Synthesis, antidepressant and antifungal evaluation of novel 2-chloro-8-methylquinoline amine derivatives

A new series of N-[(2-chloro-8-methylquinolin-3-yl)methyl]-(substituted)-aniline/butylamine/cyclohexylamine/benzylamine derivatives (4a-p) was synthesized by nucleophilic substitution reaction of 2-chloro-3-(chloromethyl)-8-methylquinoline 3 with various aliphatic and aromatic amines in absolute ethanol in the presence of triethylamine (TEA). The newly synthesized secondary amines were characterized by the combined use of IR, ¹H NMR, ¹³C NMR, mass spectral data and microanalyses. The antidepressant activity of the synthesized compounds (4a-p) was evaluated by Forced swim test in rats and their neurotoxicity was evaluated by the rotarod test. Test compounds and clomipramine were administered intraperitoneally at dose of 100 mg/kg and 20 mg/kg respectively. Preliminary antidepressant screening of compounds (4a-p) revealed that compounds 4b, 4c, 4d, 4e, 4i and 4o significantly (P < 0.01) reduces the duration of immobility time. These compounds were also tested in-vitro for MAO inhibitory effect. All the compounds were also screened for antifungal activity against Aspergillus niger MTCC 281, Aspergillus flavus MTCC 277, Monascus purpureus MTCC 369 and Penicillium citrinum NCIM 768 strains.     

越鞠升降汤对轻中度抑郁症患者躯体症状的改善作用

目的观察越鞠升降汤对轻中度抑郁症患者躯体症状的改善作用。方法将58例轻中度抑郁症患者随机分为2组,治疗组30例予越鞠升降汤治疗,对照组28例予盐酸氟西汀胶囊治疗．2组均6周为1个疗程,治疗2个疗程。比较2组疗效,观察2组治疗前后汉密尔顿抑郁量表（HAMD）评分、躯体症状评分变化。结果2组总有效比较差异有统计学意义（P〈0．05）,治疗组疗效优于对照组。2组治疗后HAMD评分、躯体症状评分均较本组治疗前降低（P〈0．01）,且治疗组降低更明显（P〈0．01）。结论越鞠升降汤治疗轻中度抑郁症安全有效,可显著改善患者的躯体症状。     

The influence of patients' preference/attitude towards psychotherapy and antidepressant medication on the treatment of major depressive disorder

Background and objectives

Preferences and attitudes patients hold towards treatment are important, as these can influence treatment outcome. In depression research, the influence of patients' preference/attitudes on outcome and dropout has mainly been studied for antidepressant medication, and less for psychological treatments. We investigated the effects of patients' preference and attitudes towards psychological treatment and antidepressant medication on treatment outcome and dropout, and tested specificity of effects.

Methods

Data are based on a randomized trial testing the effectiveness of behavioural activation (BA) vs antidepressant medication (ADM) for major depression (MDD) in Iran. Patients with MDD (N = 100) were randomized to BA (N = 50) or ADM (N = 50). Patients' preference/attitudes towards psychotherapy and ADM were assessed at baseline and associated with dropout and treatment outcome using logistic regression and multilevel analysis.

Results

High scores on psychotherapy preference/attitude and low scores on ADM preference/attitude predicted dropout from ADM, while no association between dropout and preference/attitude was found in BA. Psychotherapy preference/attitude moderated the differential effect of BA and ADM on one outcome measure, but the association disappeared after one year.

Limitations

Because in Iran most patients have only access to ADM, offering a psychological treatment for depression could attract especially those patients that prefer this newly available treatment.

Conclusions

Patients' preferences and attitudes towards depression treatments influence dropout from ADM, and moderate the short-term difference in effectiveness between BA and ADM. The fact that dropout from BA was not affected by preference/attitude speaks for its acceptability among patients.     

米氮平治疗抑郁症患者体重变化与疗效的相关性研究

目的：探讨抑郁症患者服用米氮平治疗后体重变化与其疗效的相关性。方法55例抑郁症患者接受米氮平单一抗抑郁药物治疗,开放性观察12周,以HDRS－17评价疗效,于基线及治疗后第一、二、四、八、十二周末重复测量体质量和HDRS－17评分,对连续性数据采用重复测量资料方差分析、Pearson相关分析和 ROC 分析。结果治疗12周后,患者平均体重增加值为（3．4±0．4） kg,HDRS－17总分明显改善（ F ＝893．14,P＝0．000）,体重增加（F＝2．43,P＝0．035）,差异均有统计学意义。治疗4周后,患者体重增加与量表减分率之间呈弱相关（r＝0．270～0．306,P＝0．044～0．022）,但抑郁症状的早期改善对终点体重增加没有预测价值（AUC＝0．64〔0．48－0．79〕）。结论米氮平所致患者体重增加与疗效呈弱相关相关,应注意相关健康教育以免影响患者的服药依从性。     

The effect of mepiprazole on central monoamine neurons. Evidence for increased 5-hydroxytryptamine and dopamine receptor activity

In combined biochemical, histochemical and functional studies on central monoamine neurons it has been shown that a pyrozolyl derivative with a phenyl piperazine side-chain (PAP) exerts marked effects on central dopamine (DA) and particularly 5-hydroxytryptamine (5-HT) neurons. The brain 5-HT turnover was reduced with doses down to 0.25 mg/kg, and spontaneous overflow of radioactivity from ³H-5-HT-labelled cortical slices was markedly increased by PAP in a concentration of 10^?6 M. PAP may therefore cause extragranular release of 5-HT stores, since the 5-HT levels were not affected. In agreement with this view, sexual behaviour in the female rat, which is controlled by an inhibitory 5-HT pathway, was inhibited by low doses (0.1–0.5 mg/kg) of PAP. The extensor hindlimb reflex, which is dependent of 5-HT receptor activity, was only increased with higher doses (2.5–10 mg/kg), suggesting that the spinal 5-HT nerve terminals are less sensitive to the releasing action of PAP. A certain direct activation of spinal 5-HT receptors may also be involved, since the actions of PAP in the spinal cord were independent of presynaptic 5-HT stores. The actions of PAP on the DA neurons mainly involve a presynaptic action in the DA nerve terminals leading to increased DA receptor activity. This action may primarily involve a blockade of DA uptake (50% inhibition at 10^?6 M) and/or an extragranular release of DA (two-fold increase in spontaneous overflow at 10^?6 M). The DA turnover was not clearly affected, although a trend to a reduction was observed especially in the nuc. accumbens, probably as a result of a compensatory nervous feedback reducing nervous impulse flow. In agreement with the view mentioned above, PAP mimics amphetamine and not apomorphine in the rotometer model which reveals changes in DA receptor activity. PAP in doses of 0.5–1 mg/kg causes a turning towards the denervated side. The brain noradrenaline (NA) turnover is only significantly increased with somewhat higher doses (5–10 mg/kg) and may be related ot NA receptor blockade, since the L-DOPA-induced increase in flexor activity is blocked by PAP in doses down to 0.5 mg/kg.It is suggested that the extragranular release of 5-HT caused by PAP is partly responsible for the inhibition of conditioned avoidance behaviour and the reduction of threatening behaviour found after PAP in low doses (0.05–0.5 mg/kg). In the clinic, PAP may prove to be a new therapeutic tool in the treatment of depressions due to 5-HT deficiency. Its actions on DA terminals may also prove helpful in this respect. When combined with L-DOPA, PAP may also help to alleviate the motor deficits in parkinsonian patients with a moderate degree of degeneration of the DA system in view of its action on DA uptake and/or release.     

Assessment of symptom change from improvement curves on the Hamilton depression scale in trials with antidepressants

A total of 97 patients, who participated in two studies on the relationship between the clinical effect and plasma levels of imipramine and clomipramine, were examined for improvement curves by use of weekly ratings on the Hamilton Depression Scale (HDS). Although we confirmed that our six-item HDS subscale, in contrast to the total 17-item HDS, was a one-dimensional measure of depression, the Rasch analysis showed that the weekly improvement in subscale scores only applied to the individual patient, i.e. an average improvement curve for a group of depressed patients is an abstraction to which the individual curves cannot be transferred. Our results indicate, however, that when the subscale scores are transformed into three clinical categories of depression: no, mild (minor), moderate/-severe (major) they could be described by a common improvement curve for all patients. This is illustrated by the percentage of patients who, week to week, changed from major to minor or no depression, or from minor to no depression. We found no specific improvement pattern for imipramine or clomipramine which could be used diagnostically. There is reason to assume that patients completing a controlled trial necessarily will follow a monotonic improvement curve, and the improvement pattern of all patients fulfilling the entry criteria should, therefore, always be reported. The present study thus indicates that calculation of average improvement curves is neither clinically nor statistically meaningful, and should be replaced by measures of changes in number of patients in different main severity categories, or by the final rating score. No difference in outcome between imipramine and clomipramine was shown neither on the subscale nor on the 17-item HDS.     

Dopamine D1 and D2 receptor binding sites in brain samples from depressed suicides and controls

Dopamine D₁ and D₂ receptors were measured (by saturation binding of [³H]SCH23390 and [³H]raclopride) in caudate, putamen and nucleus accumbens, obtained at post-mortem from suicide victims with a firm retrospective diagnosis of depression and matched controls. There were no differences in the number or affinity of D₁ or D₂ receptors between suicides who had been free of antidepressants for at least three months prior to death, and controls. Increased numbers and decreased affinity of D₂ receptors were however found in each brain region of antidepressant-treated suicides. We argue that these increases are related to concurrent treatment with neuroleptics rather than a direct effect of antidepressants. Increased numbers of D₁ receptors in antidepressant-treated suicides were seen only in nucleus accumbens. This increase could not be clearly attributed to neuroleptics and may be related to antidepressant treatment.     

Repeated administration of antidepressant drugs affects the levels of mRNA coding for D1 and D2 dopamine receptors in the rat brain

Summary The present study examined the effects of acute and repeated administration of three antidepressant drugs (imipramine, citalopram and (+)-oxaprotiline) on the levels of mRNA coding for dopamine D₁ and D₂ receptors in the rat brain. Quantitive in situ hybridization with³⁵S-labelled oligonucleotide probes has been utilised. The level of mRNA coding for dopamine D₁ receptor (D₁ mRNA) is decreased following repeated administration of imipramine, both in the nucleus accumbens and in the striatum. On the other hand, the repeated administration of citalopram, the selective inhibitor of serotonin reuptake, resulted in an increase in the level of D₁ mRNA in the striatum and in the core region of nucleus accumbens. A similar tendency, i.e.: an increase in the level of D₁ mRNA was observed after repeated administration of (+)-oxaprotiline, a selective inhibitor of noradrenaline reuptake. The level of mRNA coding for dopamine D₂ receptors (D₂ mRNA) was increased in all the brain regions studied, both after administration of imipramine and citalopram. (+)-Oxaprotiline did not produce any statistically significant changes in the level of D₂ mRNA.The results obtained in this study indicate that the levels of mRNA coding for dopamine D₁ and D₂ receptors are regulated by the antidepressant drugs. The changes concerning the dopamine D₂ receptors are more consistent and fit in with the previously described binding and behavioral effects and seem to be important for the mechanism of action of antidepressant drugs.