0.002, partial η2 = 0.021), with a peak at the F4 electrode site (F [1, 82] = 12.646, p < 0.001, partial η2 = 0.069). We observed no correlation between HEP and symptoms in patients with schizophrenia. A positive shift of HEP during the late component could reflect a trait abnormality in schizophrenia. Further research is required to determine the association between the altered cortical interoceptive processing indexed with HEP and self-disturbances in schizophrenia.

Development of the Japanese version of the Ego-Dissolution Inventory (EDI).

AIM: Psychedelics have recently gained attention as potential therapeutic agents for various psychiatric disorders. Previous research has highlighted that a diminished sense of self, commonly termed "ego-dissolution" is a pivotal feature of the psychedelic-induced state. While the Ego-Dissolution Inventory (EDI) is a widely acknowledged instrument for measuring this phenomenon, no Japanese version has been available. This study aimed to develop a Japanese version of the EDI. METHODS: We adhered to the "Guidelines for Best Practices in the Translation and Cultural Modification Process for Patient-Reported Outcomes Instruments: Document from the ISPOR Committee on Translation and Cultural Modification" during our translation approach. Two Japanese psychiatrists independently conducted initial translations, and a consolidated version was achieved via mutual agreement. This version was then back-translated to English and assessed by the original authors for consistency. The repetitive modification process was conducted in continuous dialogues with the original authors until they accepted the concluding back-translated version. RESULTS: The finalized, approved back-translated version of the EDI is presented in the accompanying figure. In addition, the authorized Japanese version of the EDI is included in the Appendix. CONCLUSIONS: In this study, we successfully developed the Japanese version of the EDI. This instrument will assist in assessing ego-dissolution experiences associated with psychedelic-assisted therapy among Japanese speakers. Additional studies are necessary to evaluate the reliability and validity of this newly translated instrument.

Unraveling the Influence of Age, IQ, Education, and Negative Symptoms on Neurocognitive Performance in Schizophrenia: A Conditional Inference Tree Analysis.

INTRODUCTION: The complex nature of neurocognitive impairment in schizophrenia has been discussed in light of the mixed effects of antipsychotic drugs, psychotic symptoms, dopamine D2 receptor blockade, and intelligence quotient (IQ). These factors have not been thoroughly examined before. METHODS: This study conducted a comprehensive re-analysis of the CATIE data using machine learning techniques, in particular Conditional Inference Tree (CTREE) analysis, to investigate associations between neurocognitive functions and moderating factors such as estimated trough dopamine D2 receptor blockade with risperidone, olanzapine, or ziprasidone, Positive and Negative Syndrome Scale (PANSS), and baseline IQ in 573 patients with schizophrenia. RESULTS: The study reveals that IQ, age, and education consistently emerge as significant predictors across all neurocognitive domains. Furthermore, higher severity of PANSS-negative symptoms was associated with lower cognitive performance scores in several domains. CTREE analysis, in combination with a genetic algorithm approach, has been identified as particularly insightful for illustrating complex interactions between variables. Lower neurocognitive function was associated with factors such as age>52 years, IQ<94/95,<12/13 education years, and more pronounced negative symptoms (score<26). CONCLUSIONS: These findings emphasize the multifaceted nature of neurocognitive functioning in patients with schizophrenia, with the PANSS-negative score being an important predictor. This gives rise to a role in addressing negative symptoms as a therapeutic objective for enhancing cognitive impairments in these patients. Further research must examine nonlinear relationships among various moderating factors identified in this work, especially the role of D2 occupancy.

Relationship between Loneliness and Mild Behavioral Impairment: Validation of the Japanese Version of the MBI Checklist and a Cross-Sectional Study.

Background: Mild behavioral impairment (MBI) and loneliness are associated with cognitive decline and an increased risk of dementia. Objective: Our aim was to examine the validity of the Japanese version of the MBI checklist (MBI-C) and investigate the relationship between loneliness and MBI. Methods: The participants in this cross-sectional study included 5 cognitively normal persons and 75 persons with mild cognitive impairment. MBI-C and the revised University of California at Los Angeles loneliness scale (LS) were used to assess MBI and loneliness, respectively. Diagnostic performance of MBI-C was examined using receiver operating characteristic analysis. The relationship between MBI-C and LS was examined using multiple linear regression in 67 subjects who were assessed with both scales, with MBI-C total or domain score as the dependent variable and LS as the independent variable, adjusted for age, gender, living situation, presence of visual and hearing impairment, and Mini-Mental State Examination score. Results: Per the Youden index, in this mostly MCI sample, the optimal MBI-C cut-off score was 5.5 with sensitivity 0.917 and specificity 0.949. In multiple linear regression analysis, LS score was detected as a significant predictor of MBI-C total scores, and MBI-C decreased motivation, affective dysregulation, and abnormal thought and perception scores. Conclusions: The caregiver-rated Japanese MBI-C has excellent diagnostic performance. Loneliness is associated with a greater MBI burden, especially in the decreased motivation, affective dysregulation, and abnormal thought and perception domains. Interventions for loneliness in older people may have the potential to improve MBI.

Update Lessons from PET Imaging Part II: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antidepressants.

BACKGROUND: Compared with antipsychotics, the relationship between antidepressant blood (plasma or serum) concentrations and target engagement is less well-established. METHODS: We have discussed the literature on the relationship between plasma concentrations of antidepressant drugs and their target occupancy. Antidepressants reviewed in this work are citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline, venlafaxine, duloxetine, milnacipran, tricyclic antidepressants (amitriptyline, nortriptyline, and clomipramine), bupropion, tranylcypromine, moclobemide, and vortioxetine. Four electronic databases were systematically searched. RESULTS: We included 32 articles published 1996-2022. A strong relationship between serotonin transporter (SERT) occupancy and drug concentration is well established for selective serotonin reuptake inhibitors. Lower limits of recommended therapeutic reference ranges largely corroborate with the findings from positron emission tomography studies (80% SERT occupancy). Only a few novel studies have investigated alternative targets, that is, norepinephrine transporters (NETs), dopamine transporters (DATs), or monoamine oxidase A (MAO-A). For certain classes of drugs, positron emission tomography study data are inconclusive. Low DAT occupancy after bupropion treatment speculates its discussed mechanism of action. For MAO inhibitors, a correlation between drug concentration and MAO-A occupancy could not be established. CONCLUSIONS: Neuroimaging studies are critical in TDM-guided therapy for certain antidepressants, whereas for bupropion and MAO inhibitors, the available evidence offers no further insight. Evidence for selective serotonin reuptake inhibitors is strong and justifies a titration toward suggested ranges. For SNRIs, duloxetine, and venlafaxine, NETs are sufficiently occupied, well above the SERT efficacy threshold. For these drugs, a titration toward higher concentrations (within the recommended range) should be considered in case of no response at lower concentrations.

Acetaldehyde-mediated increase in glutamatergic and N-acetylaspartate neurometabolite levels in the midcingulate cortex of ALDH2*1/*2 heterozygous young adults.

BACKGROUND: To elucidate the neurobiology underlying alcohol's effect on the human brain, we examined the acute effects of moderate alcohol administration on levels of glutamatergic neurometabolites and N-acetylaspartate, an amino acid found in neurons, may reflect disordered neuronal integrity. METHODS: Eighteen healthy Japanese participants (7 males/11 females) aged 20-30 years who were heterozygous for an inactive allele of acetaldehyde dehydrogenase-2 (ALDH/*1/*2) were included. Participants underwent an intravenous alcohol infusion using the clamp method at a target blood alcohol concentration (BAC) of 0.50 mg/mL for 90 min within a range of ±0.05 mg/mL. We examined glutamate + glutamine (Glx) and N-acetylaspartate N-acetylaspartylglutamate (NAA) levels in the midcingulate cortex (MCC) using 3 T 1 H-MRS PRESS at baseline, 90 min, and 180 min (i.e., 90 min after alcohol infusion was finished). A two-way repeated-measures analysis of variance was used to assess longitudinal changes in Glx and NAA levels, with time and sex as within- and between-subject factors, respectively. Pearson's correlation coefficients were calculated among neurometabolite levels and BAC or blood acetaldehyde concentration (BAAC). RESULTS: Both Glx (F(2,32) = 8.15, p = 0.004, η2 = 0.15) and NAA (F(2,32) = 5.01, p = 0.04, η2 = 0.07) levels were increased after alcohol injection. There were no sex or time × sex interaction effects observed. NAA levels were positively correlated with BAAC at 90 min (r(13) = 0.77, p = 0.01). There were no associations between neurometabolite levels and BAC. CONCLUSIONS: Both Glx and NAA levels in the MCC increased in response to the administration of moderate concentrations of alcohol. Given positive associations between NAA levels and BAAC and the hypothetical glutamate release via dopamine pathways, the effects of drinking on the MCC in the acute phase may be ascribed to acetaldehyde metabolized from alcohol.

Disease Progression Patterns of Brain Morphology in Schizophrenia: More Progressed Stages in Treatment Resistance.

BACKGROUND AND HYPOTHESIS: Given the heterogeneity and possible disease progression in schizophrenia, identifying the neurobiological subtypes and progression patterns in each patient may lead to novel biomarkers. Here, we adopted data-driven machine-learning techniques to identify the progression patterns of brain morphological changes in schizophrenia and investigate the association with treatment resistance. STUDY DESIGN: In this cross-sectional multicenter study, we included 177 patients with schizophrenia, characterized by treatment response or resistance, with 3D T1-weighted magnetic resonance imaging. Cortical thickness and subcortical volumes calculated by FreeSurfer were converted into z scores using 73 healthy controls data. The Subtype and Stage Inference (SuStaIn) algorithm was used for unsupervised machine-learning analysis. STUDY RESULTS: SuStaIn identified 3 different subtypes: (1) subcortical volume reduction (SC) type (73 patients), in which volume reduction of subcortical structures occurs first and moderate cortical thinning follows, (2) globus pallidus hypertrophy and cortical thinning (GP-CX) type (42 patients), in which globus pallidus hypertrophy initially occurs followed by progressive cortical thinning, and (3) cortical thinning (pure CX) type (39 patients), in which thinning of the insular and lateral temporal lobe cortices primarily happens. The remaining 23 patients were assigned to baseline stage of progression (no change). SuStaIn also found 84 stages of progression, and treatment-resistant schizophrenia showed significantly more progressed stages than treatment-responsive cases (P = .001). The GP-CX type presented earlier stages than the pure CX type (P = .009). CONCLUSIONS: The brain morphological progressions in schizophrenia can be classified into 3 subtypes, and treatment resistance was associated with more progressed stages, which may suggest a novel biomarker.

Factors Associated with Antidepressant Effects of Ketamine: A Reanalysis of Double-Blind Randomized Placebo-Controlled Trial of Intravenous Ketamine for Treatment-Resistant Depression.

INTRODUCTION: Predictors of treatment response to intravenous ketamine remain unclear in patients with treatment-resistant depression (TRD); therefore, this study aimed to clarify these predictors using the US National Institutes of Health database of clinical trials. METHODS: Data from a placebo-controlled, double-blind, randomized controlled trial were used to assess the efficacy of intravenous ketamine in adult patients with TRD (NCT01920555). For the analysis, data were used from the participants who had received therapeutic doses of intravenous ketamine (i. e., 0.5 and 1.0 mg/kg). Logistic and multivariable regression analyses were conducted to explore the demographic and clinical factors associated with response to treatment or changes in the Hamilton Depression Rating Scale 6 items (HAM-D-6) total score. RESULTS: This study included 31 patients with TRD (13 women; mean±standard deviation age, 48.4±10.9 years). Logistic regression analysis showed that the age of onset was positively correlated with treatment response after three days of ketamine administration (ß=0.08, p=0.037); however, no association was observed between treatment response and age, sex, baseline HAM-D-6 total score, or dissociative score assessed with the Clinician-Administered Dissociative States Scale 40 min after ketamine infusion. Multiple regression analysis showed that no factors were correlated significantly with the percentage change in the HAM-D-6 total score three days after ketamine administration. DISCUSSION: Later disease onset correlates with a better treatment response three days after ketamine infusion in patients with TRD. Glutamatergic signal transmission may be impaired in patients with an earlier onset of depression, resulting in decreased neuroplasticity, which diminishes ketamine response.

Development of the Japanese version of the 30-item Mystical Experience Questionnaire.

INTRODUCTION: Psychedelics have garnered increased attention as potential therapeutic options for various mental illnesses. Previous studies reported that psychedelics cause psychoactive effects through mystical experiences induced by these substances, including an altered state of consciousness. While this phenomenon is commonly assessed by the Mystical Experiences Questionnaire (MEQ30), a Japanese version of the MEQ30 has not been available. The aim of this study was to develop the Japanese version of the MEQ30. METHODS: We adhered to the "Principles of Good Practice for the Translation and Cultural Adaptation Process for Patient-Reported Outcomes (PRO) Measures: Report of the ISPOR Task Force for Translation and Cultural Adaptation" in our translation process. Two Japanese psychiatrists independently performed forward translations, from which a unified version was derived through reconciliation. This version was subsequently back-translated into English and reviewed by the original authors for equivalency. The iterative revision process was carried out through ongoing discussions with the original authors until they approved the final back-translated version. RESULTS: The final, approved back-translated version of the MEQ30 is presented in the accompanying figure. Additionally, the authorized Japanese version of the MEQ30 is included in the Appendix A. CONCLUSIONS: In this study, we successfully developed a Japanese version of the MEQ30. This scale will facilitate the assessment of mystical experiences associated with psychedelic-assisted therapy among Japanese speakers. Further research is warranted to evaluate the reliability and validity of this newly translated scale.

Update Lessons from Positron Emission Tomography Imaging Part I: A Systematic Critical Review on Therapeutic Plasma Concentrations of Antipsychotics.

BACKGROUND: Positron emission tomography (PET) and single photon emission tomography (SPECT) of molecular drug targets (neuroreceptors and transporters) provide essential information for therapeutic drug monitoring-guided antipsychotic drug therapy. The optimal therapeutic windows for D 2 antagonists and partial agonists, as well as their proposed target ranges, are discussed based on an up-to-date literature search. METHODS: This part I of II presents an overview of molecular neuroimaging studies in humans and primates involving the target engagement of amisulpride, haloperidol, clozapine, aripiprazole, olanzapine, quetiapine, risperidone, cariprazine, and ziprasidone. The systemic review particularly focused on dopamine D 2 -like and 5-HT 2A receptors. Target concentration ranges were estimated based on receptor occupancy ranges that relate to clinical effects or side effects (ie, extrapyramidal side effects). In addition, findings for other relevant receptor systems were included to further enrich the discussion. RESULTS: The reported reference ranges for aripiprazole and clozapine align closely with findings from PET studies. Conversely, for haloperidol, risperidone, and olanzapine, the PET studies indicate that a lowering of the previously published upper limits would be necessary to decrease the risk of extrapyramidal side effect. CONCLUSIONS: Molecular neuroimaging studies serve as a strong tool for defining target ranges for antipsychotic drug treatment and directing therapeutic drug monitoring.

Associations Between Structural Covariance Network and Antipsychotic Treatment Response in Schizophrenia.

BACKGROUND AND HYPOTHESIS: Schizophrenia is associated with widespread cortical thinning and abnormality in the structural covariance network, which may reflect connectome alterations due to treatment effect or disease progression. Notably, patients with treatment-resistant schizophrenia (TRS) have stronger and more widespread cortical thinning, but it remains unclear whether structural covariance is associated with treatment response in schizophrenia. STUDY DESIGN: We organized a multicenter magnetic resonance imaging study to assess structural covariance in a large population of TRS and non-TRS, who had been resistant and responsive to non-clozapine antipsychotics, respectively. Whole-brain structural covariance for cortical thickness was assessed in 102 patients with TRS, 77 patients with non-TRS, and 79 healthy controls (HC). Network-based statistics were used to examine the difference in structural covariance networks among the 3 groups. Moreover, the relationship between altered individual differentiated structural covariance and clinico-demographics was also explored. STUDY RESULTS: Patients with non-TRS exhibited greater structural covariance compared with HC, mainly in the fronto-temporal and fronto-occipital regions, while there were no significant differences in structural covariance between TRS and non-TRS or HC. Higher individual differentiated structural covariance was associated with lower general scores of the Positive and Negative Syndrome Scale in the non-TRS group, but not in the TRS group. CONCLUSIONS: These findings suggest that reconfiguration of brain networks via coordinated cortical thinning is related to treatment response in schizophrenia. Further longitudinal studies are warranted to confirm if greater structural covariance could serve as a marker for treatment response in this disease.

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

BACKGROUND: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

[Psychedelic Drugs: Past, Present, and Future].

In recent years, there has been a growing movement to apply psychedelic drugs for treating psychiatric disorders, including depression. Although the therapeutic effects of psychedelic drugs were verified in the 1960s, their abuse by the public led to their designation as narcotics in 1970, and clinical research on them was suspended for a time. However, since 1994, clinical trials have been conducted in large numbers and elicited great excitement. In this review, we consider the history of psychedelic drugs with potent therapeutic effects and outline the prospects for this field.