2nd Year Maintenance and Discontinuation of Imipramine in Panic Disorder With Agoraphobia

Background: The results from our 1 year placebo-controlled maintenance/discontinuation study in remitted panic disorder with agoraphobia patients confirmed the significant prophylactic effectiveness of imipramine maintenance treatment but suggested that this may be necessary in only 37% of the patients who relapse following discontinuation of 6 months acute imipramine treatment. This paper presents pilot data from a second year extension of the above-mentioned study with the aim of exploring the putative protective effects of maintenance imipramine therapy beyond the 1st year. Method: Eighteen patients from the 30 who survived, in stable remission, the first 12 months of the maintenance/discontinuation study gave written consent to participate in a double-blind 2nd year extension phase with the knowledge that those on placebo will continue on the same condition (N = 7, PBO–PBO) and those on imipramine (N = 11) will be rerandomized to 2nd year maintenance (N = 4, IMI–IMI) or placebo substitution (N = 7, IMI–PBO). The procedures continued unchanged from that of the 1st year of the study and patients were followed with planned assessments every 2 months over the second 12-month experimental period of the study. Results: None of the IMI–IMI patients relapsed, two (28.5%) of the IMI–PBO patients relapsed, and two (28.5%) of PBO–PBO patients relapsed. The mean estimated time without relapse was 10 months and 9 months for IMI–PBO and PBO–PBO, respectively. The estimated probability of not relapsing was .64 for IMI–PBO and .60 for PBO–PBO (Mantel-cox test ₁ ² = .84, p = .77). Conclusion: These interlocking controlled observations tentatively suggest that a substantial degree of prophylactic efficacy continues and that a substantial need for continued prophylaxis exists beyond the 1st year of maintenance imipramine treatment in panic disorder with agoraphobia patients.     

安非他酮治疗抑郁障碍的疗效和安全性

目的：评价安非他酮治疗抑郁症的疗效和安全性。方法将60例符合CCMD-3诊断标准的抑郁症患者随机分为安非他酮组和丙米嗪组各30例,分别治疗6周。采用汉密尔顿抑郁量表（ HAMD）评定疗效,采用副反应量表（ TESS）评定药物的不良反应。结果两组治疗后HAMD评分均较治疗前有显著降低（ P﹤0.05）,治疗1、2、4、6周末两组间HAMD评分均无显著差异（ P﹥0.05）。治疗第4、6周末,安非他酮组TESS评分低于丙米嗪组,差异有显著性（P﹤0.05）。结论安非他酮治疗抑郁症有效,且不良反应发生率低于丙米嗪。     

Quantification of Intracellular Accumulation and Retention of Lysosomotropic Macrocyclic Compounds by High-Throughput Imaging of Lysosomal Changes

Many marketed pharmaceuticals reach extremely high tissue concentrations due to accumulation in lysosomes (lysosomotropism). Quantitative prediction of intracellular concentrations of accumulating drugs is challenging, especially for macrocyclic compounds that mainly do not fit in current in silico models. We tested a unique library of 47 compounds (containing 39 macrocycles) specifically designed to cover the entire range of accumulation intensities observed with pharmaceuticals so far. For the first time, we show that intracellular concentration of compounds measured by liquid chromatography with tandem mass spectrometry correlates with the induction of phospholipidosis and inhibition of autophagy, but the highest correlation was observed with the increase of lysosomal volume (R = 0.95), all measured by high-throughput imaging assays. Based only on imaging data, we developed a 5-class in vitro model for the prediction of compound accumulation with the accuracy of 81%. The measured change of total lysosomal volume can thus be used in high-throughput screening for determination of the actual intensity of intracellular accumulation of new macrocyclic compounds. The models are largely based on macrocycles, greatly improving the screening and prediction of intracellular accumulation of this challenging class. However, all tested nonmacrocyclic compounds fitted well in the models, indicating potential use of the models in broader chemical space.     

米氮平与丙米嗪治疗抑郁症伴焦虑症状对照研究

目的探讨米氮平与丙米嗪治疗抑郁症伴焦虑症状的疗效及安全性。方法将112例抑郁症伴焦虑症状患者随机分为两组各56例,研究组给予米氮平30~45mg.d-1治疗,对照组给予丙米嗪100~200mg.d-1治疗,疗程6w。采用汉密顿抑郁量表、汉密顿焦虑量表及副作用量表评定临床疗效及不良反应。结果治疗6w末,抗抑郁治疗研究组显效率为73.2%,对照组为67.3%,两组差异无显著性(P>0.05);抗焦虑治疗研究组显效率为78.8%,对照组为43.6%,两组差异有显著性(P<0.05)。副作用量表评定两组差异无显著性(P>0.05)。结论米氮平具有抗抑郁抗焦虑双重作用,抗抑郁作用与丙米嗪相当,抗焦虑作用优于丙米嗪,治疗抑郁症伴焦虑症状疗效显著,安全性高、依从性好。     

Steady-state levels of imipramine and its metabolites: Significance of dose-dependent kinetics

Summary Seventeen hospitalized patients (age 39–66 years), received a loading dose of 100 mg imipramine HCl and then 50 mg b.i.d. The 12-h plasma concentration at steady-state varied between 40–637 nmol/l for imipramine, 49–1148 nmol/l for desipramine and 89–1603 nmol/l for imipramine + desipramine. Guided by plasma level monitoring, a final therapeutic plasma level between 548–910 nmol/l for imipramine + desipramine was achieved (therapeutic dose range: 50–400 mg/day). Mean time to reach the therapeutic level was 19 days. The mean 2-OH-imipramine/imipramine ratio was 0.24 and mean 2-OH-desipramine/desipramine ratio was 0.56. There was a significant intrapatient correlation between the two ratios, both during 100 mg imipramine/d and at the therapeutic dose level. A low ratio was associated with high imipramine and particularly with a high desipramine level. Well defined steady state levels were established at two different dose levels in 12 patients and at three dose levels in 5 patients. With increasing dose there was a marked and disproportionate rise in the desipramine level and to some extent in the imipramine level. Saturation of imipramine and desipramine hydroxylation appeared to be responsible for the dose-dependent kinetics. Concomitant treatment with levomepromazine and perphenazine in one patient resulted in a significant rise both in imipramine and desipramine concentration, apparently due to inhibition of the hydroxylation. Eleven out of twelve endogenously depressed patients responded completely to treatment, whereas the response was poor in the non-endogenously depressed patients despite optimal drug levels.     

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.

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.