A Double-Blind Comparison of Sertraline and Imipramine in Outpatients with Major Depression: Acute (8 Weeks) and Continuation (16 Weeks) Treatment

In a double-blind multicentre trial in patients with major depression, the efficacy and the tolerability of sertraline were compared to those of imipramine, during an 8-week acute treatment phase followed by a 16-week continuation treatment phase in treatment responders. A total of 104 patients who met DSM-III-R criteria for major depression, HAM-D 17-item≥18 and Raskin Depression score>Covi Anxiety score, were randomized to receive either sertraline or imipramine. The initial daily dosage of 50 mg of sertraline or imipramine was rapidly titrated upwards in increments of 50 mg/day at weekly intervals, tolerability permitting, to a maximum of 200 mg/day by the fourth week. Eighty-eight patients completed at least 3 weeks of treatment and were included in the efficacy evaluable population. Both treatment groups demonstrated similar improvements on depression and anxiety rating scales during acute treatment, however, sertraline demonstrated significantly more improvement relative to imipramine on the HAM-D and Covi Anxiety scales after 1 week of treatment. Sertraline was more effective (HAM-D 17-item, CGI-S, SCL-56 Total score, SCL-56 Depression score, Covi Anxiety score) than imipramine in reducing depressive symptoms at the end of 24 weeks of treatment. There were significant improvements in all rating scales at week 24 relative to week 8 in the sertraline group but not in the imipramine group. The SCL-56 Total score, SCL-56 Depression score, Raskin Depression score and Covi Anxiety score at week 24 relative to week 8 showed significantly greater improvement in the sertraline group compared to the imipramine group. Imipramine was associated with a significantly higher incidence of dry mouth, sweating, constipation, palpitations, and a significantly higher heart rate and blood pressure. Sertraline was associated with a significantly higher incidence of diarrhoea/loose stools and insomnia. This study demonstrated a faster onset of therapeutic effect for sertraline relative to imipramine, reflecting the initiation of sertraline in a therapeutic dose of 50 mg/day and the need for gradual titration of imipramine to a therapeutic dose, at the beginning of treatment. Although efficacy was similar in both treatment groups at the end of the 8 weeks of acute therapy, sertraline-treated patients continued to manifest gradual improvements in depressive and anxiety symptoms during the 16 weeks of continuation therapy such that sertraline-treated patients were significantly more improved at the end of 24 weeks of therapy. © 1997 John Wiley & Sons, Ltd.     

The effects of hypnotics on imipramine treatment

Plasma imipramine and desmethylimipramine concentrations and depression ratings were measured over a 3 week period in 3 groups of hospitalised depressed patients given standard doses of imipramine. The first group received imipramine alone, the others either amylobarbitone or nitrazepam in addition as a night sedative. The plasma antidepressant levels were consistently higher in the group receiving no hypnotic but only significantly so in the case of total IMI in the imipramine alone group compared to the group receiving imipramine plus amylobarbitone. The inter-individual differences in plasma levels were large. There was no difference between the groups with regard to changes in depression, sleep or side-effects. From a clinical point of view, there is therefore no evidence from this study of adverse effects of these drugs given in combination nor any evidence to suggest that the dosage of imipramine given should be adjusted when administered along with either of the hypnotics studied.     

Clomipramine and mianserin in chronic idiopathic pain syndrome

The reduction of pain by two antidepressants, clomipramine and mianserin, was, in this study on 253 patients with chronic idiopathic pain syndrome, found to be not better than a placebo when all patients were compared independently of the classification of pain. The improvement rate was around 40% after 6 weeks of treatment when using a 50% or better reduction in pain level. However, in patients who fulfilled a checklist definition of minor to major depression (30% of the total patient material) clomipramine was superior to mianserin and placebo with an improvement rate of 75% after 6 weeks. Using pain curves over time as outcome measure in the various clinical pain categories it was found that both mianserin and clomipramine seemed superior to placebo in patients with tension headache, but in patients with low back pain syndrome placebo was superior to the two antidepressants. No difference among the three treatments was found in patients with burning mouth syndrome or in patients with abdominal pain. These differences underline the importance of studying specific pain syndromes rather than composite groups of patients with idiopathic pain. The clinical significance of these pain curves needs further placebo controlled investigations.     

Moclobemide (Ro 11-1163) vs. clomipramine in the treatment of depression: A double-blind multicenter study in Belgium

A multicenter study to compare the antidepressant efficacy and the tolerance of moclobemide (Ro 11-1163) to clomipramine was performed in parallel groups of patients with minor depression. The duration of the study was 6 weeks, with weekly assessments by means of Hamilton Scale of Depression (HRDS) and the Clinical Global Impression (CGI). The efficacy of moclobemide was found to be as good as that of clomipramine. The results for tolerability were possibly in favor of moclobemide. It was recommended that consumption of tyramine-containing foods be kept to a minimum or avoided and no hypertensive crises were reported.     

Superiority of clomipramine over imipramine in the treatment of panic disorder: a placebo-controlled trial.

A double-blind, placebo-controlled trial was undertaken to compare the effects of imipramine and clomipramine in the treatment of panic disorder with or without agoraphobia. The number of dropouts in the placebo-treated group was 7; in the imipramine-treated group, 4; and in the clomipramine treated group, 0. Ten subjects fulfilled the 12 weeks of treatment in the placebo group, 25 in the imipramine group, and 22 in the clomipramine group. To minimize dropouts because of side effects, a flexible dose regimen with a careful escalation of doses was applied. The maximal dose allowed was 250 mg/day. The mean (+/- SEM) daily doses reached were 124 +/- 9 mg (range, 50-250 mg) of imipramine and 109 +/- 8 mg (range, 25-200 mg) of clomipramine. At the end of the trial, the number of panic attacks as well as the anxiety between attacks (measured using the Hamilton Rating Scale for Anxiety) were markedly reduced in patients treated with either of the two antidepressant drugs, but only slightly decreased in patients on placebo. With respect to all major outcome parameters, i.e., full panic attacks, total number of anxiety attacks (full plus mild), and anxiety between attacks, the effect of clomipramine was clearly and significantly superior to that of imipramine (p less than 0.001, p less than 0.002, and p less than 0.002, respectively). Moderate intake of diazepam was allowed; in the clomipramine group (p less than 0.006), but neither in the imipramine group nor in the placebo group, a significant decrement in diazepam intake was observed during the course of the trial. The finding that clomipramine may have a higher potency and/or efficacy than imipramine in the treatment of panic disorder supports the concept that the antipanic effect of antidepressant drugs is due to the influence of these compounds on serotonergic rather than noradrenergic neurotransmission.     

Concentrations plasmatiques de l'imipramine et de la desmethylimipramine et effet anti-depresseur au cours d'un traitement controlé

24 depressed inpatients received a standardized treatment by imipramine, 6 among them receiving also levomepromazine. Plasma concentrations of imipramine and DMI were controlled weekly during the study, and standardized assessment of clinical state were made by a psychiatrist who was unaware of biochemical findings.Interaction between the antidepressant and neuroleptic metabolism is shown by a significant increase of DMI levels, though the clinical effect of the drug association could not be asserted.The therapeutic effect seems mainly dependant of etiology of depression. Endogeneous depressions improve more than other types. Among endogeneous depressions a significant correlation was found between the degree of clinical improvement after three weeks and DMI level, sum of imipramine + DMI level, but not with concentration of imipramine alone.

     

24-Hour motor activity after treatment with imipramine or fluvoxamine in major depressive disorder.

Psychomotor dysfunction in depression is related to alterations in the 24-h pattern of motor activity. After antidepressant treatment the diurnal pattern may be changed due to improvement of clinical state or pharmacological actions. The purpose of this study was to evaluate in 52 depressed in-patients the effects of imipramine (tricyclic antidepressant) and fluvoxamine (SSRI) on the 24-h motor activity. Motor activity was monitored by wrist-actigraphy during a medication-free period and after 4 weeks of treatment. Clinical improvement was not different after imipramine or fluvoxamine treatment. The Hamilton depression score decreased in patients treated with imipramine, as well as in patients treated with fluvoxamine. The clinical retardation score was also reduced in both treatment groups. However, patients treated with imipramine showed higher motor activity levels during the wake period in comparison to the medication-free period, and more fragmentation of motor activity during sleep. Treatment with fluvoxamine did not result in alterations in the 24-h pattern of motor activity. The improvement of depressive mood and retardation seems to play a minor role in the change of the pattern of motor activity after imipramine.     

Clomipramine, a better reference drug for panic/agoraphobia. I. Effectiveness comparison with imipramine

An 8-week, double-blind, flexible-dose trial comparing low doses of clomipramine (mean=50 mg) with moderate doses of imipramine (mean=113.8 mg and propanteline (active placebo), was carried out in 60 out-patients with panic disorder with or without agoraphobia. Efficacy evaluation included global, anxiety and depression rating scales, and the determination of rates of relapse over up to 10 weeks of single-blind placebo follow-up. Both tricyclics were significantly more effective than propanteline, but clomipramine tended to act faster and more consistently than imipramine on most measures. Given the degree of blindness achieved and the significantly lower doses of clomipramine, this seems a better reference drug than imipramine for clinical trials in panic/agoraphobia.     

Effect of metyrapone supplementation on imipramine therapy in patients with treatment-resistant unipolar depression

The paper describes the effect of metyrapone supplementation on imipramine therapy in patients (with treatment-resistant unipolar depression) who fulfilled DSM IV criteria for major depression. Nine patients were enrolled to the study on the basis of history of their illness and therapy. Following 2 weeks of washout period, the patients were treated with imipramine twice daily (100 mg/day) for 6 weeks, and then metyrapone was introduced (twice daily, 500 mg/day), and administered jointly with imipramine for further 6 weeks. Hamilton Depression Rating Scale (HDRS) and Beck Depression Inventory (BDI) were used to assess efficacy of antidepressant therapy. Imipramine changed neither HDRS nor BDI score after 6 weeks of treatment when compared with baseline (before treatment). Metyrapone supplementation significantly reduced both HDRS and BDI scores after 6-week supplementation. Moreover, pharmacokinetic data indicate that metyrapone did not influence significantly the plasma concentration of imipramine and its metabolite, desipramine in the patients during joint treatment with metyrapone and imipramine, what suggests the lack of pharmacokinetic interaction. This preliminary study is the first demonstration of the benefit of metyrapone supplementation in imipramine therapy of treatment-resistant unipolar depression and suggests that a change in the level of neurotransmitters, hormones and immunological parameters, which are disturbed in depression, may contribute to the mechanism of the action of this drug.     

Clomipramine/bentazepam combination in the treatment of major depressive disorders

Eighty-three patients were recruited in a multicentre study concerning the usefulness of benzodiazepines (BZ) in major depressive disorders, diagnosed according to the DSM-III-R criteria. After 1 week wash-out, patients were randomized to clomipramine (CLMP) or CLMP plus bentazepam (BTZ) treatments (47 and 36 patients respectively). It was necessary to add hypnotics, usually a BZ, in 11 patients in the CLMP group and in one patient in the CLMP + BTZ group. The clinical improvement was faster in the group treated with CLMP + BTZ and, at the end of 6 weeks of treatment, the mean score in Hamilton Anxiety Scale (HAS) was lower than the one found in the group treated with CLMP. There were no significant differences found in Hamilton Depression Scale (HDS) between the groups. The side-effects observed were those due to CLMP, and only drowsiness was more frequent in the CLMP+BTZ group. However, the CLMP+BTZ combination was equally or better tolerated by patients than by those treated with CLMP alone. Similar results were found in hospitalized as well as in outpatients. The tricyclic antidepressant (TCA)/BZ association showed better results than TCA alone, producing a symptomatic improvement extensive to the anxious components of depression.     

盐酸多奈哌齐联合帕罗西汀对血管性痴呆合并抑郁患者认知功能和神经功能的影响

目的探讨盐酸多奈哌齐联合帕罗西汀对血管性痴呆合并抑郁患者认知功能和神经功能的影响。方法将52例血管性痴呆合并抑郁患者给予盐酸多奈哌齐联合帕罗西汀治疗,并于治疗前和治疗后采用简明智力检查量表（MMSE）和长谷川痴呆智能检查量表（HDS）和日常生活能力量表（ADL）评价患者的认知功能和生活能力．采用汉密尔顿抑郁量表（HAMD）评价患者抑郁情绪情况。结果治疗12周后,本组患者MMSE、ADL、HDS评分均较治疗前明显升高（P〈0．05）,HAMD评分则较治疗明显降低（P〈0．01）。治疗后,患者血尿常规、心电图、血生化等指标均在正常范围内,无严重不良反应。结论盐酸多奈哌齐联合帕罗西汀可显著改善血管性痴呆合并抑郁患者的认知功能和神经功能缺损,无明显不良反应,疗效安全可靠。     

Cardiovascular effects of paroxetine, a newly developed antidepressant, in anesthetized dogs in comparison with those of imipramine, amitriptyline and clomipramine

The cardiovascular effects of various antidepressant drugs including paroxetine, imipramine, amitriptyline and clomipramine, administered intravenously, have been assessed. Paroxetine, imipramine, amitriptyline or clomipramine potentiated the response to norepinephrine (0.1 microgram/kg, i.v.) on systemic blood pressure, while paroxetine, imipramine and amitriptyline weakened the response to tyramine (30 micrograms/kg, i.v.). A marked decrease in systemic blood pressure was observed after large doses of each drug (3 and 10 mg/kg of paroxetine; 1-10 mg/kg of imipramine, amitriptyline or clomipramine); and half of the animals died following administration of 10 mg/kg of imipramine, amitriptyline or clomipramine. Paroxetine did not show a marked effect on heart rate at a dose of up to 3 mg/kg, although 0.1-3 mg/kg of imipramine, amitriptyline or clomipramine dose-dependently caused tachycardia. ECG disturbances were observed in animals administered 10 mg/kg of imipramine, amitriptyline or clomipramine; but in contrast, 10 mg/kg of paroxetine caused only slight changes in the ECG. Prolongation of atrio-ventricular conduction time was observed with all the drugs. It was concluded that the effects of paroxetine on the canine heart are more mild in comparison with other tricyclic antidepressants used, although its pharmacological features are essentially similar to those of other drugs.     

Treatment strategies in patients with major depression not responding to first-line sertraline treatment

RATIONALE: A large proportion of patients with major depression do not respond sufficiently to any first-line treatment. OBJECTIVES: The aim of this study was to compare a strategy of sertraline dose increase with a strategy of adding mianserin in patients with major depression insufficiently responding to 6 weeks of open treatment with sertraline, controlling for the effect of an extended duration of treatment. METHODS: One thousand six hundred and twenty-nine patients, 18-65 years of age, with major depression scoring at least 18 on the 17-item Hamilton depression scale (HDS) were treated openly with 50 mg/day sertraline, and patients who after 4 weeks had not responded (achieving at least a 50% reduction in score on the HDS) were treated with 100 mg/day sertraline for an additional 2-week period. The patients who had still not responded were then randomised to double-blind treatment for an additional 5 weeks with either 100 mg/day sertraline plus placebo, 200 mg/day sertraline plus placebo or 100 mg/day sertraline plus 30 mg/day mianserin. RESULTS: After 6 weeks of open treatment, 60% had responded and 22% had dropped out, leaving 295 non-responding patients (18%) for randomisation. In the intention-to-treat-analysis, continuing the treatment with 100 mg/day sertraline resulted in response in 70% of the non-responders, similar to the response rate (67%) obtained in the patients who had mianserin added. However, increasing the sertraline dose to 200 mg/day resulted in a lower response rate at 56% ( P<0.05). Similar results were seen in the completers. A substantial increase in the accumulated response rate from week 6 to week 8 was seen. There was no influence of baseline variables, including the presence of melancholic features on the overall post-randomisation response rate. CONCLUSION: After 6 weeks of insufficient antidepressant treatment with 50-100 mg/day sertraline, a continued treatment with 100 mg/day sertraline can be considered until at least week 8 before considering changing strategy, unless the condition deteriorates.     

Attenuation of the post-decapitation convulsions after repeated treatment of rats with desipramine, imipramine and maprotiline

The effects of repeated treatment of rats with the antidepressant or potential antidepressant agents alaproclate, citalopram, clomipramine, desipramine, imipramine, maprotiline, mianserin and zimeldine on the convulsions released by decapitation were examined. The noradrenaline uptake inhibitors desipramine, imipramine and maprotiline increased significantly the latency of onset of the post-decapitation convulsions (PDC's) after repeated administration of 10 mumol/kg orally twice daily, or 66 mumol/kg orally once daily (desipramine), for 15 days. The duration of the PDC's was slightly prolonged by these agents. A single acute dose of desipramine (20 mg/kg) administered at various time intervals before decapitation (1 to 24 hours) had no effect on the PDC's nor did repeated treatment with the other compounds examined, alaproclate, citalopram, clomipramine, mianserin and zimeldine, have any effect upon the PDC latency. The results are interpreted as evidence for noradrenaline receptor subsensitivity following chronic treatment.     

A double-blind study of the efficacy and safety of sertraline and clomipramine in outpatients with severe major depression

This study compared the efficacy and safety of the selective serotonin reuptake inhibitor sertraline with that of the tricyclic antidepressant clomipramine in patients with severe depression, as defined by a baseline 17-item Hamilton Depression Rating Scale (HAM-D) of at least 25. The study included 166 outpatients, randomized to double-blind treatment with sertraline (50-200 mg) or clomipramine (50-150 mg) for 8 weeks. The efficacy of both treatments was similar, 74% of patients in the sertraline group and 71% of clomipramine patients being classified as responders at the end-point, as defined by a Clinical Global Impression-Improvement (CGI-I) score of 1 or 2. Mean HAM-D scores fell from 29.8 at baseline to 12.3 at endpoint in the sertraline group, and from 29.6-12.7 in the clomipramine group. There were more withdrawals due to adverse events in the clomipramine group than in the sertraline group (17% versus 12%). Dry mouth, tremor, dizziness and constipation were all substantially more common in the clomipramine group, whereas diarrhoea/loose stools was more common in the sertraline group. Overall, sertraline was as effective as clomipramine in this group of severely depressed outpatients, and showed better tolerability.     

Aripiprazole augmentation strategy in clomipramine-resistant depressive patients: An open preliminary study

Recent evidence supports the use of second generation antipsychotics in drug resistant depression. The aim of the present open-label study was to evaluate the effect of aripiprazole as an add-on medication in drug-resistant depressed patients who had not responded to clomipramine. Thirty-five patients with major depressive disorder (MDD) were included in the study. All patients had not responded to a previous adequate treatment with an SSRI and had been receiving clomipramine (daily doses ranging from 100 to 300 mg) for 113.9 ± 18.9 days without getting significant clinical improvement. Aripiprazole was added at the fixed dose of 5 mg/day and clinical status as well as clomipramine plasma levels were monitored before and after 4, 8, and 24 weeks of combined treatment. Hamilton depression rating scale scores significantly decreased over the follow-up period with 91.4% and 34.3% of patients getting a response or a remission, respectively, after 24 weeks of combined treatment. No worsening of clomipramine-related side effects nor new side effects were observed. The clinical improvement was accompanied by a progressive and significant increase in clomipramine plasma levels. With the limitation of an open-label design, these data suggest for the first time the putative efficacy and safety of aripiprazole in combination with a tricyclic medication in drug resistant depressed patients. The role of the observed pharmacokinetic interaction in the mechanism of aripiprazole antidepressant activity remains to be proved.     

A double-blind clinical trial of alprazolam, imipramine, or placebo in the depressed elderly.

The efficacy and safety of alprazolam as compared to imipramine or a placebo added to weekly interpersonal psychotherapy was compared in a 6-week double-blind randomized clinical trial of 35 ambulatory elderly patients with major depression. The average maximum dosage of alprazolam was 2.2 mg and the average maximum dosage of imipramine was 97.5 mg. The findings showed a rapid onset of action of alprazolam within 1 week on symptoms of depression and anxiety. The effects for imipramine were seen later in the study. There were no serious side effects that interfered with treatment. The anticholinergic effects of imipramine were the ones that most commonly interfered with treatment. Alprazolam produced the greatest number of symptoms with discontinuation, most of which were alleviated within a week. We conclude that alprazolam may be useful as an antidepressant for the elderly. More clinical trials are needed to test its efficacy in the depressed elderly with concomitant medical problems, using plasma levels. A double-blind discontinuation study of alprazolam is needed to determine the degree of symptom return.     

Clomipramine, a better reference drug for panic/agoraphobia. II. Psychomotor and cognitive effects

The present reference drugs for the treatment of panic disorder and agoraphobia are imipramine and alprazolam. The latter decreases performance and cognitive functioning. No study of such functions in panic/agoraphobia is available. Fifty four out-patients meeting DSM-III-R criteria for panic disorder with or without agoraphobia (PAG), taking part in a parallel groups controlled trial of imipramine (mean dose ±SEM 114±9 mg), clomipramine (50±4 mg) and propanteline (active placebo) over 8 weeks, were studied. A test battery of psychomotor and memory tests was administered at baseline, and after 1, 4 and 8 weeks of treatment. Their results were compared (at baseline and at the end of the trial) with those of a control group of 57 normal untreated subjects. There was no difference between treatments, and no drug effect on any test at any time. No consistent difference between patients and controls was detected. Given its apparently higher potency, and the absence of deleterious effects on cognitive measures known to be affected by benzodiazepines, we conclude that clomipramine is better than imipramine or alprazolam as a reference drug for panic/agoraphobia.     

Clomipramine. An overview of its pharmacological properties and a review of its therapeutic use in obsessive compulsive disorder and panic disorder

During the 20 years that have elapsed since clomipramine (chlorimipramine) was first marketed, it has become well established in the treatment of depressive illness, particularly treatment-resistant depression. However, in addition to its role as an antidepressant, attention is being focused on the use of clomipramine in 2 other areas of psychiatry: obsessive compulsive disorder and panic disorder. Short term clinical trials have shown that clomipramine is generally more effective than amitriptyline, imipramine, desipramine, nortriptyline or clorgiline in reducing obsessive compulsive symptoms. Clomipramine appears to produce some short term benefit with exposure therapy in patients with obsessive compulsive disorder. However, the efficacy of the drug after long term follow-up has not been fully investigated. The antiobsessional efficacy of clomipramine appears to be independent of its antidepressant activity. In patients with panic disorder with or without agoraphobia (DSM-IIIR), clomipramine reduces the frequency and severity of panic attacks within 7 to 21 days of beginning treatment and efficacy is maintained for at least 12 months. Clomipramine is more effective than imipramine, the generally accepted standard treatment for patients with panic disorder after 2 weeks' treatment, but after 6 or 10 weeks both drugs are similarly effective. Other double-blind studies have shown that clomipramine is more effective than placebo and at least as effective as fluvoxamine and oxitriptan (5-hydroxytryptophan) in reducing panic attacks and associated anxiety. Adverse effects associated with clomipramine treatment are mild to moderate in nature and are predominantly a result of the drug's anticholinergic activity. The incidence of seizures is dose related, occurring in 0.48% of all patients receiving clomipramine less than or equal to 250 mg/day and 2.1% of patients receiving greater than or equal to 300 mg/day. In conclusion, the available data indicate that clomipramine is a worthwhile addition to the limited treatments available for obsessive compulsive disorder and panic disorder, two psychiatric disorders which have previously been difficult to manage pharmacologically.     

Fluvoxamine in obsessive-compulsive disorder: similar efficacy but superior tolerability in comparison with clomipramine

Some meta-analyses have suggested that the selective serotonin reuptake inhibitors (SSRIs) are less effective than clomipramine in the treatment of obsessive-compulsive disorder (OCD). The aim of this double-blind, randomised, multicentre study was to directly compare the efficacy and safety of fluvoxamine and clomipramine in patients with OCD. A total of 227 patients were randomised to flexible doses of fluvoxamine or clomipramine (both 150-300 mg/day) for 10 weeks. Fluvoxamine and clomipramine were both clinically effective and there were no statistically significant differences between the two treatment groups, at any visit, on the National Institute of Mental Health Obsessive-Compulsive global rating scale, the Yale-Brown Obsessive-Compulsive scale (total score and obsession and compulsion subscores), the Clinical Global Impression severity of illness and global improvement subscales, the Clinical Anxiety Scale and the 17-item Hamilton Depression Rating Scale. However, there were differences in safety between the two treatments. Compared with fluvoxamine-treated patients, those treated with clomipramine had more anticholinergic side effects (dry mouth, constipation and tremor) and premature withdrawals due to adverse events (18 versus 9). The results from this controlled study indicate that fluvoxamine is as effective as clomipramine in the treatment of OCD but has a better tolerability profile. Copyright 2001 John Wiley & Sons, Ltd.