Mood disorders in eating disorder patients: Prevalence and chronology of ONSET.

OBJECTIVES: In a clinical population, we estimated the frequency of mood disorders among 271 patients suffering from Anorexia Nervosa (AN) and Bulimia Nervosa (BN) in comparison to a control group matched for age and gender. METHOD: The frequency of mood disorders was measured using the Mini International Neuropsychiatric Interview (MINI), DSM-IV version. RESULTS: Mood disorders were more frequent among eating disorder (ED) patients than among controls, with a global prevalence of the order of 80% for each ED group. The majority of the mood disorders comorbid with ED were depressive disorders (MDD and dysthymia). The relative chronology of onset of these disorders was equivocal, because mood disorders in some cases preceded and in others followed the onset of the eating disorders. LIMITATIONS: Our sample was characterized by patients with severe ED and high comorbidities, and thus do not represent the entire population of AN or BN. This also may have resulted in an overestimation of prevalence. CONCLUSION: Mood disorders appear significantly more frequently in patients seeking care for ED than in controls. These results have implications for the assessment and treatment of ED patients, and for the aetio-pathogenesis of these disorders.

[Are anxiety or depressive disorders more frequent among one of the anorexia or bulimia nervosa subtype?]. / La fréquence des troubles anxio-dépressifs diffère-t-elle entre les types diagnostiques d'anorexie mentale et de boulimie?

UNLABELLED: Our objective was to answer the following question: are there differences between diagnostic groups of eating disorders (ED) for the prevalence of depressive and anxiety disorders, when clinical differences between the groups are taken into account (ie age of subjects, ED duration, inpatient or outpatient status, and Body Mass Index)? METHOD: We evaluated the frequency of anxiety disorders and depressive disorders in 271 subjects presenting with a diagnosis of either anorexia nervosa or bulimia, using the Mini International Neuropsychiatric Interview (MINI), DSM IV version. We compared the prevalences between sub-groups of anorexics (AN-R and AN-BN), between sub-groups of bulimics (BN-P and BN-NP) and between anorexics and bulimics while adjusting for the variables defined below. RESULTS: Current or lifetime comorbidity of anxiety and depressive disorders did not differ between AN-Rs and AN-BNs, nor between BN-Ps and BN-NPs. Only current diagnoses of agoraphobia and obsessive-compulsive disorder were significantly more frequent in anorexics than in bulimics. CONCLUSION: The greater frequency of comorbidity between obsessive-compulsive disorder and AN compared to BN, already well documented, is not questioned. The remaining anxiety disorders are equally frequent among all the diagnostic types of ED.

[Is depressive disorder linked to anxiety disorder among anorexics and bulimics?]. / L'existence d'un épisode dépressif majeur est-elle liée à la présence de troubles anxieux chez les anorexiques et les boulimiques?

UNLABELLED: The primaty objective is to determine whether the presence anxiety disorders is related to depressive comorbidity in subjects suffering from ED, while taking into account certain variables which may be related to depression [subjects' age, ED duration, prior incidents of anorexia nervosa in BN subjects, inpatient or outpatient status, nutritional state (as measured by Body Mass Index or BMI)]. Our secondary objective is to evaluate the relative chronology of the onset of anxiety disorders and depressive disorders in anorexic and bulimic subjects. METHOD: We evaluated the frequency of depressive disorders in 271 subjects presenting with a diagnosis of either anorexia nervosa or bulimia, using the Mini International Neuropsychiatric Interview (MINI), DSM IV version. RESULTS: While univariate analyses show that nearly all anxiety disorders are related to major depressive episode (MDE), a separate analysis of each anxiety disorder reveals that they do not all have the same influence in terms of risk of onset of MDE in anorexics and bulimics, when adjusted for univariate variables related to MDE (subjects' age, ED duration, prior incidents of anorexia nervosa in BN subjects, inpatient or outpatient status, nutritional state). Current generalized anxiety is significantly related to lifetime presence of MDE in AN subjects, and to current MDE in AN and BN subjects. Generalized anxiety is the most frequent disorder in AN and BN subjects to according our study; it also appears to be one of the principal predictive factors for MDE, which is 2.4 to 4.2 times more frequent when GAD is present. Diagnosis of OCD has its own particular effect on lifetime risk for MDE in AN subjects, regardless of GAD: it increases the risk of depression by 3.5. It is one of the most frequent anxiety disorders among AN subjects, present in nearly a quarter of them. In bulimics, when GAD is excluded, two factors are related to current diagnosis of MDE: panic disorder and subjects' inpatient or outpatient status. Hospitalized bulimics are diagnosed with current MDE 4.4 times more often than those seen as.

[Alexithymia, depression and drug addiction]. / Alexithymie et toxicomanie:

Alexithymia is a multidimensional concept associating an emotional component focused on the difficulty in identifying and describing feelings and a cognitive one centred on the use of a concrete and poorly introspective way of thinking. Alexithymia can be assessed by self-assessment instruments and in particular by the 20 items version of the Toronto Alexithymia Scale (TAS-20). Depressive disorders have complex relationships with the construct of alexithymia and there exist few experimental works on the subject. Epidemiological studies frequently raise an overlap between alexithymia and depression, in particular in the context of addiction. The main aim of this study was to confirm the high prevalence of alexithymia among drug addicted patients taking into account socio-demographic variables (sex, age, social and economic categories). The second aim of the study was to investigate the relationships between alexithymia and depression among drug addicted patients. A sample of 128 drug addicted patients answering DSM IV criteria of dependence to a psycho-active substance (alcohol excluded) was paired according to socio-demographic variables to a control sample of 128 normal subjects. Diagnostic assessment was made using the Mini International Neuropsychiatric Interview (MINI). Alexithymia and depression were assessed with the TAS-20 and with the short version of the Beck Depression Inventory (BDI-13). The results confirm the high prevalence of alexithymia among drug addicted patients (43.5%) compared to controls (24.6%). This difference is based namely on the emotional component of alexithymia, the cognitive component failing to show any difference between the two samples. Moreover, alexithymia appears to be independent from socio-demographic variables in our sample of drug addicted patients; 66.4% of drug addicted patients presents a depressive symptomatology (which is significantly more important in female patients), compared to 26% of the controls. Studies using the TAS and the BDI with 21 items have shown that from 10 to 20% of the variance of alexithymia is explained by depression. Our own results show a shared variance of 20% between the TAS-20 and the BDI, going in the direction of a moderated correlation between alexithymia and depressive symptomatology. Moreover, when we retain only subjects without depressive symptomatology at BDI, drug addicted (n=42) are not any more alexithymic than controls (n=114). Our results plead for a positive association between depression and alexithymia in drug addicted, depressed or healthy subjects. Alexithymia and depression would be two associated dimensions, the emotional component explaining alone this association. The emotional component of the alexithymia would be thymo-dependent, whereas the cognitive component (externally oriented thought) would be independent and constitute a stable clinical feature. These results are concordant with other studies in the literature suggesting that alexithymia in its emotional component is supported by depression. Alexithymia thus did not appear as an autonomous dimension which would discriminate between drug addicted and controls, independently of the absence of a depressive state. The Authors discuss the complexity of the relationships between alexithymia and depression and the correlations between TAS and BDI scales especially for the factor Difficulty Identifying Feelings. These results deserve further studies. The cross-sectional nature of this study do not allow to establish if alexithymia is a subjacent and preexistent in the form of a psychopathological dimension in addictive behaviours, so supporting its emergence, and/or if it develops once the dependence is installed and chronicized. Longitudinal studies remain to be realised.

Predictive factors of social disability in anorexic and bulimic patients.

OBJECTIVES: The purpose of this study was to determine whether subjects suffering from anorexia nervosa (AN) or bulimia nervosa (BN) would demonstrate more severe social disability than a control group; and whether social disability could be best explained as a function of the eating disorder itself or as a function of comorbid anxiety or depressive disorders. METHOD: Subjects were 166 AN subjects, 105 BN subjects and 271 control subjects matched for age, sex and socio-economic status. Prevalence of anxiety or depressive disorders was assessed (through the Mini International Neuropsychiatric Interview), and social functioning was measured (through the Groningen scale). RESULTS: The majority of AN and BN subjects demonstrated social disability in the "social role" (leisure time, time spent with friends) and the "occupational role" (work or educational activities). A regression analysis was employed to uncover predictive factors of social disability. Eating disorders (AN and BN), anxiety disorders and depression accounted for a large portion of social disability. DISCUSSION: Anxiety and depressive disorders appear to play an important role in the type of social disability demonstrated in eating disorder patients. Therapeutic implications are discussed.

[Validation study of the Depressive Experience Questionnaire]. / Etude de validation du Depressive Experience Questionnaire.

Sidney Blatt, considering as being insufficient the categorical-symptomatic approach of depression, has worked out a theory of depression and psychopathology that integrates the contributions of psychoanalysis as well as cognitive and developmental psychology. Within a broad psychoanalytic framework, Blatt's formulation focus on the quality of interpersonal relationship, the nature of object representation and early life experiences. Personality development is viewed as the consequence of the interaction of 2 basic developmental tasks: the establishment of the capacity to form stable, enduring, mutually satisfying interpersonal relationships and the achievement of a differentiated, realistic, essentially positive identity. The relationship between these 2 developmental lines involves a complex dialectical process during which progress in each line is essential for progress in the other and which contributes to the development of both a sense of identity and the capacity for interpersonal relatedness. These developmental lines permit not only to define an during individual's primary personality configuration but also enable to identify cognitive structures that are inherent in various forms of psychopathology, including depression. Disruptions at different developmental stages create vulnerability to different subsequent psychological disturbances. Blatt characterised as anaclitic or dependent the axis concerned with interpersonal relationship and as introjective or self-critical the axis concerned with development of the sense of self and identity. Depressive Experience Questionnaire was developed by Blatt et al. to determine the validity of this model of psychopathology which emphazises continuities between normal and pathological forms of depression. The instrument was developed by Blatt et al. by assembling a pool of items describing experiences frequently reported by depressed individual. Sixty-six items were selected and administered to a large nonclinical sample (500 female and 160 male undergraduates). Principal component analysis within sex performed on the answers to DEQ confirmed his assumption in identifying two principal depressive dimensions. The first factor involved items that are primarily externally directed and refer to a disturbance of interpersonal relationships (anaclitism); the second factor consists of items that are more internally directed and reflect concerns about self-identity (self-criticism). A third factor emerged, assessing the good functioning of subject and confidence in his resources and capacities (efficacy). Scales derived from these factors have high internal consistency and substantial test-retest reliability. The solutions for men and women were highly congruent. Factor structure has been replicated in several nonclinical and clinical samples, supporting considerable evidence to the construct validity of the DEQ Dependency and Self-criticism scales. An adolescent form of DEQ (DEQ-A) has successively been developed. Factor analysis revealed three factors that were highly congruent in female and male students and with the three factors of the original DEQ. The reliability, internal consistency and validity of DEQ-A indicate that the DEQ-A closely parallels the DEQ, especially in the articulation of Dependency and Self-criticism as two factors in depression. These formulations and clinical observations about the importance of differentiating a depression focused on issues of self-criticism from issues of dependency are consistent with the formulations of others theorists which, from very different theoretical perspectives, posit 2 types of depression, one in which either perceived loss or rejection in social relationships is central and the other in which perceived failure in achievement, guilt or lack of control serves as the precipitant of depression. These 2 types of experiences have been characterized as dominant other and dominant goal , as anxiously attached and compulsively self-reliant and as sociotropic and autonomous . Our work presents the results of a validation study of both forms of Blatt's questionnaire (for adults--DEQ--and for adolescents--DEQA) translated in French in a large population of normal subjects, aged 15 to 45 years. DEQ and DEQ-A were compared by inspection of items loading strongly on each factor and by correlation of the three factors of adults and adolescents. The exploratory factor analysis of DEQ and DEQA revealed three orthogonal factors, corresponding with Blatt's original dimensions. Consistency and external validity were adequate for all 3 factors of DEQ and DEQ-A. Anaclitism and self-criticism dimensions of DEQ and DEQ-A correlate positively with measures of depression (DSM-IV, Beck Depression Inventory), consistently with the results obtained by Blatt. Differently from this author, anaclitism appears to be less differentiated in males than in females, suggesting that the concept of dependence could assume different relevance for men and women.

[Psychoactive drug use in a declared non-addicted control sample and comorbidity. Results of a study in 860 French-speaking subjects]. / Consommation de substances psycho-actives dans une population témoin déclarée non addictive et co-morbidité. Résultats d'une étude chez 860 sujets francophones.

AIMS: This study, conducted within the framework of a broader research program of the INSERM 494013 Dependence Network, was designed to estimate illicit drug use and tobacco smoking in a declared non-addicted sample and to determine whether illicit drug users differ from non-users in terms of comorbidity. METHODS: The study was conducted in an "all and sundry" sample of subjects. Patterns of drug use and comorbid factors (psychiatric disorders, suicide attempts, repeated accidents, social inadaptation) were assessed using a semi-structured interview (heteroevaluation, MINI DSM IV interview, Gröningen). RESULTS: Among 860 subjects, 107 (12.4%) used illicit drugs and 26 of these 107 (24.3%) were dependent users or abusers. Specific analysis of non-dependent non-abuser subjects who had used illicit drugs (70 occasional and 11 regular users) showed a higher rate of use in younger subjects (12.7% in the 15-24 year group, 5.7% in the 24-49 year group) and men. Except for repeated accidents (OR=5.5 [1.6-18.5]), comorbid disorders were not more frequent in non-users than in users. CONCLUSION: Besides use for recreational purposes, the rate of use of illicit drugs with abuse or dependence was high in our non-clinical sample. Although no specific comorbid psychiatric disorders were identified among non-dependent non-abuser subjects who had used illicit drugs, the frequency of repeated accidents evidenced the ill-fated side effects of illicit drugs and/or the specific biopsychological vulnerability of these subjects. This highlights the importance of not neglecting drug abuse.

Factorial structure of the 20-item Toronto Alexithymia Scale: confirmatory factorial analyses in nonclinical and clinical samples.

OBJECTIVE: The 20-item Toronto Alexithymia Scale (TAS-20) measures three intercorrelated dimensions of alexithymia: (1) difficulties identifying feelings (DIF), (2) difficulties describing feelings (DDF), and (3) externally oriented thinking (EOT). The aim of the study was to test the three-factor model of the TAS-20 using confirmatory factorial analyses (CFA). METHOD: 769 healthy subjects and 659 patients meeting the DSM-IV criteria for substance use disorders or eating disorders completed the TAS-20. The correlation matrices for each of the samples were analyzed with LISREL 7.16. RESULTS: In each sample, the three-factor model was found to be replicable. CONCLUSION: The three TAS-20 subcales can be used to explore the distinct facets of the alexithymia construct.

Psychoactive substance consumption in eating disorders.

Research investigating the comorbidity between eating disorders and substance-use disorders have reported positive but contrasting results. The aim of this study was to further explore this association by studying patterns of consumption of the entire range of psychoactive substances (alcohol, specific drugs, prescribed psychotropics) in a large sample (N=271) of eating-disorder DSM-IV subtypes. Results show that subjects suffering from anorexia of the restrictive type show significantly less drug-consumption behaviors and alcohol abuse and/or dependence disorders than purging anorexic and bulimic subjects. No difference was found in the total consumption of psychotropics among the four groups of eating disorders. However, more than half of eating-disorder subjects are regular consumers of psychotropics. Among these regular consumers, bulimics self-prescribe and increase their doses of psychotropics significantly more than anorexics. Features of impulsivity that are associated with purging and bulimic behaviors could play a specific role in these patterns of comorbidity and account for such differences.

Factorial structure of the Sensation-Seeking Scale-Form V: confirmatory factorial analyses in nonclinical and clinical samples.

OBJECTIVE: The factor structure of the Sensation-Seeking Scale (SSS)-Form V was studied in 2 large French samples, using confirmatory factorial analyses (CFA) to test the 4-dimensional model of sensation seeking postulated by Zuckerman. METHOD: The study included 769 healthy subjects and 659 patients who met the DSM-IV criteria for substance use disorders or eating disorders and completed the SSS. The correlation matrices for each of the samples were analyzed using CFA. RESULTS: In each sample, we found the 4-factor model to be replicable. CONCLUSION: The multidimensionality of sensation seeking is supported by the results, and the 4-dimensional model of sensation seeking identified by Zuckerman can be explored in French-speaking people.

Population pharmacokinetics of clomipramine, desmethylclomipramine, and hydroxylated metabolites in patients with depression receiving chronic treatment: model evaluation.

Because metabolites play a major role in the clinical response to clomipramine, the objective of the current study was to develop a population model and evaluate its performance to describe the pharmacokinetic profiles of clomipramine (C) and its active metabolites desmethylclomipramine (DC), 8-hydroxy-clomipramine (OHC) and 8-hydroxy-desmethylclomipramine (OHDC). A first sample of 14 patients served for development of a 2-molecule C and DC model, which was shown to provide reasonable estimates of AUC-based clearances, as well as precise estimation of interindividual variability. Simulated data, generated to mimic a semi-rich sampling design and chronic treatment with clomipramine, indicated that clearance estimation was feasible under routine treatment conditions. A second sample of 30 patients, recruited prospectively and followed for a median 4-week period, was used to extend the 2-molecule model to a 4-molecule model. Goodness-of-fit assessment revealed that model-predicted concentrations were reasonably close to observed concentrations for a majority of patients. Interindividual variability was 50% to 60% for hydroxylation and desmethylation clearances, and residual variability was 30%. The proposed model incorporates much of what is known about the metabolism of clomipramine and may valuably integrate the influence of genetic and environmental factors on each metabolic pathway.

[Pertinence of the addiction concept in eating behavior disorders]. / Pertinence du concept d'addiction dans les troubles des conduites alimentaires.

From a psychodynamic perspective, dependence disorders, irrespective of the object of addiction, can be seen as the expression of the subject's neurobiological, psychopathological, cultural and social vulnerability. Since vulnerability strengthens and reorganizes the personality, it can drive these subjects to perpetuate pathological behaviors. In this light, behavior disorders belong to the field of addiction diseases, especially considering that the underlying psychopathological structures are close to those observed in addiction, that depression plays a central role, and that their development into toxic addictive behavior (drugs, alcohol, psychotrope) is frequent.

Drug extrapyramidal side-effects or not: is there a dextromethorphan phenotype difference?

A recent hypothesis suggests the possible role of cytochrome P450 2D6 (CYP2D6) polymorphism (involved in the metabolism of a large number of drugs), as a potential risk factor for the development of extrapyramidal side-effects of psychotropic drugs. The CYP2D6 metabolizer phenotype (dextromethorphan test) of 31 drug treated psychiatric adult patients suffering from extrapyramidal side-effects (group 1) and of 31 matched patients without drug side effects (group 2) were compared. In the first group, 13 poor metabolizer patients (41.9 per cent) were found, characterized by a dextromethorphan metabolic ratio > 0.3, and only two patients in the second group (6.4 per cent). These data provide some support for the notion that in subjects in whom CYP2D6 is probably saturated, the risk of drug extrapyramidal side-effects may be increased. In such patients the choice of psychotropic drugs 'without' this risk must be preferred.

[Extrapyramidal side effects of neuroleptic and antidepressant treatment: assessment of potential risk factors through CYP2D6 genetic polymorphism]. / Effets indésirables extrapyramidaux des neuroleptiques et antidépresseurs--recherche de facteurs de risque: rôle du polymorphisme génétique du CYP2D6.

The objective of this study was to assign metabolizer phenotype (cytochrome P450 2D6 or CYP2D6) to drug treated psychiatric adult patients to assess if the CYP2D6 polymorphism could be a potential risk factor for the development of extrapyramidal side effects of psychotropic drugs. Twenty-eight unrelated in-patients (16 men and 12 women) treated with antidepressants and/or antipsychotic drug were phenotyped using dextromethorphan. Two groups of patients were considered depending on the presence (n = 14) or not (n = 14) of extrapyramidal side effects. The mean dextromethorphan/dextrorphan metabolic ratio (log10) did not differ between the two groups of patients (-1.13 +/- 0.9 and -1.56 +/- 0.5, NS). But significantly more patients with extrapyramidal side effects (n = 4) than patients without side effects (n = 0) were poor metabolizers. This result could be due to a quantitative difference between the 2 groups of drug treatment cosegregated with dextromethorphan, but several authors reported that extrapyramidal side effects seemed not to be always related to high plasma drug levels. So the authors concluded that the 2D6 polymorphism could be a risk factor of poor neurologic tolerance of psychotropic drugs, but not only through pharmacokinetic consequences. CYP 2D6 is indeed expressed in brain and seems to interfer with the metabolism of dopamine and other related neurotransmitters.

Citalopram: an interaction study with clomipramine in a patient heterozygous for CYP2D6 genotype.

A pharmacokinetic interaction between the selective serotonin reuptake inhibitor citalopram and a tricyclic antidepressant, clomipramine, was noted in a patient treated for major depression and obsessive-compulsive disorder. After the addition of citalopram, a desmethylclomipramine plasma level increase and an 8-hydroacy-desmethylclomipramine plasma level decrease were observed. The CYP2D6 phenotype, determined when the patient received the antidepressant comedication, characterized a poor metabolizer status (dextromethorphan metabolic ratio >0.3), despite a heterozygous genotype containing a wild-type allele with extensive metabolic capacity and a mutant non-functional allele (CYP2D6*1A/CYP2D6*4A). This case seems to be one of the first descriptions of the clinical relevance of a CYP2D6 heterozygous genotype in a patient treated with antidepressant.

[Clinical tolerance of a new antidepressant -- milnacipran]. / Tolérance clinique d'un nouvel antidépresseur, le milnacipran.

Milnacipran is a new antidepressant which has been developed for its selective inhibition of both serotonin and noradrenaline reuptake with a good safety and tolerability profile. The efficacy and tolerance profile of this antidepressant have been compared with those of tricyclic and selective serotonin reuptake inhibitor antidepressants (SSRIs) in open-label and placebo-controlled trials. But no data in clinical practice are available. The authors studied the tolerability of milnacipran (100 to 200 mg/d) in 28 depressed inpatients receiving usual comedications during a mean period of 33 days (3 to 107 days). The incidence of adverse events was determined with the help of the Pharmacovigilance Center of the Centre Hospitalo-Universitaire (Besançon, France). Among the 28 patients, milnacipran was well tolerated by 18 of them. Side-effects were noted in 10 patients, but they led to withdrawal of the antidepressant in only 2 cases, where dyspnea, palpitations, pollakiuria in a case and headache, nausea, dysuria in the other case occurred. The most frequent adverse event observed was hypotension (n = 6), but in each case it occurred just after the addition of sedative phenothiazines (n = 5) or of a comedication with phenothiazines and valpromide (n = 1). So this side-effect could not be attributed to milnacipran alone. Treatments with heptaminol or theodrenaline and cafedrine were useful. An increase of the cardiac frequency seemed to occur with milnacipran (p < 0.06). It was observed in the 5 inpatients for whom this cardiovascular parameter was recorded before and during the milnacipran treatment. In 5 other patients, the cardiac frequency seemed to decrease when milnacipran was stopped for lack of good efficacy or adverse events. Gastrointestinal disturbances were scarce isolated (nausea n = 1), but necessitated a treatment with metopimazine. The milnacipran prescription (100 mg/d) after an other antidepressant treatment had been done without a withdrawal period and without problem, even when the previous antidepressant was a SSRIs with a long half-life and CYP450 inhibitory properties. The authors concluded to the good tolerability of milnacipran in usual clinical practice.

[Grapefruit juice as a contraindication? An approach in psychiatry]. / Faut-il contre-indiquer le jus de pamplemousse? Une approche en psychiatrie.

The authors investigated in this preliminary study the influence of grapefruit juice on the metabolism of two tricyclic antidepressants. An increase of plasma concentrations is observed indeed for many drugs when administered concomitantly with grapefruit juice. This effect was mainly attributed to inhibition of cytochrome P450 1A2 and 3A4 enzymes by naringenin. These isoenzymes are involved too in the metabolism of many psychotropic drugs. Only two benzodiazepines (midazolam and triazolam) were studied in the conditions of grapefruit juice association. All these studies are performed in healthy subjects and with a study design very different from the clinical conditions. On the basis of these considerations, the authors hypothesized that grapefruit juice should inhibit tricyclic antidepressant metabolism and thus increase the bioavailability of these drugs. They want to precise if this possible drug plasma level increase could be clinically important for depressed patients. Fourteen depressed inpatients were selected for the study. Seven of them received amitriptyline (100 to 150 mg/d) and the seven others clomipramine (112.5 to 225 mg/d). Tricyclic antidepressant and desmethylated metabolite plasma levels were determined on four occasions. The first and second day samples were obtained to determined the plasma level intraindividual variability of antidepressants. On the third and fourth days, plasma levels were determined after an oral coadministration of the antidepressant and 250 ml of pure and fresh grapefruit juice. One patient was excluded from the study due to the coadministration of clomipramine and fluvoxamine. There is indeed a major drug-interaction between these two drugs, and the tricyclic antidepressant plasma levels of this patient were in the toxic range, without side effect. In this group of patients, there was no metabolic interaction between amitriptyline and grapefruit juice. But the mean plasma levels of clomipramine and desmethylclomipramine increased after coadministration of this juice (+4.5% and +10.5% respectively). The authors concluded that with these preliminary results, the potential clinical relevance of this interaction cannot be estimated.