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

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

Poor subjective sleep quality and trait impulsivity in patients with bipolar disorder.

BACKGROUND: Sleep disturbance and impulsivity are key components of mood vulnerability in bipolar disorder (BD), but few studies have assessed the association between these two symptoms among patients with BD. METHODS: Forty-seven euthymic patients with bipolar I disorder (BDI) or bipolar II disorder (BDII) and 58 age- and sex-matched healthy controls were enrolled in this cross-sectional study. Trait impulsivity was measured using the Barratt Impulsiveness Scale Version 11 (BIS-11), which yielded 3 second-order factors: attention, motor, and non-planning. Subjective sleep quality was assessed using the self-reported Pittsburgh Sleep Quality Index (PSQI). General linear models (GLMs) were used to assess the associations between subjective poor sleep and trait impulsivity with multiple testing corrections. RESULTS: Patients with BD scored higher in BIS-11 and PSQI than healthy controls. PSQI total scores positively correlated with BIS-11 total scores, while sleep disturbance and daytime dysfunction were associated with attentional impulsiveness after controlling for covariates. Participants with higher PSQI total scores (>10) had higher scores in BIS-11 total, attention, and non-planning than those with low PSQI scores (≤5). CONCLUSION: These findings support the hypothesis that poor sleep quality might lead to impulsivity and add to the growing evidence that improving sleep quality may be a therapeutic target for patients with BD.

Delay Analysis in Closed-Loop EEG Phase-Triggered Transcranial Magnetic Stimulation.

The recent development of closed-loop EEG phase-triggered transcranial magnetic stimulation (TMS) has advanced potential applications of adaptive neuromodulation based on the current brain state. Closed-loop TMS involves instantaneous acquisition of the EEG rhythm, timing prediction of the target phase, and triggering of TMS. However, the accuracy of EEG phase prediction algorithms is largely influenced by the system's transport delay, and their relationship is rarely considered in related work. This paper proposes a delay analysis that considers the delay of the closed-loop EEG phase-triggered TMS system as a primary factor in the validation of phase prediction algorithms. An in-silico validation using real EEG data was performed to compare the performance of commonly used algorithms. The experimental results indicate a significant influence of the total delay on the algorithm performance, and the performance ranking among algorithms varies at different levels of delay. We conclude that the delay analysis framework should be widely adopted in the design and validation of phase prediction algorithms for closed-loop EEG phase-triggered TMS systems.

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

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

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

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

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

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

Pharmacokinetics and Safety of Sodium Benzoate, a d-Amino Acid Oxidase (DAAO) Inhibitor, in Healthy Subjects: A Phase I, Open-label Study.

PURPOSE: N-methyl-d-aspartate receptor (NMDAR)-mediated neurotransmission plays a critical role in cognition and memory, and d-serine is a co-agonist of the receptor. d-serine is metabolized by d-amino acid oxidase (DAAO). Sodium benzoate is a DAAO inhibitor that leads to the elevation of d-serine levels and enhances NMDAR functions as a therapeutic for wide-spectrum central nervous system (CNS) disorders, including schizophrenia and dementia. For therapeutic application of sodium benzoate in CNS disorders, we conducted a Phase I study to evaluate its safety, tolerability, and pharmacokinetic profile after single-dose oral administration in healthy volunteers. In contrast to the accumulation in the CNS, sodium benzoate has a rapid pharmacokinetic profile when measured peripherally. METHODS: In this Phase I study, subjects were randomized into 4 different dose groups after a single oral administration. The pharmacokinetic parameters of sodium benzoate were assessed after exposure to 250, 500, 1000, and 2000 mg of sodium benzoate. All adverse events were investigated and recorded. FINDINGS: The Cmax and AUC of sodium benzoate exhibited a higher than dose-proportional increase within the dose range from 250 to 2000 mg under fasting conditions. The slopes were 1.78 and 2.61 and the 90% CIs were 1.41 to 2.15 and 2.20 to 3.03 for Cmax and AUC, respectively. Sodium benzoate was absorbed and converted to benzoic acid rapidly, reaching Cmax after ∼0.5 hour and elimination t1/2 after ∼0.3 hour. No subjects reported adverse events that were sodium benzoate related. IMPLICATIONS: The nonlinear pharmacokinetic response was observed within the dose range up to 2000 mg. Sodium benzoate treatment exhibited a favorable safety profile and was well tolerated at all dose levels. The study results serve as a foundation that should be useful for investigating efficacy and safety in the drug's subsequent clinical development. TRIAL REGISTRATION: TFDA-103607047.

Low-dose ketamine infusion in treatment-resistant double depression: Revisiting the adjunctive ketamine study of Taiwanese patients with treatment-resistant depression.

BACKGROUND: Whether a single low-dose ketamine infusion may have rapid antidepressant and antisuicidal effects in patients with treatment-resistant double depression remains unclear. METHODS: This study enrolled 35 patients with treatment-resistant double depression, 12 of whom received 0.5 mg/kg ketamine, 11 received 0.2 mg/kg ketamine, and 12 received normal saline as a placebo. The patients were assessed using the 17-item Hamilton Rating Scale for Depression (HDRS) prior to the initiation of infusions, at 40 and 240 min post-infusion, and sequentially on Days 2-7 and on Day 14 after ketamine or placebo infusions. RESULTS: A single 0.5 mg/kg ketamine infusion had rapid antidepressant (p = 0.031, measured by the HDRS) and antisuicidal (p = 0.033, measured by the HDRS item 3 scores) effects in patients with treatment-resistant double depression. However, 0.2 mg/kg ketamine was insufficient to exert rapid antidepressant and antisuicidal effects in this patient population with severe and chronic illness. DISCUSSION: In this patient population, the commonly used dose of 0.5 mg/kg was sufficient. Additional studies are required to investigate whether repeated infusions of low-dose ketamine may also maintain antidepressant and antisuicidal effects in patients with treatment-resistant double depression.

Subgrouping time-dependent prescribing patterns of first-onset major depressive episodes by psychotropics dissection.

BACKGROUND: Subgrouping patients with major depressive disorder is a promising solution for the issue of heterogeneity. However, the link between available subtypes and distinct pathological mechanisms is weak and yields disappointing results in clinical application. AIM: To develop a novel approach for classification of patients with time-dependent prescription patterns at first onset in real-world settings. METHODS: Drug-naive patients experiencing their first major depressive episode (n = 105) participated in this study. Psychotropic agents prescribed in the first 24 mo following disease onset were recorded monthly and categorized as antidepressants, augmentation agents, and hypnosedatives. Monthly cumulative doses of agents in each category were converted into relevant equivalents. Four parameters were used to summarize the time-dependent prescription patterns for each psychotropic load: Stability, amount, frequency, and the time trend of monthly prescriptions. A K-means cluster analysis was used to derive subgroups of participants based on these input parameters of psychotropic agents across 24 mo. Clinical validity of the resulting data-driven clusters was compared using relevant severity indicators. RESULTS: Four distinct clusters were derived from K-means analysis, which matches experts' consent: "Short-term antidepressants use", "long-term antidepressants use", "long-term antidepressants and sedatives use", and "long-term antidepressants, sedatives, and augmentation use". At the first 2 years of disease course, the four clusters differed on the number of antidepressants used at adequate dosage and duration, frequency of outpatient service use, and number of psychiatric admissions. After the first 2 years following disease onset, depression severity was differed in the four subgroups. CONCLUSION: Our findings suggested a new approach to optimize the subgrouping of patients with major depressive disorder, which may assist future etiological and treatment response studies.

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.

Low-dose ketamine infusion for treating subjective cognitive, somatic, and affective depression symptoms of treatment-resistant depression.

BACKGROUNDS: Whether the antidepressant effects of low-dose ketamine infusion and the therapeutic impact of Val66Met brain-derived neurotrophic factor (BDNF) polymorphism vary across different depression symptom domains, namely affective, cognitive, and somatic, remains unclear. METHODS: We-reanalyzed the data of Adjunctive Ketamine Study of Taiwanese Patients with Treatment-Resistant Depression (TRD). A total of 71 patients with TRD were randomized to three infusion groups: 0.5 and 0.2 mg/kg ketamine groups and the normal saline placebo group. The Beck Depression Inventory-II (BDI-II) was used to obtain self-reported scores prior to infusion and 240 min after infusion and sequentially on days 3, 7, and 14 after infusion. The three-factor model of cognitive, somatic, and affective depressive symptoms that is based on the BDI-II and proposed by Beck et al. was applied in the current study. The Val66Met BDNF polymorphism was genotyped. RESULTS: Ketamine infusion exerted rapid and sustained antidepressant effects on the affective (p = 0.014) and cognitive (p = 0.005) depression symptom domains but not on the somatic (p = 0.085) depression symptom domain. Only patients with TRD harboring any Val allele at the BDNF rs6265 polymorphism were more likely to respond (p = 0.011) to low-dose ketamine infusion. DISCUSSION: Additional studies should elucidate different mechanisms underlying the effects of ketamine infusion on cognitive, affective, and somatic depression symptom domains in patients with TRD.

Visualizing Patterns of Medication Switching Among Major Depressive Patients with Various Stability and Difficulty to Treatments.

INTRODUCTION: Efforts have been made in assessing efficacy and tolerability to various antidepressants, but understanding personalized chances of stability to medication switching sequence is still inconclusive. This study aimed to identify naturalistic switching patterns of medication in stratifying MDD patients. METHODS: MDD patients were stratified based on treatment difficulty evaluated with the "Treatment Resistance to Antidepressants Evaluation Scale for Unipolar Depression" (TRADES). The duration of the time of diagnoses until the final switch to another class of antidepressants was used as prediction of unstable to drug therapy. ROC analysis was used to determine the cutoff values. A continuous temporal events function from the visual analytic tool was employed to perform patterns of switching between distinct pharmacological class such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs). RESULTS: TRADES scores of 4.5 and not-switching times of 12.5 months were used as cutoff values to divide patients into four subgroups: stable/easy-to-treat (SE), unstable/easy-to-treat (UE), stable/difficult-to-treat (SD) and unstable/difficult-to-treat (UD). A total of 80% and 76.9% of patients initially treated with the SSRIs paroxetine or fluoxetine, respectively, were predicted to be stable to drug therapy. Approximately 70%, 44.8% and 41.4% of patients initially treated with the SNRIs fluvoxamine, sertraline and venlafaxine, respectively, were predicted to be UD, and 60% of patients using duloxetine were predicted to be stable to drug therapy. Analysis of the switching phenomenon showed that SSRIs were the first prescribed medications and mostly taken by the stable subgroups, and SNRIs were the preferentially chosen switching alternative. Medication switching patterns in unstable MDD patients are discussed. CONCLUSION: Paroxetine, fluoxetine and duloxetine users were mostly stable among MDD patients in Taiwan with various stability and difficulty to treatments. Although responsiveness to specific medication sequence is likely required for clinical application, the results provide a baseline for such studies.

Real-world evidence on the use of benzodiazepine receptor agonists and the risk of venous thromboembolism.

BACKGROUND: Venous thromboembolism (VTE) is a life-threatening disease, and some studies reported that benzodiazepine receptor agonist (BZRA) use could increase the risk of VTE, but this association lacks population-based evidence. OBJECTIVES: To investigate the association between BZRA use and the risk of VTE. PATIENTS/METHODS: A nested case-control study analyzing Taiwan's claims database was conducted of patients with at least one new BZRA prescription on record from January 1, 2002, to December 31, 2012. We included new users who did not have any BZRA prescriptions in the preceding 2 years and identified cases with VTE and disease risk score matched control subjects. We used a logistic regression model to investigate the association between BZRA exposure and the risk of VTE. The exposure duration, dose, and classes of BZRAs were comprehensively evaluated. RESULTS: We identified 2800 VTE cases and 2800 matched controls. Current BZRA prescription (≤90 days) was associated with VTE occurrence (adjusted odds ratio [aOR]: 1.83; 95% confidence interval [CI], 1.62-2.06). The point estimates of benzodiazepine hypnotics (aOR: 2.00; 95% CI, 1.45-2.76) had a marginally higher risk of VTE than nonbenzodiazepine hypnotics (aOR: 1.39; 95% CI, 1.07-1.81). The VTE risk was increased with combination BZRA use, number of BZRA used, and a higher dose of BZRA. On examination of individual BZRA, the risk of VTE was higher with flunitrazepam use (aOR: 2.99; 95% CI, 1.43-6.28) than other BZRAs. CONCLUSIONS: This study presents that current BZRA use may increase the risk of VTE. Also, benzodiazepine hypnotics, especially flunitrazepam, have a higher risk of VTE.

Sex and age differences in the association between anxiety disorders and narcolepsy: A nationwide population-based case control study.

BACKGROUND: To examine the association between narcolepsy and anxiety disorders. METHODS: This population-based, retrospective case-control study analyzed Taiwan's National Health Insurance Research Database between 2000 and 2013. We included narcoleptic patients aged at least 12 years, diagnosed according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code 347. The cases and the propensity score-matched controls were selected in a 1:4 ratio. Each subject with anxiety disorders (ICD-9-CM code 300) was required to visit the outpatient clinic at least three times within a year. Multivariate logistic regression and interaction analyses were used to calculate the association between anxiety disorders and narcolepsy. RESULTS: This study enrolled 478 and 1912 subjects with and without narcolepsy, respectively. After adjusting for covariates, patients with anxiety disorders had an approximately 2.7 odds ratio of developing narcolepsy when compared to the control subjects (adjusted odds ratio [aOR)] = 2.7; 95% confidence interval [CI] = 1.699-4.344). Interaction analysis and subgroup analysis showed a higher incidence of previously diagnosed anxiety disorders in narcoleptic patients aged 12 to 17 years and female patients (aOR = 25.9; 95% CI = 15.194-42.896; aOR = 3.6; 95% CI = 1.818-7.062, respectively). LIMITATIONS: The narcolepsy and anxiety disorders were not distinguished by validated structural diagnostic instruments. CONCLUSIONS: The results of this study revealed higher comorbidity rates of anxiety disorders in narcoleptic patients. The incidence of previously diagnosed anxiety disorders was higher in narcoleptic patients aged 12 to 17 years and female patients.

Quantifying the level of difficulty to treat major depressive disorder with antidepressants: Treatment Resistance to Antidepressants Evaluation Scale.

BACKGROUND: The present study aimed to develop a new scale to evaluate the level of difficulty in treating major depressive disorder with antidepressants based on the lifetime treatment profile. METHODS: In addition to evaluating the difficulty of treatment with antidepressants (A subscale), the Treatment Resistance to Antidepressants Evaluation Scale (TRADES) is comprised of a subscale to account for the attributes that compromise the efficacy of treatment (B subscale). One hundred and six participants aged 18 to 65 years with remitted major depressive disorder were enrolled. Eligible cases were those with at least 2 years from disease onset until the scoring date of the TRADES (the index date), with a complete treatment record. Various psychosocial and clinical features, such as neuroticism, harm avoidance, and utilization of psychiatric services, were used to validate the TRADES. RESULTS: The mean duration of the course before and after the index date were 5.5 ± 3.5 and 3.1 ± 1.7 years, respectively. In a multiple regression analysis, the final total scores of the TRADES independently correlated with higher levels of neuroticism and harm avoidance. Total scores were also associated with a higher utilization of psychiatric outpatient and admission services before the index date. Furthermore, it is thought that total scores could predict a higher number of visits to psychiatric outpatient, emergency, and admission services following the index date. CONCLUSIONS: The TRADES has acceptable validity and could help to quantify the level of treatment difficulty with antidepressants in major depressive disorder.

The Risk of Hospitalization for Motor Vehicle Accident Injury in Narcolepsy and the Benefits of Stimulant Use: A Nationwide Cohort Study in Taiwan.

STUDY OBJECTIVES: To examine the risk of hospitalization for motor vehicle accident injury (MVAI) in patients with narcolepsy and the effects of stimulant use on MVAI occurrence in patients with narcolepsy. METHODS: This is a population-based, retrospective cohort study using Taiwan's National Health Insurance Research Database between 2000 and 2013. We included patients with narcolepsy based on the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes, 347. The case and matched control participants were selected in a ratio of 1:3, and the traffic accident (ICD-9-CM codes: E810-E819) plus injury codes (ICD-9-CM codes: 800.xx-999.xx) due to MVAI following hospitalization were used for the study outcome. The type of injury, causes, intentionality, and the effects of stimulant use on patients with narcolepsy were also assessed. RESULTS: A total of 1,316 participants were enrolled, including 329 participants with narcolepsy and 987 participants without narcolepsy. During a 14-year follow-up period, a total of 104 participants had MVAI, of whom 47 (1,559.54 per 100,000 person-years) belonged to the narcolepsy cohort and 57 (556.21 per 100,000 person-years) to the non-narcolepsy cohort. After adjusting for covariates, the risk of hospitalization for MVAI among participants with narcolepsy was still significantly higher than those without narcolepsy (adjusted hazard ratio = 6.725; 95% confidence interval = 4.421-10.231; P < .001). The use of modafinil or methylphenidate, as monotherapy or combined treatment, was associated with a lower risk of MVAI in the narcolepsy cohort. CONCLUSIONS: Patients with narcolepsy may have a higher risk of hospitalization for MVAI and stimulant use could mitigate such risk.

The Association Between the Sedative Loads and Clinical Severity Indicators in the First-Onset Major Depressive Disorder.

Background: High sedative use in a major depressive episode may imply specific clinical features. This study aims to examine the correlation between sedative use and clinical severity indicators in the initial treatment phase of first-onset major depressive disorder. Methods: A study cohort in the first episode of major depressive disorder was used to conduct pharmacological dissection. All participants had at least a 2-year follow-up period with a complete treatment record. The defined daily dose of antidepressants and augmentation agents were calculated as the antidepressant load and augmentation load, respectively. Sedative use, which was calculated as the equivalent dosage of lorazepam, were defined as the sedative load. These psychotropic loads were measured monthly and the averaged psychotropic loads for each day were obtained. Results: A total of 106 individuals (75.5% female) were included. The mean duration of disease course in participants was 5.5 ± 3.5 years. In the multiple regression analysis, after controlling for other classes of psychotropics and comorbid anxiety disorders, the sedative load independently correlated with higher number of antidepressants used, higher number of antidepressant used with an adequate dose and duration, more psychiatric emergency and outpatient visits within 2 years of disease onset. Conclusion: High loading of sedatives correlated with several indicators of clinical severity in major depressive disorder. The sedative load may be used as a specifier to identify subgroups in patients with major depressive disorder.

Divalproex and its effect on suicide risk in bipolar disorder: A systematic review and meta-analysis of multinational observational studies.

BACKGROUND: Divalproex has become the most prevalent mood stabilizer for bipolar disorder. However, little is known its effects in the prevention of suicide in patients with bipolar disorder, and recent FDA announcement indicated an increased risk of suicidality when using anti-epileptic agents such as divalproex. The aim of this study is to investigate the effect of divalproex on suicide risk in patients with bipolar disorder. METHODS: A search strategy was used for the PubMed, Embase, ProQuest, ScienceDirect, Cochrane Library, ClinicalKey, Web of Science, and ClinicalTrials.gov until June 13th, 2018. Peer-reviewed observationally clinical studies in humans, investigating the association of divalproex and suicidality in patients with bipolar disorder were included. A random-effects meta-analysis was implemented to calculate the relative risk (RR) and 95% confidence intervals (CIs) for suicidality among patients receiving divalproex and those without. RESULTS: Total 6 studies were included in the final meta-analysis. There was no significant difference in the incidence rates (reported as [RR]; 95% CI) of suicide attempts (0.921; 0.383-2.215) or completed suicides (0.607; 0.180-2.043) between participants receiving divalproex vs. no medication. There was no significant difference in the incidence rates of suicide attempts (0.815; 0.453-1.466) or completed suicides (1.009; 0.410-2.484) between participants receiving divalproex and carbamazepine. LIMITATIONS: The significantly heterogeneous sample sources and study design amount the included trials. CONCLUSIONS: Treatment with divalproex did not reduce or increase the incidence of suicide-related events in patients with bipolar disorder.