Non-improvement predicts subsequent non-response to repeated-dose intravenous ketamine for depression: a re-analysis of a 2-week open-label study in patients with unipolar and bipolar depression.

There is insufficient evidence to guide dose and frequency optimization with repeated-dose ketamine for depression. This study assessed the value of symptomatic non-improvement after the first few ketamine infusions as a predictor of overall non-response in depression for early decision-making to discontinue treatment. A total of 135 individuals with major depressive disorder or bipolar disorder experiencing a current major depressive episode were administered six repeated doses of intravenous ketamine. Depressive symptoms were assessed using the Montgomery-Åsberg Depression Rating Scale (MADRS) at baseline, 4 h after the first infusion, and 24 h after each infusion. Improvement, partial response, and response were defined as a reduction rate of ≥ 20%, 30%, and 50% in MADRS scores, respectively. This study examined the relationship between improvement (as opposed to non-improvement after each infusion or consecutive non-improvements after the first few infusions) and partial response and response after the sixth infusion. This analysis was summarized using sensitivity, specificity, and other diagnostic test parameters. The sensitivities of improvement at 24 h post-infusion 4 and improvement at 24 h post-infusion 3, vs. three consecutive non-improvements, as predictors for overall partial response and response exceeded 90%. No significant reduction in depressive symptoms was seen in non-improvers following the remaining infusions after the above-identified point. Our study suggests that non-improvement after four infusions, or more conservatively three consecutive non-improvements after three infusions, could serve as a signal of overall non-response to repeated-dose intravenous ketamine for depression and that subsequent treatments would not be warranted.

The relationship between plasma cytokine levels and antidepressant response in patients with first-episode major depressive disorder.

BACKGROUND: Cytokines are involved in the pathophysiology of major depressive disorder (MDD) and treatment response. Efforts have been made to identify inflammatory markers but results are often contradictory. The present study explored the plasma levels of multiple cytokines in first-episode MDD using a longitudinal design, with the aim to determine the involvement of cytokines in depression and identify the inflammatory markers. METHOD: Fifty-four first-episode drug naïve MDD patients and 60 healthy controls (HCs) were enrolled in this study. The 17-item Hamilton Depression Rating Scale (HAMD-17) was administered and blood samples were collected at baseline and four-week posttreatment in MDD group, while blood samples were only collected once in HC group. Plasma levels of nineteen cytokines were examined by a multiplexed flow cytometric assay. RESULTS: Sixteen out of 19 cytokines levels in MDD group were significantly higher than those in HC group (all P < 0.05). After 4-week of antidepressant treatment, levels of the 14 cytokines elevated at baseline decreased to normal levels (all P < 0.05). Partial correlation showed that baseline level of interferon-inducible T cell alpha chemoattractant (ITAC) was negatively correlated with reduction in HAMD-17 score (r=-0.319, p=0.020), and multiple regression showed lower baseline ITAC level was associated with better treatment response (p = 0.020). LIMITATION: The sample size was relatively small. CONCLUSION: A range of cytokines were abnormal in patients with first-episode drug naïve MDD and most of the cytokines could be normalized after antidepressant treatment. Furthermore, baseline ITAC level could be a predictive factor of antidepressant response.

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.

Sleep improvement is associated with the antidepressant efficacy of repeated-dose ketamine and serum BDNF levels: a post-hoc analysis.

RATIONALE: Recently, the effects of ketamine on the circadian rhythm have suggested that ketamine's rapid antidepressant effects are associated with and without sleep disturbance improvement. OBJECTIVES: Here, we evaluated the antidepressant efficacy of repeated ketamine infusions in patients with sleep disturbances. METHODS: This study included 127 patients with major depressive disorder or bipolar disorder who received ketamine treatments during a 12-day period. Sleep quality was assessed by the 17-item Hamilton Depression Rating Scale sleep disturbance factor (SDF) (items 4, 5 and 6). Serum brain-derived neurotrophic factor (BDNF) was measured at baseline, day 13 and day 26. This study was a post-hoc analysis. RESULTS: Significant differences were found in the HAMD-17 score at 13 post-infusion time points compared to baseline, as well as the scores in SDF score at each of the 7 post-infusion (4 h after each infusion excluded) time points among all patients. Logistic regression and linear correlation analyses revealed that a greater reduction in the SDF after 24 h of the first ketamine infusion resulted in a better antidepressant effect in the last two follow-up visits. Moreover, BDNF levels were significantly higher in sleep responders than in non-responders. CONCLUSIONS: In the 127 patients, six ketamine infusions induced better therapeutic effects in sleep responders than in sleep non-responders and patients without sleep disturbances. The sleep response after repeated ketamine infusions was positively associated with high serum BDNF levels. Early sleep disturbance improvement (as early as 24 h after the first ketamine injection) may predict the antidepressant effect of repeated-dose ketamine.

Volumetric changes in subcortical structures following repeated ketamine treatment in patients with major depressive disorder: a longitudinal analysis.

Abnormal subcortical structures have been associated with major depressive disorder (MDD) and could be reversed by antidepressant treatment. To date no study has examined the relationship between subcortical volumes and repeated ketamine treatment. The current study investigated volume changes in specific subcortical structures and hippocampal subfields after six ketamine infusions. Forty-four patients with MDD received six subanesthetic dose infusions of ketamine. Depressive symptoms were assessed and magnetic resonance imaging scans were performed before and after six ketamine infusions. FreeSurfer software was used to process the T1 images and analyze the volumes of the subcortical regions and hippocampal subfields. After six ketamine infusions, increases were observed in the volumes of the left amygdala; the right hippocampus; the cornu ammonis 4 body, granule cell and molecular layer of the dentate gyrus body in the left hippocampus; and the cornu ammonis 4 head and molecular layer head in the right hippocampus. Positive correlations were found between symptom improvement and the pretreatment volumes of the right thalamus (r = 0.501; P = 0.001) and left subiculum head of the hippocampus (r = 0.471; P = 0.002), and changes in the volumes of the left amygdala (r = -0.452; P = 0.003) and the left cornu ammonis 4 body (r = -0.537; P < 0.001). Our findings provided evidence for critical roles of the amygdala and specific hippocampal subfields in the antidepressant effect of repeated ketamine treatment. Relatively larger volumes in right thalamus and left subiculum head in the hippocampus can predict a superior clinical outcome of ketamine treatment in MDD patients.

Alterations of multiple peripheral inflammatory cytokine levels after repeated ketamine infusions in major depressive disorder.

Increasing evidence has demonstrated that inflammatory cytokines play an important role in major depressive disorder (MDD) and are associated with treatment outcomes. Few studies have explored the trajectories of multiple inflammatory cytokines after repeated ketamine infusions in MDD. In this study, we conducted a secondary analysis to investigate the impact of ketamine on the modulation of the inflammatory pathway in depression and whether this pathway contributes to the antidepressant properties of ketamine. A total of 60 patients with depression received six ketamine infusions (0.5 mg/kg) during a 12-day period. The Montgomery-Asberg Scale (MADRS) was administered, and blood samples were collected at baseline and 24 h and 14 days after the sixth infusion (days 0, 13, and 26). Plasma levels of the 19 cytokines were measured using the Luminex assay. At baseline, inflammatory cytokines were associated with the severity of depression. The concentrations of pro- and anti-inflammatory factors, including granulocyte macrophage colony-stimulating factor (GM-CSF), fractalkine, interferon gamma (IFN-γ), interleukin (IL)-10, IL-12p70, IL-17A, IL-1ß, IL-2, IL-4, IL-23, IL-5, IL-6, IL-7, and tumor necrosis factor alpha (TNF-α), were downregulated after repeated ketamine administration (all p < 0.05). In addition, alterations in the levels of IL-17A (r = -0.259, p = 0.046) and IL-6 (r = -0.262, p = 0.043) were correlated with symptom improvement. A lower level of interferon-inducible T cell alpha chemoattractant (ITAC) at baseline was predictive of ketamine treatment response on day 13 according to a stepwise linear regression analysis (ß = -0.296, p = 0.040). Our results suggest that the inflammatory pathway may be involved in the antidepressant effects of ketamine, which may be conducive to future treatment strategy optimization.

A preliminary study of adjunctive ketamine for treatment-resistant bipolar depression.

OBJECTIVES: Ketamine has shown rapid antidepressant effects in depressed patients. However, the antidepressant and antisuicidal effects of repeated ketamine infusions in patients with treatment-resistant bipolar depression (TRBD) are not known. METHODS: TRBD patients received six intravenous infusions of 0.5 mg/kg ketamine over 40 min on a Monday-Wednesday-Friday schedule during a 12-day period followed by a 2-week follow-up period. Depressive symptoms were measured by the Montgomery-Asberg Depression Rating Scale (MADRS) at baseline and at each follow-up visit. RESULTS: Nineteen patients with TRBD were enrolled in the study, and 16 patients (84.2%) received all six ketamine infusions. After the first infusion, the rates of response and remission were 21.1% (95% CI: 0.9 to 21.2) and 15.8% (95% CI: 0 to 33.9), respectively, and after the sixth infusion, the rates of response and remission were 73.7% (95% CI: 51.9 to 95.5) and 63.2% (95% CI: 39.3 to 87.0), respectively. The average times for nineteen patients who responded and remitted were 9.1 and 12.5 days, respectively. There were large decreases in the scores on the MADRS and the Scale for Suicidal Ideation-part 1 within 4 h after the first infusion, and the decreases were maintained across subsequent infusions. There were no significant increases in dissociative and psychotomimetic symptoms as measured by the Clinician-Administered Dissociative States Scale (CADSS) and the Brief Psychiatric Rating Scale (BPRS)-4 items, respectively. CONCLUSION: These pilot findings suggest the feasibility of repeated ketamine infusions at subanaesthetic doses for patients with TRBD. Future controlled studies are needed to confirm and expand these findings.

Association between cognition and suicidal ideation in patients with major depressive disorder: A longitudinal study.

BACKGROUND: Suicidal ideation (SI) is common in patients with major depressive disorder (MDD) and often related to cognitive deficits. Limited longitudinal study has shown that cognitive improvement is associated with reduced SI. However, the comparatively study in Chinese depressed patients is still absent. The objective of this study was to explore the specific cognitive deficits in Chinese MDD with SI and investigate the relationship between changes in cognition and change in SI across antidepressant treatment. METHODS: Three hundred and five patients with MDD received four weeks of antidepressant treatment. The 17-item Hamilton Depression Rating Scale (HAMD-17) and four domains of the MATRICS Consensus Cognitive Battery (MCCB), including speed of processing, working memory, visual learning and verbal learning were measured at baseline and four-week follow-up. RESULTS: One hundred and thirty patients (42.6%) expressed suicidal ideation. Suicidal patients performed worse on verbal learning than non-suicidal patients. Change in speed of processing domain was negatively associated with change in suicidal scores over time. Logistic regression analysis showed that reduction of SI was associated with improvement of speed of processing. LIMITATION: The major limitation was that there was no healthy control group in the current study, which might limit the interpretation of cognitive deficits in depressed patients with SI. CONCLUSIONS: Our findings suggest that suicidal patients performed worse on verbal learning which can potentially serve as a cognitive biomarker of suicide risk in MDD. Moreover, reduced suicidal ideation was associated with improved speed of processing.

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.

Predictors of response to repeated ketamine infusions in depression with suicidal ideation: An ROC curve analysis.

BACKGROUND: Ketamine has rapid-acting antidepressant and antisuicidal properties, while a proportion of patients do not adequately achieve a complete response to ketamine. Our aim was to explore the applicability of using clinical factors and serum tryptophan (TRP) metabolites to predict the response to six doses of ketamine for depression with suicidal ideation. METHODS: Seventy-three depressed patients with suicidal ideation received a thrice-weekly infusion regimen of subanaesthetic doses of ketamine. Clinical symptoms were assessed by the Montgomery-Asberg Depression Rating Scale (MADRS), Beck's Scale for Suicide Ideation (SSI) and Patient Health Questionnaire-9 (PHQ-9), and serum levels of TRP, kynurenine (KYN) and kynurenic acid (KYNA) were detected by liquid chromatography-tandem mass spectrometry at baseline and day 1 (1 day after the first infusion). The potential predictors of response was evaluated using receiver operating characteristic (ROC) curve analyses. RESULTS: The area under the curve (AUC = 0.959) implied a good accuracy of the combination of early clinical response and day 1 KYN and KYNA levels as a predictor of acute antidepressant response. The combination of early clinical response and day 1 KYNA levels showed moderate discrimination of acute antisuicidal response with an AUC of 0.825 and short-term antidepressant response with an AUC of 0.813. LIMITATIONS: The patients continued receiving previous medications during ketamine treatment, which may have impacted the TRP metabolites. CONCLUSION: The combination of early clinical response and TRP metabolites at the early stage of repeated ketamine treatment could be considered an eligible predictor for acute- and short-term response for treating depression with suicidal ideation.

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.

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.

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.

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.