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Melasma is a hyperpigmented dermatological condition common in females. Drugs such as steroids, cosmetics, and photosensitizing agents are known to cause melasma. We report here a case of an adult male with obsessive-compulsive disorder, receiving clomipramine, who developed melasma.

Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8 min. The assay was linear in the range 20-500 µg/L for all compounds. Overall-assay accuracy and precision were<20% for the lower limit of quantification (LLOQ), except for CMP (CV=22.3%), and <15% at other concentrations. The initial LLOQ was 20 µg/L however for CMP and DMCP it was increased to 40 µg/L. The blood volume per spot did not influence the results, but a low hematocrit (≤ 30%) was associated with a >15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Central nervous system (CNS) monoamine deficits have been linked to a number of pathological conditions such as major depressive disorder. Individual biological variations in 5-hydroxyindoleacetic acid (5-HIAA), homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG) might account for the variation in responses of neurotransmitter systems observed after the administration of clomipramine. The prolactin response to clomipramine has been widely used to assess CNS functioning. This open label study investigates the prolactin response induced by clomipramine in the plasma of healthy volunteers and whether it is related to changes in monoamine metabolites. The effects of clomipramine challenge on prolactin, 5-HIAA, HVA and MHPG were measured in 12 healthy volunteers. Samples were drawn directly before and 50 min after clomipramine infusion. A statistically significant increase in serum prolactin concentrations was measured in women 50 min after CMI infusion, but not in men. We found no significant increases in the serum monoamine metabolite concentrations 50 min after CMI infusion. Changes in HVA and 5-HIAA correlated statistically significantly and positively with the amount of prolactin release in the whole sample. Furthermore, positive correlations were found between ∆(50-0 min) 5-HIAA and ∆(50-0 min) HVA, although we did not find a correlation between ∆(50-0 min) prolactin and ∆(50-0 min) MHPG after clomipramine challenge. The pronounced prolactin release in healthy adult women might indicate a higher physiological sensitivity. Correlations between intra-individual changes in HVA, 5-HIAA and serum prolactin might indicate a central nervous effect of clomipramine on monoamine turnover. We conclude that monoamine changes in relation to prolactin response after clomipramine challenge may be suitable for characterizing the relationship between central serotonergic and dopaminergic function.

Rationale: Norepinephrine transporter (NET) is one of the key targets for antidepressants such as combined serotonin and norepinephrine reuptake inhibitors as well as some of the tricyclic antidepressants. Clomipramine, a tricyclic antidepressant, has been reported to have an active metabolite, desmethylclomipramine, which has high affinity for NET in vitro. However, the NET occupancy of clomipramine and desmethylclomipramine has not fully been evaluated in vivo., Objectives: In this positron emission tomography (PET) study, we investigate NET occupancy by clomipramine and desmethylclomipramine, respectively, in non-human primates with a selective radioligand for NET, (S,S)-[(18)F]FMeNER-D(2)., Methods: PET measurements were performed with (S,S)-[(18)F]FMeNER-D(2) at baseline and after the intravenous administration of clomipramine and desmethylclomipramine, respectively. NET binding was calculated with the simplified reference tissue model using the caudate as reference region. NET occupancy was calculated as the difference in NET binding between the baseline and pretreatment condition. The relationship between NET occupancy and dose/plasma concentration was evaluated using hyperbolic functions., Results: NET occupancy by both clomipramine and desmethylclomipramine increased in a dose and plasma concentration-dependent manner. The mean Kd values, expressed as the dose or plasma concentration at which 50% of NET was occupied, were 0.44 mg/kg and 24.5 ng/ml for clomipramine and 0.11 mg/kg and 4.4 ng/ml for desmethylclomipramine., Conclusions: Not only desmethylclomipramine but also clomipramine was demonstrated to occupy NET in the non-human primate in vivo. It can thus be assumed that NET occupancy during clinical treatment with clomipramine is a combined effect of unchanged clomipramine and its main metabolite desmethylclomipramine.

The tricyclic antidepressant (TCA) clomipramine has been widely used in psychiatry for over 40 years. More recently, its therapeutic potential as an antineoplastic drug has been identified. However, there are no prior data on regional distribution in the brain of clomipramine and its primary metabolite (desmethylclomipramine) after chronic oral administration. The aim of this study was to determine the concentrations of clomipramine and desmethylclomipramine in different rat-brain regions and to compare those with levels in plasma and peripheral organs after chronic oral treatment of Sprague Dawley rats (15 mg/kg) for 14 days. The levels of both parent TCA and metabolite were analysed by high-performance liquid chromatography in six brain regions (cortex, hypothalamus, hippocampus, striatum, brainstem and cerebellum), five peripheral organs and in plasma. Our data show that the cerebral cortex had the highest concentration of clomipramine (2.9 microg/mg), with successively lower concentrations in the hypothalamus, striatum, cerebellum, hippocampus and brainstem. Of the peripheral organs, the lungs and liver, had the highest levels of clomipramine, while in the heart, only the metabolite was detected. The plasma concentration (0.17 microg/ml or 0.48 microM) was comparable to that in the hippocampus and cerebellum (approximately 0.20 microg/mg). The differential distribution of clomipramine in different brain regions and the regional variation in clomipramine to desmethylclomipramine ratios have implications for the use of clomipramine in psychiatry and neuro-oncology.

Obsessive-compulsive disorder (OCD) is a relatively common, often chronic and disabling disorder with high rates of partial and/or absent response to standard, recommended treatments. We report a case of treatment-resistant OCD that was successfully treated with a pharmacological augmentation of lamotrigine plus clomipramine. The patient, a 59-year-old woman, was on a stable dose of clomipramine (225 mg/day) when she was started on lamotrigine (up to 150 mg/day). After 10 weeks of this treatment, her clinical condition remarkably improved, as indicated by a significant decrease of the Yale-Brown Obsessive-Compulsive Scale. This case suggests some preliminary evidence that the addition of glutamatergic agent lamotrigine may be useful in treatment-resistant OCD. However, further controlled studies are needed to support this finding.

Background: The effect of various drugs was investigated by using transcranial magnetic stimulation (TMS) both in healthy subjects and patients, and the results indicated an influence of antidepressant drugs (ADs) on motor excitability., Objective: The aim of our study was to analyze the effects of two ADs, the tricyclic (TCA) clomipramine and the serotoninergic antidepressant (SSRI) citalopram on the motor cortex excitability in major depressed patients with TMS., Methods: Thirty affected subjects were placed into three groups: two received an intravenous dose of 25 mg clomipramine or 40 mg citalopram, and one received an injection of a placebo. Motor cortex excitability was studied by single and paired TMS before and after 3.5, 8, and 24 hours from administration of the drugs and placebo. Motor cortical excitability was measured using different TMS parameters: resting motor threshold (RMT), motor-evoked potential (MEP) amplitude, intracortical inhibition (ICI), and intracortical facilitation (ICF)., Results: The results indicated a temporary but significant increase of RMT and ICI and a decrease of ICF after the administration of both drugs, with a longer inhibition for the clomipramine rather than the citalopram. MEP amplitude was not significantly affected by the antidepressant injections., Conclusions: Our findings highlight that a single intravenous dose of clomipramine or citalopram exerts a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of drugs used in the treatment of mental disorders., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Major depression is a stress-related disorder that affects about 20% of the population, with women outnumbering men by 2:1. However, research focusing on stress/antidepressant-related immunomodulation overlooks sex differences, although an established sexual dimorphism also characterizes the immune system. We report for the first time that both chronic clomipramine treatment (10 mg/kg, twice daily) and chronic mild stress (CMS) application in rats, exert sexually dimorphic effects on cellular immunoreactivity (natural killer and lymphokine-activated killer cell cytotoxicity and interleukin-2-induced T-cell proliferation), with females presenting a relatively immunosuppressed phenotype compared to males. Moreover, following chronic antidepressant treatment, thymic monoamines presented sex-related alterations, as well as intriguing associations with peripheral T-cell responses. This study highlights the sex-related effects of chronic clomipramine treatment and CMS application on the cellular arm of immunity, and represents a preliminary exposé of a thymus-dependent route pertaining to the interactions between antidepressants and the immune system.

The open comparative study of three antidepressants with different mechanisms of action - clomipramine, pirlindole and escitalopram - in the treatment of neurotic level depression (ICD-10 items F32-F34, F43) has been carried out. Ninety-one patients have been stratified into three groups included 31, 31 and 29 patients, respectively.. Duration of the study has been 12 weeks. Clomipramine, pirlindole and escitalopram have similar effect decreasing the total HAMD score by more than 50% (in average 72%). Clomipramine appears to be more effective in the achievement of remission (63%) as compared to pirlindole (40%) and escitalopram (42%). The tolerability of pirlindole and escitalopram is higher than that of clomipramine and the authors recommend prescription of these drugs to patients with neurotic depression.

The objectives of this in vitro study were to describe cytochrome-dependent metabolism of clomipramine in canine and feline microsomes, compare metabolic profiles between cats, rats and dogs, and investigate a potential gender-related difference in metabolic activity between male and female cats. Pooled liver microsomes were incubated with clomipramine, where species and gender-specific reactions were initiated by the addition of a nicotinamide adenine dinucleotide phosphate regenerating system and quenched with methanol at 0, 5, 15, 30, 45 and 60 min, and 0, 30, 60, 90, 120, 180, 240 and 360 min respectively. Liquid chromatography tandem mass spectrometry was used to measure clomipramine and its metabolites. Preliminary results showed that cat microsomes biotransformed clomipramine slower and less efficiently than rat and dog microsomes. Moreover, gender differences in metabolic profiles suggested that male cat microsomes may be less efficient demethylators and hydroxylators than female cat microsomes. As gender metabolic differences may carry clinical significance for this antidepressant, further studies are warranted.

This study was conducted to confirm an interindividual variability in pharmacokinetic parameters of clomipramine in a large population of cats and to identify potential covariables that would explain the presence of such pharmacokinetic variability after a single dose of Clomicalm. Clomipramine hydrochloride was administered orally according to a weight-dose chart from 0.32 to 0.61 mg/kg, to 76 cats and five blood samples were then taken by direct venipuncture at 1, 3, 6, 12, and 24 h. Plasma concentrations of clomipramine and desmethylclomipramine (DCMP) were measured by LC-MS/MS. The Standard Two-Stage technique was used to assess differences and detect correlations between pharmacokinetic parameter estimates and individual covariables. A large interindividual variability in all pharmacokinetic parameters (CV% 64-124) was detected. Statistically significant gender-related differences were detected in MR and Cl/F, where female cats had a higher mean MR (0.53) and faster Cl/F (0.36 L/h.kg) than males (0.36 and 0.21 L/h.kg, respectively). No correlation could be found between clomipramine AUC0-24 h or DCMP AUC0-24 h and sedation scores. Further feline studies are required to assess these findings after multiple dosing of clomipramine and DCMP to allow clinical extrapolation.

Exercise exerts antidepressant effects in humans and rodent models of affective disorders. These effects may be mediated by the upregulation of endogenous factors that exert antidepressant actions. The physiological functions and behavioral actions of the neuropeptide galanin (GAL) suggest antidepressant activity. Previous studies have shown that various modes of exercise elevate GAL gene expression in the locus coeruleus (LC) in rats. The present experiments examined the interaction between voluntary exercise and antidepressant pharmacotherapy. Male Sprague-Dawley rats were provided access to activity wheels (exercise condition) or inoperative wheels (sedentary condition) for 28 days. Rats in each group were injected with clomipramine (10mg/kg/day) or vehicle throughout this period (for 3 weeks). Prepro-GAL mRNA in the LC was measured by in situ hybridization histochemistry. Exercise and clomipramine treatment significantly elevated GAL gene expression, though prepro-GAL mRNA levels in rats receiving both interventions did not differ from sedentary controls that received vehicle. Prepro-GAL mRNA levels were significantly correlated with running distance. The results further implicate a role for GAL in the antidepressant effects of exercise and pharmacotherapy, though the mechanisms through which these treatments influence GAL gene expression appear to differ significantly.

Sixty-seven dogs that showed signs of distress when separated from their owners (destructiveness, excessive vocalisation and house soiling) and hyperattachment were used in a randomised, blind trial to assess the potential value of a dog-appeasing pheromone in reducing the unacceptable behaviours. For ethical reasons, there was no placebo group and the effects of the pheromone were compared with the effects of clomipramine which is regularly used to treat this type of problem. The undesirable behaviours decreased in both groups, but the overall assessment by the owners indicated that there was no significant difference between the two treatments, although there were fewer undesirable events in the dogs treated with the pheromone, and the administration of the pheromone appeared to be more convenient.

Different members of tricyclic antidepressants (TCAs) were found to induce free radical and oxidative stress in vitro. Accordingly, in the present study we tried to explore the possible role of oxidative stress in TCAs-induced cardiotoxicity. Rats were given a single injection of clomipramine (45 mg/kg). The cardiotoxicity was assessed by measuring ECG parameters (heart rate and QRS widening) and serum lactate dehydrogenase activity. The oxidative stress was assessed by measuring the myocardial reduced glutathione and lipid peroxides levels as well as different antioxidant enzyme activities after 24h of drug injection. In addition, we specifically investigated whether clomipramine could induce hydroxyl radical generation in vitro. The study revealed that clomipramine-induced a significant increase in lipid peroxides level (133%) and a significant decrease in glutathione level (84%) as well as a significant decrease in the activity of glutathione peroxidase and superoxide dismutase by 64% and 73%, respectively, as compared with the control group. In addition, clomipramine at concentrations 10 microM, 25 microM, 50 microM and 100 microM increased hydroxyl radical generation by 148%, 204%, 268% and 391%, respectively. Addition of hydroxyl radical scavenger or iron chelator significantly counteracted the effect of clomipramine. In conclusion, the present study demonstrates that free radical generation and oxidative stress play a role in clomipramine-induced cardiotoxicity. In addition, clomipramine can induce hydroxyl radical in vitro.

Background: The therapeutic efficacy of adding lithium to an ongoing antidepressant in resistant depression is well known. However there is less data concerning the efficacy of giving lithium and antidepressant concurrently from the start of treatment., Methodology: The primary objective of this study was to compare the efficacy of a combination of clomipramine+lithium (C+L) with that of clomipramine+placebo (C+P) in-patients with unipolar major depression, during the first 11 days of treatment. Secondary objectives were the assessment of effectiveness after 6 weeks and assessment of the safety of the combination clomipramine and lithium carbonate. C+L and C+P groups were compared for 6 weeks in a multicenter randomized trial of 141 patients hospitalized with a DSM-IV diagnosis of major depression. Efficacy was evaluated using the standard MADRS and CGI scales., Results: Analysis of the 'as treatment ITT' population showed: the percentage reduction in MADRS scores between D0 and D11 in this population was better in the C+L group but not statistically significant (C+L: 32.1 vs. C+P: 27.4, P=0.07). Nevertheless, the comparison of mean MADRS scores showed a significant difference in the C+L group on days 4 (C+L: 25.1 vs. C+P: 27.8) and 7 (C+L: 18.6 vs. C+P: 21.5), P<0.05, and approaching significance on day 11 (C+L: 14.6 vs. C+P 17.2, P=0.054). On day 7, the number of patients in total remission was threefold higher in the C+L group than in the C+P group (15 vs. 4%, P<0.05) and twofold on day 11 (29 vs. 14%, P<0.05). CGI severity score showed C+L was superior to C+P on days 4, 7 and 11 and CGI improvement score was better in C+L group on day 11 (P<0.05). After 6 weeks of treatment no statistical difference was found between the two groups from the clinical point of view. Safety based upon clinical and laboratory parameters was satisfactory in both groups during the 6 weeks of the study., Limitations: Patients with bipolar disorder, previously treated with clomipramine or with any other mood stabilizers during the previous week; or with suicide attempt during the current episode with a score > or =3 for item 10 of the MADRS were excluded from the study., Conclusion: The results of this study suggests that lithium slightly to moderately potentiates antidepressant treatment in unipolar non-refractory patients with severe major depression in the first days of treatment but not as significantly as for the bipolar population.

Objectives: The review addresses the issue of the extent to which pharmacological treatment of obsessive-compulsive disorders (OCD) in childhood and adolescence is based on empirical studies., Methods: Current literature is evaluated, including studies of adult cohorts if these contain approaches relevant for the pharmacological treatment of children and adolescents., Results: The number of qualified empirical studies is few. These studies have shown clomipramine and serotonin-reuptake inhibitors to be very effective in the therapy of obsessive-compulsive disorders in childhood and adolescence. On the basis of the studies available, no specific recommendation can be made with regard to pharmacological dosage. For clomipramine the effective daily dose probably ranges somewhere between 75-150 mg, for fluoxetin between 20-60 mg, and for fluvoxamine between 100-250 mg. However, it must be kept in mind that in individual cases, improvement sometimes will not be noticeable until after 8 to 10 weeks of treatment have elapsed., Conclusion: Clomipramine and serotonin-reuptake inhibitors are effective in the treatment of obsessive-compulsive disorders in children and adolescents. There is an urgent need for therapy studies of obsessive-compulsive disorders in childhood and adolescence. Placebo-controlled studies of pharmacological treatment, controlled studies of psychotherapeutic treatment, and comparative studies of pharmacological and psychotherapeutic approaches are necessary.

Context: Serotonin transporters (5-HTT) are regarded as one of the major therapeutic targets of antidepressants. However, there have only been a few studies about 5-HTT occupancy, and in particular, data concerning classical antidepressants are still limited., Objective: To investigate the relationship between 5-HTT occupancy and a wide range of antidepressant dosing protocols., Design, Setting, and Participants: Antidepressant occupancies of 5-HTT were measured using positron emission tomography (PET) with [11C](+)McN5652. Twenty-seven healthy volunteers were measured with and without pretreatment with single low doses of antidepressants, and long-term doses were evaluated in 10 patients. Scan data were collected between December 12, 1995, and August 7, 2002, and data were analyzed during the 2001-2002 period at the National Institute of Radiological Sciences (Chiba, Japan). Intervention Four different doses of clomipramine hydrochloride (5-50 mg) and 3 different doses of fluvoxamine maleate (12.5-50 mg) were used for single administration. Long-term doses were 20 to 250 mg per day for clomipramine hydrochloride, and 25 to 200 mg per day for fluvoxamine maleate. Main Outcome Measure Occupancies in the thalamus were calculated using the individual baseline of [11C](+)McN5652 for single-dose studies and 2 long-term-dose studies, and the mean value of healthy volunteers as the baseline for 8 long-term-dose studies. The average data from inactive enantiomers [11C](-)McN5652 were used for the estimation of nonspecific binding., Results: Occupancy of 5-HTT increased in a curvilinear manner. Even 10 mg of clomipramine hydrochloride showed approximately 80% occupancy, which was comparable with that of 50 mg of fluvoxamine maleate. Estimated median effective dose (ED50) of clomipramine hydrochloride was 2.67 mg for oral dose and 1.42 ng/mL for plasma concentration; those of fluvoxamine maleate were 18.6 mg and 4.19 ng/mL, respectively., Conclusions: Clinical doses of clomipramine and fluvoxamine occupied approximately 80% of 5-HTT, and dose escalation would have minimal effect on 5-HTT blockade. Ten milligrams of clomipramine hydrochloride was enough to occupy 80% of 5-HTT in vivo.

The purpose of the present paper was to investigate the efficacy of augmentation of clomipramine (CMI) by tandospirone in 36 untreated outpatients with major depressive disorder. Twelve patients were treated with CMI and tandospirone (T group), 12 with CMI and diazepam (D group) and 12 with CMI alone (C group) for 6 weeks. No statistically significant differences in the percentage improvement of the Hamilton Depression Rating Scale (17 items; HDRS-17) and the Hamilton Anxiety Rating Scale (14 items; HARS-14) scores were shown among the three treatment groups. However, at 2 weeks, the percentage improvement of HDRS-17 score in the T group tended to be higher than that in the D and C groups, although there was no statistically significant difference among the three treatment groups. No change in plasma prolactin level or adverse events was induced by the addition of tandospirone. These results suggest that 6 weeks of treatment with tandospirone or diazepam was not effective for augmentation of CMI in major depressive disorder patients. However, augmentation of antidepressants by tandospirone administration for a few weeks might induce early expression of antidepressive effects.

51 patients with depressive episode (40--recurrent depressive disorder, 11--bipolar affective disorder) were treated by the clomipramine intravenous infusions. The number of infusions varied from 5 to 21 (mostly 10-16). The median of maximal dose was 150 mg. There were significant clinical improvement measured by CGI. The therapy was well tolerated.

Unlabelled: 34 patients with diagnosis of depressive episode (ICD-10) were treated for 8 weeks with tricyclic antidepressants (TCA) 22 patients were treated with clomipramine 75-175 mg daily, 11 with imipramine 75-150 mg and 1 with amitriptyline 150 mg. Following parameters were analysed: plasma concentration (FPIA, HPLC), pharmaco-EEG (spectrum power for delta, theta, alfa1, 2, beta 1, 2, 3 by the use of FFT), clinical improvement (HAMD, HARS, SGI, SERS). 50% reduction in HAMD was regarded as improvement., Results: No relationship between mental state and plasma concentration of TCA was found, initial results in SERS were prognostic for the course of treatment, pharmaco-EEG was typical for antidepressants after two weeks of treatment and reflects clinical improvement and stabilization of plasma concentration. Comparing the plasma concentration of TCA measured by the use of FPIA and HPLC method may be useful for the implementation of monitoring therapy.

Objective: The aim of this study was to determine whether age itself is a significant factor in predicting adverse drug reactions in depressed inpatients treated with clomipramine., Method: The study involved 150 hospitalized, depressed patients treated with 150 mg clomipramine per day. Changes in orthostatic blood pressure during treatment as well as the patients' complaint about side-effects was examined with regard to age. The sample was divided into younger (<56) and older (56-70) groups., Results: No significant differences between younger and older subjects were found on any of the 44 side-effects recorded. However, older depressed patients suffer from more pronounced orthostatic hypotension than younger patients., Conclusion: Older depressed patients who have been treated with clomipramine suffer from more severe orthostatic hypotension than younger patients. However, with the right precautions it is safe to treat older patient up to the age of 70 years with a tricyclic antidepressant.

The effect of acute or repeated treatment with the antidepressant clomipramine (CIM) on N-methyl-D-aspartate (NMDA) evoked changes in extracellular 5-hydroxytryptamine (5-HT) in the raphe nuclei and frontal cortex of the same rat has been studied using microdialysis. Acute injection of CIM (10 or 20 mg/kg) caused an increase in raphe extracellular 5-HT but did not significantly alter extracellular 5-HT in the frontal cortex. Infusion of 25 microM NMDA into the raphe decreased extracellular 5-HT in this region and increased terminal extracellular 5-HT in the frontal cortex. In contrast, infusion of 100 microM NMDA into the raphe was followed by an increase in local dialysate 5-HT and a decrease in 5-HT release in the cortex. When NMDA infusion, at either 25 or 100 microM was preceded by one acute injection of CIM the effects of NMDA on 5-HT release in both brain structures were generally more marked than in vehicle injected controls. Repeated (15 day) treatment with CIM (10 or 20 mg/kg) caused a dose-dependent increase in basal extracellular 5-HT in both raphe and frontal cortex. In these animals, however, the effects of infusion of both 25 and 100 microM NMDA on 5-HT release in raphe and frontal cortex were greatly attenuated or abolished. This suggests that adaptive functional changes occur in NMDA receptor function during treatment with an antidepressant. The possible significance of this in the aetiology and treatment of depression is discussed.

1. The study evaluated the efficacy of amisulpride, fluoxetine and clomipramine at the beginning of the re-feeding phase of the treatment of restricting anorexia nervosa according to DSM-IV criteria. 2. 13 patients, mean weight 37.61 kg +/- 9.80 SD, were treated with clomipramine at a mean dosage of 57.69 mg +/- 25.79 SD; 10 patients, mean weight 40.90 kg +/- 6.98 SD, were treated with fluoxetine at a mean dosage of 28.00 mg +/- 10.32 SD; 12 patients, mean weight 38.41 kg +/- 8.33 SD, were treated with amisulpride at a mean dosage of 50.00 mg +/- 0.00 SD. 3. Clinical evaluation was carried out under single-blind condition at basal time and after three months by a structured clinical interview, the Eating Disorder Interview based on Long Interval Follow-up Evaluation (LIFE II BEI). 4. Patients treated with amisulpride showed a more significant increase (p=0.016) of mean weight. Concerning weight phobia, body image disturbance and amenorrhoea, no significant difference resulted.

Eighty-one panic disorder patients with or without agoraphobia were treated with flexible doses of clomipramine under single-blind conditions. Fifty-seven (70.3%) reached operational criteria for full remission in 16.2 +/- 6.5 weeks, with a mean dose of 89.1 +/- 8.2 mg/day. Fifty-four (81%) of them received a continuous post-remission maintenance treatment at full doses of clomipramine for 4-6 months. No patient relapsed during the clomipramine maintenance phase. Their medication was then tappered and discontinued with placebo substitution under double-blind conditions. Fifty-one (63%) patients were followed-up until relapse or recurrence for up to 3 years, with periodic assessments. Three different outcome groups were identified: the first (n = 19, 19; 37.2%) experienced an early/immediate relapse (5.2 +/- 4.9 weeks after drug discontinuation); the second group (n = 22, 22; 43.1%) experienced recurrence after 42.9 +/- 35 weeks following discontinuation; and the third group (n = 10, 10; 19.6%) remained assymptomatic and functionally well throughout the follow-up. Predictors of early relapse were: (1) higher baseline score in the Beck Depression Inventory; (2) higher global score on the phobic avoidance scale after the full remission criteria; and (3) the need for higher clomipramine doses to reach full remission. The need for long-term or intermittent maintenance for most patients is emphasized.

Several recent reports suggest the possibility of monitoring pharmacological effects on brain excitability through transcranial magnetic stimulation (TMS). In these studies, paired magnetic stimulation has been used in normal subjects and on patients who were taking different antiepileptic drugs. The aim of our study was to investigate motor area excitability on depressed patients after intravenous administration of a single dose of clomipramine, a tricyclic antidepressant. Motor cortex excitability was studied by single and paired transcranial magnetic stimulation (TMS) before and after 4, 8 and 24 h from intravenous administration of 25 mg of clomipramine. Cortical excitability was measured using different TMS parameters: motor threshold (MT), motor evoked potential (MEP) amplitude, duration of cortical silent period (CSP), intracortical inhibition (ICI) and intracortical facilitation (ICF). Spinal excitability and peripheral nerve conduction was measured by F response and M wave. A temporary but significant increase of motor threshold and intracortical inhibition and a decrease of intracortical facilitation were observed 4 h following drug administration. MEP amplitude, cortical silent period, F response and M wave were not significantly affected by drug injection. Our findings suggest that a single intravenous dose of clomipramine can exert a significant but transitory suppression of motor cortex excitability in depressed patients. TMS represents a useful research tool in assessing the effects of motor cortical excitability of neuropsychiatric drugs used in psychiatric disease.

In this study, the pharmacokinetic parameters of the sustained-release (SR) dosage form of clomipramine (CMI) were compared with those obtained after the administration of the immediate-release (IR) dosage form. Two studies were performed. In the first study, a single oral dose of both products was administered in 12 healthy volunteers, and in the second study, multiple doses of both products were administered in 6 patients with depression in which steady-state plasma levels (Css) were determined. Plasma levels were assayed using an HPLC method. In the single-dose study, the mean Cmax and AUC values of CMI were 63.37 ng/mL-1 and 1375.38 ng.h/mL-1 for the reference product and 32.55 ng/mL-1 and 1285.26 ng.h/mL-1 for the test product, respectively. The mean beta and MRT values of CMI were 0.030 h-1 and 47.21 h for the reference product and 0.026 h-1 and 55.63 h for test product, respectively. Results showed that after the multiple-dose study, the mean clomipramine plus demethylclomipramine values of Cavss were 406.2 ng/mL-1 for the reference and 328.6 ng/mL-1 for the sustained-release dosage form. This product also presented less fluctuation in steady-state plasma levels (1.08 vs. 1.23). The values of MRT and tmax were higher for the SR dosage form, showing that the drug was maintained longer in the body. The mean values for the ratio metabolite/drug were 2.06 and 2.41 for the IR and SR dosage forms, respectively. Neither AUC nor elimination half-life was affected significantly after the administration of the sustained-release dosage form.

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.

Objective: To determine the effects of clomipramine hydrochloride on heart rate and rhythm in dogs., Animals: 17 healthy Beagles., Procedures: In experiment 1, 8 dogs received placebo or clomipramine (20 mg/kg of body weight, q 24 h, PO) for 7 days in a 2-way crossover design. In experiment 2, 9 dogs were evaluated for 48 hours before and 24 hours after oral administration of clomipramine (4 or 12 mg/kg) in a 2-way crossover design. Electrocardiogram and heart rate were monitored continuously by use of telemetry., Results: A significant diurnal rhythm in heart rate was detected; minimum values were recorded at night. Administration of 20 mg of clomipramine/kg induced a significant reduction in heart rate, with peak effect achieved approximately 12 hours after dosing. Administration of 4 or 12 mg of clomipramine/kg did not result in significant changes in heart rate. Sinoatrial and second-degree atrioventricular block and ventricular escape beats were observed during periods of slow heart rate in more dogs that received clomipramine (3 to 4 of 8 dogs), compared with dogs that received placebo (1 to 2 of 8 dogs), but this difference was not significant., Conclusions and Clinical Relevance: Short-term administration of clomipramine induced benign cardiovascular effects in dogs rather than the potentially dangerous arrhythmias or tachycardia reported following administration of tricyclic antidepressants to humans. Precautions regarding cardiovascular effects may not be needed for the use of clomipramine in healthy dogs.

Objective: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs after IV or oral administration of a single dose., Animals: 6 male and 6 female Beagles., Procedures: Clomipramine was administered IV (2 mg/kg), PO (4 mg/kg) after food was withheld for 15 hours, and PO (4 mg/kg) within 25 minutes after dogs were fed. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method., Results: Time to peak plasma concentrations of clomipramine and desmethylclomipramine following oral administration was 1.2 hours. For clomipramine, after IV administration, elimination half-life was 5 hours, mean residence time was 3 hours, and plasma clearance was 1.4 L/h/kg. Values for mean residence time and terminal half-life following oral administration were similar to values obtained following IV administration, and systemic bioavailability was approximately 20% for clomipramine and 140% for desmethylclomipramine, indicating fast absorption of clomipramine from the gastrointestinal tract and extensive first-pass metabolism. Administration of clomipramine with food did not alter the area under the concentration versus time curve for desmethylclomipramine but resulted in a 25% increase for clomipramine. Clomipramine and desmethylclomipramine were extensively bound (> 96%) to serum proteins. There were no significant differences in area under the concentration versus time curve between male and female dogs., Conclusions and Clinical Relevance: Results indicate that there should not be any clinically important differences in efficacy regardless of whether clomipramine is administered with or without food.

Objective: To determine pharmacokinetics of clomipramine and its principle metabolite (desmethylclomipramine) in the plasma of dogs following single-dose and repeated-dose oral administration at various dosages., Animals: 9 male and 9 female Beagles., Procedures: Clomipramine was administered orally at a dose of 1, 2, or 4 mg/kg to 3 male and 3 female dogs, first as a single dose and then, after an interval of 14 days, twice daily for 10 days. Plasma clomipramine and desmethylclomipramine concentrations were measured by use of a gas chromatography with mass-selection method., Results: Dose-related accumulation was detected following repeated-dose administration. Accumulation ratios after administration of clomipramine at dosages of 1, 2, and 4 mg/kg twice daily were 1.4, 1.6, and 3.8, respectively, for clomipramine and 2.1, 3.7, and 7.6, respectively, for desmethylclomipramine. Terminal half-life increased slightly (1.6-fold for clomipramine and 1.2-fold for desmethylclomipramine) with repeated-dose administration but remained short in all groups (< or = 4 hours). Steady state was reached within 4 days in all animals. Ratios of the areas under the concentration versus time curves from time 0 to 12 hours for clomipramine and desmethylclomipramine were 3.9, 3.1, and 1.5 after repeated administration at dosages of 1, 2, and 4 mg/kg every 12 hours, respectively. Areas under the concentration versus time curve, mean residence times, and terminal half-lives were not significantly different between male and female dogs., Conclusions and Clinical Relevance: Repeated administration of clomipramine results in higher concentrations of clomipramine than desmethylclomipramine in dogs.

The aim of the study was to compare in male NMRI mice the simultaneous evolution of blood serotonin (5-HT) concentrations, which correspond to 99% of platelet 5-HT content, and 5-HT parameters in the dorsal raphe, caudate nucleus and frontal cortex after clomipramine, fluoxetine and moclobemide treatments. After steady-state concentrations of the three compounds were reached, the 5-HT levels were significantly enhanced vs. saline-treated mice in the three brain areas studied. Tryptophan (TRP) levels in the three brain areas were significantly increased with clomipramine and fluoxetine but not with moclobemide. A significant decrease in the metabolite 5-hydroxyindoleacetic acid (5-HIAA) levels was observed only with moclobemide. After 14 days of treatment, 5-HT levels in all areas studied were found to be enhanced only with moclobemide while TRP and 5-HIAA levels were not different under the three drug regimes from those of controls. After 21 days of treatment, 5-HT levels were found enhanced only with moclobemide in the nerve terminal regions. An important depletion in platelet 5-HT content was observed after clomipramine and fluoxetine treatments at day 14 and day 21 and a significant increase was observed after moclobemide treatment at day 14 with a return to initial values after 21 days. Our results show significantly different effects between central and peripheral indices of 5-HT metabolism according to time and to the antidepressant assessed: (i) an enhancement of total tissue 5-HT levels in the three brain areas studied after steady-state achievement of the 3 antidepressants, (ii) the return to initial values of brain 5-HT levels after repeated administration of the two 5-HT re-uptake inhibitors, consistent with the presence of brain adaptative mechanisms, with a concomitant dramatic decrease of platelet 5-HT content and (iii) an apparent gradual attenuation of the brain and periphery MAOI-A effect induced by moclobemide with 5-HT levels remaining elevated only in 5-HT nerve terminal regions.

This study examined the absorption and disposition of clomipramine in rats after sublingual (5 and 50 mg/kg), oral (50 mg/kg), and iv (5 mg/kg) administration. The mean oral bioavailability of clomipramine was 24.8% and 29.7%, respectively, in conscious rats and in rats anesthetized with ketamine/xylazine (30/3 mg/kg). When given sublingually in isotonic saline at a dose of 50 mg/kg, clomipramine was rapidly absorbed, and the mean absolute bioavailability (36.2%) was increased over oral dosing. The mean AUC values of clomipramine were 2258 +/- 1762 ng.h/mL and 1891 +/- 867 ng.h/mL after oral administration to conscious and anesthetized rats, respectively, and 3303 +/- 1576 ng.h/mL after sublingual administration to anesthetized rats. Sublingual administration (5 mg/kg doses) of clomipramine formulated with a permeation enhancer, 2-hydroxypropyl beta-cyclodextrin, further increased the sublingual bioavailability to 57.1%. The sublingual route may be an alternative route of administration of clomipramine, providing enhanced bioavailability.

The cognitive potential, P300, is a phenomenon frequently studied in relation to template matching of the brain. To understand the neurochemical mechanisms of its generation, we compared the effects of three antidepressants, fluoxetine, tianeptine and clomipramine after single and repeated application as well as after 1 week of withdrawal on the P300 and N200 waves in an auditory 'odd-ball' paradigm in three parallel groups of 10 healthy volunteers. Following single administration, both fluoxetine and clomipramine reduced (-39 +/- 14%, p < 0.01) the peak amplitude of P300 at the Pz electrode. For fluoxetine and tianeptine, reduced amplitudes of 19 +/- 7% and 24 +/- 11%, respectively, were found following 8 days of treatment, 2 h after administration. However, for clomipramine no additional diminution was found on day 8 with respect to day 1. Topographic distributions tended to be significantly modified at the frontal scalp area 1 h after the tianeptine administration on day 8, whereas the postdosing changes induced by fluoxetine were localised in the midline and right centrotemporal scalp regions. Only minor reductions in peak latencies have been observed. It can be concluded that serotonin selective drugs have a slower onset of P300 amplitude decrease than clomipramine, which has additional effects on monoaminergic and on cholinergic systems. These results suggest that serotonin has a regulatory function in the neurotransmission of cerebral structures which are involved in the evaluation of stimulus relevance.

Forty-nine dogs showing signs of separation-related problems were randomly assigned to one of three groups: group A (15 dogs) received a placebo twice daily; group B (17 dogs) received clomipramine at 0.5 to 1.0 mg/kg twice daily; and group C (17 dogs) received clomipramine at 1.0 to 2.0 mg/kg twice daily. All the dogs also received behavioural therapy. Their owners were required to complete questionnaires about their dog's behaviour initially, and one, four and eight weeks after the treatment with clomipramine began. Bipolar ratings scales were used to monitor the frequencies of 'general', 'attachment-related' and 'separation-related' behaviours. Kruskal-Wallis tests and Kendall Rank correlations were used to determine any initial differences between the treatment groups, and the association between the initial scores and behavioural changes after one week of treatment with clomipramine. Extended Mantel-Haenszel statistics were used to evaluate the effects of clomipramine treatment versus the placebo, and Page's test was used to assess the effectiveness of behavioural therapy on its own. There were no significant differences in the demographic characteristics of the owners of the dogs assigned to the three groups. The dogs differed slightly in age between groups, and the dogs in the two clomipramine-treated groups were reported as showing problems at a significantly earlier age than those in the placebo group. Clomipramine treatment had a sustained suppressive effect on the dogs' general activity levels, and a more modest suppressive effect on their attachment-related tendency to want much physical contact with their owners. The typical signs of separation-related behaviour problems were not significantly affected by treatment with clomipramine, but behavioural therapy on its own was highly effective in reducing behavioural problems.

Objective: To examine the problems of establishing dose-effect and concentration-effect relationships of antidepressant therapy with clomipramine., Methods: This randomized double-blind study compared five fixed doses of clomipramine hydrochloride: 25, 50, 75, 125, and 200 mg/day in hospitalized or day patients at nine clinical centers in Denmark. A 1-week washout period was followed by 6 weeks of active treatment and weekly depression ratings. In total, 151 patients (100 women and 51 men) with major depression scoring > or =18 on the Hamilton Depression Scale (HDS) or > or =9 on the Hamilton Depression subscale (HDSS) before and after the washout period were randomized. The treatment groups (n = 29 to 32) were well balanced with respect to sex, age, and depression rating. Serum concentrations of clomipramine plus metabolites were measured at weekly intervals. A sparteine test was performed before and during drug treatment., Results: There was pronounced interpatient variability in response and kinetics at each dose. Drop-outs attributable to adverse events increased with rising doses, whereas drop-outs caused by worsening or lack of effect or nonresponse declined with increasing dose. Completer analyses showed a moderate and statistically significant relationship between depression rating and dose at all ratings after 1 to 6 weeks of treatment (trend analysis). HDS items representing core symptoms of depression showed a particularly consistent dose-effect relationship. Early sustained response occurred more frequently with the two highest doses. Serum levels of clomipramine and desmethylclomipramine showed weak correlation with depression ratings (Rs = -0.18 to -0.27; P < .05 to P < .01). A few blood pressure measurements and a few typical side-effect ratings showed a statistically significant dose-effect and concentration-effect relationship. Serum concentration of clomipramine and desmethylclomipramine showed a pronounced disproportionate increase with increasing dose. Clomipramine inhibited in a dose-dependent fashion CYP2D6 (sparteine oxidation)., Conclusion: The dose-effect curves, indicating the probability of a certain outcome at a given dose, were flat and overlapping suggesting a narrow therapeutic range. This pattern is similar to that observed with newer antidepressants.

A 79-year-old woman was admitted due to increasing dizziness during the past six days. She had been treated with clomipramine 75 mg daily for years, and in addition had received paroxetine 20 mg daily for the last eight days. Both drugs were terminated and the symptoms disappeared. Thirty-six hours after taking the last drugs, the S-clomipramine plus S-desmethylclomipramine were 790 mmol/l. The symptoms were probably related to this high serum level caused by interaction with paroxetine.

Clomipramine is a tricyclic antidepressant that has been recommended for the treatment of canine compulsive disorder. The pharmacokinetics of clomipramine in dogs have not been reported. This study describes the pharmacokinetics of clomipramine and its active metabolite, desmethylclomipramine, in six male dogs. Serial blood samples were collected following both a single oral dose of clomipramine (3 mg/kg) and 28 consecutive daily oral doses (3 mg/kg q 24 h). In addition, 'peak' and 'trough' samples were taken throughout the 28-day dosing period. Plasma was assayed for total (free and protein-bound) clomipramine and desmethylclomipramine, using gas-chromatography with mass spectrometric detection. Various pharmacokinetic parameters were then determined. Following a single dose of clomipramine, time of maximum plasma concentration (tmax) of clomipramine was 0.75-3.1 h, maximum plasma concentration (Cmax) was 16-310 ng/mL and elimination half-life (t1/2el) was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/ mL and t1/2el was 1.2-2.3 h. Following multiple dosing, there was a numeric increase in these parameters; tmax of clomipramine was 3-8 h, Cmax was 43-222 ng/mL and t1/2el was 1.2-16 h; tmax of desmethylclomipramine was 1.4-8.8 h, Cmax was 21-134 ng/mL and t1/2el was 1.2-2.3 h. Clinically significant differences between dogs and humans in the pharmacokinetics of oral clomipramine are discussed.

Objective: We compared gradually increased to pulse loaded doses of open-label, intravenous clomipramine (CMI) in patients with obsessive-compulsive disorder (OCD)., Method: We treated adult outpatients with DSM-III-R OCD, who had no prior exposure to effective treatments. Pulse loading patients received 150 mg on day 1; 150 mg or 200 mg on day 2. Gradual dosing patients received 25 mg per day increased to 200 mg per day over 2 weeks and then continued for a mean of 43 days (n=40). After i.v. dosing, all patients received oral CMI; the total treatment period was 6 months., Results: Pulse loading completers (n=7) had a rapid, dramatic response (mean Y-BOCS score decrease of 32% five days after pulse-loading). At this point (day 7), completers in the gradual intravenous group (n=20) exhibited no mean change in Y-BOCS score. The pulse loading group reached both a 25% or greater and a 50% or greater decrease in Y-BOCS score statistically and clinically significantly faster than the gradual group., Conclusions: Pulse-loaded intravenous CMI for the treatment of OCD deserves further study.

In this Research Review, several recent clinical trials in panic disorder and social phobia are reviewed. First, two social phobia studies which used the monoamine oxidase type A inhibitors brofaromine and moclobemide are considered. Then, three panic disorder studies which used clonazepam, clomipramine or paroxetine, and citalopram are examined. These studies serve to strengthen the empirical research base regarding which treatments are useful in these disorders.

Background: Controlled trials suggest that clomipramine may be a highly effective antipanic drug. Lowering the starting dose may alleviate troublesome initial side effects and increase acceptability and compliance., Method: Fifty-eight patients with DSM-III-R panic disorder with or without agoraphobia underwent 13 weeks of clomipramine treatment. Starting at 10 mg/day, the dose was gradually increased to a mean dose of 97 mg/day., Results: While completers showed highly significant improvement, the benefits were severely limited by a high dropout rate due to adverse reactions occurring mostly during the first 2 weeks of treatment., Conclusion: Given the alternatives, clomipramine should not be used as a first-line antipanic medication.