The cost-effectiveness of antidepressants for smoking cessation in chronic obstructive pulmonary disease (COPD) patients

Objectives In healthy smokers, antidepressants can double the odds of cessation. Because of its four times lower costs and comparable efficacy in healthy smokers, nortriptyline appears to be favourable compared to bupropion. We assessed which of both drugs was most effective and cost‐effective in stopping smoking after 1 year compared with placebo among smokers at risk or with existing chronic obstructive pulmonary disease (COPD). Methods A total of 255 participants, aged 30–70 years, received smoking cessation counselling and were assigned bupropion, nortriptyline or placebo randomly for 12 weeks. Prolonged abstinence from smoking was defined as a participant's report of no cigarettes from week 4 to week 52, validated by urinary cotinine. Costs were calculated using a societal perspective and uncertainty was assessed using the bootstrap method. Results The prolonged abstinence rate was 20.9% with bupropion, 20.0% with nortriptyline and 13.5% with placebo. The differences between bupropion and placebo [relative risk (RR) = 1.6; 95% confidence interval (CI) 0.8–3.0] and between nortriptyline and placebo (RR = 1.5; 95% CI 0.8–2.9) were not significant. Severity of airway obstruction did not influence abstinence significantly. Societal costs were €1368 (2.5th–97.5th percentile 193–5260) with bupropion, €1906 (2.5th–97.5th 120–17 761) with nortriptyline and €1212 (2.5th–97.5th 96–6602) with placebo. Were society willing to pay more than €2000 for a quitter, bupropion was most likely to be cost‐effective. Conclusions Bupropion and nortriptyline seem to be equally effective, but bupropion appears to be more cost‐effective when compared to placebo and nortriptyline. This impression holds using only health care costs. As the cost‐effectiveness analyses concern some uncertainties, the results should be interpreted with care and future studies are needed to replicate the findings.     

3,4—二氯苯丙烯酰另丁胺抗抑郁作用的药理研究

研究一种新的胡椒碱衍化物:3,4—二氯苯丙烯酰另丁胺(7903)对五种抑郁动物模型的影响。7903在小于TD_(50)剂量下,对所用动物模型均显示出抗抑郁效应,即在不增加动物的自主活动情况下,急性ip 7903可明显缩短小鼠及大鼠强迫游泳不动状态时间;急性ip或po明显缩短小鼠悬尾不动时间;慢性(二周)ip可明显缩短电刺激小鼠角膜引起的最长持续不动状态时间;急性ip可明显改善利血平引起的小鼠体温下降。     

Antidepressants reduce phosphoinositide-specific phospholipase C (PI-PLC) activity and the mRNA and protein expression of selective PLC beta 1 isozyme in rat brain

In order to examine whether antidepressants mediate their action by interacting with one of the key components of the phosphoinositide (PI) signaling pathway, i.e. PI-specific phospholipase C (PLC), and whether this represents a common mechanism of action of antidepressants, we determined the effects of antidepressants of various classes on PI-PLC activity and on the expression of PLC isozymes in rat brain. It was observed that chronic (21-day) but not acute (1-day) administration with desipramine (DMI), fluoxetine (FLX) and phenelzine (PHLZ), decreased PI-PLC activity in membrane and cytosol fractions of cortex and hippocampus. Similar changes were observed with alprazolam (ALP) and buspirone (BUS), who possess anxiolytic and antidepressant properties. On the other hand, an anxiogenic drug, metachlorophenylpiperazine (MCPP), increased PI-PLC activity in both membrane and cytosol fractions of cortex and hippocampus. The immunolabeling studies showed that all the antidepressants and anxiolytics that caused a decrease in PI-PLC activity also selectively decreased the protein levels of a specific isozyme of PLC, i.e. PLCβ₁, in membrane and cytosol fractions of cortex and hippocampus, whereas MCPP increased the levels of this particular isozyme. These changes were accompained with changes in the mRNA levels of PLCβ₁, as determined by quantitative RT-PCR. These antidepressants and anxiolytics did not cause significant changes in the expression of PLC δ₁ or γ₁ isozyme. Our results thus suggest that modulation of PI-PLC may be common to all classes of antidepressants, which in turn, may be associated with their mechanisms of action.     

Effect of chronic imipramine or electroconvulsive shock on the expression of mGluR1a and mGluR5a immunoreactivity in rat brain hippocampus

Previous studies showed that chronic electroconvulsive shock (ECS) or imipramine treatment induced a subsensitivity of group I metabotropic glutamate receptors (mGluR) in hippocampus. In the present study effects of antidepressant treatment on the expression of mGluR1a and mGluR5a, belonging to the group I mGluR, were investigated in rat brain hippocampus using immunohistochemical and Western blot methods, respectively. Male Wistar rats were treated singly or chronically for 21 days with imipramine, 10 mg/kg, twice daily; with ECS (90 mA, 50 Hz, 0.5 s) every second day; or with haloperidol, 1.2 mg/kg, once daily. Appropriate controls were injected with saline. Rats were sacrificed 24 h after the last treatment and their hippocampi were taken out for analysis.

It was found that the mGluR1a-immunoreactivity expression increased significantly in Ammon’s horn (CA) regions after chronic ECS. The most pronounced effect was observed in the CA3. No significant effects were found after single treatment or after haloperidol. The expression of mGluR5a increased significantly after chronic imipramine in the CA1 and after chronic ECS in the CA3 region.

The results obtained indicate an influence of antidepressant treatment on group I mGluR. This increase in the receptor protein level may be a compensatory mechanism developing after chronic treatment.     

Effect of nortriptyline and paroxetine on measures of chaos of heart rate time series in patients with panic disorder

Tricyclic antidepressants have notable cardiac side effects, and this issue has become important due to the recent reports of increased cardiovascular mortality in patients with depression and anxiety. Several previous studies indicate that serotonin reuptake inhibitors (SRIs) do not appear to have such adverse effects. Apart from the effects of these drugs on routine 12-lead ECG, the effects on beat-to-beat heart rate (HR) and QT interval time series provide more information on the side effects related to cardiac autonomic function. In this study, we evaluated the effects of two antidepressants, nortriptyline (n=13), a tricyclic, and paroxetine (n=16), an SRI inhibitor, on HR variability in patients with panic disorder, using a measure of chaos, the largest Lyapunov exponent (LLE) using pre- and posttreatment HR time series. Our results show that nortriptyline is associated with a decrease in LLE of high frequency (HF: 0.15–0.5 Hz) filtered series, which is most likely due to its anticholinergic effect, while paroxetine had no such effect. Paroxetine significantly decreased sympathovagal ratios as measured by a decrease in LLE of LF/HF. These results suggest that paroxetine appears to be safer in regards to cardiovascular effects compared to nortriptyline in this group of patients.     

慢性应激抑郁大鼠脑内亚细胞成分蛋白激酶CβⅡ表达的变化

目的探讨慢性不可预见性应激抑郁模型大鼠大脑皮层亚细胞成分蛋白激酶CβⅡ(PKCβⅡ)的表达水平以及三环类抗抑郁剂(TCAs)阿米替林、5-羟色胺再摄取抑制剂(SSRI)氟西汀对其影响。方法24只Sprague-Dewley雄性大鼠随机分为抑郁模型组6只,阿米替林治疗组6只,氟西汀治疗组6只,正常对照组6只。采用慢性轻度不可预见性应激方法建立抑郁模型,将9种刺激随机安排到18d,每天1种,应激前以及应激18d末对各组大鼠进行敞箱实验及液体消耗实验,第19天起阿米替林组、氟西汀组分别每天腹腔注射阿米替林(10mg.kg-1.d-1)、氟西汀(10mg.k-g1.d-1)1次,模型组及对照组每天腹腔注射等体积生理盐水1次,均持续21d。用蛋白质免疫印迹法检测大鼠大脑皮层亚细胞成分PKCβⅡ的表达水平。结果抑郁大鼠大脑皮层细胞膜PKCβⅡ蛋白表达水平(230.57±62.86)较对照组(331.26±17.94)明显减少(P<0.05);抑郁大鼠大脑皮层细胞浆PKCβⅡ蛋白表达水平(286.43±56.92)与对照组(343.55±70.48)比较,有下降趋势,但差异无显著性(P>0.05)。阿米替林、氟西汀治疗3周后抑郁大鼠大脑皮层亚细胞成分PKCβⅡ表达水平无明显变化(P>0.05)。结论大脑皮层细胞膜PKCβⅡ蛋白表达水平明显下降可能是抑郁症发病的重要环节。阿米替林、氟西汀对抑郁大鼠大脑皮层亚细胞成分PKCβⅡ的蛋白表达水平没有影响。     

Maprotiline and doxepin in the treatment of depression. A double-glind multicentre comparison.

Maprotiline (Ludiomil) and doxepin were compared in the treatment of depression in a double-blind multicentre trial. Four centres and 95 in- and out-patients took part in the trial. The severity of depression was evaluated with the aid of a visual analogue scale and nine target symptoms. Both maprotiline and doxepin diminished neurotic as well as psychotic depression significantly. The mean time of onset of action was 7.0 days in the maprotiline group and 7.7 days in the doxepin group. No statistically significant differences in antidepressive effect were found between the treatments. Two patients in the maprotiline group and four patients in the doxepin group discontinued the treatment because of unwanted effects, one patient in each group because of lack of efficacy and nine patients due to reasons not related to the treatment.     

The effects of antidepressants on serotonin turnover in discrete regions of rat brain

Summary Serotonin (5-HT) turnover was measured in hypothalamus, hippocampus, cortex, septum and nucleus caudatus of rats after acute or chronic treatment with antidepressants. Acute chlorimipramine (1.8–16.2 mg/kg i.p.) decreased 5-HT turnover in all the areas tested as measured by the rate of accumulation of 5-hydroxyindoleacetic acid after probenecid, or the rate of accumulation of 5-hydroxytryptophan after decarboxylase inhibition. However, chlorimipramine failed to reduce the rate of 5-HT accumulation after monoamine oxidase inhibition. Chronic chlorimipramine treatment (3 times daily for 2 weeks) did not change the 5-HT turnover.Fluoxetine, which like chlorimipramine specifically blocks 5-HT uptake also decreased 5-HT synthesis. In contrast, no change in 5-HT turnover was observed after desmethylimipramine, amitriptyline, iprindole or amphetamine which affect the catecholaminergic, but not serotoninergic systems.     

Keyword index to volume 55

The study concerned the effects of maprotiline, imipramine, clomipramine and amitriptyline on the stereotype and turning behaviour induced by apomorphine in rats. At either single or repeated doses of 25 mg/kg i.p. neither maprotiline nor imipramine changed the stereotyped responses induced by apomorphine. Clomipramine showed in contrast an inhibitory effect which increased after 7 daily injections of the drug. Moderate suppression of stereotypies was also observed after repeated administration of amitriptyline. In rats with unilateral 6-OHDA lesions of the s.nigra apomorphine-induced contralateral turning was markedly (70%) after a single 25 mg/kg i.p. injection of maprotiline. A tolerance to this effect developed after 7 daily injections of the drug. Clomipramine and amitriptyline caused an inhibition of turning which was markedly increased after repeated treatment. These results suggest that antidepressants do not uniformly affect the behavioural responses mediated by dopamine. Clomipramine and amitriptyline appear to possess dopamine receptor blocking properties which may become more pronounced after chronic treatment. In contrast, the dopamine receptor blockade by maprotiline diminished and disappeared under such conditions. Among the drugs investigated imipramine was the one which seemed to have the weakest influence on dopaminergic receptors.