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.     

Association between antidepressant side effects and functional impairment in patients with major depressive disorders

Patients with depression may not well be aware of antidepressant adverse events (AEs); however, no studies have assessed how these AEs affect their daily function. Therefore, to evaluate the relationship between the quality of AEs and functional impairment, we studied 482 outpatients with depressive disorders who were not receiving any antidepressant treatment prior to the baseline visit and started it thereafter in usual clinical settings. The Quick Inventory for Depressive Symptomatology Self-Report Japanese version and antidepressant AEs for subjective assessment (antiAS) were performed at baseline and 10 days after antidepressant initiation (i.e. second visit). Functional impairment was evaluated with the Sheehan Disability Scale (SDS) on the second visit. As a result, the SDS was positively associated with the number of AEs (β=0.089, p=0.022) in multiple linear regression analysis (adjusted R²=0.357, p<0.001). Subjects who experienced vertigo, nausea and insomnia had significantly more functional impairment than those who did not. Additionally, the number of severe AEs (β=0.151, p<0.001) was associated with a higher SDS score, and those AEs with a negative causal attribution to antidepressants in the antiAS significantly affected the SDS (β=0.105, p=0.008). AEs of antidepressants should be carefully monitored since they could negatively affect their daily function.     

甘草抗抑郁研究与应用

甘草为常用补益中药,其抗抑郁作用近年受到关注。通过检索近年国内外有关甘草抗抑郁文献,从甘草提取物、活性成分及其复方制剂的抗抑郁研究进行阐述,表明甘草及其活性成分具有明确的抗抑郁作用,其机理涉及抗氧化、抗凋亡损伤,抗单胺氧化酶、调节单胺神经递质等。通过复方配伍,具有健脾宁心、和中柔肝,和药解毒作用,用于抑郁症具有较好疗效。甘草抗抑郁作用的深入研究对揭示抑郁症发病机制、研发抗抑郁新药、提高抑郁症诊治水平均具有参考价值。     

Moderation and mediation in the psychological and drug treatment of chronic tension-type headache: The role of disorder severity and psychiatric comorbidity

We evaluated two putative moderators of treatment outcome as well as the role of Headache Management Self-Efficacy (HMSE) in mediating treatment outcomes in the drug and non-drug treatment of chronic tension-type headache (CTTH). Subjects were 169 participants (M = 38 yrs.; 77% female; M headache days/mo. = 22) who received one of four treatments in the treatment of CTTH trial (JAMA, 2001; 285: 2208–15): tricyclic antidepressant medication, placebo, (cognitive-behavioral) stress-management therapy plus placebo, and stress-management therapy plus antidepressant medication. Severity of CTTH disorder and the presence of a psychiatric (mood or anxiety) disorder were found to moderate outcomes obtained with the three active treatments and with placebo, as well as to moderate the role of HMSE in mediating improvements. Both moderator effects appeared to reflect the differing influence of the moderator variable on each of the three active treatments, as well as the fact that the moderator variables exerted the opposite effect on placebo than on the active treatments. HMSE mediated treatment outcomes in the two stress-management conditions, but the pattern of HMSE mediation was complex, varying with the treatment condition, the outcome measure, and the moderator variable. Irrespective of the severity of the CTTH disorder HMSE fully mediated observed improvements in headache activity in the two stress-management conditions. However, for patients with a mood or anxiety disorder HMSE only partially mediated improvements in headache disability, suggesting an additional therapeutic mechanism is required to explain observed improvements in headache disability in the two stress-management conditions.     

广东抗抑郁药销售市场分析

目的分析抗抑郁药在广东的销售情况和发展趋势。方法通过统计广东75家代表性医院2005-2007年抗抑郁药销售数据,了解抗抑郁药的销售情况,分析各类型抗抑郁药的销售及国内厂家与进口合资厂家药品的销售情况。结果抗抑郁药销售年均增长23.93%,5-羟色胺再摄取抑制剂（SSRIs）约占60%市场份额,进口合资药品约占87%。结论抗抑郁药销售增幅明显,SSRIs为最常用的一类抗抑郁药,国内抗抑郁药市场仍然由进口合资厂家主导,国内制药厂商迎来最好的发展机遇。     

Evidence for corticotropin-releasing factor regulation of serotonin in the lateral septum during acute swim stress: adaptation produced by repeated swimming

RATIONALE: Swim stress decreases extracellular serotonin (5-HT) levels in the rat lateral septum, and adaptation to this effect occurs with repeated swimming. Corticotropin-releasing factor (CRF) administered into the dorsal raphe nucleus (DRN) also decreases 5-HT release in the lateral septum, suggesting that CRF may mediate the effects of swim stress. OBJECTIVES: The hypothesis that endogenous CRF mediates the reduction of 5-HT levels in the lateral septum evoked by swim stress and is involved in the adaptation that occurs with repeated swim stress was tested. METHODS: Extracellular 5-HT levels in rat lateral septum were quantified by means of in vivo microdialysis. Extracellular single unit activity was recorded from the DRN. RESULTS: Intracerebroventricular (i.c.v.) administration of a CRF receptor antagonist prevented the ability of swim stress to decrease 5-HT release in the lateral septum. Prior exposure to swim stress reduced the ability of both CRF (i.c.v.) and a subsequent swim stress to decrease lateral septum 5-HT release (cross adaptation). Additionally, the effects of CRF, administered into the DRN, on DR neuronal discharge were attenuated in rats with a history of swim stress. Finally, administration of a CRF receptor antagonist (i.c.v.) between two swim stress sessions restored the neurochemical response to swim stress (i.e., 5-HT levels were reduced during the second exposure to swim). CONCLUSIONS: Endogenous CRF modulates 5-HT transmission during acute environmental stress and is also integral to adaptation of the 5-HT response produced by repeated stress. Modulation of the 5-HT system by CRF during acute stress may underlie certain coping behaviors, while stress-induced adaptation of this effect may be involved in psychiatric manifestations of repeated stress.     

Rosmarinic acid and caffeic acid produce antidepressive-like effect in the forced swimming test in mice

We previously showed that rosmarinic acid from the leaves of Perilla frutescens Britton var. acuta Kudo (Perillae Herba) has antidepressive-like activity. The aim of the present study was to examine (i) whether caffeic acid, a major metabolite of rosmarinic acid, also has antidepressive-like activity, and (ii) whether these substances inhibit either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity. Rosmarinic acid (2 mg/kg, i.p.) and caffeic acid (4 mg/kg, i.p.) each significantly reduced the duration of immobility in the forced swimming test in mice. In contrast, neither substance, at doses that produced a significant reduction in the immobile response in the forced swimming test, affected spontaneous motor activity. These results indicate that, like rosmarinic acid, caffeic acid also possesses antidepressive-like activity. In neuropharmacological studies, neither rosmarinic acid (10 x (-9)-10 x (-3) M) nor caffeic acid (10 x (-9)-10 x (-3) M) affected either the uptake of monoamines to synaptosomes or mitochondrial monoamine oxidase activity in the mouse brain. These results suggest that both caffeic acid and rosmarinic acid may produce antidepressive-like activity via some mechanism(s) other than the inhibition of monoamine transporters and monoamine oxidase.     

The effects of antidepressant treatment on serotonergic and dopaminergic systems in Fawn-Hooded rats: a quantitative autoradiography study

Fawn-Hooded (FH) rats exhibit a phenotype including depressive behaviour and high alcohol preference, and as such tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) reduce alcohol consumption in this rat strain [Psychiatr. Genet. 12 (2002) 1-16]. However, the neurochemical effects of these antidepressants on monoamine systems in the brain, especially in mesolimbic areas have not been studied in FH rats. Therefore, the present study investigated neurochemical effects of subchronic treatment (10 days) with desipramine (DMI) and sertraline on several neurochemical markers of serotonin and dopamine systems. Binding to these markers including dopamine transporters (DATs), 5-HT transporters (SERTs), 5-HT(1A)- and 5-HT(2A)-receptors in rat brain sections was performed by quantitative autoradiography. The findings from the present study revealed that DMI and sertraline exhibited differential effects on SERTs and DATs in FH rat brain. For example, DMI caused a dramatic up-regulation of DATs whereas sertraline had no effect on DAT binding. In addition, both antidepressants showed some common and some differential effects on the binding to 5-HT(1A)- and 5-HT(2A)-receptors dependent upon region. These data demonstrate that DMI and sertraline differentially effect serotonergic and dopaminergic systems in mesolimbic regions in FH rats, suggesting that there may be different neurochemical mechanisms underlying their efficacy to reduce ethanol consumption in this animal model.     

Differential effects of the 5-HT2 receptor antagonist on the anti-immobility effects of noradrenaline and serotonin reuptake inhibitors in the forced swimming test

The effects of the 5-HT(2) receptor antagonist, LY 53857 on the effects of noradrenaline and serotonin reuptake inhibitors were investigated using the forced swimming test. LY 53857 enhanced anti-immobility effects of clomipramine and maprotiline, which can inhibit reuptake of noradrenaline. However, LY 53857 did not affect the immobility time of mice treated with the selective serotonin reuptake inhibitors (SSRIs) fluoxetine and fluvoxamine. These results suggest that antagonism of the 5-HT(2) receptor leads to potentiation of the antidepressant effects of noradrenaline reuptake inhibitors but not SSRIs and that LY 53857 may modify the activity of noradrenergic neurons.     

Duloxetine 60 mg once daily dosing versus placebo in the acute treatment of major depression

Existing therapies for major depressive disorder (MDD) have either limited efficacy and/or poor tolerability. The present study examined the effects of duloxetine, a potent and balanced dual reuptake inhibitor of serotonin (5-HT) and norepinephrine (NE), in patients with MDD. Adult patients (N=267) with MDD were randomly assigned to receive duloxetine (60 mg/day) or placebo in this 9-week, multi-center, double-blind, parallel-group clinical trial. Efficacy was evaluated using the 17-item Hamilton Depression Rating Scale (HAMD₁₇), Visual Analog Scales (VAS) for pain, Clinical Global Impression of Severity (CGI-S), Patient's Global Impression of Improvement (PGI-I), and Quality of Life in Depression Scale (QLDS). Safety was evaluated by assessing discontinuation rates, adverse event rates, vital signs, and laboratory tests. Duloxetine (60 mg QD) significantly reduced the HAMD₁₇ total score compared with placebo at the end of 9-week therapy. Estimated probabilities of response and remission were 65 and 43%, respectively, for duloxetine compared with 42 and 28% for placebo. Duloxetine also reduced overall pain, back pain, shoulder pain and time in pain while awake significantly more than placebo. Global measures of improvement, including PGI-I and QLDS, were significantly improved by duloxetine compared with placebo. Discontinuations due to adverse events were more frequent for duloxetine-treated patients (12.5%) than for placebo-treated patients (4.3%). Nausea, dry mouth, dizziness, and constipation were more frequent for duloxetine than placebo. There was no significant incidence of hypertension, nor any other safety issues. Duloxetine 60 mg administered once daily appears to be a safe and effective treatment for MDD.