CGP 4718 A, a new potential antidepressant with a dual mode of action

The ergolene derivative MPME (PTR 17402; (5R,8R)-8-(4-p-methoxyphenyl)-1-piperazynylmethyl-6- methylergolene], a dopamine (DA) receptor agonist acting mainly at DA D-1 receptors linked to dotted types of forebrain DA nerve terminals, induces a characteristic behavioural syndrome consisting of increased locomotion, head-bobbing and sniffing activity without oral stereotypies or increased rearing. Haloperidol and cis-flupenthixol, nonselective DA receptor antagonists, but not selective D-2 receptor antagonists such as remoxipride and sulpiride, could significantly counteract the locomotion and head-bobbing behaviour induced by MPME. In contrast, the sniffing behaviour induced by MPME was only marginally affected by haloperidol and cis-flupenthixol pretreatment. These results suggest that activation of D-1 receptors in the forebrain mainly linked to the dotted types of DA nerve terminals in the striatum, and in the limbic forebrain, can result in behavioural effects which differ from those caused by stimulation of D-2 receptors located mainly within the diffuse types of DA nerve terminal systems.     

Lithium and bupropion antagonise the phasic changes in locomotor activity caused by dopamine infused into the rat nucleus accumbens

Dopamine infused persistently (25 g/24 h for 13 days) into the nucleus accumbens of rat brain caused phasic increases in spontaneous locomotor activity during the period of infusion. This phasic responding was prevented by lithium administered throughout the infusion period in divided doses (3×daily administrations of 2.5 mg/kg IP) or as a continuous IP infusion (7.5 mg/kg/24 h), and by bupropion treatment (5–20 mg/kg 3 × daily). In contrast, imipramine, amitriptyline and nomifensine failed to prevent the phasic locomotor response to dopamine at doses which did not by themselves cause marked motor changes. Locomotor activity was measured using individual photocell cages, and rats preselected to (–)NPA were those initially showing a modest locomotor activity. Fourteen to twenty-eight days after discontinuing the dopamine infusion rats showed increased responsiveness to (–)NPA which persisted throughout the remainder of the 70-day withdrawal period. This long-term change was prevented when lithium was given continuously throughout the period of dopamine infusion, but not when lithium was given in divided doses, showing the importance of the mode of drug delivery. The long-term change caused by the dopamine infusion could also be prevented by bupropion but not by imipramine, amitriptyline or nomifensine to show again that the actions of classical antidepressant drugs may be differentiated from those of lithium and bupropion. Therefore, it is suggested that the model of phasic hyperactivity described may provide a means for more closely analysing, both behaviourally and biochemically, the site and mechanism of action of lithium (and bupropion) in the control of the short- and long-term consequences of an enhanced mesolimbic dopamine activity. Offprint requests: B. Costall     

Ball mill and microwave assisted synthetic routes to Fluoxetine

Remarkable advances have been made in the development of an environmentally-friendly approach for the rapid and simple construction of the Active Pharmaceutical Ingredient (API) Fluoxetine (1). These include the use of ball milling and microwave irradiation as greener alternatives ? compared to conventional heating ? to provide the energy needed for the chemical transformations.     

Voluntary exercise and clomipramine treatment elevate prepro-galanin mRNA levels in the locus coeruleus in rats

Exercise exerts antidepressant effects in humans and rodent models of affective disorders. These effects may be mediated by the upregulation of endogenous factors that exert antidepressant actions. The physiological functions and behavioral actions of the neuropeptide galanin (GAL) suggest antidepressant activity. Previous studies have shown that various modes of exercise elevate GAL gene expression in the locus coeruleus (LC) in rats. The present experiments examined the interaction between voluntary exercise and antidepressant pharmacotherapy. Male Sprague–Dawley rats were provided access to activity wheels (exercise condition) or inoperative wheels (sedentary condition) for 28 days. Rats in each group were injected with clomipramine (10 mg/kg/day) or vehicle throughout this period (for 3 weeks). Prepro-GAL mRNA in the LC was measured by in situ hybridization histochemistry. Exercise and clomipramine treatment significantly elevated GAL gene expression, though prepro-GAL mRNA levels in rats receiving both interventions did not differ from sedentary controls that received vehicle. Prepro-GAL mRNA levels were significantly correlated with running distance. The results further implicate a role for GAL in the antidepressant effects of exercise and pharmacotherapy, though the mechanisms through which these treatments influence GAL gene expression appear to differ significantly.     

Effect of chronic administration of antidepressant drugs on 5-HT2-mediated behavior in the rat following noradrenergic or serotonergic denervation

Summary Chronic (14 day) administration of several pharmacologically-distinct antidepressant drugs resulted in marked reductions in the serotonin₂ (5-HT₂)-mediated quipazine-induced head shake response which were accompanied by significant reductions in the density of cortical -adrenergic and 5-HT₂ binding sites. Noradrenergic (DSP4[N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine]-induced) and serotonergic (5,7-DHT[5,7-dihydroxytryptamine]-induced) lesions either attenuated or blocked antidepressant-induced reductions in 5-HT₂-mediated behavior. DSP4- and 5,7-DHT lesions did not alter the down-regulation of 5-HT₂ binding sites produced by imipramine, desipramine, phenelzine or iprindole. To a large extent, the antagonism of antidepressant-induced reductions in 5-HT₂-mediated behavior was coincident with the blockade of down-regulation of -adrenergic binding sites by both noradrenergic and serotonergic denervation. The functional interrelationship of 5-HT₂ and -adrenergic receptors suggested by the present findings may provide insight into a common mechanism underlying the action of pharmacologically-distinct antidepressant drugs.     

认知-行为治疗对抑郁障碍疗效的循证研究

本文从循证医学角度综述了CBT、抗抑郁药或二者联合治疗抑郁障碍的研究现状。多数研究支持认知一行为治疗对抑郁障碍的疗效，但可能有部分研究存在设计方面的不足，CBT的适用对象和疗效的持续时间尚无定论．国内对CBT疗效的大样本研究基本空白。     

Chronic oral administration of clomipramine decreases sexual behavior in the male Syrian hamster (Mesocricetus auratus)

Previous studies have demonstrated that clomipramine (CLI), a selective serotonin reuptake inhibitor, has negative side effects on sexual behavior when administered to adult rats and humans. In addition, neonatal rat pups given chronic doses of CLI display similar sexual deficits upon sexual maturity. This study used two experiments to test the hypothesis that 2 weeks of CLI would cause a decrease in sexual motivation and performance in the male Syrian hamster (Mesocricetus auratus). Experiment 1 administered 0, 40, or 60 mg/kg CLI for 14 days to adult male hamsters via a sugar water solution. Experiment 2 administered 0, 40, or 60 mg/kg CLI for 14 days to pregnant dams during gestation (also via a sugar water solution). We hypothesized that this administration of CLI via the pregnant mother would have long-lasting developmental effects on the male hamster pups resulting in later dysfunction in male sexual behavior. Results from Experiment 1 indicate that CLI administration to adult males caused a significant decrease in the number of ejaculations compared to controls. The only significant difference in sexual behavior between those males whose mothers received CLI during pregnancy compared to males from untreated mothers was an increase in the number of intromissions in the highest dosage group. These findings demonstrate that CLI inhibits sexual performance in adult male Syrian hamsters, and also suggest that oral administration of CLI via a sugar water solution is an effective mode of administration.     

Efficacy of antidepressants: bias in randomized clinical trials and related issues

Introduction: Countless antidepressant randomized trials were conducted and showed statistically significant benefits of selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) over placebo. Meanwhile, critics are increasing regarding the efficacy of antidepressants in the treatment of MDD because at least a proportion of clinical trials could be hampered by various biases. In contrast, number of failed trials is increasing in the recent years which have made developing psychiatric medications progressively more time-consuming and expensive.

Areas covered: Biases and related issues in clinical trials for antidepressants can be identified as an important common contributing factor to the two paradoxical phenomenon. This review identifies possible biases that can occur before, during, and after clinical trials of antidepressant.

Expert commentary: Recent studies not only may over-estimate efficacy of antidepressants, but also may exaggerate placebo response because of various biases. Sponsorship and publication biases have been one of the targets of the criticism and ethical debate. Thus, initiating new trend of research by re-organizing academic-industry partnership will be the most important task in the next five years.     

An antidepressant behaviour in mice carrying a gene-specific InsP3R1, InsP3R2 and InsP3R3 protein knockdown

Evidence has accumulated for the involvement of Ca²⁺ in the pathophysiology of mood disorders. Elevations in both resting and stimulated intracellular Ca²⁺ levels in patients with affective disorders have been reported. The role of inositol-1,4,5-trisphosphate receptors (InsP3Rs), which allow mobilization of intracellular Ca²⁺ stores, was, then, investigated in the mouse forced swimming test. InsP3R antagonists (heparin, xestospongin C) as well as an inositol monophosphatase inhibitor (LiCl) showed an antidepressant activity of intensity comparable to clinically used antidepressants. InsP3Rl, InsP3R2 and InsP3R3 knockdown mice were obtained to investigate the role of InsP3R isoforms. We generated mice carrying a cerebral knockdown of InsP3Rl, InsP3R2 and InsP3R3 proteins by administering antisense oligonucleotides complementary to the sequence of InsP3Rl, InsP3R2 and InsP3R3. These antisense-treated mice showed a specific InsP3R protein level reduction in the mouse cerebral cortex and hippocampus, demonstrated by immunoblotting, immunoprecipitation and immunocytochemistry experiments. Knockdown mice for each InsP3R isoforms showed an antidepressant behaviour and the induced phenotype was reversible disappearing 7 days after the end of the treatment. The absence of impairment of locomotor activity and spontaneous mobility in InsP3R knockdown mice was revealed. These results indicate the involvement of the InsP3R-mediated pathway in the modulation of depressive conditions and may be useful for the development of new therapeutical strategies for the treatment of mood disorders.