[Clozapine-resistant schizophrenia related to an increased metabolism and benefit of fluvoxamine: four case reports]. / Inefficacité de la clozapine en rapport avec un métabolisme augmenté et intérêt de la fluvoxamine: à propos de quatre cas.

OBJECTIVE: Although clozapine currently remains the most effective option in treatment-resistant schizophrenia, approximately 40-70% of antipsychotic-resistant patients do not respond, or respond only partially, to clozapine. Because clozapine-resistant patients have limited alternative treatment options, in this study we propose a clozapine augmentation strategy with evidence-based support for some of them. BACKGROUND: Clozapine-resistance is often of metabolic origin. Clozapine is metabolized by N-oxidation and N-demethylation in the liver, predominantly by CYP450 1A2. Due to the influence of inhibitors, inducers, and genetic factors on CYP450 1A2-activity, there is extensive interindividual variability in clozapine plasma concentrations at a fixed dose. Consequently, monitoring of clozapine plasma concentrations is recommended. Several studies have suggested a significantly higher response rate at clozapine plasma concentration of less than 350 microg/l. Unfortunatly, some patients, especially young male smokers, do not achieve this minimum plasma concentration, even at doses higher than 900 mg/day and are nonresponders. CASE-REPORTS: We report the case of a 30 year-old smoker suffering from refractory schizophrenia, and responding poorly to treatments, including clozapine. Monitoring of the clozapine plasma concentration showed a very low level of clozapine, below the minimal effective dose of 350 microg/l. We initially suspected noncompliance with the treatment regime, but genetic analyses revealed another explanation: a gene polymorphism of the CYP450 1A2, principal enzyme that breaks down clozapine. The variability of CYP450 1A2 is explained by a gene polymorphism in intron 1. The A/A genotype confers high CYP450 1A2 inductivity in smokers. Certain smoking patients with A/A polymorphism have ultrarapid CYP450 1A2 activity, which causes the patient to metabolize clozapine too quickly. These patients do not respond to clozapine, even with doses higher than 900 mg/day. However, several factors can counter this elevated CYT activity, in particular fluvoxamine. The interaction between clozapine and fluvoxamine occurs via the inhibition of CYP450 1A2. Several studies have shown that administration of fluvoxamine to patients receiving clozapine therapy may increase the steady-state serum concentrations of clozapine by a factor of 5. Low doses of fluvoxamine inhibit the CYT activity, enough to raise the level of clozapine even when the dose of clozapine was reduced by 50%. The patient unfortunately developed a maniac episode during treatment with fluvoxamine, despite the absence of a previous history of bipolar illness, and we had to initiate treatment with lithium. Together, the three medications stabilized his condition satisfactorily for eight months. We describe three additional cases of treatment-refractory patients with schizophrenia and low-clozapine plasma levels despite high doses. They exhibited similar metabolic abnormality, as confirmed by a caffeine test, because plasma caffeine ratios reflect CYP450 1A2 activity. We then describe its correction, with low doses of fluvoxamine. These patients became responders when the plasma levels increased above the threshold. CONCLUSION: Consequently, we propose a therapeutic drug monitoring strategy. In the case of a clozapine-resistant schizophrenic patient, plasma clozapine levels should be tested. If the rate is normal, the resistance is not metabolic in origin. If the rate is low, a caffeine test should be done. If the results are normal, the patient is noncompliant with the treatment. If the caffeine test is abnormal, metabolic resistance is suspected. In such patients, we propose the addition of low-dose fluvoxamine while closely monitoring clozapine levels. Based on our experience, reducing the clozapine dose by 50% and prescribing 50 mg of fluvoxamine, so as to reach a minimum effective clozapine plasma concentration of more than 350 microg/l should provide an effective therapeutic strategy. This treatment may benefit the significant number of schizophrenic patients whose response to clozapine is hindered by metabolic hyper inductivity. Although this strategy may carry some risks for certain patients, the protocol we propose reduces the latter and the potential benefits should outweigh them.

Lack of initiative and interest in Alzheimer's disease: a single photon emission computed tomography study.

Apathy is defined as a lack of motivation. The aim of this study was to investigate the relation between two major dimensions of apathy (lack of initiative and lack of interest) and brain perfusion. in patients with Alzheimer's disease (AD). Brain perfusion was measured by single photon emission tomography (SPECT). Thirty-one AD patients were included. Lack of initiative and interest were assessed with the Apathy Inventory. Nineteen AD subjects presented a lack of initiative and interest pathological score whereas 12 AD subjects did not. The lack of initiative and interest score correlated significantly with the right frontal and the right inferior temporal lobes. The AD patients with lack of initiative and interest showed a significantly lower perfusion in the right anterior cingulate than the AD patients without lack of initiative and interest. These results derive from rather small subgroups of patients but have the interest to dismantle the complementary aspects of emotion and motivation in apathy and suggest that the latter one is more related to cingulate area.

[Treatment of clozapine-induced granulocytopenia with lithium (two observations)]. / Correction par le lithium des neutropénies induites par la clozapine (deux cas).

Despite the availability of new treatments, the antipsychotic effectiveness of clozapine has not been matched yet. Unfortunately, its regulation is limited by the side effects. The most detrimental is the hematologic toxicity (neutropenia and agranulocytosis) which requires a regular biological monitoring. Treatment with clozapine must be stopped in those cases of secondary granulocytopenia for about 3% of the patients. The current psychiatric drug lithium carbonate has an opposite effect: it can induce leukocytosis. Thus, lithium carbonate is administered in leukopenia, as well as in many hematologic and immunological diseases. However, few teams have used lithium in order to alleviate clozapine-induced granulocytopenia. We report here 2 patients who developed severe neutropenia (neutrophil count<1.5 yen 10 (9)/L) and for whom the use of lithium enabled us to continue the treatment by clozapine. The first patient had a granulocyte rate constitutionally low which rapidly decreased with clozapine. Thanks to the administration of lithium, he recovered quickly a normal blood cell count, which in fact was much higher than his normal rate. According to our research, it's the first time that lithium is reported to be so efficacious in a patient with such a low rate of granulocytes before treatment. It may be that clozapine is not used for those kinds of patients. The second patient developed granulocytopenia after one year of treatment with clozapine. The use of lithium increased so much the number of granulocytes that we continued the treatment with clozapine alone. After 4 months, there is no reappearance of granulocytopenia. We must take into account the partial and contradictory reports in the literature. However, if this result is confirmed, it could be of a high interest to extend the prescription of clozapine, the most effective current antipsychotic drug.

Evaluation of the supervisory system in elderly subjects with and without disinhibition.

UNLABELLED: Disinhibition and irritability, defined as loss of behavioral and emotional control, are frequent in the elderly. The working hypothesis for this study was that these disorders are associated with a cognitive alteration of control processes that manifests as non-routine behavior because of the dysfunction of a general executive component known as the supervisory attentional system (SAS). METHODS: A total of 28 elderly subjects with mild cognitive impairment were recruited and divided into two groups using the Neuropsychiatric Inventory. Fourteen subjects were allocated to the disinhibited group and 14 subjects matched for age, sex and educational level formed a disinhibition-free control group. The neuropsychological battery included the following tests: Mini Mental Score Evaluation, Boston Naming test, Token test, Trail Making and Verbal Fluency. Two tasks were specifically designed to stress the SAS: 1) A specific verbal sentence arrangement task in which subjects had to use sequential reasoning with verbal material. Each test sequence consisted of a series of words shown in jumbled order. The construction of some sequences had to be done by using familiar routine associations (valid conditions). In contrast, other sequences required the overriding selection of familiar routine associations, which were inappropriate within the general context of the task (invalid conditions). 2) Using the Continuous Performance Test, four aspects were evaluated: sustained, selective, preparation and suppressive attention. RESULTS: The only group differences in neuropsychological test results were the following: 1) the sentence arrangement task. In comparison with the control group, the disinhibited group was impaired in invalid conditions and the calculated difference between the number of correct responses in invalid conditions minus that in valid conditions was significantly higher; and 2) the CPT. Disinhibited subjects had a significantly lower number of hits, exclusively in the 'suppressive attention' paradigm. These results suggest that subjects with disinhibition have impaired supervisory system function.

Relationship between impulsivity and platelet serotonin content in adolescents.

The relationship between impulsivity and serotonin function was explored in impulsive and non-depressed adolescents. Platelet serotonin content was chosen as a peripheral indicator of central serotonin function. Impulsivity was assessed with a questionnaire. All measures were performed once a week over a 6-week period for all subjects. Subjects comprised eight adolescent inpatients who were hospitalized as a result of their impulsive acts and eight healthy age- and sex-matched control subjects. Mean platelet serotonin concentration was significantly higher in the impulsive group than in the control group. Platelet serotonin concentration was positively correlated with the intensity of impulsivity in the patient group.

The safety and tolerability of zolpidem--an update.

Zolpidem belongs to a new class of hypnotic agents, chemically distinct from the pre-existing ones, and has a unique neuropharmacological profile. It induces sedative/hypnotic effects in rodents at doses much lower than those for anticonvulsant and myorelaxant activities. Clinically, zolpidem is indicated for the short term treatment of insomnia. It has a short half-life (2.4h), with no active metabolite, and does not accumulate during repeated administration. The pharmacokinetic profile associated with the absence of active metabolites is consistent with the short duration of action and absence of residual effects that have been observed. Polysomnographic experience indicates that zolpidem induces a sleep pattern which is similar to that of physiological sleep, and which produces either no or only minimal effects on sleep architecture after abrupt discontinuation. Aspects of the general safety of zolpidem have been studied in data obtained from healthy volunteers and patients, both adult and elderly, during its clinical development and in post-marketing experience. Zolpidem appears to be well-tolerated in adults and in the elderly, when administered in accordance with prescribing instructions. The available data indicate that, in these circumstances, the risk of abuse or dependence is minimal.

Initiation and supervisory processes in schizophrenia and depression.

Clinical studies show that schizophrenic and depressive subjects have problems with daily life activities, and neuropsychological studies tend to explain these problems in terms of a dysexecutive syndrome. Verbal fluency and sentence arrangement are tasks considered to focus on two aspects of the dysexecutive syndrome known as initiation and supervision processes, respectively. In this study, we assessed performance in these two tasks in schizophrenia and depression. Twenty-six schizophrenic subjects (chronic schizophrenia, DSM IV definition) were compared with 26 control subjects balanced for sex, age and educational level, and 16 depressive subjects (major depression episode, DSM IV) were compared with 11 similarly balanced control subjects. Switching and clustering scores were evaluated during a semantic fluency task as two components underlying the initiation and organization processes. Capture errors specific to failure of the supervisory system and differences between the number of correct responses in two conditions (valid/invalid) were evaluated as indexes of the supervision process in a sentence arrangement task. In the semantic fluency task, switching scores were significantly lower in the schizophrenic and depressive subjects than in their respective controls. In the sentence arrangement task, only the schizophrenic subjects made significantly more capture errors than their controls and had significantly fewer correct sequences in invalid conditions than in valid conditions. This study shows a dissociation between supervision and initiation processes in two different psychiatric populations. Initiation is impaired, but supervision is preserved in depression, whereas both initiation and supervision are impaired in schizophrenia.

Whole blood serotonin content, tryptophan concentrations, and impulsivity in anorexia nervosa.

BACKGROUND: We hypothesized that anorectics with or without bulimic features would differ on impulsivity and indices of central serotoninergic function (high impulsivity being correlated with reduced serotoninergic function). METHODS: For all patients impulsivity rating scales and questionnaires detailing severity of eating disorder were assessed, and whole blood serotonin concentration (5-HT), free and total tryptophan (TT) concentrations, and large neutral amino acids (LNAA) were assayed. RESULTS: Nineteen patients with anorexia nervosa were included, 10 presented associated bulimic features and nine did not. Twelve healthy matched controls were also included. Our hypothesis was not verified. However, tryptophan concentration and the ratio of tryptophan concentration to LNAA allow us to separate controls from anorectics, whereas 5-HT concentration does not. Two significant and positive correlations were found: between impulsivity and anxiety in the total anorectic population, and between anxiety and serotonin in the impulsive group. CONCLUSIONS: All measured peripheral biologic indices except 5-HT concentration may be of interest in this pathology. Impulsivity and anxiety seem to be two personality components involved in anorexia nervosa. This study lead us to the necessity of redefining impulsivity in anorexia nervosa.

Clustering and switching strategies in verbal fluency tasks: comparison between schizophrenics and healthy adults.

Verbal fluency tasks are frequently used in clinical neuropsychology. Clustering (the production of words within semantic subcategories) and switching (the ability to shift between clusters) have been described as 2 components underlying fluency performance. We compared the use of clustering and switching in schizophrenic patients and healthy subjects. Seventy-eight schizophrenic subjects (DSM-IV criteria) and 64 control participants matched for age and educational level were recruited. Negative, disorganized, and productive clinical dimensions were evaluated using the SANS and SAPS scales. The number of words generated per semantic-phonemic cluster and the number of switches were evaluated during 2 verbal fluency tasks (phonemic and semantic). In the healthy controls switching and clustering were closely related to the total number of words generated in the verbal fluency tests. The role of the 2 components was partly dependent on the specific task. Switching was prevalent in formal fluency, while both switching and clustering contributed to semantic fluency. In comparison to the healthy controls, the overall group of schizophrenic patients showed a significant impairment of switching in the formal fluency task and of both switching and clustering in the semantic fluency task, and both the negative and disorganized dimensions correlated with verbal fluency performance, the number of swtiches during the phonemic fluency task, and the clustering during semantic fluency task.

Use of a sequencing task designed to stress the supervisory system in schizophrenic subjects.

BACKGROUND: We investigated whether schizophrenic subjects are impaired in non-routine behaviour because of the dysfunction of a general executive component labelled, in neuropsychological terms, the supervisory system. METHODS: A specific verbal sequencing test was designed for this purpose. Subjects had to perform sequential reasoning with verbal material. Each test sequence consisted of a series of words presented in jumbled order. The construction of some sequences had to be done using familiar routine associations (valid conditions). In contrast, some other sequences required the overriding selection of familiar routine associations, which were inappropriate within the general context of the task (invalid conditions). Twenty verbal sequences (10 valid-10 invalid) were administered. Thirty-seven DMS-IV schizophrenic patients and 21 normal volunteers matched for age and educational level were recruited. RESULTS: Compared to the control group the schizophrenic group was impaired in both valid and invalid conditions. The number of 'capture errors' specific to supervisory system failure was significantly higher in the schizophrenic group and only the schizophrenic patients had significantly fewer correct sequences in invalid conditions than in valid conditions. Poor performance in invalid conditions alone was observed only among the schizophrenic subjects without a general cognitive defect. CONCLUSIONS: These findings suggest that sequencing procedures requiring an executive input are impaired in schizophrenia.

Verbal fluency in schizophrenia: The role of semantic clustering in category instance generation.

The aim of this study was to determine whether schizophrenic patients' impairment in semantic verbal fluency tasks is due to difficulties in organizing their search or, in other words, in organizing output in terms of clusters of meaningfully related words. Consecutive association of words belonging to subcategories of the semantic task was defined as semantic clustering. A categorical verbal fluency task was first administered to 100 healthy subjects and then to 22 schizophrenic patients and 22 healthy subjects matched for sex, age and education. In the normal population, semantic clustering was found to be involved in word generation. A large number of semantic clusters indicated efficient organization of semantic knowledge and led to better word production. Schizophrenic patients showed impaired verbal fluency and generated a smaller number of semantic clusters than the control subjects. These findings point to a defect in self-initiation of semantic categorization in schizophrenia.

[Neurocognitive subtypes of schizophrenia according to performance at verbal fluency tasks]. / Différenciation de sous-types de troubles schizophréniques en fonction des performances au test de fluence verbale.

UNLABELLED: There is a general agreement that schizophrenia is an heterogeneous disorder and cognitive performances could be an interesting feature in order to allow a better description of specific subtypes. The aim of this study was: 1) to describe clinical and neuropsychological performances of 45 DSM IV schizophrenic patients divided in two groups according to their performances in verbal fluency task; 2) to compare each group with the performances of healthy subjects matched for sex, age and education. METHOD: The differentiation criteria was the total number of words generated during 3 formal and 3 semantic fluency tasks. Data were analysed using a disjoint clustering procedure with Euclidean distance. A two cluster solution was considered optimal. Cluster S1 includes 21 schizophrenic subjects defined as low performer (range: 40-83, mean 66.7). Cluster S2 includes 24 schizophrenic subjects (range: 87-158, mean 102.8). All schizophrenic patients were clinically evaluated with SANS, SAPS and a psychosocial aptitude rating scale (PARS). Patients and controls were assessed with the following battery: verbal fluency, Trail making test A & B, Stroop test, Brown Peterson paradigm for evaluation of working memory. RESULTS: Patients with low verbal fluency had significantly higher scores at the SANS and PARS. Furthermore, the low performers (cluster S1) were differentiated from those with better performances (cluster S2) by significantly poorer results in all neuropsychological tests. Comparison with healthy subjects indicated that cluster S1 patients also had significantly poorer results in all neuropsychological tests. Relative to their 24 controls cluster S2 patients performances was lower in all measures excepted in one subscore of the Stroop test and in the number of cluster produced. This later result could indicate that some capacities for willed intention were preserved in this group and that the alteration in verbal fluency performances were better explained by impairment of the other cognitive processes. DISCUSSION: These findings point out that: 1) use of performance in cognitive executive task such as verbal fluency is a possible criteria in order to separate different types of schizophrenic patients; 2) in the two groups of schizophrenic subjects, various processes defects underline cognitive performances indicating the presence of different neurobiological dysfunctioning.

[Hysterical personality disorder]. / La personnalité hystérique.

The hysteric personality disorder is characterized by: 1. an intense need for affection; it is a child-like need, seeking protection and affection, making the patient subject to suggestibility and dependence, along with an erotic behaviour which is in reality associated to fear of sexuality; 2. an exaggerated and rapidly shifting expression of emotion leading to unstable, theatrical and histrionic expression of emotions giving an impression of shallowness and lack of authenticity; 3. a highly imaginative thinking pattern with flight of reality and tendency to dreaming, mythomania, memory reconstruction.

A single photon emission computed tomography study of cerebral regional perfusion changes induced by a learning task in subjects with mild memory impairment.

Fifteen nondemented subjects with memory complaints underwent serial single photon emission computed tomography (SPECT) studies with technetium-99m-d, l-hexamethyl-propylene amine oxime (HMPAO) as tracer. Scans were carried out under a baseline conditions and during the learning phase of the Memory Efficiency Profile (MEP), a combined visual perception and memory task developed by Rey. Results indicate a positive correlation between activation, as indexed by HMPAO uptake, and neuropsychological assessment. Right temporal activation was correlated with MEP immediate recall. The right cerebellum was correlated with both MEP immediate and delayed recall. This study suggests that SPECT can show cortical activation during cognitive performance in subjects with mild memory impairment.

[Efficacy of antidepressants and thymoregulators in the long-term evolution of depression]. / Efficacité des antidépresseurs et thymorégulateurs dans l'évolution à long terme des dépressions.

Official recommendations pointed out the long term maintenance treatment of recurrent unipolar depression on the basis of a significant effect of antidepressants and mood-stabilizers versus placebo. The results of controlled studies, mainly using imipramine or lithium salts, have not been encouraging in term of long term prognosis, due to the limited success rate for maintenance phase ranging from 30 to 48%. The "Pittsburgh study" maximized the recurrence potential by defining patients selection on at least 3 previous episodes of unipolar depression, with the immediate previous episode being no more than 2.5 years earlier, beginning the experimental maintenance therapy phase after patients remain relatively symptom free for a total of 20 weeks, and scheduled the imipramine withdrawal in the randomly assigned placebo group by a progressive reduction of 33% per week. Survival analysis in the 5 years maintenance outcome of previously imipramine responders patients demonstrated an increased risk of depressive recurrence at the beginning of discontinuation but did not prove a true prophylactic effect. Furthermore these findings do not prove that treatment are not more effective than placebo, suggesting at least a revisitation of the clinical concept of response. The putative efficacy of biological treatment should be an operational criteria to elicit vulnerability markers, mainly in the field of sleep research.

Antidepressant effect of 5-methoxypsoralen: The melatonin synchronizer hypothesis.

5-methoxypsoralen (5-MOP) stimulates pineal melatonin secretion, and a decrease in dark phase melatonin levels has been described in major depression. As exogenous melatonin has shown synchronizer properties, authors hypothesized that giving 5-MOP would have antidepressant properties. Twenty-six inpatients meeting the criteria of major depressive disorders were enrolled in a four-week, double blind trial of 5-MOP versus amitriptyline. Clinical improvement was identical in both treatment groups but biological changes were different in each group: 5-MOP patients showed an early nocturnal surge of melatonin levels that was maintained at the fourth treatment week, while melatonin levels remained unchanged in patients treated with amitriptyline.

[Plasma tryptophan in a protein controlled diet in depressed patients]. / Tryptophane plasmatique à apport protéique contrôlé chez des déprimés.

Cerebral serotonin is synthetized from its blood precursor: tryptophan (TRP), an essential amino acid (6). TRP has been extensively studied since serotonine has been reported to be involved in the pathogenesis of depression (9). In one hand, brain serotonin content depends on regulation by plasma large neutral amino acids (LNAA): leucine, isoleucine, valine, tyrosine and phenylalanine that compete with TRP to cross over the blood brain barrier (7, 13). In the other hand TRP is largely linked with albumin. So, we have studied plasma total TRP, free TRP and the ratio TRP on LNAA as potential cerebral serotonin index. The aim of this study is to observe the blood variations of the biological parameters in fasting and postprandial conditions in 8 depressed women, aged from 57 to 78 years, on a short protein controlled diet: 4 women had TRP poor then rich diet and the others 4 rich then poor. Alimentary proteins modulated diets and each patient was his own control: the results under modulated diet were compared with those under normal diet at the same time. More over, 2 psychotic patients aged 58 and 70 years have been studied at the same time, in each group. Biological datas were compared with clinical evolution.