The relationship between the gut microbiota and oxidative stress in the cognitive function of schizophrenia: A pilot study in China.

Cognitive impairment is a core symptom of schizophrenia. The gut microbiota (GM) and oxidative stress may play important roles in the pathophysiological mechanisms of cognitive impairment. This study aimed to explore the relationship between GM and oxidative stress in the cognitive function of schizophrenia. GM obtained by 16S RNA sequencing and serum superoxide dismutase (SOD) levels from schizophrenia patients (N = 68) and healthy controls (HCs, N = 72) were analyzed. All psychiatric symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Cognitive function was assessed using the MATRICS Consensus Cognitive Battery (MCCB). Correlation analysis was used to explore the relationship between GM, SOD, and cognitive function. Machine learning models were used to identify potential biomarkers. Compared to HCs, the relative abundances of Collinsella, undefined Ruminococcus, Lactobacillus, Eubacterium, Mogibacterium, Desulfovibrio, Bulleidia, Succinivibrio, Corynebacterium, and Atopobium were higher in patients with schizophrenia, but Faecalibacterium, Anaerostipes, Turicibacter, and Ruminococcus were lower. In patients with schizophrenia, the positive factor, general factor, and total score of MCCB positively correlated with Lactobacillus, Collinsella, and Lactobacillus, respectively; SOD negatively correlated with Eubacterium, Collinsella, Lactobacillus, Corynebacterium, Bulleidia, Mogibacterium, and Succinivibrio, but positively correlated with Faecalibacterium, Ruminococcus, and MCCB verbal learning index scores; Faecalibacterium and Turicibacter were positively correlated with MCCB visual learning index scores and speed of processing index scores, respectively. Our findings revealed a correlation between SOD and GM and confirmed that cognitive dysfunction in patients with schizophrenia involves abnormal SOD levels and GM changes.

Association of serum homocysteine levels with intestinal flora and cognitive function in schizophrenia.

Some studies have indicated that elevated homocysteine (Hcy) levels and intestinal flora may be involved in schizophrenia (SZ) cognition pathophysiology. This study was the first to investigate the association among Hcy, intestinal flora and schizophrenia cognition. Here, 140 individuals were divided into two groups: SZ patients (N = 68) and healthy controls (HCs, N = 72). Participant data on serum Hcy levels, intestinal flora and cognitive function evaluation using the MATRICS Consensus Cognitive Battery (MCCB) were collected. Clinical symptoms of patients were evaluated using the Positive and Negative Syndrome Scale. Serum Hcy levels and the incidence of hyperhomocysteinaemia were considerably increased in SZ patients compared with HCs. Hcy levels were significantly negatively associated with verbal learning index scores (r = -0.425, p < 0.001) but positively associated with Eubacterium (r = 0.32, p = 0.007), Lactobacillus (r = 0.32, p = 0.008), Corynebacterium (r = 0.26, p = 0.035), Mogibacterium (r = 0.31, p = 0.01), and Bulleidia (r = 0.31, p = 0.01) in SZ patients. Our findings suggest that serum Hcy levels are associated with cognitive function and intestinal flora in SZ patients. However, the mechanism of the interaction between Hcy and intestinal flora and its effects on cognitive function in SZ patients requires further investigation.

The effectiveness of repeated intravenous ketamine on subjective and objective psychosocial function in patients with treatment-resistant depression and suicidal ideation.

BACKGROUND: Ketamine has rapid and robust antidepressant effects in adults with treatment-resistant depression (TRD), while its effects on functional outcomes have not been sufficiently evaluated. The aim was to evaluate the efficacy of ketamine treatment on both subjective and objective functioning, and to explore whether improvements in depressive symptom and cognition mediated changes in functioning. METHODS: Adults (n=111) with TRD and/or suicidality received six infusions of ketamine (0.5mg/kg, thrice-weekly). Depression symptoms were assessed with the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were measured with the MATRICS Consensus Cognitive Battery, and subjective and objective functioning were measured with the Sheehan Disability Scale (SDS) and the Global Assessment of Functioning (GAF) at the same time-points. RESULTS: Significant improvement was observed in SDS total score (effect size [ES]=-1.563) and GAF score (ES=1.700) during the 26-day observation. Results from path analysis indicated that reductions of the total MADRS score and improvements in processing speed aggregately significantly mediated the reductions of SDS total score (total indirect effect coef=-3.993, 95%CI [-4.9, -3.2], direct effect coef=-1.374, 95%CI [-2.4, -0.4]) as well as the increases of GAF score (total indirect effect coef=6.022, 95%CI [4.5, 7.8], direct effect coef=3.987, 95%CI [2.1, 5.8]). CONCLUSION: Six infusions of ketamine was associated with improvements in functional outcomes in adults with TRD and/or suicidality. Depressive symptoms severity and processing speed performance were significant partial mediators of objective and subjective functioning improvements.

Prevalence and associated factors of campus bullying of primary and secondary school students in Haidian District of Beijing / 中国学校卫生

Objective@#To understand the prevalence and associated factors of school bullying among primary and secondary school students in Haidian District, and to provide scientific basis for intervention plan.@*Methods@#From September to October 2021, 1 906 primary and secondary school students in Haidian District were selected by stratified cluster random sampling for electronic questionnaire survey,an electronic questionnaire survey was conducted on students by using the questionnaire of the Student Health Status and Influencing Factors Questionnaire.@*Results@#The prevalence of campus bullying among primary and secondary school students in Haidian District was 4.3%, of which primary school (7.6%) > junior middle school (4.1%) > vocational high school (2.5%) > senior high school (1.9%) ( χ 2=23.49, P ＜0.01), boys (5.5%) were more than girls (3.0%) ( χ 2=7.44, P ＜ 0.01 ), students from abnormal families (6.9%) were higher than students from normal families (3.9%) ( χ 2=4.24, P =0.04). Multivariate Logistic regression analysis showed that students in primary school had a higher risk of being bullied in school ( OR =2.13). Abnormal family ( OR = 1.07 ), smoking experience ( OR =2.28), experience of being beaten and scolded by parents( OR =2.49) and fighting behavior ( OR =1.84) were positively correlated with school bullying ( P <0.05).@*Conclusion@#Campus bullying is prevalent in primary and secondary schools in Haidian District, which warrents further attention of schools and education departments. Family school partnership and targeted prevention and intervention measures for key populations are expected.

The potential pro-cognitive effects with intravenous subanesthetic ketamine in adults with treatment-resistant major depressive or bipolar disorders and suicidality.

BACKGROUND: Ketamine has rapid and robust antidepressant effects in depression, while its effects on cognitive measures are less clearly understood. This aim of the study herein is to determine whether ketamine has direct pro-cognitive effects in real-world treatment depression and/or suicidality. METHODS: Subjects with unipolar (n = 84) and bipolar (n = 27) depression suffering treatment resistance or suicidality received six infusions of ketamine (0.5 mg/kg) during a 12-day period. Depression symptoms were assessed using the Montgomery-Asberg Depression Rating Scale at baseline, day 13 and day 26. Cognitive domains, including processing speed, working memory, visual learning and verbal learning were also measured using the MATRICS Consensus Cognitive Battery at the same time-points. RESULTS: Significant improvement was observed in processing speed at day 13 (effect size [ES] = 0.501) and day 26 (ES = 0.654), and verbal learning at day 13 (ES = 0.362). Path analysis showed significant direct (ß = 2.444, P = 0.017) and indirect (ß = 1.220, P = 0.048) effect of ketamine on processing speed, indicating its improvement was partly independent of improvement in depressive symptoms. The direct effect (ß = -1.963, P = 0.052) of ketamine on verbal learning was not significant, whereas the indirect effect (ß = 1.386, P = 0.024) was significant, indicating treatment with ketamine indirectly improved verbal learning performance, via changes in depressive symptom. CONCLUSION: Six infusions of ketamine have a potential mood independent pro-cognitive effect on processing speed in adults with treatment depression and/or suicidality. The potential pro-cognitive effects of ketamine provide the basis for hypothesizing that other clinical outcomes (e.g., suicidality, functional impairment) reported with ketamine treatment may be in part mediated by improvement in cognition.

Plasma inflammatory cytokines and treatment-resistant depression with comorbid pain: improvement by ketamine.

BACKGROUND: Treatment-resistant depression (TRD) and pain frequently coexist clinically. Ketamine has analgesic and antidepressant effects, but few studies have evaluated individual differences in antidepressant outcomes to repeated ketamine in TRD patients with comorbid pain. Our aims were to determine the difference in ketamine's antidepressant effects in TRD patients with or without pain and then to examine whether inflammatory cytokines might contribute to ketamine's effect. METHODS: Sixty-six patients with TRD received six infusions of ketamine. Plasma levels of 19 inflammatory cytokines were assessed at baseline and post-infusion (day 13 and day 26) using the Luminex assay. Plasma inflammatory cytokines of sixty healthy controls (HCs) were also examined. RESULTS: TRD patients with pain had a higher antidepressant response rate (χ2 = 4.062, P = 0.044) and remission rate (χ2 = 4.062, P = 0.044) than patients without pain. Before ketamine treatment, GM-CSF and IL-6 levels were higher in the pain group than in the non-pain and HC groups. In the pain group, levels of TNF-α and IL-6 at day 13 and GM-CSF, fractalkine, IFN-γ, IL-10, MIP-3α, IL-12P70, IL-17α, IL-1ß, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, MIP-1ß, and TNF-α at day 26 were lower than those at baseline; in the non-pain group, TNF-α levels at day 13 and day 26 were lower than those at baseline. In the pain group, the changes of IL-6 were associated with improvement in pain intensity (ß = 0.333, P = 0.001) and depressive symptoms (ß = 0.478, P = 0.005) at day 13. Path analysis showed the direct (ß = 2.995, P = 0.028) and indirect (ß = 0.867, P = 0.042) effects of changes of IL-6 on improvement in depressive symptoms both were statistically significant. CONCLUSION: This study suggested that an elevated inflammatory response plays a critical role in individual differences in TRD patients with or without pain. Ketamine showed great antidepressant and analgesic effects in TRD patients with pain, which may be related to its effects on modulating inflammation. TRIAL REGISTRATION: ChiCTR , ChiCTR-OOC-17012239. Registered on 26 May 2017.

Working memory associated with anti-suicidal ideation effect of repeated-dose intravenous ketamine in depressed patients.

Suicide is a tremendous threat to global public health, and a large number of people who committed suicide suffered the pain of mental diseases, especially major depressive disorder (MDD). Previous study showed that ketamine could reduce suicidal ideation (SI), potentially by improving the impaired working memory (WM). The objective of current study was to illuminate the relationship between WM and SI in MDD with repeated ketamine treatment. MDD patients with SI (n = 59) and without SI (n = 37) completed six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days (Day 1, 3, 5, 8, 10 and 12). The severity of depressive symptoms, SI and WM were assessed at baseline, day 13 and day 26. We found that WM was significantly improved after 6 ketamine infusions (F = 161.284, p = 0.009) in a linear mixed model. Correlation analysis showed that the improvement of depressive symptom was significantly associated with WM at baseline (r = - 0.265, p = 0.042) and the reduction in SSI-part I was related to the change of WM (r = 0.276, p = 0.034) in the MDD patients with SI. Furthermore, Logistic regression analysis showed that improvement in WM might predict the anti-SI response of ketamine. Our findings suggest that the improvement of working memory may partly account for the anti-SI effect of ketamine, and intervention of improving working memory function may be capable of reducing suicidal ideation.

Baseline insomnia as a predictor of antidepressant efficacy to repeated intravenous ketamine for unipolar and bipolar depression: A preliminary study.

OBJECTIVE: Ketamine has been demonstrated to have robust and rapid antidepressant effects, and few studies have focused on the relationship between insomnia and the efficacy of ketamine. The objective of this study was to examine whether baseline insomnia predicted the antidepressant efficacy of repeated intravenous ketamine infusions for unipolar and bipolar depression. METHOD: Patients with high insomnia (n = 64) or low insomnia (n = 68) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days (Monday-Wednesday-Friday). The Montgomery-Asberg Depression Rating Scale (MADRS) without sleep item was used to assess depressive symptoms. Response was defined as a MADRS total score ≥ 50%, and remission was defined as a MADRS total score ≤ 10. RESULT: There were no differences in response or remission rates between patients with high and low insomnia. However, the logistic regression model showed that high insomnia predicted an increased likelihood of response and remission. Cox proportional hazards models showed a reduced latency to respond and remit in patients with high insomnia. A linear mixed model showed that the high insomnia subgroup had greater improvement than the low insomnia subgroup (all p < 0.05). LIMITATION: The major limitation of this study is the open-label design. CONCLUSION: When given six ketamine infusions, patients with high insomnia were more likely to respond and remit than those with low insomnia. Patients with high insomnia showed not only a shorter latency to respond and remit, but also greater improvement than those with low insomnia.

Repeated intravenous infusions of ketamine: Neurocognition in patients with anxious and nonanxious treatment-resistant depression.

BACKGROUND: Recent studies have suggested that neurocognition is changed after repeated infusions of ketamine in patients with treatment-resistant depression (TRD). The objective of this study was to investigate whether differences existed in the neurocognitive effect of six ketamine infusions in patients with anxious and nonanxious TRD and to determine the association between baseline neurocognition and changes in symptoms after the infusions. METHOD: Patients with anxious (n = 30) and nonanxious TRD (n = 20) received six intravenous infusions of ketamine (0.5 mg/kg over 40 min) over 12 days. Speed of processing (SOP), working memory (WM), verbal learning and memory (VBM), visual learning and memory (VSM) and the severity of depressive and anxious symptoms were assessed at baseline, one day after the last infusion (day 13) and two weeks after the completion of the serial infusions (day 26). A linear mixed model was used to determine whether the neurocognitive changes differed between the two groups. Pearson correlation analysis was used to determine the relationship between baseline neurocognition and the changes in the symptomatic scores. RESULTS: Patients with anxious TRD had significant increases in SOP on day 13 and day 26 (both p < 0.001), and in VBM on day 13 (p = 0.028). However, no significant increase in any neurocognitive domain was found in patients with nonanxious TRD. Faster SOP at baseline was associated with greater improvement of anxious symptoms in patients with anxious TRD, and better VSM at baseline was associated with greater improvement of depressive symptoms in patients with nonanxious TRD. LIMITATION: The major limitation of this study is the open-label design. CONCLUSION: After six ketamine infusions, neurocognitive improvement was observed in patients with anxious TRD but not in patients with nonanxious TRD.

A preliminary study of anti-suicidal efficacy of repeated ketamine infusions in depression with suicidal ideation.

BACKGROUND: Suicide is a tremendous public health crisis and is demanded urgent intervention. Previous studies found that ketamine intervention could rapidly reduce suicidal ideation in depression. However, the comparatively study in Chinese population remains absence. The current study aims to assess the anti-suicidal efficacy of repeated ketamine infusions for Chinese depressed suicidal patients, especially distinguish between low suicidal ideation (SI) group and high SI group. METHODS: Eighty-six unipolar and bipolar depressive patients with current suicidal ideation received six ketamine infusions during a 12-day period. Hamilton Depression Rating Scale (HAMD) and Beck Scale for Suicide Ideation (SSI) was measured at baseline, 4 h and 24 h after each infusion, and two-week naturalistically follow-up. RESULTS: Forty-nine (57.0%) patients relief of suicidal ideation after first infusion and 56 (65.1%) after six infusions. Anti-suicidal response rate in low SI group were higher than high SI group, and anti-suicidal response at 4 h after first infusion was significant predictor of response at 24 h after sixth infusion. Furthermore, at 24 h after the sixth infusion, correlation between changes in suicidal ideation and depression was 0.23, accounting for 7.4% in the variance of suicidal ideation change. LIMITATION: The major limitation of this study was that lack of a placebo or other control group limits the interpretation of efficacy. CONCLUSIONS: We confirmed that six repeated ketamine infusions for Chinese suicidal depressed patients were effective in generating a rapid response of suicidal ideation, especially low SI achieved more benefits from ketamine infusions.

Investigation of medical effect of multiple ketamine infusions on patients with major depressive disorder.

OBJECTIVE: Single-dose intravenous ketamine has rapid but time-limited antidepressant effects. We aimed to examine the sustained effects of six consecutive ketamine infusions in Chinese patients with major depressive disorder. METHODS: Seventy-seven patients with major depressive disorder were eligible to receive augmentation with six ketamine infusions (0.5 mg/kg over 40 min) administered over the course of 12 days (Monday-Wednesday-Friday). The coprimary outcome measures were the rates of response and remission as measured on the 10-item Montgomery-Asberg Depression Rating Scale. Psychotomimetic and dissociative symptoms were measured with the Brief Psychiatric Rating Scale-positive symptoms and the Clinician Administered Dissociative States Scale, respectively. RESULTS: After the first ketamine infusion, only 10 (13.0%) and 6 (7.8%) patients responded and remitted, respectively; after six ketamine infusions, 52 (67.5%) patients responded and 37 (48.1%) remitted. There was a significant mean decrease in Montgomery-Asberg Depression Rating Scale score at four hours after the first ketamine infusion (7.0±7.5, p<0.001), and this decrease was maintained for the duration of the infusion period. The response to ketamine treatment was positively associated with no history of psychiatric hospitalization (odds ratio=3.56, p=0.009). Suicidal ideation rapidly decreased across the entire study sample, even among the nonresponder group. No significant differences were found regarding Brief Psychiatric Rating Scale and Clinician Administered Dissociative States Scale scores from the first infusion at baseline to four hours post-infusion. CONCLUSION: Six ketamine infusions increased rates of response and remission when compared to a single-dose ketamine infusion in patients with major depressive disorder. Future controlled studies are warranted to confirm and expand these findings.

Mediating effect of neurocognition between severity of symptoms and social-occupational function in anxious depression.

BACKGROUND: Major depressive disorder (MDD) is associated with neurocognitive impairment and reduced social-occupational function. However, neurocognition and social-occupational function in patients with anxious depression have been under-investigated. An increasing number of studies have demonstrated that neurocognition plays an important role in social-occupational function. The objective of this study was to investigate the association of severity of symptoms, neurocognition and social-occupational function in patients with anxious depression. METHOD: Using a cross-sectional design, 214 patients with MDD were recruited consecutively and evaluated using the 17-item Hamilton Depression Rating scale (HAMD-17), the MATRICS Consensus Cognitive Battery (MCCB) and the Global Assessment of Functioning (GAF). RESULT: The prevalence of anxious depression in MDD patients was 64.5%. Compared to non-anxious subjects, the anxious group had more severe symptoms. Moreover, in the anxious group, social-occupational function was associated with several domains of symptoms and neurocognition, while social-occupational function was associated with only one aspect of depressive symptoms (cognitive disturbance) in the non-anxious group. In addition, there was a mediating effect of neurocognition on the association between the severity of symptoms and social-occupational function in the anxious group. LIMITATIONS: The major limitation of the present study is the use of a cross-sectional design that is unable to illuminate causal relationships. CONCLUSION: Our results suggest that the severity of symptoms is negatively associated with neurocognition and social-occupational function and that neurocognition is positively associated with social-occupational function in patients with anxious depression.

Cross-sectional relationship between kynurenine pathway metabolites and cognitive function in major depressive disorder.

OBJECTIVE: Cognitive impairment is common among patients with major depressive disorder (MDD), but its pathological mechanism is complex and not fully understood. Evidence suggests that the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression, but few studies have explored the association between the KYN pathway and cognitive impairment in MDD. Our aim was to examine the relationship between cognitive impairment and KYN pathway metabolites in patients with MDD. METHODS: A total of 146 patients with MDD according to DSM-V and 72 healthy controls (HCs) were enrolled, and the severity of depressive symptoms using the 17-item Hamilton Depression Rating Scale (HAMD-17) and cognitive performance including speed of processing, working memory, visual learning and verbal learning were assessed. Blood samples were collected, and serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by liquid chromatography-tandem mass spectrometry. RESULTS: In females with MDD, there was a significant negative association between the KYN level and verbal learning (B=-0.039, adjusted p = 0.018), and the KYN/TRP ratio was negatively correlated with speed of processing (B=-470.086, adjusted p = 0.029), verbal learning (B=-544.251, adjusted p = 0.002) and visual learning (B=-513.777, adjusted p = 0.004). Those associations were not present in male individuals with MDD or in HCs, except for a significant negative correlation between the KYNA/KYN ratio and category fluency (B=-0.373, adjusted p = 0.039) in female HCs. CONCLUSION: Our results suggest that learning function and speed of processing in female MDD were associated with KYN serum level and the KYN/TRP ratio, potentially implicating the KYN pathway in the pathological mechanism of cognitive function in female MDD.

Neurocognitive performance and repeated-dose intravenous ketamine in major depressive disorder.

OBJECTIVE: Ketamine has demonstrated a rapid antidepressant and antisuicidal effect in patients with major depressive disorder (MDD), but the neurocognitive effects of ketamine are relatively unknown. This study aims to examine the neurocognitive effects of six ketamine infusions and the association of baseline neurocognitive function and the change in severity of depressive symptoms after the last infusions. METHODS: Sixty-four patients with MDD completed six intravenous infusions of ketamine (0.5 mg/kg over 40 min) administered over a 12-day period (Monday-Wednesday-Friday), and were followed by a 2-week observational period. Four domains of neurocognitive function (including speed of processing, working memory, visual learning and verbal learning) were assessed using the MATRICS Consensus Cognitive Battery (MCCB) at 0, 13 and 26 days. RESULTS: In linear mixed model, significant improvements were found in terms of speed of processing (F = 20.7, p < 0.001) and verbal learning (F = 11.1, p < 0.001). The Sobel test showed the improvement of speed of processing (Sobel test = 2.8, p < 0.001) and verbal learning (Sobel test = 3.6, p < 0.001) were significantly mediated by change in depressive symptoms. Other two neurocognitive domains showed no significant changes over time. Correlation analysis showed no significant association of change in depressive symptoms with neurocognitive function at baseline. CONCLUSION: Our findings suggest that six ketamine infusions were associated with the improvement of speed of processing and verbal learning, which were partly accounted for by improvement in the severity of depression symptoms over time.

Rapid and longer-term antidepressant effects of repeated-dose intravenous ketamine for patients with unipolar and bipolar depression.

OBJECTIVE: Single-dose intravenous (IV) injection of ketamine has shown rapid but transient antidepressant effects. The strategy of repeated-dose ketamine infusions to maintain antidepressant effects has received little systematic study. This study was conducted to examine the efficacy and tolerability of six ketamine infusions in Chinese patients with unipolar and bipolar depression. METHODS: Ninety seven patients with unipolar (n = 77) and bipolar (n = 20) depression received repeated ketamine infusions (0.5 mg/kg over 40 min) with continuous vital sign monitoring. Depressive symptoms were measured by the Montgomery-Asberg Depression Rating Scale (MADRS). Suicidal ideation was assessed using the Scale for Suicidal Ideations (SSI)-part 1. Anxiety symptoms were evaluated with the 14-item Hamilton Anxiety Scale (HAMA). Adverse psychopathological and dissociative effects were assessed using the Brief Psychiatric Rating Scale (BPRS)-positive symptoms and Clinician Administered Dissociative States Scale (CADSS), respectively. Patients were assessed at baseline, 4 and 24 h, and 3, 4, 5, 6, 8, 9, 10, 11, 12, 13 and 26 days. RESULTS: After six ketamine infusions, the response and remission rates were 68.0% and 50.5%, respectively. There were significant decreases in MADRS, SSI-part 1, and HAMA scores within four hours following the first ketamine infusion, and the decreases were sustained over the subsequent infusion period. The nonresponder subgroup manifested rapid significant improvement in suicidal ideations throughout the course of treatment. After the six ketamine infusions, the response was positively associated with the response at 24 h after the first infusion (OR = 8.94), personal income ≥4000 yuan/month (OR = 3.04), and no history of psychiatric hospitalization (OR = 3.41). Only CADSS scores had a mild but marginally significant increase after the first infusion but with a significant BPRS score decrease. CONCLUSION: Six ketamine infusions were safe and effective in patients with unipolar and bipolar depression. The rapid and robust antidepressant and antisuicidal effects of ketamine infusion within four hours were sustained following the subsequent infusions.

Antidepressant effect of repeated ketamine administration on kynurenine pathway metabolites in patients with unipolar and bipolar depression.

Ketamine has rapid antidepressant effects on treatment-resistant depression, but the biological mechanism underpinning this effect is less clear. Our aims were to examine whether kynurenine pathway metabolites were altered by six infusions of ketamine and whether these biological factors could act as potential biomarkers to predict ketamine's antidepressant effects. Six intravenous infusions of ketamine (0.5 mg/kg) were administered to 84 patients with unipolar and bipolar depression over a 12-d period. Symptom severity and response were assessed using the Montgomery-Asberg Scale (MADRS), and blood samples were collected at baseline and 24 h following the first infusion and at 24 h and 14 d after the sixth infusion (24 h, 13 d and 26 d). Blood samples from sixty healthy controls were collected for comparison with samples from the patients. Serum concentrations of tryptophan (TRP), kynurenine (KYN) and kynurenic acid (KYNA) were measured by the liquid chromatography-tandem mass spectrometry method. At baseline, serum levels of TRP and KYNA and the KYNA/KYN ratio were lower and the KYN/TRP ratio was greater in depressed patients than in healthy controls. Overall, fifty (59.5%) patients responded to ketamine at 13 d. Ketamine responders had a greater KYNA level and KYNA/KYN ratio than nonresponders at 24 h and 13 d (all P < 0.05). Elevations in the KYNA levels and KYNA/KYN ratio at 24 h were significantly associated with reductions in MADRS scores at 24 h, 13 d and 26 d in the linear regression analysis (all P < 0.05). Our results showed a possible involvement of the kynurenine pathway in the rapid antidepressant effect of ketamine. Early changes in serum KYNA levels and the KYNA/KYN ratio could be potential predictors of antidepressanteffects of repeated ketamine administration.

Neurocognitive effects of six ketamine infusions and the association with antidepressant response in patients with unipolar and bipolar depression.

BACKGROUND: Ketamine has proven to have rapid, robust antidepressant effects on treatment-resistant depression. However, whether repeated ketamine infusions would cause short-and long-term neurocognitive impairments was not clear. Our aims were to investigate the neurocognitive effects of six ketamine infusions and to examine the association between these infusions and the antidepressant response in patients with unipolar and bipolar depression. METHODS: Six intravenous infusions of ketamine (0.5 mg/kg) over a 12-day period were administered to 84 patients with unipolar and bipolar depression. Severity of depressive symptoms and four domains of neurocognition, including speed of processing, working memory, visual learning and verbal learning, were assessed at baseline, one day following the last infusion and again two weeks post-infusion. RESULTS: Significant improvements were found on speed of processing ( F=9.344, p<0.001) and verbal learning ( F=5.647, p=0.004) in a linear mixed model. The Sobel test showed significant indirect effects between time and improvement in speed of processing (Sobel test=3.573, p<0.001) as well as improvement in verbal learning (Sobel test=6.649, p<0.001), which were both significantly mediated by change in depressive symptoms. Logistic regression analysis showed ketamine responders had better visual learning at baseline than non-responders (B=0.118, p<0.001). CONCLUSIONS: Our findings suggest that neurocognitive function would not deteriorate after six ketamine infusions, while verbal learning and speed of processing improved over 13 days and 26 days of observation, respectively. However, this change was mainly accounted for by improvements in severity of depressive symptoms over time. Greater baseline visual learning predicted an antidepressant response over six ketamine infusions.