The aim of the present work was to evaluate the distribution of the different clones of the parasite prevailing after treatment with benznidazole (BZ) and clomipramine (CLO), in mice infected with Trypanosoma cruzi, Casibla isolate which consists of a mixture of two discrete typing units (DTUs). Albino Swiss mice were infected and treated with high and low concentrations of BZ (100 or 6.25 mg/kg), CLO (5 or 1.25 mg/kg), or the combination of both low doses (BZ6.25 + CLO1.25), during the acute phase of experimental infection. Treatment efficacy was evaluated by comparing parasitaemia, survival and tissular parasite presence. For DTUs genotyping, blood, skeletal and cardiac muscle samples were analysed by multiplex quantitative polymerase chain reaction. The combined treatment had similar outcomes to BZ6.25; BZ100 was the most effective treatment, but it failed to reach parasite clearance and produced greater histological alterations. Non-treated mice and the ones treated with monotherapies showed both DTUs while BZ6.25 + CLO1.25 treated mice showed only TcVI parasites in all the tissues studied. These findings suggest that the treatment may modify the distribution of infecting DTUs in host tissues. Coinfection with T. cruzi clones belonging to different DTUs reveals a complex scenario for the treatment of Chagas disease and search for new therapies.

The genetic cytochrome P450 polymorphism is reported in factors affecting the individual response to drugs. The interindividual variation at steady-state levels or also in elimination of drugs, finds an explanation in genetic differences in the metabolism. In particular, activities of the P450-IID6 isoenzyme are related to the sparteine/debrisoquine oxidation polymorphism. Phenotyping such a system has been proposed to analyse variability in the tricyclic antidepressant level. To analyse clinical relevance of a pharmacogenetic approach, we studied the cytochrome P450 CYP2D6 genotypes and the clinical responses to clomipramine in 21 hospitalised patients who met DSM-III-R criteria for major depression. Three patients were predicted as poor metabolizers. We suggested a limitation of clomipramine (CMI) hydroxylation in poor metaboliser (PM) patients which is balanced by a desmethylation. The clinical efficacy pattern does not differ in poor metaboliser and early metaboliser patients. Firstly, there is no significant differences in the evolution of scores on MADRS and specific retardation scale into the two groups. Secondly, outcome of side effects does not occur more frequently in PM patients. Clinical relevance of such an approach needs further study.

Two cases of bipolar psychosis presented a rapid manic switch following administration of tricyclic antidepressants. In both cases the oxidation capacity was genetically deficient. The role of oxidation deficit is discussed in the pathogenesis of switch process and preventive measures are considered.

In patients with chronic idiopathic pain disorders we have analysed the construct validity of the Melancholia Scale as compared to the results with the scale in primary depression. The patients (n= 253) were treated in a placebo controlled trial with either clomipramine or mianserin independently of the Melancholia score. The construct validity of the Melancholia Scale was further analysed by the testing of the intensity model of depression versus anxiety using the Beck Depression Inventory, the Hamilton Anxiety Scale, the Spielberger State-Trait Anxiety Scale, and the Melancholia Scale. The construct validity in terms of scale homogeneity was analysed by Loevinger coefficients which can be considered as a latent structure evaluation. The Melancholia Scale showed acceptable homogeneity, while the Hamilton Anxiety Scale lacked sufficient homogeneity. In total, 33% of the patients had a score of 10 or more on the Melancholia Scale (corresponding to 13 or more on the Hamilton Depression Scale). The predictive validity of the Melancholia Scale was evaluated using active treatment versus placebo response after 6 weeks of therapy. It was shown that in patients with a Melancholia Scale score of 10 or more (corresponding to “less than major depression”) 72% had full recovery when treated with clomipramine, while 36% of the placebo treated patients obtained a full recovery (P≤0.05). The patients treated with mianserin obtained a full recovery in 52%. The group of patients with a Melancholia Scale score of 10 or more scored higher also on the anxiety scales indicating that the relation between depression and anxiety is a matter of severity. The depressed patients had significantly lower imipramine binding sites than the non-depressed patients.

The aim of this study was to compare the efficacy, safety, and tolerability of sertraline and clomipramine in the treatment of obsessive-compulsive disorder (OCD). Outpatients with DSM-III-R defined OCD for 1 year or longer and scores of ≥ 20 on the YaleBrown Obsessive Compulsive Scale (Y-BOCS), ≥ 7 on the National Institute of Mental Health Global Obsessive-Compulsive Scale (NIMH-OC), ≥ 4 on the Clinical Global Impression Severity of Illness Scale (CGI-S) and ≤17 on the Hamilton Depression Scale (17 item HAMD) were randomized to sertraline (n = 86) or clomipramine (n = 82) once daily for 16 weeks. Initial daily doses of sertraline and clomipramine were 50 mg. After a minimum of 4 weeks, these doses could be increased by 50 mg increments every 2 weeks to a maximum of 200 mg daily if the response was thought inadequate. Efficacy was assessed at the end of 1, 2, 4, 6, 8, 12 and 16 weeks of therapy using the Y-BOCS, NIMH-OC, CGI-S, CGI Improvement Scale (CGI-I) and Clinical Anxiety Scale (CAS). One hundred sixty-eight patients were randomized and received at least one dose of double-blind medication; 86 received sertraline and 82 clomipramine. Mean final daily doses at final visit were clomipramine 90 mg (efficacy evaluable patients 101 mg, completers 110 mg), and sertraline 129 mg (efficacy evaluable patients 132 mg, completers 136 mg). Mean baseline Y-BOCS, NIMH-OC and CGI-S totals were 27.7, 10.1 and 5.5, respectively, for sertraline and 27.4, 9.9 and 5.5, respectively, for clomipramine. Sertraline demonstrated greater efficacy than clomipramine in the intent-to-treat patient group: mean baseline to final visit changes were 50.8% (Y-BOCS), 41.9% (NIMH-OC) and 37.7% (CGI-S) for sertraline and 42.9% (Y-BOCS), 33.8% (NIMH-OC) and 30.0% (CGI-S) for clomipramine (P < 0.05). The number of patients withdrawing because of adverse events was substantially greater for clomipramine (26%) than sertraline (11%) (P < 0.05). The most frequent adverse events for clomipramine were dry mouth (20%), anxiety (17%), constipation (16%), nausea (15%) and somnolence (11%), and for sertraline, diarrhea (12%) and nausea (12%). In this study, sertraline was more effective than clomipramine in the intent-to-treat analysis. The difference in efficacy between the treatments is almost wholly accounted for by a greater number of clomipramine withdrawals due to the poor patient acceptance of clomipramine. The superior tolerability of sertraline and the lower rate of premature treatment withdrawal relative to clomipramine may offer considerable quality of life and compliance benefits in the long-term management of a chronic disorder such as OCD.

The authors investigated the comorbidity between obsessive-compulsive disorder (OCD) and other psychiatric disorders in a group of 154 outpatients. The influence of an associate major depressive disorder (MDD) on the outcome of treatment with clomipramine was examined in a subgroup of 52 patients. The results showed that MDD was the most frequent disorder associated with OCD (almost 20% of the patients), followed by generalized anxiety and panic disorder. The co-presence of depression delayed the effect of clomipramine.

The first breakthrough in the treatment of obsessive-compulsive disorder (OCD) came in 1967, when Fernandez and Lopez-Ibor reported on the efficacy of clomipramine (CMI) in the treatment of 16 patients with OCD (Fernandez and Lopez-Ibor, 1967). However, controlled studies with CMI were not published until 1980 (Montgomery, 1980; Thoren et al, 1980), and only in the last 5 years have large well-controlled studies been published (Clomipramine Collaborative Study, 1991). Several studies demonstrated that among the tricyclics (TCA), only CMI is effective in OCD, while effective antidepressants with a noradrenergic profile, such as desipramine (DMI), appear to be totally ineffective (Zohar and Insel, 1987; Goodman et al, 1990; Leonard et al, 1989). This selective response to TCA with a serotonergic profile led to the formulation of the serotonergic hypothesis of OCD and to the development and use of other serotonergic agents in the treatment of this disorder. Several drugs, possessing a serotonergic profile are currently being studied worldwide, among them CMI, fluoxetine, fluvoxamine, sertraline, paroxetine and citalopram. Currently, as the knowledge regarding the pharmacological approach to OCD is only beginning to accumulate, very little is known regarding treatment duration in OCD. In this review we shall attempt to examine the existing data regarding treatment duration in OCD.

We report the case of a patient with major depression and obsessive-compulsive disorder who had simultaneously high serum citalopram, clomipramine, and alprazolam concentrations probably due to the reciprocal competitive inhibition of the cytochrome P450-catalyzed oxidative metabolism.

Chagas infection is a major endemic disease affecting Latin American countries. The persistence of Trypanosoma cruzi generates a chronic inflammatory reactivity that induces an immune response directed to the host's tissues. The effectiveness of the treatment in the chronic phase is still unsatisfactory due, amongst other reasons, to the collateral effects of the drugs used. We investigated the effect of clomipramine, a tricyclic antidepressant that, when used as a treatment of T. cruzi-chronically infected mice, inhibits trypanothione reductase, an exclusive and vital enzyme of T. cruzi. Clomipramine improved survival (P<0·05) by diminishing the parasite intensity as demonstrated by PCR studies in the heart and skeletal muscle, and significantly prevented the evolution to fibrosis of the inflammatory infiltrates. Clomipramine could be a good candidate for the treatment of chronic Chagas disease.

We present a case showing inducement of acute dystonia by clomipramine therapy and discuss the possible explanations. We could find no previous reports of this phenomenon.

Cent douze patients hospitalisés pour un épisode dépressif majeur (75% appartenant au sous-type mélancolique), d’origine endogène selon les critères de Newcastle, ont reçu du milnacipran (100 mg/24 h) ou de la clomipramine (150 mg/24 h) pendant une durée maximale de 3 mois lors d‘un essai réalisé en double-insu. Après exclusion d‘une observation du groupe clomipramine (arrêt à J3 pour nausées), restaient 111 observations exploitables pour l’analyse de l’activité : (milnacipran : 55 ; clomipramine: 56). Quatre-vingt-quatorze pour cent des patients ont atteint 4 semaines de traitement, 78% 8 semaines et 74% 12 semaines. Le nombre de sorties d’essai était comparable dans les 2 groupes, le pourcentage de celles qui étaient liées à un défaut d’activité étant identique (12,5%). A tous les temps étudiés, de J7 à J84, les évolutions obtenues sous milnacipran et sous clomipramine ont été comparables, pour les scores totaux des échelles de dépression de Hamilton (1967), de Montgomery et Asberg (1979) (MADRS) et de ralentissement de Widlocher (1981), mais aussi pour chacun des items de ces échelles. L’amélioration moyenne du score total de la MADRS a été, à partir d’un score initial de 38, de: 41% à J14; 66% à J28; 74% à J56; 76% à J84 sous milnacipran; 41% à J14; 59% à J28; 76% à J56; 83% à J84 sous clomipramine. Pour tous les paramètres étudiés, les niveaux de signification étaient particulièrement élevés (P = 0,3 à 0,9), indiquant des profils d’activité pharmacodynamique identiques pour le milnacipran et la clomipramine. L’appréciation du rapport bénéfice/risque (CG1-3), a été constamment favorable au milnacipran, avec des différences significatives à J14, J21, J28, J56 et J70: ces résultats favorables traduisaient la meilleure tolérance du milnacipran, notamment vis-à-vis des sécheresses buccales, des vertiges et des tremblements. Les activités antidépressives du milnacipran 100 mg et de la clomipramine 150 mg ont été identiques tout au long de cet essai de 3 mois. Le milnacipran a été mieux toléré que la clomipramine. Les résultats de cette étude ont confirmé ceux d‘études antérieures, en référence à d‘autres tricycliques ou à un placebo.

Une étude contrôlée comparative de la viloxazine et de la clomipramine injectables, par la méthode du cotateur aveugle avec temps aveugle, a été conduite chez 30 sujets des 2 sexes hospitalisés dans un service spécialisé lors de la survenue d’un épisode dépressif majeur. Une répartition homogène de la population recrutée pour cet essai a été obtenue en recourant à la méthode d’homogénéisation décrite par Taves. La comparabilité des 2 groupes ainsi recrutés à partir des variables définies préalablement à cet essai s’est révélée satisfaisante. Deux sujets n’ont pas terminé l’essai, un dans chaque groupe de traitement. Les résultats globaux mettent en évidence une efficacité antidépressive non significativement différente entre les 2 groupes à 21 jours de traitement dont 7 jours de perfusion à la posologie de 300 mg de viloxazine ou 75 mg de clomipramine suivis d’un relais à 600 mg de viloxazine ou de 150 mg de clomipramine. Une analyse en composante principale des instruments d’évaluation semble indiquer une polarité d’action plus marquée de la clomipramine sur l’humeur, tandis que la viloxazine voit ses effets plus marqués sur le ralentissement. Le suivi des concentrations plasmatiques de viloxazine réalisé dans le cadre de cet essai a confirmé les principales caractéristiques pharmacocinétiques de la viloxazine et mis en évidence l’absence de modification des concentrations après le passage de la forme IV à la forme comprimés. Elle n’a pas, enfin, mis en évidence de corrélation entre les taux plasmatiques et la réponse thérapeutique.

Part I of this paper presents a comprehensive review of plasma level monitoring of tricyclic antidepressants (TCAs) and their relationship to clinical response to antidepressant therapy. Imipramine, nortriptyline, amitriptyline, clomipramine and desipramine are the most widely studied TCAs in this regard. Typical therapeutic plasma concentration ranges are suggested for some of these agents, although a consensus is lacking.