Paroxetine efficacy in the treatment of generalized anxiety disorder

Recently, there has been a renewed interest in alternatives to the benzodiazepines for the treatment of generalized anxiety disorder (GAD). The aim of the present study was to compare the efficacy of paroxetine vs. imipramine and 2′-chlordesmethyldiazepam in 81 patients with a DSM-IV diagnosis of GAD. Approximately two-thirds of the patients who completed the study improved greatly or moderately on all three active drugs. During the first 2 weeks of treatment, 2′-chlordesmethyldiazepam treatment resulted in the greatest improvement in anxiety ratings. Both paroxetine and imipramine treatment resulted in more improvement than 2′-chlordesmethyldiazepam by the fourth week of treatment. Paroxetine and imipramine affect predominantly psychic symptoms, whereas 2′-chlordesmethyldiazepam affects predominantly somatic symptoms. Our results suggest that paroxetine is effective for the treatment of GAD.     

Efficacy of venlafaxine in depressive illness in general practice

A double-blind, placebo-controlled study of 229 patients with a Research Diagnostic Criteria diagnosis of major, minor or intermittent depression was used to compare the clinical profiles of venlafaxine and imipramine in general practice. Venlafaxine produced a significant improvement compared to placebo in symptoms of depression and anxiety as rated by the total MADRS and percentage of responders, the CGI improvement, the CGI severity of illness, the BSA psychic anxiety item and the HSCL. On a number of these measures, venlafaxine was also significantly more effective than imipramine. Venlafaxine was significantly superior to both imipramine and placebo for the SARS total score and the items 'socialeisure’and‘extended family.’A similar proportion of patients discontinued treatment in each group, but fewer patients on venlafaxine discontinued treatment because of an unsatisfactory response.     

Different effects of antidepressants on dissociation of H-imipramine from solubilized binding sites of rat brain

1. 1. The effects of several antidepressants and 5-hydroxytryptamine on dissociation of ³H-imipramine from solubilized binding sites were investigated.

2. 2. Binding sites were solubilized from rat brain membranes and gelfiltrated on a column of Sephacryl S-300.

3. 3. Most of the agents used allowed biphasic dissociation with 1mM of displacing agent and without using dilution-induced dissociation. This biphasic dissociation without nonspecific effects of membranes may be due to the existence of low-affinity binding sites.

4. 4. Dissociation of up to 40 min followed first-order kinetics. The dissociation half-life of ³H-imipramine with the various displacing agents was calculated at from 15.0 to 25.0 min, and the differences among the agents were not so significant as the attenuation or the acceleration of the dissociation was indicated. The lower concentration of the displacing agents may obscure the modulation of the dissociation.

Phosphatidylserine as a Determinant for the Tissue Distribution of Weakly Basic Drugs in Rats

Interorgan variation in tissue distribution of weakly basic drugs such as quinidine, propranolol, and imipramine was investigated as a function of binding to phosphatidylserine (PhS) in tissues. Tissue distributions of these drugs were determined using 10 different tissues at a steady-state plasma concentration and were expressed as tissue-to-plasma partition coefficients (K _p values). The concentration of PhS in the tissue was determined by two-dimensional thin-layer chromatography. Plotting of K _p values, except for brain, against the tissue PhS concentrations showed a linear relationship, indicating that PhS is a determinant in the interorgan variation of these tissue distributions. Further, differences in tissue distribution among the drugs was considered to be due to the difference in binding potency to PhS. Drug binding parameters to individual standard phospholipid were determined using a hexane-pH 4.0 buffer partition system. Binding was highest to PhS, and a linear relationship was found between the log nK [product of the number of binding sites (n) and the association constant (K) for PhS binding] obtained in vitro and K _p values of drugs in tissues in vivo. The empirically derived equation, K _p = 14.3 × (log nK) × (PhS cone.) – 8.09, was found to predict K _p values in vivo of weakly basic drugs. Thus, a determinant of interorgan variation in the tissue distribution of the weakly basic drugs studied was the tissue concentration of PhS and the drug binding affinity to PhS.     

药物与农药中毒的快速分析Ⅲ．反相HPLC法测定血清及其它体液中三环类抗抑郁药

本文介绍用反相ＨＰＬＣ法同时测定三环类抗抑郁药：多虑平、丙咪嗪、阿米替林、氯丙咪嗪的血药浓度。流动相为甲醇－水－四甲基乙二胺（７０∶３０∶１），冰醋酸调ｐＨ至６．４。选用安定为内标，体液样本在碱性条件下，用无水乙醚提取，氮气流挥干后用流动相溶解进样。线性范围为１０～６００ｎｇ／ｍｌ，最低检测浓度为５～１０ｎｇ／ｍｌ，回收率为９３．３３％～９７．７９％，相对标准偏差为１．００％～１．８２％，并用该方法对患者血清进行了测定。     

A controlled trial of imipramine for the treatment of methamphetamine dependence

At the Drug Detoxification Program of the Haight Ashbury Free Clinics, we conducted a randomized clinical trial of imipramine in the treatment of methamphetamine dependence. The purposes of the trial were to test the efficacy of imipramine as a treatment for methamphetamine dependence and to establish the feasibility of conducting a controlled clinical trial at the Clinic. Thirty-two subjects were randomly assigned to receive either 10 or 150 mg/day of imiprine for 180 days. Imipramine 10 mg/day was the control. Subjects received intensive counseling. Retention in treatment was significantly longer for subjects who were treated with 150 mg of imipramine compared to control (median days: 33.0 vs. 10.5). There were no consistent differences in percent of urine samples positive for methamphetamine, Beck Depression Inventory scores, or craving. Determination of the full extent of imipramine's utility in the treatment of methamphetamine dependence awaits a larger trial.     

EFFECTS OF IMIPRAMINE ON THE ORTHOSTATIC CHANGES IN BLOOD PRESSURE, HEART RATE AND PLASMA CATECHOLAMINES

2. Imipramine caused a moderate increase in supine systolic blood pressure, and a pronounced increase in the rise in heart rate, when the subjects assumed erect position. 3. The orthostatic drop in systolic blood pressure was in most cases only moderately increased after ingestion of imipramine, but in three subjects pronounced orthostatic hypotension developed when the sodium balance was low, whereas no clinical symptoms were seen in the same subjects when tested after imipramine ingestion on a high sodium balance. 4. The plasma catecholamine levels in supine and standing position were not influenced by imipramine or by the changes in sodium balance. 5. The data may suggest that inhibition of presynaptic reuptake of noradrenaline and/or α-adrenoceptor blockade causes the moderate rise in supine blood pressure, whereas α,-adrenoceptor blockade, mainly affecting the venous part of the vascular bed, may explain the orthostatic reactions.     

曲唑酮与丙咪嗪治疗焦虑性神经症效果比较

①目的　比较曲唑酮与丙咪嗪治疗焦虑性神经症的效果及副作用。②方法　 72例符合CCMD 3诊断标准的焦虑性神经症病人 ,随机分为两组 ,分别应用曲唑酮或丙咪嗪治疗 6周。采用焦虑自评量表 (SAS)、Hamilton焦虑量表 (HAMA)和副作用量表 (TESS)评定疗效及副作用。③结果　曲唑酮与丙咪嗪治疗焦虑性神经症的效果比较差异无显著性 (χ2 =1.0 7,P >0 .0 5 ) ,但曲唑酮副作用明显低于丙咪嗪 (t =3.5 2 ,P <0 .0 1)。④结论　曲唑酮治疗焦虑性神经症安全有效 ,副作用小。     

High affinity [3H]imipramine and [3H]paroxetine binding sites in suicide brains

Summary Specific binding of [3H]imipramine and [3H]paroxetine was simultaneously examined in human brains (frontal cortex, temporal cortex, cingulate cortex, hypothalamus, hippocampus and amygdala) from 11 controls and 11 depressed suicide victims. A single saturable high affinity site was obtained for both radioligands. Age was not related to significant changes in [3H]imipramine and [3H]paroxetine binding parameters, which indicates the stability of the brain serotonergic system with increasing age.A major finding of the present study concerns the existence of a significant decrease in the maximum number (Bmax) of [3H]imipramine binding sites in hippocampus from depressed suicides as compared with the control group, without changes in the binding affinity (Kd). In contrast, when [3H]paroxetine was used as radioligand, no changes in either Bmax or Kd were detected in any of the brain regions studied. These findings suggest that [3H]imipramine may be a better marker than [3H]paroxetine when alterations in the presynaptic serotonergic uptake site are to be detected.     

Unaltered 5-HT- and desipramine-sensitive [3H]imipramine binding and [3H]5-HT uptake in rat brain after chronic imipramine and norzimeldine treatment

Several reports have shown heterogeneity of [³H]imipramine binding to brain membranes. Recently, a high affinity and 5-HT sensitive [³H]imipramine binding site of protein nature, that was suggested to be identical to the substrate recognition site for 5-HT uptake, was demonstrated. Since most studies on the regulation of the [³H]imipramine binding sites by antidepressants have used desipramine displaceable binding, which is heterogenous in nature and contains binding not related to 5-HT uptake sites, the present report studies the possible effects of chronic (3 weeks) administration of imipramine or norzimeldine (10 mg/kg intraperitoneally twice daily) on 5-HT sensitive [³H]imipramine binding sites. For comparison, desipramine sensitive binding was also studied, as well as the physiological correlate 5-HT uptake. There were no changes in either [³H]imipramine binding or 5-HT uptake after the antidepressant treatment.Supported by the Swedish Medical Research Council Offprint requests to: J. Marcusson at Dept. of Geriatric Medicine