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.

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.

A longitudinal study of the association between pro-inflammatory cytokines and mood symptoms in bipolar disorder.

BACKGROUND: Because of a relative dearth of longitudinal studies, the directionality of the relationship between mood and inflammation among patients with bipolar disorder (BD) is still unclear. We aimed to investigate the longitudinal associations of pro-inflammatory markers with mood symptom severity in BD. METHODS: Hundred and thirty-two adult patients with BD were enrolled. At the baseline and 1-year follow-up visit, all participants received mood assessment with Montgomery Åsberg depression rating scale (MADRS) and Young mania rating scale, and underwent blood draws to quantify metabolic profile and serum levels of the pro-inflammatory markers, including soluble interleukin-6 receptor, soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), monocyte chemoattractant protein-1, and C-reactive protein. A four-factor model of MADRS, consisting of sadness, negative thoughts, detachment, and neurovegetative symptoms, were applied. RESULTS: At baseline, 65 patients with BD were in depressed state, and 67 patients with BD were in euthymic state. Among patients in depressed state, baseline MADRS total score positively correlated with sTNF-αR1 level at follow-up. While baseline sTNF-αR1 level positively predicted sadness symptom in euthymic patients with BD who later developed depression (n = 22), sadness in patients with bipolar depression predicted later increase in serum sTNF-αR1 level even after remission (n = 17). Moreover, lithium had a stronger effect of lowering peripheral sTNF-αR1 level as compared with other mood stabilizers. CONCLUSION: Our results indicate the bidirectional inflammation-depression relationship in BD.

Pro-inflammatory cytokines and cognitive dysfunction among patients with bipolar disorder and major depression.

AIM: Bipolar disorder and major depressive disorder (MDD) have been demonstrated to be associated with proinflammatory states and cognitive function deficits. We aimed to investigate the differences of cognitive function and proinflammatory cytokines between patients with bipolar I disorder (BDI), bipolar II disorder (BDII), and MDD. METHODS: Thirty-seven patients with BDI, 33 with BDII, 25 with MDD, and 54 age-, sex-matched controls were enrolled. All patients had a clinical global impression-severity scale ≤2. Serum levels of proinflammatory markers, including soluble interleukin-6 receptor, C-reactive protein, and soluble tumor necrosis factor receptor 1 (sTNF-αR1) were measured. Performance in the Word List Memory Task (WLMT), Wisconsin Card Sorting Task (WCST), 2-back task, Go/No-Go task, and divided attention task was assessed. RESULTS: Patients with BDI had higher levels of sTNF-αR1 than patients with MDD and controls (P < 0.001). Patients with BDI performed worse on WLMT, WCST, 2-back task, divided attention_visual and divided attention_auditory tasks than the other three groups (all P < 0.05). Furthermore, sTNF-αR1 levels were negatively correlated with cognitive function measured using the WLMT and divided attention_auditory (all P < 0.05). CONCLUSIONS: Patients with BDI had higher levels of sTNF-αR1 and cognitive function impairments than the remaining groups. Future studies are needed to explore the pathophysiology of sTNF-αR1 in the contribution of cognitive alterations.

The risk of insomnia after surgical operation: A longitudinal, population-based, case-crossover study.

BACKGROUND: The acute onset of insomnia following surgical operations has long been neglected, and long-term outcomes are not clear. Our aims were (1) to evaluate the risk of postoperative insomnia, (2) to identify which surgeries are related, and (3) to follow patients with postoperative insomnia for the development of major mental and physical disorders. METHODS: We conducted a case-crossover study comprising 9898 participants with new-onset insomnia from the Taiwan National Health Insurance Research Database between 1997 and 2011. We determined the odds of having surgery in the case period (30 days) before the onset of insomnia by logistic regression analysis. Types of surgery that postoperative insomniacs had undergone were compared with age-/gender-/timing-matched controls. Longitudinal follow-up of postoperative and non-postoperative insomniacs was performed. RESULTS: The odds ratio of surgical exposure vs. nonexposure within 30 days was 12.05 (p < 0.001) before new-onset insomnia. Surgery of musculoskeletal and nervous systems predisposed to insomnia. The duration of hypnotic drug use (0.83 years) was shorter and with a nearly 2-fold faster remission rate in postoperative than in non-postoperative insomniacs (1.45 years). Approximately 25% of each insomnia group developed persistent sleep disturbance. CONCLUSION: Surgery is associated with subsequent insomnia, which has a shorter duration and a faster remission than non-postoperative insomnia. Our data provide a reference for postoperative care, and warrant future studies.

Cancer risk in patients with bipolar disorder and unaffected siblings of such patients: A nationwide population-based study.

Increasing evidence suggests that patients with bipolar disorder are more likely to develop malignant cancer than in the general population. However, the overall cancer risk in the unaffected siblings of such patients remains unknown. From the National Health Insurance Research Database of Taiwan, 25 356 patients with bipolar disorder, 25 356 age-matched unaffected siblings of patients with bipolar disorder and 101 422 age-matched controls without severe mental disorders between 1996 and 2010 were enrolled in our study. Patients who developed cancer between the time of enrollment and the end of 2011 were identified. Cancers were divided into three subgroups based on the related layer of embryonic development: ectodermal, mesodermal and endodermal cancers. Patients with bipolar disorder (odds ratio [OR] = 1.22, 95% confidence interval [CI]: [1.06, 1.40]) and unaffected siblings of such patients (OR = 1.17, 95% CI [1.02, 1.34]) had greater risk of developing malignant cancer than did controls. Furthermore, only those aged <50 years, for both patients with bipolar disorder (OR = 1.90, 95% CI [1.38, 2.61]) and unaffected siblings (OR = 1.65, 95% CI [1.19, 2.28]), were more likely to develop the ectodermal cancer, especially breast cancer, than the control group. The associations of bipolar disorder and susceptibility to bipolar disorder with increased cancer risk in the younger population may imply a genetic overlap in neurodevelopment and malignancy pathogenesis. Our findings may encourage clinicians to monitor cancer risk factors and warning signs closely in patients with bipolar disorder and unaffected siblings of such patients.

Efficacy of non-invasive brain stimulation interventions in reducing smoking frequency in patients with nicotine dependence: a systematic review and network meta-analysis of randomized controlled trials.

BACKGROUND AND AIMS: Nicotine is a highly addictive substance in tobacco products that dysregulates several neurotransmitters in the brain and impairs executive function. Non-invasive brain stimulation (NIBS) methods such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) are promising treatments for nicotine dependence. We investigated the efficacy and acceptability of NIBS in managing smoking cessation through a systematic review and network meta-analysis (NMA). METHODS: We conducted a systematic review to identify randomized controlled trials (RCTs) that investigated the efficacy of NIBS for smoking cessation. All pairwise meta-analyses and NMA procedures were conducted using random-effects and frequentist models. The co-primary outcomes were (1) the change in number of cigarettes smoked per day (change in frequency of smoking) in patients with nicotine dependence after NIBS and (2) acceptability (the dropout rate). The effect sizes for co-primary outcomes of change in frequency of smoking and acceptability were assessed according to standardized mean difference (SMD) and odds ratio, respectively. RESULTS: Twelve RCTs with 710 participants (mean age: 44.2 years, 31.2% female) were included. Compared with the sham control, 10-Hz rTMS over the left dorsolateral prefrontal cortex (DLPFC) was associated with the largest changes in smoking frequency [SMD = -1.22, 95% confidence interval (95% CI) = -1.77 to -0.66]. The 2-mA bifrontal tDCS (SMD = -0.97, 95% CI = -1.32 to -0.62) and 10-Hz deep rTMS over the bilateral DLPFC with cue provocation (SMD = -0.77, 95% CI = -1.20 to -0.34) were associated with a significantly larger decrease in smoking frequency versus the sham. None of the investigated NIBSs was associated with dropout rates significantly different from those of the sham control groups. CONCLUSION: Prefrontal non-invasive brain stimulation interventions appear to reduce the number of cigarettes smoked with good acceptability.

Pro-inflammatory cytokines and suicidal behavior among patients with bipolar I disorder.

OBJECTIVE: Suicidal behavior and different mood states of bipolar I disorder (BD) have been shown to be associated with dysregulated proinflammatory cytokines. Only a few studies have examined the association between inflammation and SB in BD, and the association between proinflammatory cytokines, SB, and cognitive deficits in patients with BD remains unclear. METHODS: 77 patients with BD and 61 age-/sex-matched healthy controls were recruited. Patients were divided into two groups: with suicidal ideation (SI; n = 21) and no SI (n = 56). SI was defined by a score of ≥1 in item 10 of Montgomery Åsberg Depression Rating Scale. Levels of proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), soluble tumor necrosis factor-α receptor type 1 (sTNF-αR1), and C-reactive protein (CRP), were measured, and cognitive function was assessed using 2-back task and Go/No-Go task. RESULTS: Patients with SI had higher levels of sTNF-αR1 than those without SI and the controls (p = .004). BD patients with or without a history of suicide attempt had higher levels of CRP than the controls. SI was associated with serum levels of sTNF-αR1 and IL-6sR, even after additionally controlling for working memory and inhibitory control (p < .05). CONCLUSION: This study indicates that serum levels of sTNF-αR1 have distinct differences between BD patients with or without SI, and our findings strengthen the hypothesis of a link between suicidal behavior and neuro-inflammation pathophysiology in BD.

Is one or two infusions better in the first week of low-dose ketamine treatment for medication-resistant depression? A post hoc pooled analysis of randomized placebo-controlled and open-label trials.

BACKGROUND: Whether a second ketamine infusion in the first week improves the antidepressant, antisuicidal, and anti-inflammatory effects of the first low-dose ketamine infusion remains unclear. METHODS: A total of 78 patients with medication-resistant depression were allocated to receive two ketamine infusions (n = 30; days 1 and 4), a single ketamine infusion (n = 24; only day 1), or normal saline placebo infusion (n = 24; only day 1). The Montgomery-Asberg Depression Scale (MADRS) and 17-item Hamilton Rating Scale for Depression (HDRS) were administered before and at 40 min, 240 min, day 2, day 4, day 5, and day 7 after infusion. Serum concentrations of interleukin (IL)-2 and tumor necrosis factor (TNF)-α were assessed. RESULTS: Two ketamine infusions improved the overall depressive symptoms (p < 0.001) and melancholic symptoms (p < 0.001) than a single ketamine or placebo infusion. The antisuicidal effect did not differ between the ketamine treatment groups. Two ketamine infusions increased TNF-α levels compared with a single ketamine or placebo infusion (p = 0.015). A single ketamine infusion improved the TNF-α-to-IL-2 ratio, an index of average anti-inflammatory effect, than two ketamine infusions or a single placebo infusion (p = 0.027). DISCUSSION: Repeated low-dose ketamine infusions improved the antidepressant effect, but not the antisuicidal effect, compared with a single infusion. However, repeated ketamine infusions may exert a lesser anti-inflammatory effect than a single infusion.

Obsessive-Compulsive Disorder and Dementia Risk: A Nationwide Longitudinal Study.

BACKGROUND: Several case reports have suggested an association between obsessive-compulsive disorder (OCD) and dementia. However, the exact relationship remains unclear. METHODS: Using the Taiwan National Health Insurance Research Database, 1,347 patients with OCD (ICD-9-CM code 300.3) aged ≥ 45 years and 13,470 controls matched for age, sex, residence, income, and dementia-related comorbidities were included between 1996 and 2013 for investigation of subsequent dementia from enrollment to the end of 2013. Stratified Cox regression analysis on each matched pair was applied to assess the dementia risk between the OCD and control groups. The analysis for the current study was performed in 2018. RESULTS: Patients with OCD had increased risk of developing any dementia (hazard ratio [HR] = 4.28; 95% confidence interval [CI], 2.96-6.21), Alzheimer's disease (HR = 4.04; 95% CI, 1.55-10.54), and vascular dementia (HR = 3.95; 95% CI, 1.70-9.18) compared with controls. DISCUSSION: Future research on the pathogenic mechanisms and molecular underpinnings of the relationship between OCD and dementia may lead to the development of novel therapeutics.

Role of obesity in systemic low-grade inflammation and cognitive function in patients with bipolar I disorder or major depressive disorder.

BACKGROUND: Studies have suggested the detrimental effects of obesity and systemic inflammation on the cognitive function of patients with bipolar or major depressive disorder. However, the complex associations between affective disorder, obesity, systemic inflammation, and cognitive dysfunction remain unclear. METHODS: Overall, 110 patients with affective disorder (59 with bipolar I disorder and 51 with major depressive disorder) who scored ≥61 on the Global Assessment of Functioning and 51 age- and sex-matched controls were enrolled. Body mass index ≥25 kg/m2 was defined as obesity or overweight. Levels of proinflammatory cytokines-including interleukin-6, tumor necrosis factor (TNF)-α, and C-reactive protein (CRP)-were measured, and cognitive function was assessed using various methods, including the Wisconsin Card Sorting Test (WCST) and go/no-go task. RESULTS: Patients with bipolar I disorder or major depressive disorder were more likely to be obese or overweight, had higher CRP and TNF-α levels, and had greater executive dysfunction in the WCST than the controls. TNF-α level (P < .05) but not affective disorder diagnosis or obesity/overweight was significantly associated with cognitive function deficits, although obesity/overweight and diagnosis were significantly associated with increased TNF-α level. CONCLUSIONS: Our findings may indicate that proinflammatory cytokines, but not obesity or overweight, have crucial effects on cognitive function in patients with bipolar I disorder or major depressive disorder, although proinflammatory cytokines and obesity or overweight were found to be strongly associated. The complex relationships between affective disorder diagnosis, proinflammatory cytokine levels, obesity or overweight, and cognitive function require further investigation.

Proinflammatory Cytokine Dysregulation and Cognitive Dysfunction Among Patients with Remitted Bipolar I and II Disorders.

BACKGROUND: Euthymic patients with bipolar disorder reportedly demonstrated increased levels of proinflammatory cytokines and cognitive function deficits. Because uncertain differences exist in cognitive function and proinflammatory cytokines between remitted bipolar I (BD1) and bipolar II (BD2) disorders, we performed this study to further investigate these differences. METHOD: We enrolled 58 patients with remitted BD1 and 27 with remitted BD2, and matched them for age and sex with 51 controls. Proinflammatory cytokines, including soluble interleukin-6 receptor (sIL-6R), C-reactive protein, and soluble tumor necrosis factor receptor 1 (sTNFR1) were measured, and performance in the Word List Memory Task (WLMT) and Wisconsin Card Sorting Task (WCST) was assessed. RESULTS: Significantly elevated levels of sTNFR1 were observed among patients with BD1 (p < .001) and BD2 (p = .038) compared with the controls; however, they did not differ between patients with BD1 and BD2 (p =.130). Working memory deficit measured by the WLMT was significantly greater in patients with BD1 (p < .001) and BD2 (p < .05) compared with controls, but did not differ between patients with BD1 and BD2 (p > 0.1). Furthermore, sTNFR1 levels were negatively correlated with cognitive function measured using the WLMT and WCST (all p < .05). DISCUSSION: Our results showed that euthymic patients with BD1 and BD2 showed similar levels of sTNFR1 and cognitive function (especially working memory) impairments. Further investigation is required to explore whether a common pathophysiology may contribute to the shared inflammatory and cognitive alterations between BD1 and BD2.

Association of Central Noninvasive Brain Stimulation Interventions With Efficacy and Safety in Tinnitus Management: A Meta-analysis.

Importance: Tinnitus has a prevalence of 10% to 25% and is frequently associated with numerous complications, such as neuropsychiatric disease. Traditional treatments have failed to meet the needs of patients with tinnitus. Noninvasive brain stimulation (NIBS) can focally modify cortical functioning and has been proposed as a strategy for reducing tinnitus severity. However, the results have been inconclusive. Objective: To evaluate the association between different central NIBS therapies and efficacy and acceptability for treatment of tinnitus. Data Sources: ClinicalKey, Cochrane CENTRAL, Embase, ProQuest, PubMed, ScienceDirect, and Web of Science databases were searched from inception to August 4, 2019. No language restriction was applied. Manual searches were performed for potentially eligible articles selected from the reference lists of review articles and pairwise meta-analyses. Study Selection: Randomized clinical trials (RCTs) examining the central NIBS method used in patients with unilateral or bilateral tinnitus were included in the current network meta-analysis. The central NIBS method was compared with sham, waiting list, or active controls. Studies that were not clinical trials or RCTs and did not report the outcome of interest were excluded. Data Extraction and Synthesis: Two authors independently screened the studies, extracted the relevant information, and evaluated the risk of bias in the included studies. In cases of discrepancy, a third author became involved. If manuscript data were not available, the corresponding authors or coauthors were approached to obtain the original data. This network meta-analysis was based on the frequentist model. Main Outcomes and Measures: The primary outcome was change in the severity of tinnitus. Secondary outcomes were changes in quality of life and the response rate related to the NIBS method in patients with tinnitus. Results: Overall, 32 unique RCTs were included with 1458 unique participants (mean female proportion, 34.4% [range, 0%-81.2%]; mean age, 49.6 [range, 40.0-62.8] years; median age, 49.8 [interquartile range, 48.1-52.4] years). The results of the network meta-analysis revealed that cathodal transcranial direct current stimulation over the left dorsolateral prefrontal cortex combined with transcranial random noise stimulation over the bilateral auditory cortex was associated with the greatest improvement in tinnitus severity (standardized mean difference [SMD], -1.89; 95% CI, -3.00 to -0.78) and quality of life (SMD, -1.24; 95% CI, -2.02 to -0.45) compared with the controls. Improvement in tinnitus severity ranked more favorably for continuous theta-burst stimulation (cTBS) over both auditory cortices (SMD, -0.79; 95% CI = -1.57 to -0.01) than cTBS over only the left auditory cortex (SMD, -0.30; 95% CI, -0.87 to 0.28), compared with controls. Repetitive transcranial magnetic stimulation with priming had a superior beneficial association with tinnitus severity compared with the strategies without priming. None of the investigated NIBS types had a significantly different dropout rate compared with that of the control group. Conclusions and Relevance: This network meta-analysis suggests a potential role of NIBS interventions in tinnitus management. Future large-scale RCTs focusing on longer follow-up and different priming procedure NIBS are warranted to confirm these findings.

Increased Proinflammatory Cytokines, Executive Dysfunction, and Reduced Gray Matter Volumes In First-Episode Bipolar Disorder and Major Depressive Disorder.

BACKGROUNDS: The association between systemic inflammation, executive dysfunction, and gray matter (GM) volume difference in first-episode affective disorders, including bipolar and major depressive disorders, is unclear. METHODS: Twenty-two patients with first-episode bipolar disorder, 22 age- and sex-matched patients with first-episode major depressive disorder, and 22 matched controls were enrolled in our study; all patients underwent comprehensive assessments, including clinical assessment, executive function examination (Wisconsin card sorting test [WCST]), proinflammatory cytokine receptors (soluble interleukin-6 receptor and tumor necrosis factor-α receptor 1 [TNFR1]), and brain magnetic resonance imaging. Voxel-based morphometry was performed to analyze the GM volume difference between bipolar and major depressive disorders. RESULTS: Patients with bipolar disorder were more likely to exhibit higher levels of TNFR1 (P = .038), more number of deficits in WCST (P < .05), and smaller GM volume in the middle frontal cortex (uncorrected voxel level P < .001) compared with those with major depressive disorder and healthy controls. Positive associations were observed between the middle frontal cortex volume, executive function, and the TNFR1 level. DISCUSSION: GM volume reduction in the middle frontal cortex, a greater level of systemic inflammation, and executive dysfunction were observed in first-episode affective disorders, especially bipolar disorder. A positive correlation between middle frontal cortex volume, executive function, and the TNFR1 level may indicate a divergent effect of brain and systemic inflammation functioning in the early phase (first episode) of affective disorder.

Esketamine Nasal Spray Plus Oral Antidepressant in Patients With Treatment-Resistant Depression: Assessment of Long-Term Safety in a Phase 3, Open-Label Study (SUSTAIN-2).

OBJECTIVE: To evaluate long-term safety and efficacy of esketamine nasal spray plus a new oral antidepressant (OAD) in patients with treatment-resistant depression (TRD). METHODS: This phase 3, open-label, multicenter, long-term (up to 1 year) study was conducted between October 2015 and October 2017. Patients (≥ 18 years) with TRD (DSM-5 diagnosis of major depressive disorder and nonresponse to ≥ 2 OAD treatments) were enrolled directly or transferred from a short-term study (patients aged ≥ 65 years). Esketamine nasal spray (28-mg, 56-mg, or 84-mg) plus new OAD was administered twice a week in a 4-week induction (IND) phase and weekly or every-other-week for patients who were responders and entered a 48-week optimization/maintenance (OP/MAINT) phase. RESULTS: Of 802 enrolled patients, 86.2% were direct-entry and 13.8% were transferred-entry; 580 (74.5%) of 779 patients who entered the IND phase completed the phase, and 150 (24.9%) of 603 who entered the OP/MAINT phase completed the phase. Common treatment-emergent adverse events (TEAEs) were dizziness (32.9%), dissociation (27.6%), nausea (25.1%), and headache (24.9%). Seventy-six patients (9.5%) discontinued esketamine due to TEAEs. Fifty-five patients (6.9%) experienced serious TEAEs. Most TEAEs occurred on dosing days, were mild or moderate in severity, and resolved on the same day. Two deaths were reported; neither was considered related to esketamine. Cognitive performance generally either improved or remained stable postbaseline. There was no case of interstitial cystitis or respiratory depression. Treatment-emergent dissociative symptoms were transient and generally resolved within 1.5 hours postdose. Montgomery-Åsberg Depression Rating Scale total score decreased during the IND phase, and this reduction persisted during the OP/MAINT phase (mean [SD] change from baseline of respective phase to endpoint: IND, -16.4 [8.76]; OP/MAINT, 0.3 [8.12]). CONCLUSIONS: Long-term esketamine nasal spray plus new OAD therapy had a manageable safety profile, and improvements in depression appeared to be sustained in patients with TRD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02497287.

A comparison study of metabolic profiles, immunity, and brain gray matter volumes between patients with bipolar disorder and depressive disorder.

BACKGROUND: Previous individual studies have shown the differences in inflammatory cytokines and gray matter volumes between bipolar disorder (BD) and unipolar depression (UD). However, few studies have investigated the association between pro-inflammatory cytokines and differences in brain gray matter volumes between BD and UD. METHODS: In this study, 72 BD patients and 64 UD patients were enrolled, with comparable gender and age distributions (33.8% males and an average age of 39.3 ± 13.7 years). Each participant underwent metabolic profiling (including body mass index (BMI), glucose, triglyceride, high-density lipoprotein (HDL), leptin, insulin, adiponectin), pro-inflammatory cytokine (including soluble interleukin-6 receptor (sIL-6R), soluble interleukin-2 receptor (sIL-2R), C-reactive protein (CRP), soluble tumor necrosis factor receptor type 1 (sTNF-R1) examinations, and structural magnetic resonance imaging exams. Voxel-based morphometry was performed to investigate the gray matter volume differences between BD and UD patients. Correlations between pro-inflammatory cytokines and the gray matter volume difference were analyzed. RESULTS: Compared to UD patients, the BD group had significantly higher BMI, and higher levels of sIL-6R and sTNF-R1 than the UD patients. The BMI significantly correlated with the level of pro-inflammatory cytokines. Adjusted for age, sex, BMI, duration of illness and total intracranial volume, the BD individuals had significantly more reduced gray matter volumes over 12 areas: R. cerebellar lobule VIII, R. putamen, L. putamen, R. superior frontal gyrus, L. lingual gyrus, L. precentral gyrus, R. fusiform gyrus, L. calcarine, R. precuneus, L. inferior temporal gyrus, L. hippocampus, and L. superior frontal gyrus. These 12 gray matter volume differences between BP and UD patients negatively correlated with sIL-6R and sTNF-R1 levels. CONCLUSIONS: Our results suggested that BD patients had higher BMI and pro-inflammatory cytokine levels in comparison to UD patients, especially IL-6 and sTNF-R1, which may contribute to greater gray matter reductions in BD patients in comparison to UD patients. The results support the neuro-inflammation pathophysiology mechanism in mood disorder. It is clinically important to monitor BMI, which, in this investigation, positively correlated with levels of inflammatory cytokines.

Analgesic effects of repetitive transcranial magnetic stimulation on modified 2010 criteria-diagnosed fibromyalgia: Pilot study.

AIM: Fibromyalgia is often comorbid with depression, and less than half those patients achieve satisfactory improvement after adequate pharmacological intervention. The investigation of repetitive transcranial magnetic stimulation (rTMS) at left dorsolateral prefrontal cortex for modified-2010 American College of Rheumatology (ACR) fibromyalgia and major depressive disorder (MDD) is still in its infancy. METHODS: In this double-blind, randomized, sham-control study, subjects diagnosed with ACR-2010 fibromyalgia and DSM-IV-TR MDD were recruited and received either active or sham interventions for 2 weeks. Hamilton Depression Rating Scale (HDRS) and the 10-cm visual analogue pain scale were evaluated at baseline, week 1, and week 2. Multivariable generalized estimating equations analysis was performed for the association between depression and pain scores at each checkpoint. RESULTS: Twenty subjects were recruited. There was a significant difference over the 2 weeks between the rTMS and sham stimulation groups (P = 0.029), but subgroup analyses were further performed due to significant interaction of group and HDRS on pain outcomes (P = 0.020). The active group had significant improvement in pain at week 2 compared with week 1 (P = 0.021), but the control group did not have any improvement in pain (P = 0.585). Of the mild-moderate depression patients, the pain score in the active group was significantly lower than in the sham group at week 1 (P = 0.001) and at week 2 (P < 0.001). For the severe depression group, there was significantly lower pain over the 2 weeks in the active group (P = 0.045) but the sham group had significantly relapsing pain at week 2 (P < 0.001). CONCLUSION: Left prefrontal rTMS has an analgesic effect in modified-ACR 2010-defined fibromyalgia and MDD patients. Further investigation is required, however, in order to determine how to regulate the different rTMS treatment protocols according to individual baseline depression severity in patients with MDD and fibromyalgia.

Rapid inflammation modulation and antidepressant efficacy of a low-dose ketamine infusion in treatment-resistant depression: A randomized, double-blind control study.

Increasing evidence supports the rapid antidepressant effect of a low-dose ketamine infusion in treatment-resistant depression (TRD). Proinflammatory cytokines play a crucial role in the pathophysiology of TRD. However, it is unknown whether the rapid antidepressant effect of ketamine is related to the rapid suppression of proinflammatory cytokines. Seventy-one patients with TRD were randomized into three groups according to the treatment received: 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, and normal saline infusion. Proinflammatory markers, including C-reactive protein (CRP), interleukin (IL)-6, and tumor necrosis factor (TNF)-α were examined at baseline and at 40 min, 240 min, Day 3, and Day 7 postinfusion. Montgomery-Åsberg Depression Rating Scale (MADRS) was assessed for depressive symptoms across time. Log-transformed IL-6 and TNF-α levels differed significantly over time. The decrease in TNF-α between baseline and 40 min postinfusion was positively correlated with a decrease in MADRS scores across time in the 0.5 mg/kg ketamine group. This is the first clinical study to support a positive correlation between changes in cytokine levels after ketamine infusion and improvements in depressive symptoms with TRD. The rapid suppression of proinflammatory cytokines may contribute to the rapid antidepressant effect of the ketamine infusion.

Risk of Type 2 Diabetes in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder: A Nationwide Longitudinal Study.

BACKGROUND: Studies have suggested there is an association between attention-deficit/hyperactivity disorder (ADHD) and type 2 diabetes mellitus (DM)-related risk factors, such as obesity, hypertension, and dyslipidemia. However, the association between ADHD and type 2 DM remains unknown. METHODS: Using the Taiwan National Health Insurance Research Database, we enrolled 35,949 adolescents and young adults with ADHD (ICD-9-CM code: 314) and 71,898 (1:2) age- and sex-matched controls from 2002 through 2009 and followed up with them until the end of 2011. Participants who developed type 2 DM during the follow-up period were identified. RESULTS: Adolescents (hazard ratio [HR] = 2.83; 95% CI, 1.96-4.09) and young adults (HR = 3.28; 95% CI, 1.41-7.63) with ADHD had a higher risk of developing type 2 DM than did the controls after adjustment for demographic characteristics, use of ADHD medications and atypical antipsychotics, and medical comorbidities. Individuals with ADHD had a shorter mean ± SD duration between enrollment and onset of type 2 DM (3.17 ± 2.33 vs 4.08 ± 2.11 years, P = .004) during the follow-up compared with the controls. Sensitivity analyses after excluding first-year (HR = 2.36; 95% CI, 1.65-3.38) and first-3-year (HR = 1.92; 95% CI, 1.19-3.09) observation periods were consistent. Long-term use of atypical antipsychotics was associated with a higher likelihood of subsequent type 2 DM (HR = 2.82, 95% CI, 1.74-4.58). DISCUSSION: Adolescents and young adults with ADHD were more likely than non-ADHD controls to develop type 2 DM in later life. In addition, those with ADHD taking atypical antipsychotics exhibited a higher risk. Although correlation does not equal causation, our findings merit further study about the relationship between ADHD and type 2 DM.

Post-traumatic stress disorder and risk of osteoporosis: A nationwide longitudinal study.

Several studies suggested a relationship between stress and related mental illnesses, such as depression and osteoporosis. However, it was unclear whether patients with post-traumatic stress disorder (PTSD) were at risk of developing osteoporosis in later life. In this study, 6,041 patients with PTSD and 24,164 age- or sex-matched controls were enrolled between 2002 and 2009 in our study and followed up to the end of 2011. Cases of osteoporosis were identified during the follow-up. Patients with PTSD had an elevated likelihood of developing osteoporosis (HR: 2.66, 95% CI [1.91, 3.71]) in later life compared with the controls. Sensitivity tests after excluding the first year observation (HR: 2.46, 95% CI [1.72, 3.53]) and the first 3-year observation (HR: 1.88, 95% CI [1.18, 3.01]) were consistent. Patients with PTSD had a higher risk of developing osteoporosis at an earlier age compared with those without PTSD. Further studies would be necessary to clarify the pathophysiology between PTSD and osteoporosis.