Piperazine derivatives with central pharmacological activity used as therapeutic tools

Medicinal chemistry is a science applied to the search and discovery of new therapeutic agents for the treatment of various diseases. Therefore, promising structures have been identified; one of these structures is the piperazine moiety, a cyclic molecule containing two nitrogen atoms in positions 1 and 4 as well as four carbon atoms. Many piperazine derivatives have central pharmacological activity that mainly involves the activation of the monoamine pathway. Thus, piperazine derivatives have been the subject of research for many central therapeutic applications, including antipsychotic, antidepressant and anxiolytic applications. Benzylpiperazine is the prototype of piperazine derivatives; this substance is the main component of recreational drugs, partly due to its stimulant and euphoric effects. This paper describes some piperazine derivatives used therapeutically as antipsychotic (clozapine), antidepressant (vortioxetine) and anxiolytic (buspirone) drugs.     

A pilot investigation of an intensive theta burst stimulation protocol for patients with treatment resistant depression

IntroductionAccelerated or intensive forms of repetitive transcranial magnetic stimulation (rTMS) are increasingly being explored for their potential to produce more efficient and rapid treatment benefits in major depressive disorder (MDD). However, accelerated or intensive protocols using standard forms of rTMS are still quite time-consuming to apply. Theta burst stimulation (TBS) is a novel form of magnetic stimulation with the potential to produce similar anti-depressant effects but in a much abbreviated period of time. The aim of this study was to investigate the comparative efficacy of an intensive TBS protocol compared to standard rTMS treatment.Methods74 outpatients (36 female, mean age 44.36 ± 12.1 years) with MDD received either intensive TBS (3 intermittent TBS treatments per day for 3 days in week 1, 3 treatments a day for 2 days in week 2, and 3 treatments in 1 day in week 3 and in week 4, or standard rTMS (5 daily sessions per week for 4 weeks). Patients were assessed weekly throughout the treatment course, and at 4 weeks after treatment end.ResultsThere were no significant differences in the degree of reduction in depressive symptoms, the rate of reduction in depressive symptoms, remission or response rates (response rates = 27.8% for intensive group, 26.3% for the standard group, p > 0.05 for all analyses) between the intensive TBS and standard rTMS treatment groups. However, the overall response and remission rates were limited in both groups. There was no difference in rates of side effects, no serious adverse events and no alterations in cognitive performance.ConclusionIntensively applied TBS appears to have similar efficacy to standard rTMS when these were applied as delivered in this study but does not produce more rapid clinical benefits. The overall response rates in both groups in this study were limited, most likely by the total doses provided in both study arms.Clinical trials registrationAustralian New Zealand Clinical Trials Registry: ACTRN12616000443493.     

Physical activity as an adjuvant therapy for depression and influence on peripheral inflammatory markers: A randomized clinical trial

IntroductionRegular exercise is recommended for people with major depressive disorder (MDD) by major treatment guidelines (e.g. the NICE guideline, 2009). In addition, an effect of antidepressant (AD) treatment on pro-inflammatory markers has been reported. However, it remains unclear whether physical activity as an adjuvant to AD treatment increases clinical response rates and is associated with levels of inflammatory markers.MethodsA four-week single-blind clinical trial involving forty people with major MDD, divided into an AD group (sertraline) and AD + exercise (40 min/day, four times weekly for four weeks) group was conducted. Peripheral inflammatory markers (IL-12, IL-10, IL-8, IL-6, IL-1β, TNF-α) and cortisol were collected at baseline and at endpoint.ResultsWe observed a significant decrease in cortisol levels over time, but this change did not differ between the AD and AD + exercise groups. None of the other inflammatory markers showed a significant change in level during the trial. Also, most of the individuals who achieved remission were from the AD + exercise group.ConclusionAlthough our study failed to find that the association of physical activity as an adjunct to antidepressants promotes a change in cortisol or interleukins in people with MDD, we found that cortisol seems to be the most sensitive biomarker to antidepressant treatment. Further studies involving larger samples of, longer duration and with other classes of antidepressants and types of exercise should be conducted to better elucidate the link between inflammatory markers and depression.     

Research on the Pathological Mechanism and Drug Treatment Mechanism of Depression

Depression is one of the prevalent and persistent psychiatric illnesses. It brings heavy socioeconomic burden such as healthcare expenditures and even higher suicide rates. Despite many hypotheses about its mechanism have been put forward, so far it is still unclear, not to mention the precise and effective diagnostic or therapeutic methods. In this paper, the current conditions of pathological and pharmacological mechanism of depression were reviewed systematically. Firstly, the most recent hypotheses and metabolomics based research including hereditary, neurotransmitter systems, brain derived neurotrophic factor (BDNF), hyperactivity of the hypothalamic pituitary adrenal (HPA) axis and inflammatory as well as metabolomics were summarized. Secondly, the present situation and development on antidepressant drugs at home and abroad were reviewed. Finally, a conclusion and prospect on the pathological and pharmacological mechanism of depression were provided primarily.     

抗惊恐障碍药物的临床研究进展

本文综述了临床上用于治疗惊恐障碍的相关药物,评价并比较这些药物的疗效、不良反应及差异。结果发现,在当前选择性5－羟色胺再摄取抑制剂西酞普兰、依他普仑、氟伏沙明、氟西汀、帕罗西汀、舍曲林,5－羟色胺和去甲肾上腺素再摄取抑制剂、三环抗抑郁药和苯二氮艹卓类为治疗惊恐障碍的有效药物。另外,β受体阻断剂、抗惊厥药、孕激素、肌醇、丁螺环酮等在惊恐障碍的治疗中也有使用。因此,当前惊恐障碍药物的临床研究很好的反应了这些药物的作用和差异,这有助于临床医护工作者有效的选择药物。     

Depression and pain: An appraisal of cost effectiveness and cost utility of antidepressants

BackgroundAlthough depression and chronic pain frequently co-occur, there is a lack of clarity in the literature regarding the cost-effectiveness and cost-utility of antidepressants in the presence of these two conditions. From the perspective of healthcare provider, the current study aims to compare the cost-effectiveness and cost-utility of antidepressants in a national cohort of depressed patients with and without comorbid pain conditions.MethodsAdult patients prescribed with antidepressants for depression were identified from the National Health Insurance Research Database in Taiwan (n = 96,501). By using remission as effectiveness measure and quality-adjusted life years (QALYs) as utility measure, the cost-effectiveness and cost-utility were compared across selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), and tricyclic antidepressants (TCAs), as well as by the presence of comorbid painful physical symptoms (PPS).ResultsSSRIs dominated SNRIs in both the cost-effectiveness and cost-utility regardless of comorbid PPS. In comparison with TCAs, SSRIs were likely to be the cost-effective option for patients without PPS. In patients with PPS, the cost-utility advantage for SSRIs over TCAs varied with threshold willingness-to-pay levels. Comorbid PPS may be considered an effect modifier of the cost-utility comparisons between SSRIs and TCAs.ConclusionsFor depressed patients without PPS, SSRIs are likely to be cost-effective in improving remission rates and QALYs compared to TCAs and SNRIs. However, to improve cost-utility in those with comorbid PPS, people need to choose between SSRIs and TCAs according to threshold willingness-to-pay levels. Future research is warranted to clarify the impacts of different pain conditions on the economic evaluations of pharmacological treatments in patients with depression.     

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.