Thalamocortical functional connectivity and rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression.

Previous studies have shown an association between the thalamocortical dysconnectivity and treatment-resistant depression (TRD). Whether a single subanesthetic dose of ketamine may change thalamocortical connectivity among patients with TRD is unclear. Whether these changes in thalamocortical connectivity is associated with the antidepressant and antisuicidal effects of ketamine treatment is also unclear. Two resting-state functional MRIs were collected in two clinical trials of 48 patients with TRD (clinical trial 1; 32 receiving ketamine, 16 receiving a normal saline placebo) and 48 patients with TRD and strong suicidal ideation (clinical trial 2; 24 receiving ketamine, 24 receiving midazolam), respectively. All participants underwent rs-fMRI before and 3 days after infusion. Seed-based functional connectivity (FC) was analyzed in the left/right thalamus. FCs between the bilateral thalamus and right middle frontal cortex (BA46) and between the left thalamus and left anterior paracingulate gyrus (BA8) increased among patients in the ketamine group in clinical trials 1 and 2, respectively. FCs between the right thalamus and bilateral frontal pole (BA9) and between the right thalamus and left rostral paracingulate gyrus (BA10) decreased among patients in the ketamine group in clinical trials 1 and 2, respectively. However, the associations between those FC changes and clinical symptom changes did not survive statistical significance after multiple comparison corrections. Whether ketamine-related changes in thalamocortical connectivity may be associated with ketamine's antidepressant and antisuicidal effects would need further investigation. Clinical trials registration: UMIN Clinical Trials Registry (UMIN-CTR): Registration number: UMIN000016985 and UMIN000033916.

Effects of Low-Dose Ketamine Infusion on the Positive and Negative Domains of Hopelessness and Suicidal Thoughts.

Background: Low-dose ketamine infusion has been demonstrated to exert antisuicidal effects on patients with treatment-resistant depression (TRD) and strong suicidal ideation. Although evidence suggests an association between hopelessness and suicidality, very few studies have investigated the antihopelessness effects of ketamine.Methods: This study included 84 patients with TRD and strong suicidal ideation. The diagnosis of depression was based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, diagnostic criteria for major depressive disorder. They were randomly assigned to receive a single infusion of either 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. Hopelessness and suicidal symptoms were assessed at baseline, at 240 minutes postinfusion, and on Days 2, 3, 7, and 14 postinfusion. The assessments were performed using the self-report Beck Hopelessness Scale (BHS) and Positive and Negative Suicide Ideation Inventory (PANSI). The analysis focused on the positive and negative domains of the BHS and PANSI, respectively. The clinical trial was conducted between August 15, 2018, and November 30, 2021.Results: Statistical analyses performed using a generalized linear model revealed that the ketamine group had significantly higher PANSI-positive (P = .008) and lower PANSI-negative (P = .015) suicidal ideation scores on Day 2 postinfusion than did the midazolam group. At 240 minutes postinfusion, the ketamine group had significantly lower BHS-negative domain scores than did the midazolam group (P = .031). Notably, the observed ketamine-induced reduction in hopelessness at 240 minutes postinfusion was associated with its antisuicidal effect on Day 2 postinfusion.Discussion: A single infusion of low-dose ketamine resulted in a brief (∼4 hours) yet significant reduction in hopelessness. Subjective antisuicidal effects of ketamine were noted on Day 2 postinfusion. Further studies are needed to elucidate the neuromechanisms underlying the antihopelessness and antisuicidal effects of ketamine.Trial Registration: UMIN Clinical Trials Registry identifiers: UMIN000033916 and UMIN000033760.

Correlation of Disease Severity, Proinflammatory Cytokines, and Reduced Brain Gray Matter Volumes in Patients with Atopic Dermatitis.

Background: Atopic dermatitis (AD) is a chronic inflammatory skin disease. However, few studies have investigated brain changes associated with chronic inflammation. We hypothesized that chronic inflammation might be related to brain structural alterations in patients with AD. Objectives: To investigate the association between disease severity (Eczema Area and Severity Index [EASI]), proinflammatory cytokines, and differences in brain gray matter (GM) volume in patients with AD. Methods: Nineteen patients with AD and 19 age- and sex-matched healthy subjects were enrolled. All participants underwent clinical assessment and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze GM volume differences. Results: Patients with AD exhibited significantly decreased GM volume in many brain regions, such as bilateral precentral gyrus, right frontal pole, and right middle temporal gyrus (P < 0.001), compared with healthy subjects. Notably, in patients with AD, the GM volume in right middle temporal gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R [soluble interleukin 2 receptor] and TNF-α receptor-1), whereas the GM volume in left precentral gyrus was negatively associated with both EASI score and proinflammatory cytokines (sIL-2R and CRP). Conclusion: Patients with AD demonstrated significant brain GM volume reduction in many brain regions, which is related to disease severity and proinflammatory cytokines.

Association between cortical thickness or surface area and divergent thinking in patients with bipolar disorder.

OBJECTIVE: Divergent thinking is a critical creative cognitive process. Its neural mechanisms have been well-studied through structural and functional imaging in healthy individuals but are less explored in patients with bipolar disorder (BD). Because of the traditional link between creativity and BD, this study investigated the structural correlates of divergent thinking in patients with BD through surface-based morphometry. METHODS: Fifty-nine patients diagnosed with BD I or BD II (35.3 ± 8.5 years) and 56 age- and sex-matched controls (33.9 ± 7.4 years) were recruited. The participants underwent structural magnetic resonance imaging and an evaluation of divergent thinking by using the Chinese version of the Abbreviated Torrance Test for Adults (ATTA). FreeSurfer 7.0 was used to generate thickness and surface area maps for each participant. Brainwise regression of the association between cortical thickness or surface area and ATTA performance was conducted using general linear models. RESULTS: Divergent thinking performance did not differ significantly between the patients with BD and the healthy controls. In these patients, total ATTA score was negatively correlated with cortical thickness in the right middle frontal gyrus, right occipital, and left precuneus but positively correlated with the surface area of the right superior frontal gyrus. By contrast, total ATTA scores and cortical thickness or surface area were not significantly correlated among the controls. CONCLUSION: The findings indicate that divergent thinking involves cerebral structures for executive control, mental imagery, and visual processing in patients with BD, and the right prefrontal cortex might be the most crucial of these structures.

Current suicide risk, but not lifetime history of attempted suicide, predicts treatment response to low-dose ketamine infusion: Post Hoc analysis of adjunctive ketamine study of Taiwanese patients with treatment-resistant depression.

Whether current suicide risk or a history of attempted suicide is related to the antidepressant effect of a low-dose ketamine infusion remains unclear. In total, 47 patients with treatment-resistant depression (TRD), including 32 with low current suicide risk and 15 with moderate or high current suicide risk, were randomized to groups receiving a low-dose ketamine infusion of either 0.2 or 0.5 mg/kg. Among the patients, 21 had a lifetime history of attempted suicide. Suicide risk was assessed based on the Suicidal scale of the Mini-International Neuropsychiatric Interview. The 17-item Hamilton Depression Rating Scale (HDRS) was used to measure depressive symptoms at baseline, at 40 and 240 min after infusion, and sequentially on Days 2-7 and 14 after ketamine infusion. Generalized estimating equation models indicated that the time effects of both 0.5 and 0.2 mg/kg ketamine infusions were significant during the study period. The models also indicated that current suicide risk (p = .037) but not lifetime history of attempted suicide (p = .184) was related to the trajectory of total HDRS scores. Patients with moderate-to-high current suicide risk benefited more from the low-dose ketamine infusion compared with those with the low current suicide risk. Patients with TRD having moderate or high current suicide risk may be prioritized to receive a low-dose ketamine infusion, which may aid suicide prevention. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Effects of melancholic features on positive and negative suicidal ideation in patients with treatment-resistant depression and strong suicidal ideation receiving low-dose ketamine infusion.

The role of melancholic features on the antisuicidal effect of 0.5 mg/kg ketamine infusion has remained unclear in patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI). Whether ketamine diminishes suicidal ideation in patients with TRD-SI was also unknown. We enrolled 84 patients with TRD-SI, including 27 with melancholic features and 57 without, and then randomly administered a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The clinician-rated Montgomery-Åsberg Depression Rating Scale (MADRS) item 10, Columbia Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS), and self-reported Positive and Negative Suicide Ideation Inventory (PANSI) were used to assess suicidal symptoms from baseline to day 7. Generalized estimating equation models showed that only patients without melancholic features (MADRS item 10: infusion group effect, p = 0.017; CSSRS-ISS: infusion group × time effect, p = 0.008; PANSI-negative suicidal ideation: infusion group effect, p = 0.028) benefited from the antisuicidal effect of low-dose ketamine. The PANSI-positive ideation scores were higher in the ketamine group than in the midazolam group (p = 0.038) for patients with melancholic features. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI. Additional studies are necessary to clarify the neuromechanisms underlying the ketamine-related positive effect against SI and antisuicidal effects among patients with TRD-SI.

Role of klotho on antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression and suicidal ideation.

OBJECTIVE: Previous studies have found an association between klotho, an anti-aging hormone, and major depressive disorder. However, whether low-dose ketamine infusion alters klotho levels among patients with treatment-resistant depression (TRD) remains unknown. METHODS: In total, 48 patients with TRD and strong suicidal ideation were randomly assigned to a single 0.5 mg/kg ketamine or 0.045 mg/kg midazolam regimen and were subjected to a 2-week follow-up. Depressive and suicidal symptoms were assessed before the infusion and during the follow-up. The serum levels of klotho were assessed at baseline and 3 days postinfusion. RESULTS: A generalized linear model with adjustment of baseline klotho levels showed that, despite the fact that ketamine did not significantly increase levels of klotho, patients in the ketamine group had higher levels of klotho at Day 3 postinfusion than patients in the midazolam group (p = 0.043). However, we found no association between changes in klotho levels and changes in depressive and suicidal symptoms (all p > 0.05). Higher klotho levels at baseline were associated with poorer antidepressant effect of low-dose ketamine during postinfusion follow-up. DISCUSSION: Klotho may play a role in the antidepressant effect of low-dose ketamine. Additional molecular studies are necessary to elucidate the neuromechanisms of TRD, ketamine, and klotho.

Effects of low-dose ketamine infusion on vascular endothelial growth factor and matrix metalloproteinase-9 among patients with treatment-resistant depression and suicidal ideation.

BACKGROUND: Evidence indicates that vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) influence the pathophysiology of depression. However, whether low-dose ketamine regulates VEGF and MMP-9 levels and whether changes in VEGF and MMP-9 levels are associated with the antidepressant and antisuicidal effects of ketamine remained unclear. METHODS: Forty-eight patients with treatment-resistant depression and strong suicidal ideation (TRD-SI) were randomly assigned to a single infusion of 0.5-mg/kg ketamine or 0.045-mg/kg midazolam. The Montgomery-Åsberg Depression Rating Scale (MADRS) and Columbia-Suicide Severity Rating Scale-Ideation Severity Subscale (CSSRS-ISS) were used at baseline and subsequently at several postinfusion timepoints. VEGF and MMP-9 serum levels were analyzed at baseline and on day 3 postinfusion. RESULTS: After adjustment for baseline levels, no significant differences in VEGF (p = .912) and MMP-9 (p = .758) levels were identified on day 3 postinfusion between the study groups. Baseline VEGF levels but not MMP-9 levels were negatively associated with MADRS and CSSRS-ISS scores following infusion. DISCUSSION: A single infusion of low-dose ketamine did not alter the VEGF and MMP-9 levels of the patients with TRD-SI. Higher baseline VEGF levels were associated with greater antidepressant and antisuicidal effects of single low-dose ketamine infusion.

Next generation antidepressants with novel mechanisms for treatment resistant depression.

Evidence has suggested that the modulation of N-methyl-d-aspartate receptors (NMDARs) and 5-hydroxytryptamine receptors (5-HTRs) via the psychedelic drugs, such as ketamine and psilocybin, rapidly alters the state of consciousness and the neuroplasticity. The United State Food and Drug Administration approved the indications of esketamine for treatment-resistant depression (TRD) in 2019 and major depressive disorder with suicidal ideation in 2020. The phase 2 clinical trials also discovered the rapid and sustained antidepressant effects of psilocybin among patients with TRD. In this chapter, we discussed the complex among the consciousness, neuroplasticity, and novel rapid-acting antidepressants and their possible neuromechanisms.

Association of Neurofilament Light Chain With the Antidepressant Effects of Low-Dose Ketamine Infusion Among Patients With Treatment-Resistant Depression.

BACKGROUND: The role of neurofilament light chain (NFL) in treatment-resistant depression (TRD) is unclear. Whether baseline NFL concentrations are associated with the antidepressant effects of low-dose ketamine infusion has not been determined. METHODS: The NFL concentrations of 71 patients with TRD and 17 healthy controls were assessed. Patients with TRD were randomly administered a single infusion of 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline. Depressive symptoms were assessed before infusion and sequentially at postinfusion timepoints (after 240 minutes and after 2-7 and 14 days) using the Hamilton Depression Rating Scale (HDRS). RESULTS: After adjustment for age, sex, and body mass index, patients with TRD were more likely to have higher concentrations of NFL than healthy controls (P < .001). A generalized estimating equation model with adjustments for infusion group, age, sex, body mass index, and baseline HDRS scores showed that baseline NFL concentrations were positively associated with subsequent HDRS scores following low-dose ketamine infusion (P = .038). DISCUSSION: Higher concentrations of NFL were observed among patients with TRD compared with healthy controls. Baseline NFL concentrations may predict the antidepressant effects of low-dose ketamine infusion.

Baseline cognitive function predicts full remission of suicidal symptoms among patients with treatment-resistant depression and strong suicidal ideation after low-dose ketamine infusion.

BACKGROUND: Whether pretreatment working memory and response inhibition function are associated with the rapid and sustained antisuicidal effect of low-dose ketamine among patients with treatment-resistant depression (TRD) and strong suicidal ideation is unclear. METHODS: We enrolled 65 patients with TRD, comprising 33 who received a single infusion of 0.5 mg/kg ketamine and 32 who received a placebo infusion. The participants performed working memory and go/no-go tasks prior to infusion. We assessed suicidal symptoms at baseline and on postinfusion Days 2, 3, 5, and 7. RESULTS: The full remission of suicidal symptoms persisted for 3 days after a single ketamine infusion and the ketamine-related antisuicidal effect persisted for 1 week. Lower cognitive impairment at baseline (indicated by a higher rate of correct responses on a working memory task) was associated with the rapid and sustained antisuicidal effect of low-dose ketamine in patients with TRD and strong suicidal ideation. DISCUSSION: Patients with TRD and strong suicidal ideation but low cognitive impairment may benefit the most from the antisuicidal effect of low-dose ketamine.

Right dorsolateral prefrontal cortex volumetric reduction is associated with antidepressant effect of low-dose ketamine infusion: A randomized, double-blind, midazolam-controlled PET-MRI clinical trial.

BACKGROUND: Evidence has shown a rapid antidepressant and antisuicidal effects of low-dose ketamine infusion among patients with treatment-resistant depression (TRD) and prominent suicidal ideation (SI). The dorsolateral prefrontal cortex (DLPFC) plays a crucial role in the TRD pathomechanisms. OBJECTIVE: Whether the structural and functional changes of the DLPFC, particularly Brodmann area 46, are associated with the antidepressant and antisuicidal effects of ketamine infusion among such patients is unknown. METHODS: We randomized 48 patients with TRD and SI into groups receiving a single infusion of 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. The Hamilton Depression Rating Scale and the Montgomery-Asberg Depression Rating Scale were used to assess symptoms. Positron emission tomography (PET)-magnetic resonance imaging was conducted prior to infusion and on Day 3 postinfusion. We performed longitudinal voxel-based morphometry (VBM) analysis to evaluate the gray matter (GM) volume changes of the DLPFC. The standardized uptake value ratio (SUVr) of 18F-fluorodeoxyglucose PET images was calculated using the SUV of the cerebellum as a reference region. RESULTS: The VBM analysis revealed a small but significant volumetric reduction in the right DLPFC in the ketamine group compared with that in the midazolam group. A greater reduction in depressive symptoms was associated with a smaller decrease in right DLPFC volumes (p = 0.025). However, we found no SUVr changes of the DLPFC between baseline and post-Day 3 ketamine infusion. DISCUSSION: The optimal modulation of the right DLPFC GM volumes may play an essential role in the antidepressant neuromechanisms of low-dose ketamine.

Brain structural abnormalities and trait impulsivity in suicidal and non-suicidal patients with bipolar disorder.

BACKGROUND: Impulsivity is a characteristic of patients with bipolar disorder (BD) and may result in a higher risk of suicide attempt (SA). Although brain structural abnormalities have been suggested in the pathophysiology of BD, the relationship to impulsivity and suicide in BD is still not clear. METHODS: 52 euthymic patients with BD (26 of them had a history of SA) and 56 age- and sex-matched healthy controls were recruited. All participants received clinical assessment, including Barratt impulsiveness scale (BIS), and underwent structural magnetic resonance imaging examination. An automated surface-based method (FreeSurfer) was used to measure brain volume and cortical surface area. A general linear model was applied to analyze the association between brain-wise greater gray matter volume (GMV), surface area and BIS scores separately for BD patients with and without SA history. RESULTS: BD patients with SA history scored higher in BIS total score and subscores in attention, motor, cognitive complexity and cognitive instability than those without SA history and controls (all p < 0.01). In patients with SA history, higher BIS scores were associated with greater GMV in the left pars triangularis and greater surface area in left pars opercularis (all p < 0.01). BD patients with SA history showed a greater GMV in inferior frontal gyrus than patients without SA history (p < 0.05). LIMITATION: The cross-sectional design precluded examination of chronological relationships of SA, brain structural abnormalities, and trait impulsivity among BD. CONCLUSIONS: The findings indicate that the prefrontal cortex, especially the left inferior frontal gyrus, plays a vital role in trait impulsivity and suicidal behavior among patients with BD.

Effect of low-frequency repetitive transcranial magnetic stimulation as adjunctive treatment for insomnia patients under hypnotics: A randomized, double-blind, sham-controlled study.

BACKGROUND: Pharmacotherapy of insomnia is prescribed often but may be complicated by drug dependence. Cognitive-behavioral therapy for insomnia is effective, but requires time to take effect. Repetitive transcranial magnetic stimulation (rTMS) is effective for depression but of uncertain benefit for insomnia. We studied low-frequency rTMS of the left dorsal medial prefrontal cortex (DMPFC) as an adjunctive therapy of insomnia. METHODS: We recruited 60 patients with insomnia, of whom 49 completed the study. We applied 1 Hz rTMS to the DMPFC in the experimental group (n = 36) and sham coil for the placebo group (n = 13). Outcome measures included objective polysomnography (PSG) and subjective Pittsburgh Sleep Quality Index (PSQI). All participants were requested to continue prescribed pharmacotherapy. RESULTS: After 10 sessions of low-frequency DMPFC-rTMS, the experimental group demonstrated a reduction of duration of wake after sleep onset (WASO) from 75.4 (±53.3) to 51.2 (±75.1) min ( p = 0.011). Sleep efficiency (SE) increased from 74.6% (±15.6) to 80.8% (±13.8) ( p = 0.004). The sham group experienced improved SE from 79.4% (±30.7) to 88.9% (±5.6) ( p = 0.039). After controlling for baseline PSG parameters and hypnotic dosage, the sham group exhibited better effects of sleep onset latency and SE than the rTMS group but no difference on PSQI. CONCLUSION: Although the effects of rTMS and sham coil on insomnia were similar (which implied significant placebo effect), low-frequency DMPFC-rTMS might offer a safe, non-invasive, and useful adjunctive therapy of insomnia by reducing WASO. The DMPFC may represent a new target for future rTMS insomnia studies.

A Randomized, Double-Blind, Midazolam-Controlled Trial of Low-Dose Ketamine Infusion in Patients With Treatment-Resistant Depression and Prominent Suicidal Ideation.

BACKGROUND: The benefits of low-dose ketamine for patients with treatment-resistant depression (TRD) and prominent suicidal ideation require further investigation. The effects of treatment refractoriness, the duration of the current depressive episode, and the number of prior antidepressant failures on ketamine efficacy also require clarification. METHODS: We recruited 84 outpatients with TRD and prominent suicidal ideation-defined as a score ≥4 on item 10 of the Montgomery-Åsberg Depression Rating Scale (MADRS)-and randomized them into 2 groups to receive 0.5 mg/kg ketamine or 0.045 mg/kg midazolam. We assessed depressive and suicidal symptoms prior to infusion; 240 minutes post infusion; and 2, 3, 5, 7, and 14 days post infusion. RESULTS: According to the MADRS scores, the antidepressant effect (P = .035) was significantly noted in the ketamine group up to 14 days than in the midazolam group. However, the antisuicidal effect of ketamine, as measured by the Columbia-Suicide Severity Rating Scale Ideation Severity Subscale (P = .040) and MADRS item 10 (P = .023), persisted only 5 days post infusion. Furthermore, the antidepressant and antisuicidal effects of ketamine infusion were noted particularly in patients whose current depressive episode lasted <24 months or whose number of failed antidepressants was ≤4. CONCLUSIONS: Low-dose ketamine infusion is a safe, tolerable, and effective treatment for patients with TRD and prominent suicidal ideation. Our study highlights the importance of timing; specifically, ketamine is more likely to achieve therapeutic response when the current depressive episode lasted <24 months and the number of failed antidepressants is ≤4.

Cortical inhibition function is associated with baseline suicidal symptoms and post-ketamine suicidal symptom reduction among patients with treatment-resistant depression and strong suicidal ideation.

BACKGROUND: Whether cortical excitation and inhibition functions differ between patients with treatment-resistant depression (TRD) and strong suicidal ideation (SI) and healthy subjects and whether 0.5 mg/kg ketamine infusion can modulate cortical excitation and inhibition functions among patients with TRD-SI remain unclear. METHODS: A total of 29 patients with TRD-SI and 35 age- and sex-matched healthy controls were assessed using paired-pulse transcranial magnetic stimulation. The patients were randomly assigned to receive either a single 0.5-mg/kg ketamine or 0.045-mg/kg midazolam infusion. Depressive and suicidal symptoms were assessed at baseline and 240 min after infusion. Intracortical facilitation (ICF), short-interval intracortical inhibition (SICI), and long-interval intracortical inhibition (LICI), all of which reflect cortical excitability and inhibition functions, were measured at the same time points. RESULTS: The patients with TRD-SI had lower ICF (p < 0.001) estimates (worse cortical excitatory function) and higher SICI (p = 0.032) and LICI (p < 0.001) estimates (worse cortical inhibitory function) compared with the control group. Higher SICI estimates at baseline were associated with greater baseline suicidal symptoms. No differences were found in the SICI, ICF, and LICI estimates at 240 min after the infusion between the two groups. Low-dose ketamine did not alter the cortical excitation and inhibition functions of the patients with TRD-SI. However, decreased SICI estimates (greater cortical inhibition function) were related to the reduction of suicidal symptoms. DISCUSSION: Dysfunction of cortical excitation and inhibition may play a crucial role in the pathomechanisms of TRD and suicidal symptoms. However, we found a lack of predictive ability of the baseline cortical excitation and inhibition parameters on the antidepressant and antisuicidal effect of low-dose ketamine infusion.

Cytokine- and Vascular Endothelial Growth Factor-Related Gene-Based Genome-Wide Association Study of Low-Dose Ketamine Infusion in Patients with Treatment-Resistant Depression.

BACKGROUND AND OBJECTIVE: Ketamine may work as an anti-inflammatory agent, and it increases the levels of vascular endothelial growth factor (VEGF) in patients with treatment-resistant depression. However, whether genes related to pro-inflammatory and anti-inflammatory cytokines and VEGF may predict the treatment response to ketamine remains unknown.Therefore the aim of this study was to analyze whether specific genes related to inflammatory processes and VEGF were associated with treatment response to low-dose ketamine in patients with treatment-resistant depression. METHODS: Based on the genome data from our clinical trial, this study was a secondary analysis of candidate genes correlated with different timepoints of depressive symptoms. In total, 65 patients with treatment-resistant depression (n = 21 for ketamine 0.5 mg/kg, 20 for ketamine 0.2 mg/kg, and 24 for normal saline) were genotyped for 684,616 single nucleotide polymorphisms. Genes associated with 80 cytokines (i.e., interleukin [IL]-1, IL-6, tumor necrosis factor-α, and adiponectin) and VEGF (i.e., VEGF and VEGF receptors) were selected for the gene-based genome-wide association study on the antidepressant effect of a ketamine infusion. RESULTS: Specific single nucleotide polymorphisms, including rs2540315 and rs75746675 in IL1R1 and rs79568085 in VEGFC, were related to the rapid (within 240 min) antidepressant effect of a ketamine infusion; specific single nucleotide polymorphisms, such as Affx-20131665 in PIGF and rs8179353, rs8179353, and rs8179353 in TNFRSF8, were associated with the sustained (up to 2 weeks) antidepressant effect of low-dose (combined 0.5 mg/kg and 0.2 mg/kg) ketamine. CONCLUSIONS: Our findings further revealed that genes related to both anti-inflammatory and pro-inflammatory cytokines (i.e., IL-1, IL-2, IL-6, tumor necrosis factor-α, C-reactive protein, and adiponectin) and VEGF-FLK signaling predicted the treatment response to a ketamine infusion in patients with treatment-resistant depression. The synergic modulation of inflammatory and VEGF systems may contribute to the antidepressant effect of ketamine. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR) number: UMIN000016985.

Procollagen type 1 N-terminal propeptide, neurofilament light chain, proinflammatory cytokines, and cognitive function in bipolar and major depressive disorders: An exploratory study of brain- bone axis and systemic inflammation.

BACKGROUND: Higher levels of neurofilament light chain (NfL) and proinflammatory cytokines (i.e., tumor necrosis factor [TNF]-α) were observed in patients with bipolar disorder (BD) and major depressive disorder (MDD). Procollagen type 1 N-terminal propeptide (P1NP), a bone turnover biomarker, is related to MDD. The association among the brain-bone axis, systemic inflammation, and cognitive function remains unclear in severe affective disorders. METHODS: Overall, 25 patients with BD, 24 with MDD, and 29 matched controls were enrolled in the current study and underwent the measurements of the NfL, P1NP, and proinflammatory cytokine levels and 1-back and 2-back working memory tasks. Generalized linear models (GLMs) were used to examine the aforementioned biomarkers between the groups and clarify the association with each other. RESULTS: GLMs showed increased levels of NfL (p = 0.001, p = 0.020) and P1NP (p = 0.050, p = 0.032) in the patients with BD and MDD than in the controls and suggested significant correlations between the NfL level and the mean time of the 2-back working memory task (p = 0.038) and between P1NL and TNF-α levels (p < 0.001). DISCUSSION: Our study revealed the dysregulated brain-bone axis, indicated by elevated NfL and P1NP levels, and related cognitive impairment and systemic inflammation in the patients with BD and MDD. Additional studies are necessary to elucidate definite pathomechanisms underlying those conditions.

Inflammatory cytokines in and cognitive function of adolescents with first-episode schizophrenia, bipolar disorder, or major depressive disorder.

BACKGROUND: Few studies have explored the complex relationship of pro- and anti-inflammatory cytokines with cognitive function in adolescents with first-episode schizophrenia, bipolar disorder, or major depressive disorder. METHODS: In total, 26, 35, and 29 adolescents with first-episode schizophrenia, bipolar disorder, and major depressive disorder, respectively, and 22 age- and sex-matched controls were included in the current study. Cytokines, namely interleukin (IL)-2, IL-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP), were assessed. The Wisconsin Card Sorting Test (WCST) and the working memory task were administered to assess cognitive function. RESULTS: Using generalized linear models with adjustment for demographic data and clinical symptoms, patients with bipolar disorder were found to exhibit the highest levels of CRP (P = .023), IL-6 (P = .022), and TNF-α (P = .011), and had the lowest IL-2 levels (P = .034) among the four groups. According to the results of the WCST and working memory task, adolescents with schizophrenia exhibited the lowest performance in cognitive function. In addition, among the assessed cytokines, only CRP levels (P = .027) were negatively associated with WCST scores. DISCUSSION: Dysregulated pro- and anti-inflammatory cytokines and impaired cognitive functioning were observed in first-episode adolescent-onset schizophrenia, bipolar disorder, and major depressive disorder. The altered cytokine profiles may play important roles in the pathophysiology of schizophrenia, bipolar disorder, and major depressive disorder.

Classifying Temporomandibular Disorder with Artificial Intelligent Architecture Using Magnetic Resonance Imaging.

This study proposes a new diagnostic tool for automatically extracting discriminative features and detecting temporomandibular joint disc displacement (TMJDD) accurately with artificial intelligence. We analyzed the structural magnetic resonance imaging (MRI) images of 52 patients with TMJDD and 32 healthy controls. The data were split into training and test sets, and only the training sets were used for model construction. U-net was trained with 100 sagittal MRI images of the TMJ to detect the joint cavity between the temporal bone and the mandibular condyle, which was used as the region of interest, and classify the images into binary categories using four convolutional neural networks: InceptionResNetV2, InceptionV3, DenseNet169, and VGG16. The best models were InceptionV3 and DenseNet169; the results of InceptionV3 for recall, precision, accuracy, and F1 score were 1, 0.81, 0.85, and 0.9, respectively, and the corresponding results of DenseNet169 were 0.92, 0.86, 0.85, and 0.89, respectively. Automated detection of TMJDD from sagittal MRI images is a promising technique that involves using deep learning neural networks. It can be used to support clinicians in diagnosing patients as having TMJDD.