Sheng Min Wang

A review of current evidence for acetyl-l-carnitine in the treatment of depression.

Despite numerous antidepressants available, many patients with depression do not achieve adequate response rendering needs for novel antidepressants with different mechanism of actions. Acetyl-l-carnitine (ALC) is a potential antidepressant with novel mechanism of action because of its diverse functions related with neuroplasticity. Animal and cellular models suggest that ALCs neuroplasiticity effect, membrane modulation, and neurotransmitter regulation may play an important role in treatment of depression. Four randomized clinical studies (RCT) demonstrated the superior efficacy of ALC over placebo (PBO) in patients with depression. Two RCTs showed its superior efficacy over PBO in dysthymic disorder, and 2 other RCTs showed that it is equally effective as fluoxetine and amisulpride in treatment of dysthymic disorder. ALC was also effective in improving depressive symptoms in patients with fibromyalgia and minimal hepatic encephalopathy. It was also found to be equally tolerable to PBO and better tolerable than fluoxetine and amisulpride. In conclusion, ALC may be potentially effective and tolerable next treatment option with novel action mechanisms for patients with depression, in particular older population and patients with comorbid medical conditions who are vulnerable to adverse events from antidepressants. However, more clinical trial data with adequately-powered, well-designed and advanced methodology will be mandatory to conclude whether ALC as a monotherapy or augmentation agent may be efficacious and clinically beneficial for depression.

Vortioxetine, a multimodal antidepressant for generalized anxiety disorder: A systematic review and meta-analysis

Vortioxetine has a beneficial pharmacological profile for reducing anxiety and depression. Recently, a number of randomized, double-blind, placebo-controlled clinical trials (RCTs) of vortioxetine have been conducted in patients with generalized anxiety disorder (GAD); however, the results from GAD RCTs are inconsistent. With an extensive search of databases and clinical trial registries, four published short-term RCTs were identified and included in the present meta-analysis. The mean change in total scores on the Hamilton Anxiety Rating Scale (HAMA) from baseline was the primary endpoint. The secondary endpoints included the response and remission rates, as defined by a ≥50% reduction in HAMA total scores and a ≤7 change in the HAMA total score at the end of treatment. In addition, the mean change in the HAMA total score from baseline in the subgroup with a HAMA total score ≥25 at baseline was included. Vortioxetine was significantly more effective than was placebo, with a standardized mean difference (SMD) ofxa0-0.118 (95% CIs,xa0-0.203 toxa0-0.033, Pxa0=xa00.007). In particular, those with severe GAD (HAMA total score ≥25 at baseline) had a significantly greater benefit from vortioxetine than those without (SMDxa0=xa0-0.338, 95% CIsxa0=xa0-0.552 toxa0-0.124, pxa0=xa00.002). The odds ratios (ORs) for vortioxetine for response and remission were 1.221 (95% CIs, 1.027 to 1.452, Pxa0=xa00.024) and 1.052 (95% CIs, 0.853 to 1.296, Pxa0=xa00.637), respectively. Discontinuation due to adverse events (AEs) (ORxa0=xa01.560, 1.006 to 2.419, pxa0=xa00.047) was marginally higher in vortioxetine than placebo treatment, whereas discontinuation due to any reason (ORxa0=xa00.971, 0.794 to 1.187, pxa0=xa00.771) and inefficacy (ORxa0=xa00.687, 0.380 to 1.243, pxa0=xa00.215) were not significantly different among treatment groups. Although our results suggest that vortioxetine may have a potential as an another treatment option for GAD (especially for severe GAD), they should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of RCTs.

The potential role of atypical antipsychotics for the treatment of posttraumatic stress disorder

Despite the fact that the majority of currently available treatment guidelines propose antidepressants as the first-line pharmacological therapy for posttraumatic stress disorder (PTSD), a substantial portion of patients fail to show an adequate response following this type of treatment. In this context, a number of small, open-label studies and randomized controlled clinical trials (RCTs) have found atypical antipsychotics (AAs) to be a beneficial treatment for patients with PTSD. Thus, the present meta-analysis was conducted to enhance the sample size power and further the current understanding of the role of AAs for the treatment of PTSD. An extensive search of several databases identified 12 appropriate RCTs and available data from 9 of these (nxa0=xa0497) were included in the final meta-analysis. AAs may have potential benefits for the treatment of PTSD as indicated by changes from baseline of the total score on the Clinician Administered PTSD Scale (CAPS; standardized mean difference [SMD]xa0=xa0-0.289, 95% confidence intervals [CIs]xa0=xa0-0.471,xa0-0.106), Pxa0=xa00.002). Additionally, AAs were found to be significantly more effective (Pxa0<xa00.0001) than a placebo in terms of change from baseline for the intrusion sub-score on the CAPS (SMDxa0=xa0-0.373, 95% CIsxa0=xa0-0.568,xa0-0.178) but there were no significant reductions for the avoidance and hyperarousal sub-symptoms. The responder rate and rate of improvement of depressive symptoms were also significantly higher in the AA group than the placebo group (Pxa0=xa00.004 and Pxa0<xa00.0001, respectively). However, the present results should be interpreted carefully and be translated into clinical practice only with due consideration of the limited quality and quantity of existing RCTs included in this analysis.

Aripiprazole augmentation versus antidepressant switching for patients with major depressive disorder: A 6-week, randomized, rater-blinded,prospective study

No study has directly compared the efficacy and tolerability of aripiprazole augmentation (AA) and antidepressant switching (SW) in patients with major depressive disorder (MDD). This is the first 6-week, randomized, rater-blinded, direct comparison study between AA and SW in outpatients. An inadequate response to antidepressants was defined as a total score ≥ 14 on the Hamilton Depression Rating Scale-item 17 (HDRS-17) despite adequate antidepressant dosage for at least 6 weeks in the current depressive episode. The primary endpoint was change in the total score of the Montgomery-Åsberg Depression Rating Scale (MADRS) from baseline to the end of treatment. Secondary efficacy measures included the response and remission rates as priori defined at the end of treatment: changes in total scores of the HDRS-17, Iowa Fatigue Scale (IFS), and Sheehan Disability Scale (SDS) from baseline to the end of treatment and the proportion of patients who scored 1 or 2 on the Clinical Global Impression-Improvement Score (CGI-I) at the end of treatment. Tolerability was assessed with the Barnes Akathisia Rating Scale (BARS) and Arizona Sexual dysfunction scale (ASEX), and the numbers of adverse events were compared between the two groups. A total of 101 patients were randomized to either AA (n = 52) or SW (n = 49). The mean change in the MADRS score from baseline was significantly higher in the AA, with a difference in magnitude of -8.7 (p < 0.0001). The intergroup difference was first evident in week 2. The numbers of responders (p = 0.0086) and remitters (p = 0.0005) were also significantly higher in the AA (60% and 54%, respectively) compared with the SW (32.6% and 19.6%, respectively). On most secondary endpoints, AA showed better clinical outcomes compared to SW. The tolerability profiles were comparable between the two groups. Overall, AA yielded potentially beneficial clinical outcomes compared to SW. Given the methodological shortcomings of the present study, adequately powered, more rigorously controlled clinical trials are strongly warranted to confirm the present findings.

Curcumin as a putative antidepressant

Due to inadequate efficacy of antidepressants, various new chemical entities and agents of natural origin have been tested for therapeutic efficacy both alone and to augment existing antidepressants, producing varied clinical results. This article summarizes the basic properties of curcumin and its mechanisms of action, with specific emphasis on the etiopathogenesis of depression, preclinical and current clinical evidence, and future research directions, to better understand the possible role of curcumin in treating depression. Curcumin may have antidepressant activities with diverse mechanisms of action involving primarily neurotransmitters, transcription pathways, neurogenesis, the hypothalamic–pituitary–adrenal axis and inflammatory and immune pathways, as demonstrated in various animal and human studies. Current published randomized clinical trials suggest a small, non-significant benefit of curcumin for major depression. More adequately-powered and methodologically improved studies are mandatory.

Aripiprazole augmentation, antidepressant combination or switching therapy in patients with major depressive disorder who are partial- or non-responsive to current antidepressants: A multi-center, naturalistic study

There has been no studies comparing the clinical benefits of aripiprazole augmentation (AT), antidepressant combination (AC), and switching to a different antidepressant (SW) in patients with major depressive disorder (MDD) patients partially or not responding to an initial antidepressant. AT, AC, or SW was chosen by patients. The primary efficacy measure was the proportion of patients showing an improvement in the Clinical Global Impression-Clinical Benefit (CGI-CB) score at week 8. Secondary efficacy measures included changes in CGI-CB, CGI-Severity (S) and subjective satisfaction scores. Remission and responder analysis were also employed. A total of 295 patients were enrolled. The most preferred strategy was AT (nxa0=xa0156, 52.9%), followed by AC (nxa0=xa093, 31.5%) and SW (nxa0=xa046, 15.6%). The improver was significantly higher in AT (74.1%) compared with AC (48.1%; pxa0<xa00.001) and similar to SW (73.5%, pxa0=xa00.948), whereas no significant difference was found between AC and SW. Similar results were also found in the most secondary endpoint measures proving a superiority of AT over AC without differences between AT and SW. Tolerability profiles were similar across the three groups; however, the mean weight gain for SW (-0.1xa0kg) was significantly less than that for AC (1.3xa0kg, pxa0<xa00.05). Patients preferred AT to AC or SW when an antidepressant was ineffective in treating their depression. Among the three treatment strategies, overall AT yielded greater clinical benefit than did AC and SW. Adequately powered, well-controlled clinical trials are strongly warranted to confirm our findings due to methodological shortcomings.

Asenapine, blonanserin, iloperidone, lurasidone, and sertindole: distinctive clinical characteristics of 5 novel atypical antipsychotics.

AbstractSchizophrenia is a serious, chronic, and devastating mental illness with a substantial impact on psychological, physical, social, and economical areas of an individual and society. To treat such critical mental illness, a number of first-generation (typical) and second-generation (atypical) antipsychotics are currently available in the market. Despite such treatment options, most of patients with schizophrenia have a poor treatment outcome and become treatment resistant, causing continual deterioration on positive, negative, and cognitive symptoms, resulting in impairment of socio-occupational functioning. Hence, additional novel antipsychotics with better efficacy, safety, and tolerability profiles are needed to enable clinicians to diversify treatment options to improve treatment of schizophrenia. Recently, the 3 antipsychotics, including iloperidone (2009), asenapine (2009), and lurasidone (2010), have been approved by the US Food and Drug Administration. Two other atypical antipsychotics, including sertindole and blonanserin, are approved and used outside the United States for treatment of schizophrenia. Sertindole, after it has been voluntarily suspended by the manufacturer in 1998 due to its potential risk in causing cardiovascular-related death, was relaunched to the European market in 2005. More recently, blonanserin was approved in Japan (2008) and in Korea (2009) for the management of schizophrenia. Individual antipsychotic may have differential pros and cons compared with other antipsychotic in terms of efficacy, safety, tolerability, restoration of functional capacity, and economic aspect reflecting relapse prevention. The purpose of this review was to provide distinctive clinical characteristics and up-to-date of clinical trial data of the 5 novel atypical antipsychotics for the management of schizophrenia, which may deliver clinicians better understanding in the use of such atypical antipsychotics for the treatment of schizophrenia in clinical practice.

Modafinil for the treatment of attention-deficit/hyperactivity disorder: A meta-analysis

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common and a debilitating neuro-behavior disorder in the pediatric population. Although numerous effective psychostimulants are available, more than 30% of patients still do not show adequate treatment response rendering diverse pharmacological options. We aimed at assessing the efficacy and safety of modafinil in the treatment of children and adolescents with ADHD by conducting a meta-analysis. An extensive search of databases and clinical trial registries resulted in five published short-term randomized, double-blind, placebo-controlled trials. Primary efficacy measures were mean change in ADHD Rating Scale-IV Home (ADHD-RS-IV Home) and School Version (ADHD-RS-IV School) from baseline to study end point. The results showed that modafinil more significantly improved ADHD-RS-IV Home (SMD,xa0-0.77 [95%CI,xa0-1.11 toxa0-0.44]) and School (SMD,xa0-0.71 [95%CI,xa0-0.96 toxa0-0.47]) than placebo. Dropout rate due to adverse event did not significantly differ between two groups. In terms of commonly observed side effects, modafinil showed significantly higher incidence of decreased appetite (RRxa0=xa05.02, 95% CIs, 2.55 to 9.89, Pxa0<xa00.00001) and insomnia (RRxa0=xa06.16, 95% CIs, 3.40 to 11.17, Pxa0<xa00.00001). Modafinil did not cause a clinically significant increase of heart rate, systolic blood pressure, and diastolic blood pressure. Although we found that modafinil may be another treatment option in children and adolescents with ADHD, the results should be interpreted and translated into clinical practice with caution, as the meta-analysis was based on a limited number of clinical trials.

Criticisms of drugs in early development for the treatment of depression: what can be improved?

Major depressive disorder (MDD) is a common and debilitating mental illness, which leads to serious functional impairment in patients, and treatment-wise, there are currently a number of different classes of antidepressants already on the market. However, emerging evidence from numerous clinical trials has confirmed that there is still an unmet need for antidepressant efficacy in terms of response and remission. Approximately only 30% of patients with MDD may remit after adequate treatment with antidepressants in clinical practice. The drawbacks of the currently available antidepressants also include inadequate overall efficacy, safety issues and the lag prior to onset of clinical improvement. The need for new agents with novel mechanisms of action has led to the development of several newer antidepressants including vilazodone, edivoxetine, ketamine, atomoxetine and vortioxetine, which have been approved for the treatment of MDD. However, the efficacy and safety of these next-generation antidepressants, in clinical trials, are still unsatisfactory. This paper provides a brief updated overview of the progress and critical limitations in the development of novel antidepressants.

Characteristic Risk Factors Associated with Planned versus Impulsive Suicide Attempters.

Objective The present study aimed to investigate predictors for planned suicide attempters. Methods This study included 1,003 patients who attempted suicide and visited emergency department. They were divided into two groups, planned suicide attempters (SAs; n=133 [13.3%]) and impulsive SAs (n=870, [86.7%]), and the demographic variables, clinical characteristics, factors related to suicide, and psychiatric resources of the groups were compared. Results Major depressive disorder and substance use disorders were more common among planned SAs than among impulsive SAs. Additionally, the planned SAs were older, more likely to be divorced, separated or widowed, and more likely to have comorbid medical illnesses, severe depression, higher suicidality, and self-blaming tendencies than the impulsive SAs. Financial problems and physical illnesses were more common in planned SAs but interpersonal conflicts were more frequent in impulsive SAs. Planned SAs had fewer previous suicide attempts but these were more serious suicide attempts. The presence of the hope to die, a written will, and suicidal ideation of a repetitive, intense, and continuous nature were predictive of planned SAs. Conclusion The present findings demonstrated that planned SAs had more severe psychopathology and medical illnesses than impulsive SAs. Therefore, screening for depression, substance use disorders, and suicidal plans among old and medically ill patients may be important for preventing suicide attempts.