Evaluation of vilazodone for the treatment of depressive and anxiety disorders

Introduction: Major Depressive Disorder (MDD) and General Anxiety Disorder (GAD) significantly contribute to the global burden of disease. Vilazodone, a combined serotonin reuptake inhibitor and 5-HT1A partial agonist, is an approved therapy for the treatment of MDD and which has been further investigated for GAD.

Areas covered: This article covers the pharmacokinetics and pharmacodynamics of vilazodone and provides an evaluation of the clinical usefulness of vilazodone for the treatment of MDD and anxiety disorders. A literature search was performed using PubMed/MEDLINE, Web of Science and the Cochrane Library.

Expert opinion: Studies have shown that vilazodone is significantly superior to placebo. However, vilazodone cannot as yet be recommended as a first-line treatment option for MDD as it is unclear whether the drug’s dual mechanism of action provides greater efficacy than prevailing treatment options. Moreover, more phase IV studies are needed to establish its efficacy and long-term safety in larger and more diverse populations. Although vilazodone may have an additional advantage for the treatment of anxiety symptoms in MDD, here also additional studies are required to confirm its efficacy over and above SSRI alternatives and other antidepressant treatments. Therefore, presently, vilazodone should be considered as a second- or third-line treatment option for MDD and GAD.     

Flerobuterol: a potential antidepressant drug related to β-adrenergic agonists. Experimental profile in mice

The potential antidepressant effect of flerobuterol (dl-(fluoro-2 phenyl)-1 t-butylamino-2 ethanol), a new drug related to beta-adrenoceptor agonists, was evaluated and compared with imipramine and salbutamol using classical psychopharmacological tests in mice. Like imipramine and salbutamol, flerobuterol (0.5-32 mg kg-1, ip) fully prevented apomorphine (16 mg kg-1, sc)- and partly reversed reserpine- and oxotremorine-induced hypothermia. At higher doses (16-32 mg kg-1), flerobuterol enhanced the toxic effects of yohimbine. Unlike imipramine, flerobuterol and salbutamol did not reduce immobility duration in the behavioural despair test. Salbutamol and flerobuterol decreased locomotor activity. Flerobuterol did not induce mydriasis, did not prevent oxotremorine-induced tremors or salivary and lacrimal gland secretion and did not reduce reserpine-induced palpebral ptosis. Propranolol (8 mg kg-1, ip) but not alpha-methyl-paratyrosine (75 mg kg-1, ip) prevented the flerobuterol-induced antagonism of apomorphine-induced hypothermia. Our results suggest that flerobuterol demonstrates potential antidepressant activity, which could be related to beta-adrenoceptor activation in mice.     

Inhibin and renin in follicular fluids of patients with one or two ovaries stimulated with a GnRH agonist and gonadotrophins

Follicular fluids from eight patients with one ovary and from ten patients with two ovaries were investigated for bioactive inhibin, total renin, oestradiol (E2) and progesterone (P4) concentrations. Four follicular fluids were pooled per patient before assessment. All women had been stimulated similarly using a protocol including a GnRH agonist, HMG and HCG. Renin levels were significantly lower and P4 significantly higher in pools of follicular fluid from patients with one ovary, whereas inhibin and E2 concentrations were similar in both patient groups. A significant negative correlation was found in the pools of follicular fluid between inhibin and E2 in both groups. These results suggest a role for inhibin and renin in the paracrine and autocrine control of stimulated follicular development.     

Reversal of stress-induced anhedonia by the dopamine receptor agonist,pramipexole

Chronic exposure to mild unpredictable stress has previously been found to depress the consumption of a palatable (1%) sucrose solution, and to attenuate food-induced place preference conditioning. In this study the effects of pramipexole (SND-919), a dopamine D₂ agonist, were studied during 7–9 weeks of chronic treatment. Pramipexole (1.0 mg/kg per day) reversed the suppression of sucrose intake in stressed animals, increasing sucrose intakes above the levels seen in untreated nonstressed controls. Pramipexole also increased sucrose intake in nonstressed animals; these effects were accompanied by increases in water intake and tended to correlate with weight loss. Drug-treated stressed animals also lost weight, but in this case water intake was unaffected. A second group of animals received a higher dose of pramipexole (2.0 mg/kg per day). The effects of the two doses were very similar. After three weeks of treatment, these animals were switched to a lower dose of pramipexole (0.1 mg/kg per day). Increases in sucrose intake were maintained over three weeks of treatment at the lower dose, with significant recovery of body weight. Two further groups received the same doses of pramipexole (1.0 mg/kg for 6 weeks or 2.0 mg/kg for 3 weeks followed by 0.1 mg/kg thereafter), but received intermittent (twice-weekly) drug treatment. Intermittent pramipexole treatments also tended to increase sucrose intakes, but the results were less consistent from week to week. Following 6–8 weeks of pramipexole treatment, food-induced place preference conditioning was studied in all animals. Untreated stressed animals showed no evidence of place conditioning. Normal conditioning was seen in both groups of stressed animals treated daily with pramipexole (at 1.0 and 0.1 mg/kg) and in the group treated twice weekly at the higher dose (1.0 mg/kg); intermittent treatment at the lower dose (0.1 mg/kg) was ineffective. The results indicate that pramipexole exerts rapid anti-anhedonic effects in the chronic mild stress model. This conclusion is complicated, but not undermined, by drug-induced weight loss and by the presence of significant drug effects in nonstressed control animals.     

SDZ 208-911, an amino-ergoline with partial dopamine agonist properties,dose dependently increases cocaine self-administration in the rat

Brain dopamine neurotransmission appears to be an important component of the neural pathways involved in the maintenance of intravenous (IV) cocaine self-administration in rats. The effects of a novel partial dopamine agonist, SDZ 208–911, on intravenous cocaine self-administration in rats was studied. SDZ 208–911 at a dose range of 0.025–1.6 mg/kg SC dose-dependently increased the number of lever presses and drug intake in rats exposed to limited (3-h) daily access to cocaine on a continuous reinforcement schedule (0.75 mg/kg per injection). This behavioral profile is similar to that observed following administration of dopamine antagonist drugs and has been hypothesized to reflect a compensatory increase in drug intake due to a reduction of the reinforcing efficacy of the drug, probably because of functional antagonism at the receptor site. These results suggest that dopamine partial agonists may act as functional dopamine antagonists in the face of pharmacologically induced activation of brain dopamine function.     

Antipsychotics with inverse agonist activity at the dopamine D3 receptor

Summary In NG 108-15 cells expressing the recombinant human D₃ receptor, dopamine agonists enhance [³H]thymidine incorporation and decrease cAMP accumulation. In these cells, but not in wild type cells, haloperidol, fluphenazine, and various other antipsychotics inhibited basal [³H]thymidine incorporation in a concentration-dependent manner. In contrast, other dopamine antagonists such as nafadotride or (+)AJ 76, two D₃-preferring antagonists, were without effect. The concentration-response curve of haloperidol was shifted to the right in presence of nafadotride, with a potency compatible with its nanomolar apparent affinity as neutral antagonist. Pertussis toxin treatment abolished or markedly reduced the responses to haloperidol or fluphenazine. In contrast, no significant enhancement of cAMP accumulation could be observed, under the influence of haloperidol or eticlopride. These data indicate that some dopamine antagonists behave as inverse agonists, and thus appear to inhibit an agonist-independent activity of the D₃ receptor on [³H]thymidine incorporation pathway, but not on the cAMP pathway.     

超长方案促性腺激素释放激素激动剂降调节对子宫内膜异位症体外受精-胚胎移植结局的影响

本中心对129例经腹腔镜证实为美国生殖医学会(ASRM)II-IV期子宫内膜异位症(内异症)合并其他不育因素而行体外受精-胚胎移植(IVF-ET)治疗的病例,进行了回顾性统计和分析。一、资料和方法1.临床资料:从2005年4月至2007年3月,在本中心接受IVF-ET治疗经腹腔镜证实为ASRMII-IV期内异症合并其他不育因素的129个周期病例;对照组为输卵管性不育的1,543个周期。内异症组根据有无促性腺激素释放激素激动剂(GnRH-a)药物降调节分为A、B两组进行分析,A组:中重度内异症在手术后接受长效GnRH-a(3.75 mg/支,每28 d一支,共2~6支)抑制治疗的39个…     

胫骨前肌疲劳时比目鱼肌诱发肌电图H波的变化及其机制探讨

为了解主动肌疲劳时拮抗肌脊髓运动神经元兴奋性变化的规律 ,本研究采用踝关节背屈运动形式 ,对胫骨前肌 (主动肌 )疲劳状态下的比目鱼肌 (拮抗肌 )诱发肌电图H波成分进行了观察。并以压迫阻断胫骨前肌Ⅰa类神经纤维传导的方法 ,对比目鱼肌H波变化机制进行了分析探讨。结果发现 :(1)胫骨前肌疲劳后 ,比目鱼肌H波明显受到抑制 ,与安静时比较呈非常显著性差异 ;(2 )胫骨前肌Ⅰa类神经纤维传导被阻断后 ,比目鱼肌H波的抑制现象没有解除。表明 ,胫骨前肌疲劳时比目鱼肌H波被抑制的原因 ,可能是由于主动肌内的代谢产物激活了Ⅲ·Ⅳ类神经纤维的感受器 ,Ⅲ·Ⅳ类神经纤维的传入冲动增加 ,使Ⅰa抑制性中间神经元被激活 ,导致拮抗肌脊髓运动神经元的兴奋性受到了抑制