Treatment of obsessive-compulsive disorder with clomipramine and desipramine in children and adolescents. A double-blind crossover comparison

Forty-eight children and adolescents with severe primary obsessive-compulsive disorder completed a 10-week double-blind crossover trial of clomipramine hydrochloride (mean dose [+/- SD], 150 +/- 53 mg/d) and desipramine hydrochloride (mean dose [+/- SD], 153 +/- 55 mg/d). Clomipramine was clearly superior to desipramine in significantly reducing obsessive-compulsive symptoms. Age at onset, duration and severity of illness, type of symptom, and plasma drug concentrations did not predict clinical response to clomipramine. Sixty-four percent of patients who received clomipramine as their first active treatment showed at least some sign of relapse during desipramine treatment. We further document the specificity of the antiobsessional effect of clomipramine and the need for maintenance treatment.     

Controlled comparisons of clomipramine and fluoxetine in the treatment of obsessive-compulsive disorder. Behavioral and biological results

Treatment with fluoxetine hydrochloride was compared with treatment with clomipramine hydrochloride in two groups of patients with obsessive-compulsive disorder using two different experimental designs. In the first group of 11 patients with obsessive-compulsive disorder studied using a randomized, double-blind, crossover design, treatment with fluoxetine for 10 weeks was found to produce therapeutic effects similar to treatment with clomipramine for 10 weeks. There were significantly fewer total side effects reported during fluoxetine than clomipramine treatment. Drug tapering and placebo substitution in the 4-week crossover interval phase led to substantial relapses in obsessive-compulsive disorder symptoms and depression. Furthermore, responses to the second drug took as long to occur as responses to the first drug, although both drugs are thought to act by a common mechanism, serotonin uptake inhibition. A second group of 21 patients with obsessive-compulsive disorder that had been previously stabilized on clomipramine treatment with at least partial benefit were crossed over to fluoxetine treatment in a double-blind fashion. After 10 weeks of fluoxetine administration, most patients manifested behavioral rating scores of obsessive-compulsive disorder and depressive symptoms that were comparable with precrossover ratings completed during clomipramine treatment. A significant exacerbation in obsessive-compulsive disorder and depression ratings as well as a similar lag in therapeutic efficacy were also noted in this second cohort of patients with obsessive-compulsive disorder. Platelet 5-HT concentrations were reduced 95% during both clomipramine and fluoxetine treatment periods. These results suggest that fluoxetine may represent a viable alternative to clomipramine in the treatment of obsessive-compulsive disorder, although further studies with larger sample sizes are needed.     

Biochemical changes during clomipramine treatment of childhood obsessive-compulsive disorder

Peripheral measures of serotonergic and noradrenergic function were obtained in 29 obsessive-compulsive adolescents and 31 age- and sex-matched controls, as well as in a subsample of 22 patients after five weeks of treatment with clomipramine hydrochloride (134 +/- 33 mg/d) (mean +/- SD) given in a double-blind placebo-controlled trial. Drug-free obsessive-compulsive subjects did not differ from controls on measures of platelet serotonin and monoamine oxidase (MAO) activity, nor on plasma epinephrine or norepinephrine concentrations at rest and after a standard orthostatic challenge procedure. Compared with placebo, treatment with clomipramine was clinically effective and produced a marked decrease in platelet serotonin concentration, a trend toward a reduction in platelet MAO activity, and a rise in standing plasma norepinephrine. Clinical improvement during drug therapy was closely correlated with pretreatment platelet serotonin concentration and MAO activity, as well as with the decrease in both measures during clomipramine administration. This suggests that the effects of clomipramine on serotonin uptake may be essential to the antiobsessional action observed.     

Clomipramine treatment of childhood obsessive-compulsive disorder. A double-blind controlled study

Nineteen children (mean [+/- SD] age, 14.5 +/- 2.3 years) with severe, primary obsessive-compulsive disorder completed a ten-week, double-blind, controlled trial of clomipramine hydrochloride (mean dosage, 141 mg/day) or placebo, each of which was administered for five weeks. Half of the subjects had not responded to previous treatment with other tricyclic antidepressants. There was a significant improvement in observed and self-reported obsessions and compulsions that was independent of the presence of depressive symptoms at baseline. Improvement in obsessive-compulsive symptoms did not correlate significantly with plasma concentrations of the drug or its metabolites. Clomipramine appears to be effective in the treatment of children with obsessive-compulsive disorder and the treatment seems to be independent of an antidepressant effect.     

米氮平和氯米帕明维持治疗抑郁症对照观察

目的:比较抑郁症患者用米氮平和氯米帕明维持治疗的疗效.方法:将60例门诊抑郁症患者随机分为服用米氮平组和氯米帕明组,均治疗54周,用汉密尔顿抑郁量表(HAMD)临床疗效总评量表(CGI)和副反应量表(TESS)在治疗前及治疗12、54周末比较两组的疗效和依从性.结果:治疗12周两组均有非常显著的疗效,两组间比较差异无显著性;治疗54周以米氮平组显著较好.米氮平组不良反应发生率远低于氯米帕明组.结论:抑郁症患者对米氮平依从性高主要是因疗效好,不良反应轻.     

Are gender differences important for the clinical effects of antidepressants?

OBJECTIVE: Gender differences in antidepressant treatment response, side effects, dropout rates, and plasma concentrations were examined in patients with major and predominantly melancholic depression. METHOD: The study included a subgroup of 292 inpatients (96 men, 196 women) from three Danish double-blind, randomized, controlled trials. All patients completed a 5-week treatment period and fulfilled the DSM-III or DSM-III-R criteria for major depression. Clomipramine (150 mg/day) was the reference treatment, and comparable treatments were citalopram (40 mg/day), paroxetine (30 mg/day), and moclobemide (400 mg/day). Assessments were performed by using the 17-item Hamilton Depression Rating Scale and the Udvalg for Kliniske Unders?gelser Side Effect Rating Scale. In a subgroup of 110 patients, weekly measurements of clomipramine plasma concentrations were obtained. Nonparametric statistical tests and multiple linear and logistic regression models were used for statistical evaluations. RESULTS: Both genders had similar remission rates (Hamilton depression scale score <8) when treated with clomipramine and had significantly higher remission rates with clomipramine than with the comparable treatments. The plasma concentrations of clomipramine were significantly higher for female than for male patients. No gender differences were found in posttreatment Hamilton depression scale scores, nor did the therapeutic effects of treatment depend on gender. Rates of dropout and side effects were similar for men and women. No relationship between plasma concentrations, gender, and therapeutic outcome was found. CONCLUSIONS: In a group of patients with major and predominantly melancholic depression, differentiation according to gender was not important in treatment with common antidepressants. Women appeared to have higher plasma concentrations of tricyclic antidepressants than men. The consequences of this difference for clinical effects are unclear. Gender-specific recommendations for dosing of tricyclic antidepressants may be considered.     

Clomipramine treatment of obsessive-compulsive disorder. II. Biochemical aspects

Concentrations of the serotonin metabolite 5-hydroxyindoleacetic acid (5-HIAA), the dopamine metabolite homovanillic acid, and the noradrenaline metabolite 4-hydroxy-3-methoxyphenyl glycol were measured in CSF before and after three weeks' treatment of severe obsessive-compulsive disorder with clomipramine hydrochloride. Patients who responded to clomipramine treatment had significantly higher CSF levels of 5-HIAA before treatment. The amelioration of obsessive-compulsive symptoms was positively correlated to the reduction of CSF concentrations of 5-HIAA during clomipramine treatment but negatively correlated to plasma concentrations of clomipramine. Reduction of CSF concentrations of 5-HIAA, which probably reflects drug action on central serotonin neurons, was maximal at a plasma clomipramine concentration of about 300 nmole/L. At higher levels, the reduction of CSF levels of 5-HIAA was smaller. The antiobsessive effect of clomipramine may be connected to its capacity to inhibit serotonin uptake.     

Comparison between zimelidine and desipramine in endogenous depression. A cross-over study

Depressed patients, who did not respond after 4 weeks treatment with zimelidine 100 mg b.i.d. (five patients) or desipramine 75 mg b.i.d. (11 patients) in a double-blind randomized study were crossed over, after 1 placebo week, to 4 weeks of treatment with the other drug. The three zimelidine non-responders who responded to desipramine were significantly more retarded compared with eight desipramine non-responders who responded to zimelidine. It was observed that two patients with bipolar depression developed mania during crossover treatment with desipramine, while two patients with bipolar depression who were treated with zimelidine during the second treatment period did not show any symptoms of mania. Three patients who were non-responders during both treatment periods had lower plasma concentration of the drugs compared with respective responding groups.     

Cardiovascular and antidepressant effects of imipramine in the treatment of secondary depression in patients with ischemic heart disease

The authors report on 12 men with ischemic heart disease who developed secondary depression following myocardial infarction or coronary artery bypass-graft surgery and were treated with imipramine hydrochloride for 4 weeks. Imipramine had an antiarrhythmic effect, manifested by reduction in premature ventricular contractions during treatment. This drug did not produce clinically significant disturbances in cardiac conduction, but orthostatic hypotension led to early termination of the drug treatment in 1 subject. Imipramine treatment was associated with significant improvement in both observer-rated and patient-rated depression scales.     

Clomipramine in obsessive-compulsive disorder. Further evidence for a serotonergic mechanism of action

Data from several previous studies link clomipramine's potent serotonergic effects to its clinical efficacy in reducing the symptoms of obsessive-compulsive disorder (OCD). To investigate this relationship further, we administered the serotonin (5-HT) receptor antagonist, metergoline, and placebo to ten patients with OCD in a crossover study carried out under double-blind, random-assignment conditions. In a previous study of untreated patients with OCD, we found no differences in the behavioral response to single-dose administration of metergoline or placebo. In the present study, patients with OCD receiving clomipramine hydrochloride on a long-term basis (with an average 40% lessening in OC symptoms) responded to a four-day period of administration of metergoline with significantly greater self- and observer-rated anxiety compared with the four-day placebo period. Obsessive-compulsive symptoms also tended to be greater during the metergoline phase, with significant drug-time interactions for both OC symptoms and anxiety peaking on day 4 of the metergoline phase. As anticipated, metergoline lowered plasma prolactin concentrations (providing evidence of physiologically significant 5-HT antagonism) but did not alter plasma clomipramine concentrations. These data further support the hypothesis that clomipramine's therapeutic behavioral effects in OCD are mediated via serotonergic mechanisms.     

Six-year follow-up after exposure and clomipramine therapy for obsessive compulsive disorder

To determine whether gains from exposure therapy are lasting in patients with chronic obsessive compulsive disorder, the authors followed up 34 (85%) of 40 such patients who had been treated 6 years earlier with exposure therapy for 3 or 6 weeks and with clomipramine or placebo for 36 weeks. Severity of obsessive compulsive disorder was assessed by rating the discomfort caused by the time devoted to four target rituals, the Behavioral Avoidance Test, and the Compulsion Checklist. Mood was assessed by the 17-item Hamilton Rating Scale for Depression, the Wakefield Self-Assessment Depression Inventory, and the Anxiety scale. In addition, the patients' general adjustment was assessed. The authors found that the group as a whole remained significantly improved on obsessive compulsive symptoms, work and social adjustment, and depression; however, the group returned to pretreatment levels (slight to moderate) of general anxiety. They found that neither clomipramine nor placebo affected long-term outcome and that the majority of patients who were taking clomipramine or other antidepressants at follow-up were no more improved that those who were not taking antidepressants. Better long-term outcome correlated with more exposure therapy (6 weeks of therapy vs. 3 weeks) and with better compliance with the exposure therapy homework. The best predictor of long-term outcome was improvement at the end of treatment. Subjects who had initially been most depressed were more likely to receive psychotropic medication during follow-up. Initial severity of illness did not preclude benefit from exposure therapy.     

Psychodynamic psychotherapy and clomipramine in the treatment of major depression

OBJECTIVE: The authors compared a combination of clomipramine and psychodynamic psychotherapy with clomipramine alone in a randomized controlled trial among patients with major depression. METHODS: Seventy-four patients between the ages of 20 and 65 years who were assigned to ten weeks of acute outpatient treatment for major depression were studied. Bipolar disorder, psychotic symptoms, severe substance dependence, organic disorder, past intolerance to clomipramine, and mental retardation were exclusion criteria. RESULTS: Marked improvement was noted in both treatment groups. Combined treatment was associated with less treatment failure and better work adjustment at ten weeks and with better global functioning and lower hospitalization rates at discharge. A cost savings of 2,311 dollars per patient in the combined treatment group, associated with lower rates of hospitalization and fewer lost work days, exceeded the expenditures related to providing psychotherapy. CONCLUSIONS: Provision of supplemental psychodynamic psychotherapy to patients with major depression who are receiving antidepressant medication is cost-effective.     

Medication Outcome in ECT-Resistant Depression

The outcome of antidepressant treatment in 12 cases of electroconvulsive therapy (ECT)-resistant depression is presented. Eight patients had been refractory to a clinically adequate course of ECT (Hamilton Depression Scale improvement <20%) and four were partial responders (improvement 20-49%). All remitted completely on antidepressant medication within 2.2 +/- 1.1 (mean +/- SD) months of the ECT course. Remission was associated with clomipramine treatment (139 +/- 49.7 mg/day) in seven cases and maprotiline (125 mg/day) in one case. Four patients who did not respond to a tricyclic antidepressant alone remitted following supplementation (of clomipramine in 2 cases, clomipramine + haloperidol in 1 case, and imipramine in 1 case) with lithium carbonate. Although a delayed therapeutic response to ECT cannot be excluded, the results suggest that ECT may alter the sensitivity of refractory patients to antidepressant medication.     

Panic-induced elevation of plasma MHPG levels in phobic-anxious patients. Effects of clonidine and imipramine

Six subjects with the phobic-anxiety syndrome were treated in a controlled, crossover trial of clonidine hydrochloride v imipramine hydrochloride for periods of four weeks each. During each drug trial and during baseline placebo treatment, each patient exposed himself or herself to a situation that previously elicited panic attacks. Self-rated anxiety and plasma levels of 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were measured to study the effect of the drug treatments on noradrenergic activity and anxiety. Plasma MHPG level correlated highly with rated anxiety under all conditions, and was consistent with significant symptom reduction by clonidine or imipramine. Diminished suppression of plasma MHPG concentrations in two subjects was associated with the continued emergence of panic symptoms in response to phobic stimuli.     

Risperidone in the treatment of psychotic depression

In the preset study, the authors investigated that effects of the antipsychotic drug risperidone on psychotic depression and examined the mechanism of risperidone to ameliorate psychotic depression. Fifteen patients met the DSM-IV criteria for major depressive disorder with psychotic features and the remaining five patients met those for bipolar I disorder (most recent episode depressed) with psychotic features (M/F: 8/12, age: 54+/-18). All patients were evaluated regarding their clinical improvement using the Hamilton Rating Scale for Depression (Ham-D), and Positive and Negative Syndrome Scale (PANSS). In addition, plasma concentrations of HVA and MHPG were analyzed by HPLC. Patients with a 50% or more improvement in Ham-D score were defined as responders. Three were prescribed risperidone alone, and the other 17 were administered risperidone as an addition to preexisting antidepressants or mood stabilizers. The preexisting antidepressants or mood stabilizers were as follows: paroxetine (6), lithium (3), valproic acid (3), clomipramine (2), fluvoxamine (1), amitriptyline (1), amoxapine (1). The average dose of risperidone was 1.8+/-0.5 mg/day. Eleven of twenty patients (55%) turned out to be responders 4 weeks after initiation of risperidone administration. No differences were observed between responders and nonresponders with respect to age, sex, Ham-D score before risperidone treatment, dose and plasma level of risperidone or its active metabolite, 9-hydroxyrisperidone. Plasma HVA levels before risperidone administration in responders were significantly higher than those in nonresponders. In addition, a significant correlation was observed between changes in plasma HVA level and the percentage improvement on Ham-D score. These results indicate that treatment with risperidone is effective to ameliorate psychotic depression, and the influence of risperidone on dopaminergic activity is associated with its efficacy.     

Correlations of plasma and urinary phenylacetic acid and phenylethylamine concentrations with eating behavior and mood rating scores in brofaromine-treated women with bulimia nervosa.

Women with bulimia nervosa undergoing treatment with the reversible monoamine oxidase type A inhibitor, brofaromine, were rated for mood and eating behaviour and their plasma and urine were assessed for phenylacetic acid (unconjugated and total) and unconjugated phenylethylamine prior to and after four weeks of drug treatment. Changes in plasma unconjugated phenylacetic acid concentrations were significantly and negatively correlated with the corresponding changes in Hamilton Depression scores but not with eating behavior measures. There were no significant correlations between changes in phenylethylamine levels and changes in rating scores. Patients diagnosed as suffering concurrently from severe depression (Hamilton Depression score of 17 or higher) had lower plasma and urinary phenylacetic acid levels than did those whose depression was not severe (Hamilton score less than 17). Phenylethylamine concentrations were not different between the severely and mildly depressed subgroups. The results confirm earlier studies on the relationship between phenylacetic acid and depression while showing that a similar relationship does not pertain to phenylacetic acid and eating behavior in bulimia nervosa.     

Effects of clomipramine treatment on cerebrospinal fluid monoamine metabolites and platelet 3H-imipramine binding and serotonin uptake and concentration in major depressive disorder.

In an open study of 12 inpatients who met the DSM-III criteria for a major depressive episode, the effects of clomipramine (CI) on the monoamine metabolites 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA), 4-hydroxy-3-methoxyphenyl glycol (HMPG) in cerebrospinal fluid (CSF) were measured simultaneously with the effects on 3H-imipramine binding, serotonin (5-HT) uptake and 5-HT concentration in platelets after 3 and 6 weeks of treatment. Drug (CI and desmethylclomipramine) plasma concentrations were determined. The concentrations of 5-HIAA and HMPG decreased substantially, and the concentration of HVA remained unchanged. There was also a large and significant reduction of the number of imipramine binding sites (Bmax) and of the platelet 5-HT concentration. The 5-HT uptake was not measurable after 3 weeks of treatment. None of the parameters changed significantly between weeks 3 and 6. There were no significant correlations between antidepressant effect (measured by the Montgomery-Asberg Depression Rating Scale) and plasma drug concentrations, although a tendency to a significant correlation between antidepressant effect and CI was observed at 3 weeks. There were no significant intercorrelations between the different 5-HT parameters and no other significant correlations between the biochemical measures and clinical outcome.     

Effects of somatic treatments on mood in endogenous depression

The effects of ECT, amitriptyline, clomipramine, maprotiline and desipramine on the course of endogenous depression were compared in 105 patients using repeated self-administered mood questionnaires as the outcome measure. Remission was more rapid after ECT therapy than psychopharmacological treatment, but the absolute improvement did not differ significantly between ECT and other somatic therapies. Improvement in response to clomipramine was more rapid than to other psychopharmacological agents, and did not differ from that in response to ECT. The advantages and disadvantages of ECT for endogenous depression are discussed.     

Acute antidepressant effect following pulse loading with intravenous and oral clomipramine

A double-blind, randomized trial of oral vs intravenous clomipramine hydrochloride pulse-loading dosing regimens was conducted. After a two-week drug-free assessment period, 22 inpatients with a diagnosis of major depressive disorder were given either an evening infusion of 150 mg of clomipramine hydrochloride and placebo tablets or 150 mg of oral clomipramine hydrochloride and an isotonic saline infusion. Twenty-four hours later, this procedure was repeated using a dose of 200 mg of clomipramine hydrochloride. Patients received no further medication over the next five days. The mean Hamilton Depression Rating Scale score for all patients, five days after pulse loading, had dropped by 35% (range, 13.3% to -82.4%). This improvement was significant, as was the amelioration in the Raskin Severity for Depression Scale and the Beck Depression Inventory scores. Although the bioavailability of parenteral clomipramine was greater, there were no significant differences in either efficacy or side effects between the two groups. Pronounced early improvements in severe depressive symptoms may be achieved via loading dose regimens with clomipramine in the absence of continuous treatment.     

A comparison of clomipramine and doxepin in neurotic depression

Results of a double-blind 4-week trial in depressed outpatients given clomipramine (N = 30) or doxepin (N = 36) are reported. Both groups showed significant improvement in physician-rated measures after 1 week of treatment; comparison of the groups favored clomipramine over doxepin for four of six measures. The response to treatment was less clear-cut with the patient-rated measures. The overall incidence and severity of adverse experiences were similar for both treatment groups. Clomipramine was effective, safe, and well tolerated as compared to doxepin in the treatment of outpatients with neurotic depression.