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Background: Evidence suggests that clinical markers, such as comorbid anxiety, body weight, and others can assist in predicting response to low-dose ketamine infusion in treatment resistant depression patients. However, whether a composite of clinical markers may improve the predicted probability of response is uncertain. Methods: The current study investigated the results of our previous randomized placebo-controlled and open-label trials in which 73 patients with treatment-resistant depression (TRD) received a single ketamine infusion of 0.5 mg/kg. Clinical characteristics at baseline, including depression severity, duration of the current episode, obesity, comorbidity of anxiety disorder, and current suicide risk, were assessed as potential predictors in a classification and regression tree model for treatment response to ketamine infusion. Results: The predicted probability of a composite of age at disease onset, depression severity, duration of current episode, and obesity/overweight was significantly greater (area under curve = .736, p = .001) than that of any one marker (all p > .05). The most powerful predictors of treatment response to ketamine infusion were younger age at disease onset and obesity/overweight. The strongest predictors of treatment nonresponse were longer duration of the current episode and greater depression severity at baseline. Discussion: Depression severity, duration of the current episode, obesity, and age at disease onset may predict treatment response versus nonresponse to low-dose ketamine infusion. However, whether our predicted probability for a single infusion may be applied to repeated infusions would require further investigation. Clinical trial registration: UMIN Clinical Trials Registry (UMIN000023581 and UMIN000016985).

Background Although repetitive transcranial magnetic stimulation (rTMS) and prolonged intermittent theta-burst stimulation (piTBS) can induce changes in synaptic plasticity, the influence of brain-derived neurotrophic factor (BDNF) genotypes on their antidepressant effects remain unknown. Hence, we investigated the BDNF polymorphism contribution to the antidepressant effect of different forms left-sided prefrontal stimulations in a randomized, sham-controlled study Methods Seventy-five patients with medication-resistant depression were randomly assigned into three monotherapy groups: piTBS, high-frequency(HF) rTMS, or sham. The acute treatment period was two weeks. 17-item Hamilton Depression Rating scale (HDRS-17) were applied at baseline, week-1, and week-2. The primary outcome was percentage changes of HDRS-17 (%HDRS-17 changes) analyzed by generalized estimating equation (GEE) model. Results The GEE analysis revealed a significant interaction between group, time, and BDNF genotypes effects on %HDRS-17 changes over time. In patients carrying Val homozygotes, piTBS and HF-rTMS both exhibited significantly greater %HDRS reduction than sham at week-2. In Met carriers, only piTBS showed better efficacy than sham at week-2 (piTBS vs. sham, -41.1% vs.-18.9%, p=0.004). Regarding the influence of different BDNF genotypes on antidepressant efficacy in each intervention, only HF-rTMS exhibited significantly different degrees of %HDRS-17 changes between Val homozygotes and Met carriers (-68.5% vs. -26.4%, p=0.012, respectively), but piTBS delivered the consistent efficacy regardless of the BDNF polymorphism. Conclusions This is the first study to confirm the different impacts of BDNF genotypes on the effect of different left-sided prefrontal brain stimulation. BDNF Val66Met polymorphism may play a role in the antidepressant response of piTBS and HF-rTMS. (Trial Registration Number UMIN-CTR:UMIN000020892: Registration date: Feb.4, 2016)

Background: Growing evidence suggests a rapid antisuicidal effect of low-dose ketamine infusion in Caucasian patients with treatment-resistant depression (TRD). However, the antisuicidal effects of ketamine on Taiwanese patients with TRD remains unknown. Methods: Seventy-one patients with TRD were randomly classified into three treatment groups: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or normal saline (placebo) infusion. The Hamilton Depression Rating Scale (HAMD) and Montgomery-Asberg Depression Rating Scale (MADRS) were applied prior to initiation of test infusions, at 40, 80, 120, and 240 min postinfusion, and sequentially on Days 2, 3, 4, 5, 6, 7, and 14 after ketamine or placebo infusion. Item 3 (suicide) of the HAMD and item 10 (suicidal thoughts) of the MADRS were extracted for generalized estimating equation (GEE) model analyses to investigate the antisuicidal effects of ketamine infusion. Brain-derived neurotrophic factor (BDNF) Val66Met polymorphism was genotyped. Results: The GEE model revealed significant group (p = 0.007) and time (p = 0.004) effects on suicidal symptoms over times (prior to infusion to day 14 postinfusion). The group that received 0.5 mg/kg ketamine infusion exhibited a significantly lower score in item 3 of the HAMD and item 10 of the MADRS compared with the groups that received 0.2 mg/kg ketamine or placebo infusion. Among those carrying any Val allele of BDNF, both 0.5 and 0.2 mg/kg ketamine infusions were effective in reducing suicidal thoughts; however, among those with Met/Met of BDNF, only 0.5 mg/kg ketamine infusion was effective in reducing suicidal thoughts. Discussion: A single low-dose ketamine infusion was effective in reducing suicidal ideation among Taiwanese patients with TRD. BDNF Val66Met polymorphism may play a crucial role in the antisuicidal effects of ketamine infusion.

A single low-dose ketamine infusion exhibited a rapid antidepressant effect within 1h. Despite its short biological half-life (approximately 3h), the antidepressant effect of ketamine has been demonstrated to persist for several days. However, changes in brain function responsible for the persistent antidepressant effect of a single low-dose ketamine infusion remain unclear METHODS: Twenty-four patients with treatment-resistant depression (TRD) were randomized into three groups according to the treatment received: 0.5mg/kg ketamine, 0.2mg/kg ketamine, and normal saline infusion. Standardized uptake values (SUVs) of glucose metabolism measured through 18F-FDG positron-emission-tomography before infusion and 1day after a 40-min ketamine or normal saline infusion were used for subsequent whole-brain voxel-wise analysis and were correlated with depressive symptoms, as defined using the Hamilton Depression Rating Scale-17 (HDRS-17) score RESULTS: The voxel-wise analysis revealed that patients with TRD receiving the 0.5mg/kg ketamine infusion had significantly higher SUVs (corrected for family-wise errors, P = 0.014) in the supplementary motor area (SMA) and dorsal anterior cingulate cortex (dACC) than did those receiving the 0.2mg/kg ketamine infusion. The increase in the SUV in the dACC was negatively correlated with depressive symptoms at 1day after ketamine infusion DISCUSSION: The persistent antidepressant effect of a 0.5mg/kg ketamine infusion may be mediated by increased activation in the SMA and dACC. The higher increase in dACC activation was related to the reduction in depressive symptoms after ketamine infusion. A 0.5mg/kg ketamine infusion facilitated the glutamatergic neurotransmission in the SMA and dACC, which may be responsible for the persistent antidepressant effect of ketamine much beyond its half-life.

Background Add-on repetitive transcranial magnetic stimulation (rTMS) is effective in treating medication-resistant depression (MRD), but little is known about the rTMS antidepressant mechanism and pathophysiology underlying MRD. Methods Twenty MRD patients received 2 weeks of navigated add-on rTMS to the left dorsolateral prefrontal cortex (DLPFC). Treatment response was defined as a ≥ 50% decrease in HDRS after treatment. Cerebral glucose metabolism was measured from all MRD patients twice, before and 3 months after rTMS, and from 20 healthy controls once at baseline. Results At baseline, MRD subjects presented significant hypometabolism at the bilateral DLPFC and anterior cingulum, as well as hypermetabolism at several limbic and subcortical regions compared to the controls. Higher metabolism at the medial PFC and rostral anterior cingulum, and lower metabolism at the limbic structures, including the left parahippocampus and fusiform gyrus, predicted a response to rTMS. After successful rTMS treatment, the abnormally elevated metabolism in the left middle temporal cortex and fusiform gyrus decreased significantly, suggesting a reversal of metabolic imbalances. However, the overall metabolic pattern was still abnormal, even after their depression was under control. In contrast, the non-responders showed a worsening pattern of increased metabolism in the bilateral temporal cortex and fusiform gyrus. Conclusions The antidepressant mechanism of add-on rTMS may be reflected as suppression of hyperactivity in the left temporal cortex and fusiform gyrus, perhaps through enhancing the function of the medial prefrontal cortex and anterior cingulum. The limbic-cortical dysregulation of glucose metabolism might be a trait of an underlying mechanism of MRD.

Background Essential in dopamine degradation, it was suggested that catechol-O-methyltransferase (COMT) might be involved in the action of antidepressants and may therefore be a promising candidate for antidepressant pharmacogenetic studies. Methods COMT Val158met polymorphism was genotyped in 334 Chinese major depressive disorder (MDD) patients who were treated with fluoxetine for at least 4 weeks. Clinical response was evaluated using the 21-item Hamilton Rating Scale for Depression (HAM-D21). In the analysis of association, response was defined as ≥ 50% decrease in HAM-D21 score after treatment and then further clarified by intra-individual changes in HAM-D21 score. Results We found that the COMT val158met polymorphism was not associated with 4-week fluoxetine therapeutic response; however, association analysis showed that patients with the COMT Val/Val genotype had poorer responses in the eighth week (CLUMP T1 P = 0.020) and consistently showed significantly smaller reductions in HAM-D21 scores in the eighth week (P = 0.027). Further stratification based on gender revealed an isolated effect of the COMT genotype in males (P = 0.035) but not in females (P = 0.650) in percent reduction in HAM-D21 scores in the eighth week. Limitations There was a lack of placebo control and the serum fluoxetine concentration was not taken into account. Conclusions This identified association between the COMT genetic variation and antidepressant response may be useful either as a clinical predictor in the future.

Background: Depressive patients are more likely to smoke than the general population and nicotine was found to reduce the incidence and severity of depressive symptoms in many studies. These findings suggest that nicotinic acetylcholine receptors (nAChRs) may be implicated in major depressive disorder. We tested the hypothesis that the allelic variant, 2 bp deletion, of the partially duplicated α7 nAChR gene confers susceptibility to major depressive disorder. Methods: We genotyped α7 nAChR in 72 patients with major depressive disorder and 103 normal controls. Results: The distribution of the partially duplicated α7 nAChR genotypes (P=0.027) and alleles (P=0.037) suggests a modest difference between depressive patients and controls. Limitations: The −2 bp allele is thought to be present only in the duplicated exon 6, and the impact of the partially duplicated α7 nAChR and its −2 bp variant remain to be determined. Conclusions: The −2 bp allele of partially duplicated α7 nAChR may have an influence on the risk for development of major depressive disorder. The levels of significance achieved are modest and the findings must be replicated in other studies.