A double blind study in out-patients with primary non-agitated depression treated with imipramine in combination with placebo, diazepam or dixyrazine

Sixty-three out-patients suffering from primary non-agitated depression were included in a double-blind, between-patient randomized study. All patients were treated with imipramine (100-200 mg-day) combined with either placebo, diazepam (10 mg/day) or dixyrazine (50 mg/day) for 8 weeks. The clinical efficacy assessed with a subscale of CPRS was significantly (p1 less than or equal to 0.05) better for the imipramine-dixyrazine combination than for the imipramine-diazepam or imipramine-placebo combination. Serum concentration of imipramine was significantly higher (p1 less than or equal to 0.05) in the group treated with dixyrazine than in the other two groups. Further, serum concentration of imipramine in the diazepam group was significantly lower (p1 less than or equal to 0.05) than in the placebo group. At the end of the study, 67% in both the placebo and the diazepam group and 86% in the dixyrazine group were practically symptom-free.     

Withdrawal reactions to diazepam in combined imipramine/diazepam treatment of primary nonagitated depressed outpatients

Twenty-seven outpatients who had primary nonagitated depression that had been treated for 3.5 months with imipramine were included in the study. Of these, 14 patients were given additional diazepam treatment (10 mg/day) and 13 patients got placebo. The additional medication was stopped, and withdrawal reactions were observed after two weeks. The depression scores (both global evaluation and CPRS) increased significantly in the diazepam group, without any changes in the placebo group. Eleven patients in the diazepam group and four in the placebo group reported their condition as impaired after discontinuing their additional medication. Four patients in the placebo group and none in the diazepam group reported improvement. The level of working activity decreased significantly in the diazepam group and increased in the placebo group. The serum level of imipramine decreased in the placebo group (P = 0.07), but not in the diazepam group. Serum levels of desipramine decreased significantly in both groups (P less than 0.05). Our study indicates that the discontinuation of diazepam, even when given in moderate dosage over a relatively short period of time, may cause withdrawal reactions in combined antidepressant/diazepam treatment. This may be caused by a possible tendency for the depression to become chronic. Such chronicity may be the reason for secondary dependency to diazepam.     

Effects of intraperitoneally injected lithium, imipramine and diazepam on nitrate levels in rat amygdala

Nitric oxide (NO) has been studied in relation to the etiologies of various neurologic and psychiatric diseases. However, little is known about whether clinically available psychotropic drugs affect the NO system in the brain. Using an in vivo brain microdialysis method, the effects of intraperitoneally administered lithium, imipramine and diazepam on levels of , a marker of in vivo NO production, were investigated in the rat amygdala. Lithium significantly reduced, while imipramine raised, levels as compared with controls. These observations suggest that lithium and imipramine induce opposite effects on NO-related systems in the brain.     

Effect of concurrent anxiety on response to sertraline and imipramine in patients with chronic depression

Anxiety commonly complicates the clinical presentation of depression and has been associated with poorer long-term outcome, but little information is available on the clinical correlates, and comparative effect on treatment response, of subsyndromic or secondary anxiety. Patients diagnosed with chronic major or double depression were randomized to 12 weeks of double-blind treatment with either sertraline or imipramine in a 2:1 ratio. A high anxiety subgroup was operationally defined by a HAM-D anxiety/somatization factor score > or = 7. The effect of study treatment was measured utilizing the HAM-D, CGI, HAM-D anxiety/somatization factor, as well as a quality of life measure (Q-LES-Q) and a measure of psychosocial functioning (the MOS-SF-36). Two hundred nine patients were treated with imipramine and 426 patients were treated with sertraline. Thirty-six percent of the total met criteria for the high anxiety subgroup. According to Kaplan-Meier probability estimates, patients with significant concurrent anxiety symptoms were more likely to respond by 12 weeks (66.4%) than those without significant anxiety symptoms (54.2%). There was no significant difference in response rates for sertraline vs. imipramine. Both drugs were effective at treating high baseline levels of anxiety, with 60% of sertraline patients and 58% of imipramine patients having 50% or greater reduction from baseline in HAM-D anxiety/somatization factor scores, and only 4.6% and 9.9%, respectively, reporting treatment-emergent worsening in anxiety at study endpoint. Despite the chronicity of depressive illness, acute treatment with both sertraline and imipramine significantly improved psychosocial and quality of life measures. High baseline levels of anxiety did not reduce overall antidepressant response but did somewhat delay the onset of response to sertraline or imipramine in patients with chronic depression.     

文拉法辛与丙米嗪治疗抑郁症对照分析

目的:观察文拉法辛与丙米嗪治疗抑郁症的疗效。方法:80例抑郁症患者随机分为两组,分别以文拉法辛及丙米嗪治疗。疗程6周。采用汉密尔顿抑郁量表(HAMD)、临床疗效总评量表疾病严重程度(CGI-SI)评定疗效,用副反应量表(TESS)观察不良反应。结果:文拉法辛组显效率80%,丙米嗪组75%,两组相仿。HAMD焦虑/躯体化因子分下降以文拉法辛组更为显著,文拉辛组不良反应较少,程度较轻,不需处理。结论:文拉法辛治疗抑郁症的疗效与丙米嗪相当,不良反应较少,依从性好。     

Relapse prevention by means of paroxetine in ECT-treated patients with major depression: a comparison with imipramine and placebo in medium-term continuation therapy

In-patients with severe major depression were treated in the acute phase with electroconvulsive therapy (ECT) in combination with antidepressants. The drug treatment consisted of two randomized trials which were both extended into the post-ECT continuation phase. Patients with electrocardiological impairment were randomized to either 30 mg paroxetine daily or placebo under blind conditions. Patients without electrocardiological impairment were randomized to either 30 mg paroxetine daily or 150 mg imipramine daily. There was a high level of agreement between the Hamilton Depression Scale and the Melancholia Scale, demonstrating that the patients treated with ECT plus imipramine in the acute phase showed greater symptom reduction than those treated with ECT plus paroxetine. However, in the post-ECT phase paroxetine was superior to both imipramine and placebo in preventing relapse. Thus in the post-ECT phase 65% of the placebo-treated patients relapsed, compared to 30% of the imipramine-treated patients and 10% of the paroxetine-treated patients. The psychometric analysis of the Melancholia Scale in the continuation or post-ECT phase showed that relapsing patients displayed a pattern with lack of interests, impaired concentration, depressed mood and anxiety among the less severe symptoms (first-compartment symptoms). In other words, these symptoms represent the gate to full-blown depression (second-compartment symptoms). Serotonin-selective antidepressants such as paroxetine appear I to be more effective in controlling the first-compartment symptoms.     

A double blind comparison of lofepramine,imipramine and placebo in patients with primary depression

The results of a double blind trial in which 139 patients with primary depression were randomly assigned to either lofepramine (46), imipramine (48), or placebo (45) are discussed. After treatment with either active drug, lofepramine or imipramine, the clinical outcome was significantly greater than with placebo. No significant differences were found in clinical responses between lofepramine and imipramine. With regard to reported side effects, however, a statistically significant lower number of severe and/or moderate side effects were reported for the lofepramine group than for the imipramine group. In particular, for severe and/or moderate occurrences of dry mouth, the statistically significant lower incidence in favor of lofepramine is by almost a factor of 3 (8 lofepramine vs 21 imipramine patients).     

A 12-week double-blind multi-centre study of paroxetine and imipramine in hospitalized depressed patients

Fifty-seven inpatients with major depression (DSM-III-R) entered a 12-week study comparing paroxetine and imipramine. Trends (not reaching statistical significance) in favour of paroxetine were seen on the Hamilton Depression Rating Scale (HDRS) and the Montgomery-Åsberg Depression Rating Scale (MADRS). The UKU Side Effect Rating Scale showed a significant difference in favour of paroxetine on reduced salivation. Global evaluation of side effect symptoms showed that significantly more paroxetine patients had no side effects, both in the investigators’ and the patients’ opinion. These results are in line with previous findings of paroxetine being an effective and well tolerated antidepressant.     

A comparison of fluoxetine and imipramine in the treatment of outpatients with major depressive disorder

A double-blind clinical trial was undertaken to evaluate the clinical efficacy and safety of fluoxetine compared with imipramine in the treatment of 59 outpatients suffering from major depressive disorder. The mean scores of all depression rating scales showed that the drugs had comparable efficacy. The side effect profile of imipramine was found to be mainly anticholinergic, which was not the case for fluoxetine, where it was mainly found to be gastrointestinal, such as nausea and diarrhoea. In both groups the total number of adverse events reported were the same. Fluoxetine treatment resulted in weight loss, whereas imipramine treatment resulted in a slight but significant weight increase.     

Dexamethasone suppression test identifies a subset of elderly depressed patients with reduced platelet serotonin transport and resistance to imipramine inhibition of transport

Dysregulation of the hypothalamus-pituitary-adrenal axis (HPA) is more common in elderly patients with depression than in younger depressed patients, and glucocorticoids are known to influence serotonergic function. Elderly depressed patients are also reportedly more resistant to therapeutic effects of antidepressants. In the current study, we measured platelet serotonin transporter binding sites and transport function in young and elderly depressed patients and determined the relationship to HPA status as assessed with the dexamethasone suppression test (DST). The density and affinity of transporter molecules showed no differences between young and elderly depressed patients, regardless of DST results. Nevertheless, transporter function showed a substantial interaction of aging with DST: elderly DST suppressors showed a deficit in [³H]serotonin uptake capabilities and resistance to imipramine inhibition of uptake. No such defects were seen in the young depressed cohort, regardless of DST status, nor in elderly depressed DST non-suppressors. These results are consistent with the view that depression in the elderly exhibits basic biological differences from depression in earlier life, and that such distinctions may account in part for therapeutic ineffectiveness of antidepressants in specific subgroups, associated with the presence or absence of appropriate HPA regulation. Depression and Anxiety 6:19–25, 1997. © 1997 Wiley-Liss, Inc.     

Differential effects of acute diazepam on emotional and neutral memory tasks in acutely hospitalized depressed patients

With the hypothesis that depression affects memory through a mechanism other than that of the benzodiazepines, the present study evaluated the acute effect of diazepam 10 mg upon explicit memory in patients with major depression. A double-blind, placebo (starch 50 mg) controlled experiment was carried out with 19 patients randomly divided into diazepam (n = 10) and placebo (n = 9) groups. They were evaluated by the Mini-Mental State Examination, and tests were conducted for immediate and delayed (short-term) memory with emotionally toned stimuli (negative, positive, neutral), recognition, and semantic memory in visual or auditory modality. The Visual Analog Mood scale (VAMS) was applied to measure anxiety and mood changes after the administration of drugs (30 minutes and 6 hours). Higher scores in the positively toned list among patients who received diazepam were observed, at the 30-minute compared with the 6-hour evaluation. The recall index of positive words in the diazepam group was positive and significantly different from the index of the placebo group. No anterograde amnesia following diazepam was observed. The neural model of a dysfunction of limbic prefrontal cortical structures that impairs the modulation of the amygdala in major depression may explain the present results. Consequently, the action of diazepam on the amygdala, which has been proposed to be the basis of its anxiolytic action, might be altered, modifying the modulation of memory in our patients.     

A comparative clinical trial of fluoxetine, mianserin and placebo in depressed outpatients

Fluoxetine, a selective serotonin reuptake inhibitor, was compared with mianserin and placebo in a double-blind study. In total, 81 depressed patients were included. Patients were rated weekly on the Hamilton Depression Rating Scale (HDRS) and the Montgomery & Asberg Depression Rating Scale (MADRS). The duration was 6 weeks, and 52 patients completed the study. Significantly more patients on fluoxetine improved than patients on placebo. For mianserin no significant differences were found with either fluoxetine or placebo. Mean HDRS at the end of the study was also statistically significantly lower for fluoxetine, but not for mianserin, than placebo. Subscores of the MADRS showed improved sleep on mianserin at weeks 2 and 3. Suicidal feelings were reduced to a greater degree on fluoxetine than on mianserin and placebo at weeks 6 and 7. Fluoxetine induced weight loss, while patients on mianserin gained weight. Side effects were present in most patients on the two active drugs; those on fluoxetine experienced nausea and vomiting, and those on mianserin drowsiness.     

Double-blind study of the efficacy and safety of milnacipran and imipramine in elderly patients with major dipressive episode

The novel antidepressant agent milnacipran is a dual and equipotent serotonin and noradrenaline reuptake inhibitor. The aim of this double-blind study was to compare the efficacy and safety of milnacipran (50 mg twice daily) with that of imipramine (50 mg twice daily) in elderly patients with major depressive episode. A total of 219 patients were randomly assigned to 8 weeks of double-blind treatment with either milnacipran or imipramine; 72 patients withdrew from the study. At the end of treatment no significant differences were found between milnacipran and imipramine in antidepressant efficacy. A significantly greater number of side-effects, particularly anticholinergic effects, was observed in the imipramine group. Milnacipran may be preferable to imipramine in elderly depressed patients, as it provides the same antidepressant activity as imipramine with a lower incidence of side-effects, and does not impair cognitive ability.     

Effects of genetic defects in the CYP2C19 gene on the N-demethylation of imipramine, and clinical outcome of imipramine therapy

Abstract  The relationship between the genetic polymorphism of S-mephenytoin 4'-hydroxylation catalyzed by CYP2C19 and the N-demethylation of imipramine was examined in 10 Japanese depressed patients. Five patients, who were poor metabolizers of S-mephenytoin, were determined to be either homozygous for a mutation in exon 5 or heterozygous for mutations in exon 4 and exon 5 of the CYP2C19 gene. In contrast, five patients, who were extensive metabolizers, had no mutations. The demethylation index (the desipramine/imipramine ratio) was significantly lower in patients with genetic defects. Plasma levels of imipramine and 2-hydroxyimipramine normalized by the daily dose (mg) per weight (kg) were significantly higher in patients with genetic defects. This suggests that the N-demethylation of imipramine is impaired in patients with genetic defects in the CYP2C19 gene, and that genotype determination may be useful in preventing side effects induced by unexpectedly elevated levels of imipramine.     

Symptom reduction in depression after treatment with L-tryptophan or imipramine. Item analysis of Hamilton rating scale for depression.

Thirty-eight in-patients with endogenous- and 20 in-patients with non-endogenous depression, took part in a multi-centre 3-week double-blind trial where patients were randomly allocated to treatment with either 6 g L-tryptophan or 150 mg imipramine daily. Item analysis of Hamilton ratings, before the investigation and weekly during the trial period demonstrated few statistically different mean scores on individual items between the two treatment groups. After 3 weeks' treatment a statistically significant item mean reduction on the 0.1% level was found in the item Agitation in favour of imipramine-treated, and in the item Work and Activities in favour of L-tryptophan-treated endogenously depressed patients. After 3 weeks' treatment a statistically significant item mean reduction on the 5% level was found in the item Suicide in favour of imipramine-treated non-endogenously depressed patients. The present study has shown that, after 3 weeks' treatment, imipramine and L-tryptophan has decreased the mean score on individual items of HRS in about the same degree.     

Low serum BDNF levels in depressed patients cannot be attributed to individual depressive symptoms or symptom cluster

Objectives. Low serum BDNF levels have been found in depressed patients. No study has systematically investigated whether individual symptoms or symptom profiles within a depressed population contribute to low BDNF levels found in depressed subjects. Methods. All 1070 patients with a past 6-month diagnosis of major depressive disorder from the Netherlands Study of Depression and Anxiety (NESDA) were included. Composite International Diagnostic Interview (CIDI) and Inventory of Depressive Symptoms (IDS) items were tested individually in separate multiple regression analyses with serum BDNF level as the dependent and the CIDI or IDS item as independent variable. Subsequently, we compared BDNF levels between patients with seasonal affective disorder (based on the Seasonal Pattern Assessment Questionnaire) and melancholic depression, atypical depression and moderate depression (based on a latent class analysis). All analyses were adjusted for confounders. Results. Only one item was significantly associated with serum BDNF levels, namely the CIDI item “loss of interest” (β = 0.14; P < 0.01). Counterintuitively the presence of this symptom was associated with higher BDNF levels. Other items and the comparison between different types of depression did not reveal significant differences. Conclusions. Decreased serum BDNF levels in depression cannot be attributed to a specific symptom or symptom cluster.     

Effect of a selective serotonin uptake inhibitor in agoraphobia with panic attacks. A double-blind comparison of zimeldine, imipramine and placebo

A double-blind clinical trial of zimeldine, a potent inhibitor of central serotonin reuptake, versus imipramine and placebo was carried out on 44 patients suffering from agoraphobia with panic attacks. Zimeldine was a superior treatment on all rating scales other than a global rating scale which did not reach statistically significant superiority. Imipramine was not shown to be superior to placebo. The implications of these results for further research on the underlying pathophysiology of agoraphobia with panic attacks are discussed.     

Clinical and sociodemographic predictors of response to augmentation, or dose increase among depressed outpatients resistant to fluoxetine 20 mg/day

OBJECTIVE: Patients with major depressive disorder often show only partial or no response to antidepressants, necessitating next-step interventions such as dose increase or augmentation. Factors moderating response to these next-step interventions are not well-studied. METHOD: In this randomized, double-blind investigation of next-step treatments in 101 outpatients who failed to respond to fluoxetine 20 mg for 8 weeks, the impact of depressive course and sociodemographic factors on likelihood of treatment response following dose increase or lithium or desipramine augmentation was examined. RESULTS: After controlling for depression severity at baseline, current marriage and earlier onset of depression were associated with greater likelihood of response in a logistic regression. Intervention strategy was not predictive of response. CONCLUSION: Marital status and earlier onset of depression may be clinically useful in predicting outcome following any next-step intervention for treatment resistance, rather than with particular strategies.     

A double-blind comparison of alprazolam vs. imipramine and placebo in the treatment of major depressive disorder

In a 6-week double-blind trial 129 outpatients with major depressive disorder received either alprazolam, imipramine or placebo. Dosage was adjustable from 0.5 mg alprazolam, 25 mg imipramine or two capsules placebo b.i.d. to 4.5 mg alprazolam, 225 mg imipramine or three capsules placebo t.i.d. Both active drugs were more effective than placebo according to all the rating scales used. Alprazolam and imipramine did not differ consistently except in the somatic symptom cluster on the Hamilton Anxiety Rating Scale. Mean final daily dosage was 2.7 mg alprazolam, 117.3 mg imipramine and 7.2 capsules placebo. Patients on alprazolam reported fewer side effects than patients on imipramine and approximately the same number as patients on placebo. Anticholinergic side effects were commonly associated with imipramine; drowsiness was the most frequent side effect with alprazolam.