The pattern of cortical thickness associated with executive dysfunction in MCI and SCC: The MEMENTO cohort.

BACKGROUND: The association between the pattern of cortical thickness (CT) and executive dysfunction (ED) in mild cognitive impairment (MCI) and subjective cognitive complaints (SCC) is still poorly understood. We aimed to investigate the association between CT and ED in a large French cohort (MEMENTO) of 2323 participants with MCI or SCC. METHODS: All participants with available CT and executive function data (verbal fluency and Trail Making Test [TMT]) were selected (n=1924). Linear regressions were performed to determine relationships between executive performance and the brain parenchymal fraction (BPF) and CT using FreeSurfer. RESULTS: The global executive function score was related to the BPF (sß: 0.091, P<0.001) and CT in the right supramarginal (sß: 0.060, P=0.041) and right isthmus cingulate (sß: 0.062, P=0.011) regions. Literal verbal fluency was related to the BPF (sß: 0.125, P<0.001) and CT in the left parsorbitalis region (sß: 0.045, P=0.045). Semantic verbal fluency was related to the BPF (sß: 0.101, P<0.001) and CT in the right supramarginal region (sß: 0.061, P=0.042). The time difference between the TMT parts B and A was related to the BPF (sß: 0.048, P=0.045) and CT in the right precuneus (sß: 0.073, P=0.019) and right isthmus cingulate region (sß: 0.054, P=0.032). CONCLUSIONS: In a large clinically based cohort of participants presenting with either MCI or SCC (a potential early stage of Alzheimer's disease [AD]), ED was related to the BPF and CT in the left pars orbitalis, right precuneus, right supramarginal, and right isthmus cingulate regions. This pattern of lesions adds knowledge to the conventional anatomy of ED and could contribute to the early diagnosis of AD.

The RAPID-II Neuropsychological Test battery for subjects aged 20 to 49 years: Norms and cognitive profile.

INTRODUCTION: Cognitive evaluation of young subjects is now widely carried out for non-traumatic diseases such as multiple sclerosis, HIV, or sleep disorders. This evaluation requires normative data based on healthy adult samples. However, most clinicians use a set of tests that were normed in an isolated manner from different samples using different cutoff criteria. Thus, the score of an individual may be considered either normal or impaired according to the norms used. It is well established that healthy adults obtained low-test scores when a battery of tests is administered. Thus, the knowledge of low base rates is required so as to minimize false diagnosis of cognitive impairment. The aim of this study was twofold (1) to provide normative data for RAPID-II battery in healthy adults, and (2) estimate the proportion of healthy adults having low scores across this battery. METHODS: Norms for the 44 test scores of the RAPID-II test battery were developed using the overall sample of 335 individuals based on three categories of age (20 to 29, 30 to 39, and 40 to 49 years) and two educational levels: Baccalaureate or higher educational degree (high educational level), lower than baccalaureate (low educational level). The 5th, 25th, 50th, and 75th percentiles were calculated from the six age and education subsamples and used to define norms. The frequency of low scores on the RAPID-II battery was calculated by simultaneously examining the performance of 33 primary scores. A low score was defined as less than or equal to the 5th percentile drawn from the six age and education normative subsamples. In addition, the percentages of low scores were also determined when all possible combinations of two-test scores across the RAPID-II were considered in the overall normative sample. RESULTS: Our data showed that 59.4% subjects of the normative sample obtained at least one or more low score. With more than 9 test scores, this percentage was equal to 0% in the normative sample. Among all combinations of two-test scores, 96% had a false positive rate<2%. CONCLUSION: Low scores are very common in young healthy subjects and are more obvious when simultaneously analyzing test scores across a battery of tests and are thus not necessarily indicative of cognitive impairment. The combinations of two-test scores can be a useful tool to improve the interpretation of low scores.

Mast cells' involvement in inflammation pathways linked to depression: evidence in mastocytosis.

Converging sources of evidence point to a role for inflammation in the development of depression, fatigue and cognitive dysfunction. More precisely, the tryptophan (TRP) catabolism is thought to play a major role in inflammation-induced depression. Mastocytosis is a rare disease in which chronic symptoms, including depression, are related to mast cell accumulation and activation. Our objectives were to study the correlations between neuropsychiatric features and the TRP catabolism pathway in mastocytosis in order to demonstrate mast cells' potential involvement in inflammation-induced depression. Fifty-four patients with mastocytosis and a mean age of 50.1 years were enrolled in the study and compared healthy age-matched controls. Depression and stress were evaluated with the Beck Depression Inventory revised and the Perceived Stress Scale. All patients had measurements of TRP, serotonin (5-HT), kynurenine (KYN), indoleamine 2,3-dioxygenase 1 (IDO1) activity (ratio KYN/TRP), kynurenic acid (KA) and quinolinic acid (QA). Patients displayed significantly lower levels of TRP and 5-HT without hypoalbuminemia or malabsorption, higher IDO1 activity, and higher levels of KA and QA, with an imbalance towards the latter. High perceived stress and high depression scores were associated with low TRP and high IDO1 activity. In conclusion, TRP metabolism is altered in mastocytosis and correlates with perceived stress and depression, demonstrating mast cells' involvement in inflammation pathways linked to depression.

Slowing of information processing speed without motor slowing in multiple sclerosis observed during two crossing-off tasks.

INTRODUCTION: Slowing of information processing speed (IPS) is often considered one of the primary deficits seen in multiple sclerosis (MS). IPS is usually measured by tasks that involve many cognitive functions. The aim of this study was to determine whether similar IPS slowing can also be observed during two simple, timed, psychomotor crossing-off tasks. METHOD: The Crossing-Off Test (COT), a simple psychomotor task, was performed under two conditions (COT1 corresponded to writing habits, COT2 used horizontal sweeping) in 25 relapsing-remitting MS patients (EDSS 0-1) and 25 healthy controls. RESULTS: The MS group compared with the control group was impaired on COT1 (P=0.0043) and not on COT2 (P=0.4), and the COT1 performance of MS patients with EDSS 1 was more impaired than those of patients with EDSS 0 (P=0.008). DISCUSSION/CONCLUSION: These results indicate that only some of the IPS cognitive subcomponents linked with COT1 tasks are initially involved in the slowing of IPS during MS, suggesting that different mechanisms are involved in each tested version of the COT.

[Specificities of the logopenic variant of primary progressive aphasia]. / Particularités du variant logopénique au sein des aphasies progressives primaires.

The logopenic variant of primary progressive aphasia is a syndrome with neuropsychological and linguistic specificities, including phonological loop impairment for which diagnosis is currently mainly based on the exclusion of the two other variants, semantic and nonfluent/agrammatic primary progressive aphasia. The syndrome may be underdiagnosed due (1) to mild language difficulties during the early stages of the disease or (2) to being mistaken for mild cognitive impairment or Alzheimer's disease when the evaluation of episodic memory is based on verbal material and (3) finally, it is not uncommon that the disorders are attributed to psychiatric co-morbidities such as, for example, anxiety. Moreover, compared to other variants of primary progressive aphasia, brain abnormalities are different. The left temporoparietal junction is initially affected. Neuropathology and biomarkers (cerebrospinal fluid, molecular amyloid nuclear imaging) frequently reveal Alzheimer's disease. Consequently this variant of primary progressive aphasia does not fall under the traditional concept of frontotemporal lobar degeneration. These distinctive features highlight the utility of correct diagnosis, classification, and use of biomarkers to show the neuropathological processes underlying logopenic primary progressive aphasia. The logopenic variant of primary progressive aphasia is a specific form of Alzheimer's disease frequently presenting a rapid decline; specific linguistic therapies are needed. Further investigation of this syndrome is needed to refine screening, improve diagnostic criteria and better understand the epidemiology and the biological mechanisms involved.

[Assessment of 10 years of memory consultations in the Franche-Comté: Description and analysis of the RAPID regional database]. / Bilan de 10ans de consultations mémoire en Franche-Comté: description et analyse de la base de données RAPID.

The aim of this study was to evaluate the impact, on a regional scale (Franche-Comté), of 3 National Alzheimer care plans, particularly concerning the development of the offer of care management by clinicians as well as the panel of diagnoses concerned. Data on sociodemographic, neuropsychological and diagnostic characteristics were retrieved from the RAPID regional database between 1st January 2003 and 31st December 2012. These analyses focused exclusively on patients who had an initial consultation (n=12,017) during the same period. The existence of a previously established health network capable of carrying out governmental health plans has produced an effective interface between regional administrative structures responsible for the implementation of these plans and health professionals responsible for carrying out them out. This network study, the use of a battery of tests and a common software database have enabled the development of patient care management throughout the Franche-Comté region. It also showed the diversification of diagnoses mentioned over the past years as well as changes in clinical practices on how to address the issue of cognitive impairment.

[Sexual dysfunction and depression: Validity of a French version of the ASEX scale]. / Validation française de l'échelle psychométrique ASEX d'évaluation des troubles sexuels dans la dépression.

BACKGROUND: Since the Beck study (1967), it is well known that sexual dysfunction is particularly prevalent in depressive patients compared to the general population, at 70% and 30% respectively. Depression, psychotropics and antidepressants are responsible for altering sexuality, and patients are considerably affected by these symptoms that dramatically decrease their quality of life. Screening for sexual dysfunctions seems essential, and a scale such as the Arizona Sexual Experience Scale (ASEX) may help practitioners. The English version of this scale was validated in 2000 (McGahuey et al. [9]), and is widely used in scientific research. The aim of this study was to assess the validity of the French version of the ASEX scale. METHODS: Following authorization from the University of Arizona, the ASEX scale was translated into French by our team at the University hospital of Besançon (France), by the back translation technique, and then checked by a professional translator. ASEX, Mini International Neuropsychiatric Interview (MINI), Beck Depression Inventory (BDI) and Hamilton Depression Rating Scale (HDRS) were filled out by 37 depressed inpatients, and ASEX and PHQ-9 by 64 controls (hospital employees, residents and students at the University of Besançon), and again one to two weeks later. Bivariate correlations were performed using total ASEX scores to determine the test-retest reliability. Internal consistency of the ASEX scale was assessed using Cronbach's alpha analysis. Analyses of variance (Anova) were performed to determine the validity of the ASEX scale to compare patients to controls for total ASEX score and for individual ASEX item scores. In order to determine whether the ASEX criteria accurately reflect sexual dysfunction (determined by the HDRS rating or self-report), positive and negative predictive value and sensitivity and specificity were measured. To determine how well the total ASEX score differentiates between individuals with sexual dysfunction and those without, a Receiver Operating Characteristic (ROC) analysis was performed. We expected similar results between the French version of the ASEX scale and the original one (McGahuey and al., 2000). RESULTS: Patients and controls were similar in terms of sex and age. The test-retest reliability was good, and the internal consistency was excellent using Cronbach's alpha analysis (alpha=0.9451). Analyses of variance (Anova) showed strong differences between the two groups, confirming the validity of the ASEX scale to compare patients to controls for total ASEX score and individual ASEX item scores. Positive and negative predictive values were respectively 89.66% (PPV) and 85.33% (NPV). Specificity and sensitivity were respectively 95.31% (Sp) and 70.27% (Se). The ROC analysis showed the area under the curve (AUC=0.8457) and the best ASEX criteria to demonstrate that sexual dysfunction had been correctly identified (total ASEX score ≥ 18). CONCLUSION: This study assessed the validity and reliability of the French version of the ASEX scale. These findings demonstrate the highly acceptable psychometric properties of ASEX in patients with depression.

[Diagnostic norms of RAPID neuropsychological battery tests for subjects aged 60 to 89 years with Alzheimer's disease]. / Normes diagnostiques de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 60 à 89ans présentant une maladie d'Alzheimer.

INTRODUCTION: The aim of this study was to propose diagnostic norms for the rapid neuropsychological battery, in the detection of cognitive impairment due to Alzheimer's disease. POPULATION AND METHODS: Three hundred and fifty-two control subjects (mean MMSE : 27.3 ± 2.5) and 676 patients with Alzheimer's disease (mean MMSE : 22.9 ± 2.6) at a mild stage (CDR = 1) were selected according to age (60-69, 70-79 and 80-89 years) and educational level (French primary Education Certificate or lower versus Certificate of Professional Aptitude or the School Leaving Certificate versus the Baccalaureate or higher). Age and education-adjusted cut-off scores were calculated using Receiver Operating Characteristic curves so as to determine the discriminative ability (sensitivity, specificity) of each test from the RAPID neuropsychological battery. Cut-off scores with a specificity set at least at 90% were also proposed. RESULTS: The Free and Cued Recall Test exhibited good sensitivity (from 87% to 100% for free recall and from 85% to 98% for total recall) and specificity (from 85% to 96% for free recall and from 86% to 100% for total recall). For the other tests, sensitivities and specificities were lower. CONCLUSION: The use of these two types of cut-off scores should help the clinician in the diagnosis of Alzheimer's disease by limiting the risk of false positives and false negatives. The choice of the cut-off scores will depend on the patient's individual clinical context.

[Comparative norms of RAPID neuropsychological battery tests for subjects aged between 50 and 89 years]. / Normes comparatives de la batterie de tests neuropsychologiques RAPID pour les sujets âgés de 50 à 89 ans.

INTRODUCTION: RAPID, a battery of rapid neuropsychological tests, includes neuropsychological tests calibrated for different populations according to diverse methodologies. This makes the comparison and interpretation of the results difficult. The aim of this study was to build comparative norms for the RAPID battery using a single methodology in a unique population. POPULATION AND METHODS: The RAPID Battery includes nine different tests: the Memory Impairment Screen, the Isaacs Set Test, the Mini-Mental State Examination, the Free and Cued Recall Test, the Trail Making Test, a test for copying geometric figures as part of the BEC 96, a test for verbally naming images and a test for matching categories. A cohort of 476 subjects aged 50 to 89 were randomly selected from the medical records of 11 practitioners. RESULTS: The norms were stratified according to age (50-59, 60-69, 70-79 and 80-89 years) and education level of the subjects. The first level includes subjects with the French Primary Education Certificate or lower. The second level includes subjects with the Certificate of Professional Aptitude or the Brevet (equivalent to the GCSE). The third level includes subjects with the Baccalaureate or higher. Given that most of the tests did not satisfy the normal distribution, percentiles (tenth, twenty-fifth, seventy-fifth, ninetieth percentile and median) were used to define age and education norms. The results show a high participation rate (75 %) and are similar to those obtained in the literature: The results decreased with age and improved in grade level. Nevertheless, the results exhibited great variability for the tenth percentile in comparison with results reported in the literature. CONCLUSION: The development of comparative norms for the RAPID battery from a same sample facilitates the interpretation of individual results in terms of cognitive profile.

Pilot study of feasibility of the effect of treatment with tDCS in patients suffering from treatment-resistant depression treated with escitalopram.

OBJECTIVE: This double-blind, sham-controlled trial investigated the effects of two daily tDCS sessions over a 5-day period in treatment-resistant depression. METHOD: Twenty-four treatment-resistant depressed patients received two daily sessions of active or sham anodal tDCS to the left prefrontal cortex (2 mA, 10 sessions over 1 week). Depression severity, psychomotor retardation and cognitive function were assessed. RESULTS: Active tDCS was not significantly superior to sham tDCS on the HDRS at week 4, as well as on the MADRS and SRRS scales, and on neuropsychological tests. Response rates were not significantly higher with active tDCS. tDCS was well tolerated, with mild adverse events limited to transient scalp discomfort. CONCLUSION: tDCS did not induce clinically relevant antidepressant effect in active and sham stimulation groups. There was no impact on psychomotor and neuropsychological functioning. SIGNIFICANCE: tDCS efficacy on specific symptom profiles in pharmacotherapy-resistant depression is limited. The use of optimized stimulation protocol and longer period of follow up may valuably contribute to specify the place of tDCS in treatment-resistant depression.

Tricyclic antidepressant-induced extrapyramidal side effects.

Two cases of tricyclic antidepressant-related extrapyramidal side effects are reported and, the authors review the literature describing these effects. Despite clear case reports, these side effects are not well known. Given the wide prescription of tricyclic antidepressants (TCA) and the low number of case reports, the prevalence of these side effects is indeed low, but clinical implications exist. The extrapyramidal symptoms induced by TCA alone are acute or tardive dyskinesia, akathisia, myoclonus, rabbit syndrome and dystonia. These symptoms seem to be non age-related, but often dose-related, and were responders to antiparkinsonian agents or propranolol. The factors that predispose an individual to the development of these side effects are not completely understood. Some risk factors such as prior exposure to neuroleptics and/or lithium or estrogens could facilitate the development of these side effects. In some cases, they can disappear even though the same dose of TCA is continued, and they do not seem to be a drug class reaction. The susceptibility of each individual patient to the development of these disorders may be limited to only one or a few of these agents.

CYP 2D6 PM phenotype hypothesis of antidepressant extrapyramidal side-effects.

Extrapyramidal symptoms occur as side-effects of neuroleptics. For many years, case reports of such side-effects, linked to antidepressant treatments, have been published, but this phenomenon is not well known. Tricyclic and serotonergic antidepressants are both involved. The authors present an hypothesis which provides one possible neurobiochemical explanation for the aetiology of these side-effects. The proposed explanation is related to the inhibition of the CYP 2D6 isoenzyme by antidepressants (or neuroleptics) that may be involved in the genesis of the observed extrapyramidal side-effects.

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.

[Undesirable effects of drugs. Epidemiologic study at a psychiatric service of a university hospital]. / Effets indesirables medicamenteux. Etude epidemiologique dans un service de psychiatrie hospitalo-universitaire.

The authors reviewed the drug side effects observed in their ward during the 5 last years (1988-92). These alleged effects occurred at a very low incidence, 3 per cent, (116 cases on 3809 hospitalizations). As mentioned in the literature, the occurrence was higher in females (60 per cent), than in males. The age seemed not to be a risk factor in that population, the mean age being 44 for the men and 45 for the women. All side effects disappeared after decreasing or stopping the suspected drug. In 6 cases the suspected drug was not a psychotropic agent. The authors presented some of the more often reported cases, and some of the more recently known, such as extrapyramidal side effects with antidepressants, increase of the libido with serotonergic antidepressants. The problem fo polytherapy is discussed. In half (59/116) of the cases there was a psychotropic association. The side effect may be due to a pharmacokinetic interaction in 16 cases, either with enzymatic inhibitors like dextropropoxyphene, valpromide, valproic acid, fluvoxamine and fluoxetine, or with enzymatic inducers like carbamazepine. The authors compared the side effects of the antidepressants mainly used in their ward (amitriptyline, clomipramine, fluvoxamine and fluoxetine).

[Treatment of depression secondary to psychotic disorders]. / Traitement des dépressions secondaires à des troubles psychotiques.

More than 25% patients suffering from psychotic disorders would show during their evolution some depressive disorders. More than 10% would die from suicide. Secondary depressions following psychotic disorders are heterogeneous. They have to be specified in order to assess therapeutics including biological psychological and socio-environmental approaches. Treatment of depressive disorders correlated to psychotic symptomatology, being mood congruent or not, is the same as characterized depression. However it is preferred to associate antidepressant and neuroleptic or electroconvulsivotherapy. Depressive symptomatology in psychotic disorders is mostly secondary due to delusion, negative or even deficit symptomatology. It often requires to adapt individual choice and posology of antipsychotic treatment. Depressive states in "post-psychotic" phase, secondary to acute phase or in the evolution of chronic psychosis, may be for some of them linked to neuroleptic treatment side effects: in this case, posology and indication have to be discussed. In other cases, it may be indicated to prescribe antidepressant or even electroconvulsivotherapy after having considered the existence of psycho-dynamic reorganization and the need of psychotherapic, social or institutional support. The existence of depressive disorders in the evolution of psychosis leads to ask about their significance: psychological reaction, comorbidity of two distinct pathologies, evidence of continuum between affective disorders and schizophrenia.

[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.

[Abuse of tianeptine. A case report]. / Abus de tianeptine. A propos d'un cas.

The authors report a case of tianeptine abuse in a 30 year-old woman. After a medical prescription of the recommended dosage of 12.5 mg 3 times daily of oral tianeptine for a depressive illness, the patient spontaneously increased the dosage which after two months reached 150 tablets per day. No severe toxic effects were observed. As adverse effects, the patient, in the beginning of this high treatment period suffered from nausea, vomiting, abdominal pain, anorexia with weight loss, constipation. These side effects progressively disappeared. The biological tolerance was excellent, and hepatic parameters were not affected. The patient experienced and seek a psychostimulant effect. After seven months of such a therapy, she was hospitalized to undergo a withdrawal. The discontinuation of the tianeptine treatment occurs in four days. A withdrawal syndrome marked by myalgia, and cold feeling was transient, and alleviated by sedative phenothiazine (cyamemazine) and myorelaxant benzodiazepine (tetrazepam).

[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.

[Fluoxetine and tricyclic antidepressants: clinical tolerance in short-term combined administration]. / Fluoxétine et antidépresseurs tricycliques: tolérance clinique à court terme de l'association.

The tricyclic SSRI antidepressant association is often used in the treatment of resistant depressive illness. The pharmacokinetic interaction existing between these two types of drugs is well known, with as result, an increase of tricyclic antidepressant plasma levels. The aim of this work was to assess the clinical tolerance of the association of fluoxetine and tricyclic antidepressants, prescribed at usual doses. In 10 patients, having a bad response to a tricyclic antidepressant treatment, with in the therapeutic window adjusted plasma levels since 3 weeks, an association of fluoxetine (20 mg/d) to the tricyclic was prescribed. The other associated treatments were unmodified. The clinical evolution was recorded with the MADRS and the UKU scale for side effects, before the tricyclic antidepressant treatment adjustment (D-21) and just before the fluoxetine association (D1) and every 7 days after this association too. The tricyclic plasma levels (amitriptyline and clomipramine) and the patient phenotype CYP 2D6 and 2C19 were determined before and 7 days after the fluoxetine addition. A good clinical evolution was noted since the 7th day after the fluoxetine association to tricyclic (mean MADRS scores on D-21, D1, D7 and D14; 35.4, 33.1, 23.9, 16.8 respectively). In 3 patients, an anxiety increase on day 6, 14 and 16 respectively, after fluoxetine addition, induces a stop of the serotonergic antidepressant. In one patient all the treatment was stopped due to the appearance of a mood inversion. In another patient, after 14 days of antidepressant association, EC were prescribed as asked by the patient, due to an insufficient mood improvement, with a good clinical result and tolerance. The evolution of the side effects was surprising. There was no increase of the UKU score mean during the associated treatment, despite an increase of the tricyclic plasma levels that reached, in three patients, the toxic level (510, 605 and 860 ng/ml of amitriptyline + nortriptyline or clomipramine + demethylclomipramine). The UKU psychic score mean significatively decreased (7.7, 6.8, 5.3, 4 on D-21, D1, D7, D14 respectively). The fluoxetine association did not modify the neurological, neuro-endocrinologic and the skin side effects. None increase of headheck was noted. The increase of anxiety, observed in 3 patients, was not considered as a side effect of the antidepressant association, but an effect of the stimulant potency of fluoxetine in anxious patients. The pharmacogenetic results confirmed the strong inhibition potenty of fluoxetine on the CYP 2D6 isoenzyme. In 5 patients indeed, the extensive metabolizer phenotype was modified in a poor metabolizer phenotype, seven days after the association of fluoxetine. The CYP 2C19 phenotype was unchanged after this association. The patient phenotype did not seem to interfere with the clinical results. In conclusion, in this group of patients, the short-term clinical tolerance of the tricyclic antidepressant and fluoxetine association was very good, despite the pharmacokinetic interaction existing between these two types of drugs.

[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.