Development of the Japanese version of the Challenging Experience Questionnaire.

INTRODUCTION: The therapeutic potential of psychedelics for various mental disorders has gained significant interest. Previous studies have highlighted that psychedelics induce psychoactive effects, including challenging aspects of experiences. These experiences are assessed using the Challenging Experience Questionnaire (CEQ), yet its Japanese version has been unavailable. This study aimed to create a Japanese version of the CEQ. METHODS: We followed 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." Initially, two Japanese psychiatrists independently conducted the forward translations. These were then reconciled into a single version, which was back-translated into English. The original authors reviewed this back-translation for accuracy, leading to revisions through continuous dialogue until the original authors approved the final version. RESULTS: The final, approved back-translated version of the CEQ is presented in the figure. CONCLUSIONS: This study developed a Japanese version of the CEQ, enabling the assessment of challenging experiences during psychedelic-assisted therapy for Japanese speakers. Further studies are needed to assess the reliability and validity of this newly translated version.

The effect of second-generation antipsychotics on anxiety/depression in patients with schizophrenia: A systematic review and meta-analysis.

OBJECTIVE: Despite the high prevalence of anxiety in schizophrenia, no established guideline exists for the management of these symptoms. We aimed to synthesize evidence on the effect of second-generation antipsychotics (SGAs) on anxiety in patients with schizophrenia. METHODS: We systematically searched Medline, Embase, PsycInfo, Web of Science, PubMed, and Cochrane library to identify randomized controlled trials of SGAs that reporting anxiety measures in schizophrenia. The search was limited to English-language articles published before February 2024. Data were pooled using a random-effects model. RESULTS: Among 48 eligible studies, 29 (n = 7712) were included in the meta-analyses comparing SGAs to placebo, haloperidol, or another SGAs for their effect on anxiety/depression. SGAs had a small effect on anxiety/depression versus placebo (SMD = -0.28 (95 % CI [-0.34, -0.21], p < .00001, I2 = 47 %, n = 5576)) associated with efficacy for positive (z = 5.679, p < .001) and negative symptoms (z = 4.490, p < .001). Furthermore, SGAs were superior to haloperidol (SMD = -0.44, 95 % CI [-0.75, -0.13], p = .005, n = 1068) with substantial study-level heterogeneity (I2 = 85 %). Excluding one study of quetiapine in first-episode patients (SMD = -3.05, n = 73), SGAs showed a small effect on anxiety/depression versus haloperidol without heterogeneity (SMD = -0.23, 95 % CI [-0.35, -0.12], p = 01; I2 = %0). Risperidone's effect on anxiety/depression was comparable to olanzapine (SMD = -0.02, 95 % CI [-0.24,0.20], p = .87, I2 = 45 %, n = 753) and amisulpride (SMD = 0.27, 95 % CI [-1.08,0.61], p = .13, I2 = 50 %, n = 315). CONCLUSION: While SGAs showed a small effect on anxiety/depression, the findings are inconclusive due to scarcity of research on comorbid anxiety in schizophrenia, heterogeneity of anxiety symptoms, and the scales used to measure anxiety. Further studies employing specific anxiety scales are required to explore antipsychotics, considering their receptor affinity and augmentation with serotonin/norepinephrine reuptake inhibitors or benzodiazepines for managing anxiety in schizophrenia.

Elevated intrinsic cortical curvature in treatment-resistant schizophrenia: Evidence of structural deformation in functional connectivity areas and comparison with alternate indices of structure.

BACKGROUND: Research suggests structural and connectivity abnormalities in patients with treatment-resistant schizophrenia (TRS) compared to first-line responders and healthy-controls. However, measures of these abnormalities are often influenced by external factors like nicotine and antipsychotics, limiting their clinical utility. Intrinsic-cortical-curvature (ICC) presents a millimetre-scale measure of brain gyrification, highly sensitive to schizophrenia differences, and associated with TRS-like traits in early stages of the disorder. Despite this evidence, ICC in TRS remains unexplored. This study investigates ICC as a marker for treatment resistance in TRS, alongside structural indices for comparison. METHODS: We assessed ICC in anterior cingulate, dorsolateral prefrontal, temporal, and parietal cortices of 38 first-line responders, 30 clozapine-resistant TRS, 37 clozapine-responsive TRS, and 52 healthy-controls. For comparative purposes, Fold and Curvature indices were also analyzed. RESULTS: Adjusting for age, sex, nicotine-use, and chlorpromazine equivalence, principal findings indicate ICC elevations in the left hemisphere dorsolateral prefrontal (p < 0.001, η2partial = 0.142) and temporal cortices (LH p = 0.007, η2partial = 0.060; RH p = 0.011, η2partial = 0.076) of both TRS groups, and left anterior cingulate cortex of clozapine-resistant TRS (p = 0.026, η2partial = 0.065), compared to healthy-controls. Elevations that correlated with reduced cognition (p = 0.001) and negative symptomology (p < 0.034) in clozapine-resistant TRS. Fold and Curvature indices only detected group differences in the right parietal cortex, showing interactions with age, sex, and nicotine use. ICC showed interactions with age. CONCLUSION: ICC elevations were found among patients with TRS, and correlated with symptom severity. ICCs relative independence from sex, nicotine-use, and antipsychotics, may support ICC's potential as a viable marker for TRS, though age interactions should be considered.

A comparative study of the dorsolateral prefrontal cortex targeting approaches for transcranial magnetic stimulation treatment: Insights from the healthy control data.

Repetitive transcranial magnetic stimulation (rTMS) to the left dorsolateral prefrontal cortex (DLPFC) is an established treatment for medication-resistant depression. Several targeting methods for the left DLPFC have been proposed including identification with resting-state functional magnetic resonance imaging (rs-fMRI) neuronavigation, stimulus coordinates based on structural MRI, or electroencephalography (EEG) F3 site by Beam F3 method. To date, neuroanatomical and neurofunctional differences among those approaches have not been investigated on healthy subjects, which are structurally and functionally unaffected by psychiatric disorders. This study aimed to compare the mean location, its dispersion, and its functional connectivity with the subgenual cingulate cortex (SGC), which is known to be associated with the therapeutic outcome in depression, of various approaches to target the DLPFC in healthy subjects. Fifty-seven healthy subjects underwent MRI scans to identify the stimulation site based on their resting-state functional connectivity and were measured their head size for targeting with Beam F3 method. In addition, we included two fixed stimulus coordinates over the DLPFC in the analysis, as recommended in previous studies. From the results, the rs-fMRI method had, as expected, more dispersed target sites across subjects and the greatest anticorrelation with the SGC, reflecting the known fact that personalized neuronavigation yields the greatest antidepressant effect. In contrast, the targets located by the other methods were relatively close together with less dispersion, and did not differ in anticorrelation with the SGC, implying their limitation of the therapeutic efficacy and possible interchangeability of them.

Real-world case series of maintenance theta burst stimulation therapy following response to acute theta burst stimulation therapy for difficult-to-treat depression.

OBJECTIVE: Treatment and management for difficult-to-treat depression are challenging, especially in a subset of patients who are at high risk for relapse and recurrence. The conditions that represent this subset are recurrent depressive disorder (RDD) and bipolar disorder (BD). In this context, we aimed to examine the effectiveness of maintenance transcranial magnetic stimulation (TMS) on a real-world clinical basis by retrospectively extracting data from the TMS registry data in Tokyo, Japan. METHODS: Data on patients diagnosed with treatment-resistant RDD and BD who received maintenance intermittent theta burst stimulation (iTBS) weekly after successful treatment with acute iTBS between March 2020 and October 2023 were extracted from the registry. RESULTS: All patients (21 cases: 10 cases with RDD and 11 cases with BD) could sustain response, and 19 of them further maintained remission. In this study, maintenance iTBS did not exacerbate depressive symptoms in any of the cases, but may rather have the effect of stabilizing the mental condition and preventing recurrence. CONCLUSIONS: This case series is of great clinical significance because it is the first study to report on the effectiveness of maintenance iTBS for RDD and BD, with a follow-up of more than 2 years. Further validation with a randomized controlled trial design with a larger sample size is warranted.

Evaluation of the Glymphatic System in Schizophrenia Spectrum Disorder Using Proton Magnetic Resonance Spectroscopy Measurement of Brain Macromolecule and Diffusion Tensor Image Analysis Along the Perivascular Space Index.

BACKGROUND AND HYPOTHESIS: The glymphatic system (GS), a brain waste clearance pathway, is disrupted in various neurodegenerative and vascular diseases. As schizophrenia shares clinical characteristics with these conditions, we hypothesized GS disruptions in patients with schizophrenia spectrum disorder (SCZ-SD), reflected in increased brain macromolecule (MM) and decreased diffusion-tensor-image-analysis along the perivascular space (DTI-ALPS) index. STUDY DESIGN: Forty-seven healthy controls (HCs) and 103 patients with SCZ-SD were studied. Data included 135 proton magnetic resonance spectroscopy (1H-MRS) sets, 96 DTI sets, with 79 participants contributing both. MM levels were quantified in the dorsal-anterior cingulate cortex (dACC), dorsolateral prefrontal cortex, and dorsal caudate (point resolved spectroscopy, echo-time = 35ms). Diffusivities in the projection and association fibers near the lateral ventricle were measured to calculate DTI-ALPS indices. General linear models were performed, adjusting for age, sex, and smoking. Correlation analyses examined relationships with age, illness duration, and symptoms severity. STUDY RESULTS: MM levels were not different between patients and HCs. However, left, right, and bilateral DTI-ALPS indices were lower in patients compared with HCs (P < .001). In HCs, age was positively correlated with dACC MM and negatively correlated with left, right, and bilateral DTI-ALPS indices (P < .001). In patients, illness duration was positively correlated with dACC MM and negatively correlated with the right DTI-ALPS index (P < .05). In the entire population, dACC MM and DTI-ALPS indices showed an inverse correlation (P < .01). CONCLUSIONS: Our results suggest potential disruptions in the GS of patients with SCZ-SD. Improving brain's waste clearance may offer a potential therapeutic approach for patients with SCZ-SD.

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.

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.

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.

Short-Term Effect of Auditory Stimulation on Neural Activities: A Scoping Review of Longitudinal Electroencephalography and Magnetoencephalography Studies.

Explored through EEG/MEG, auditory stimuli function as a suitable research probe to reveal various neural activities, including event-related potentials, brain oscillations and functional connectivity. Accumulating evidence in this field stems from studies investigating neuroplasticity induced by long-term auditory training, specifically cross-sectional studies comparing musicians and non-musicians as well as longitudinal studies with musicians. In contrast, studies that address the neural effects of short-term interventions whose duration lasts from minutes to hours are only beginning to be featured. Over the past decade, an increasing body of evidence has shown that short-term auditory interventions evoke rapid changes in neural activities, and oscillatory fluctuations can be observed even in the prestimulus period. In this scoping review, we divided the extracted neurophysiological studies into three groups to discuss neural activities with short-term auditory interventions: the pre-stimulus period, during stimulation, and a comparison of before and after stimulation. We show that oscillatory activities vary depending on the context of the stimuli and are greatly affected by the interplay of bottom-up and top-down modulational mechanisms, including attention. We conclude that the observed rapid changes in neural activitiesin the auditory cortex and the higher-order cognitive part of the brain are causally attributed to short-term auditory interventions.

Neuroplasticity of the left dorsolateral prefrontal cortex in patients with treatment-resistant depression as indexed with paired associative stimulation: a TMS-EEG study.

Major depressive disorder affects over 300 million people globally, with approximately 30% experiencing treatment-resistant depression (TRD). Given that impaired neuroplasticity underlies depression, the present study focused on neuroplasticity in the dorsolateral prefrontal cortex (DLPFC). Here, we aimed to investigate the differences in neuroplasticity between 60 individuals with TRD and 30 age- and sex-matched healthy controls (HCs). To induce neuroplasticity, participants underwent a paired associative stimulation (PAS) paradigm involving peripheral median nerve stimulation and transcranial magnetic stimulation (TMS) targeting the left DLPFC. Neuroplasticity was assessed by using measurements combining TMS with EEG before and after PAS. Both groups exhibited significant increases in the early component of TMS-evoked potentials (TEP) after PAS (P < 0.05, paired t-tests with the bootstrapping method). However, the HC group demonstrated a greater increase in TEPs than the TRD group (P = 0.045, paired t-tests). Additionally, event-related spectral perturbation analysis highlighted that the gamma power significantly increased after PAS in the HC group, whereas it was decreased in the TRD group (P < 0.05, paired t-tests with the bootstrapping method). This gamma power modulation revealed a significant group difference (P = 0.006, paired t-tests), indicating an inverse relationship for gamma power modulation. Our findings underscore the impaired neuroplasticity of the DLPFC in individuals with TRD.

Development of Artificial Intelligence for Determining Major Depressive Disorder Based on Resting-State EEG and Single-Pulse Transcranial Magnetic Stimulation-Evoked EEG Indices.

Depression is the disorder with the greatest socioeconomic burdens. Its diagnosis is still based on an operational diagnosis derived from symptoms, and no objective diagnostic indicators exist. Thus, the present study aimed to develop an artificial intelligence (AI) model to aid in the diagnosis of depression from electroencephalography (EEG) data by applying machine learning to resting-state EEG and transcranial magnetic stimulation (TMS)-evoked EEG acquired from patients with depression and healthy controls. Resting-state EEG and single-pulse TMS-EEG were acquired from 60 patients and 60 healthy controls. Power spectrum analysis, phase synchronization analysis, and phase-amplitude coupling analysis were conducted on EEG data to extract feature candidates to apply different types of machine learning algorithms. Furthermore, to address the limitation of the sample size, dimensionality reduction was performed in a manner to increase the quality of information by featuring robust neurophysiological metrics that showed significant differences between the two groups. Then, nine different machine learning models were applied to the data. For the EEG data, we created models combining four modalities, including (1) resting-state EEG, (2) pre-stimulus TMS-EEG, (3) post-stimulus TMS-EEG, and (4) differences between pre- and post-stimulus TMS-EEG, and evaluated their performance. We found that the best estimation performance (a mean area under the curve of 0.922) was obtained using receiver operating characteristic curve analysis when linear discriminant analysis (LDA) was applied to the combination of the four feature sets. This study showed that by using TMS-EEG neurophysiological indices as features, it is possible to develop a depression decision-support AI algorithm that exhibits high discrimination accuracy.

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.

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.

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.

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.