[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.

5-Methoxypsoralen increases the plasma melatonin levels in humans.

The aim of this study was to evaluate the acute effects of 5-methoxypsoralen (5-MOP) on the melatonin secretion in humans. Eleven normal volunteers were investigated before (drug-free) and after 6-day periods of treatment with oral 5-MOP, first administered daily at 9 A.M. and after a 1-week free interval administered daily at 9 P.M. Under nyctohemeral conditions, the plasma melatonin levels were evaluated over a 24-h period in each session by hourly blood samples and radioimmunoassay. The sensitivity of the retina to light was also evaluated by means of electroretinography performed at 11 A.M. before and after a morning administration of 5-MOP. Plasma levels of melatonin were significantly increased from the second hour after 5-MOP administration. The hourly mean levels were significantly higher after 5-MOP administration compared to baseline values. This increased secretion was more pronounced after evening than after morning administration. Also, 5-MOP increases the sensitivity of the retina to light under photopic conditions and in the early stages of the dark adaptation period, as observed under scotopic conditions.

5-Methoxypsoralen as a specific stimulating agent of melatonin secretion in humans.

The endocrine effects of the linear furocoumarin, 5-methoxypsoralen (Bergapten), were investigated in 11 normal adults according to a cross-over design with 2 conditions: a 1-week trial with 5-methoxypsoralen (5MOP) administered daily (40 mg/orally) at 0900 h, and after a 1-week period of washout, a similar 1-week trial with daily administrations of 5MOP at 2100 h. The subjects were living under normal nychtohemeral conditions. The plasma levels of melatonin, cortisol, TSH, PRL, and GH were evaluated by hourly blood samples over 24-h periods on the preceding day and on the last day of each condition. Our main finding is that 5MOP specifically stimulates melatonin secretion in humans, with a pronounced effect when administered during the dark phase of the day (at 2100 h). The other endocrine rhythms were unaffected by 5MOP administration. Melatonin has been shown to interact with the regulation of the human circadian system; this specific stimulation may, therefore, be of great interest in disorders associated with abnormalities of circadian rhythms.

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.

Abnormal melatonin response to 5-methoxypsoralen in dementia.

The authors investigated the melatonin response to 5-methoxypsoralen in 39 healthy adult and elderly subjects and in 13 demented, 13 depressed, and 13 schizophrenic inpatients. Subjects' plasma melatonin levels were evaluated before they took single, oral 40-mg doses of 5-methoxypsoralen and 3 hours afterward. The preliminary results indicate that the melatonin response of the pineal gland to 5-methoxypsoralen is reduced in demented patients compared to that in healthy elderly subjects. Depressed and schizophrenic patients had a normal melatonin response to the drug. This finding suggests that the pineal gland may be functionally impaired in dementia but not in depression.

Twenty-four-hour profiles of body temperature and plasma TSH in bipolar patients during depression and during remission and in normal control subjects.

The 24-hour patterns of body temperature and plasma thyrotropin (TSH) were measured in eight bipolar patients in both depressed and recovered (after 3 weeks of treatment) states and in eight normal control subjects. Clear circadian patterns were detected for both temperature and TSH. Nocturnal body temperature was increased and the nocturnal surge of TSH was blunted during depression; these abnormalities were corrected after recovery. The inverse relationship between changes in body temperature and TSH levels at night suggests that changes in thermoregulation may be responsible for the neuroendocrine disturbance and may play a role in the pathophysiology of depression.

Antidepressant effect of 5-methoxypsoralen: a preliminary report.

5-Methoxypsoralen (5 MOP) administered daily (40 mg at 9 p.m.) was compared with placebo in the treatment of severe depression. The clinical response was evaluated using the Hamilton Depression Rating Scale after 1 week of treatment. Our preliminary data indicate that patients receiving 5 MOP improved significantly after 1 week, whereas patients treated with placebo did not. The stimulating effect of 5 MOP on the melatonin secretion may be involved in this clinical effect.

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.

Diurnal variation in total plasma tryptophan in controls and in depression.

Circadian rhythms of total tryptophan were investigated by assays of hourly blood samples over 25 h. The study population consisted of four endogenously depressed patients investigated in the absence of any treatment and six healthy controls. The abnormalities detected by statistical analyses in untreated depression consisted mainly of amplitude reduction; the phase positions of the depressed patients were similar to those of the controls.

Trimipramine: acute and lasting effects on sleep in healthy and major depressive subjects.

The acute effects of trimipramine on sleep EEG patterns were investigated in six depressed inpatients and six healthy volunteers. The effects of long-term administration were then assessed in depressed patients after 4 weeks of treatment. Sedative effects of the drug were more pronounced in healthy subjects while sleep parameters of depressed patients seemed less sensitive to the drug. Chronic effects tended to correct most of the sleep disturbances seen in depressed subjects with respect to the natural organization of sleep. The major sleep effect of trimipramine concerned REM latency which was lengthened in both groups, independently of the treatment protocol.

Antidepressant effects of the sleep/wake cycle phase advance. Preliminary report.

Five patients with endogenous depression were asked to participate in a phase-advance procedure consisting in advancing by 5 h the time schedule of the major external synchronizers such as light/dark, sleep/wake, meal time and social activity cycles. Clinical and biological parameters were observed throughout this 2-week process which followed one night of partial sleep deprivation. All patients improved with partial sleep deprivation and four of the five showed continuing remission during the phase-advance process. The antidepressant effects of the phase-advance process are discussed in light of different chronobiological models for depression.

Seasonality of suicides: environmental, sociological and biological covariations.

The monthly rates of completed suicides in France from 1978 until 1982 were analyzed. The seasonal variations of environmental (daylight and sunlight durations, mean temperature, geomagnetism), sociological (unemployment, deaths of all causes, birth and conception rates), and biological (melatonin, cortisol and serotonin circannual rhythms) factors were compared to the seasonal patterns of suicides. A clear seasonal variation (with peaks in May and September) in suicidal behavior was detected. These patterns tended to differ as a function of age (bimodal in young, unimodal in old people). The component analysis clearly pointed out that seasonal patterns of suicides may be considered as the sum of two components, unimodal and bimodal. Almost similar covariations were found between the main seasonal (unimodal) component of suicides and environmental (daylight duration and mean monthly temperature) or sociological factors whereas the secondary component was more correlated to variations in environmental factors and, to some extent, to biological parameters.

5-Methoxypsoralen: effect on the noradrenaline circadian rhythm of sleep-deprived subjects.

5-methoxypsoralen (5-MOP), a serotonin analogue, stimulates the secretion of melatonin, which plays an important role in circadian rhythm regulation. Melatonin production is essentially controlled by noradrenaline (NA). To investigate the effect of 5-MOP on the 24 hr NA rhythm, hourly plasma NA concentrations measured over 24 hr in 7 healthy young subjects who took 40 mg 5-MOP orally at 21:00 hr the evening before were compared with values obtained in drug-free subjects. All subjects were sleep-deprived and under conditions in which sympathetic nervous system activation was repeated every hour over 24 hr. In both series of patients, a significant difference was observed between mean morning values and mean night values, reflecting persistence of a circadian rhythm. In subjects given 5-MOP, a significant difference was also observed between mean afternoon values and mean night values. However, MANOVA analysis failed to find any difference between the two series of subjects. Acute administration of 5-MOP thus had no significant effect on the NA circadian rhythm under our study conditions.

Circadian variation in total plasma tryptophan. Antidepressant treatment: drugs and phase advance.

The authors investigated hourly total plasma tryptophan concentrations over a 24 hour period in 3 patients with bipolar depression during 2 types of treatment: a phase advance process and conventional antidepressant therapy. Both treatment modalities increased the 24 hour mean tryptophan levels and the amplitude of circadian tryptophan concentrations. By contrast, in a previous study, moderately decreased tryptophan levels and a blunted amplitude in the circadian rhythm were observed in these same patients in a depressive phase.

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.

Open trial of a calcium antagonist, nimodipine, in acute mania.

Following previous works showing an action of calcium channel blockers in mania, this trial explores the clinical efficiency of another anticalcic agent, nimodipine, which has been selected for its specific action on the CNS. Our design has been a 7-day controlled open trial. We included six inpatients diagnosed according to DSM III-R criteria as having mild to acute mania. Evaluations have been made by clinical scales, electroencephalography, electrocardiography, and extensive biological blood tests. No other medication than nimodipine was allowed excepted i.m. droperidol in case of severe excitement. We used nimodipine at a dose of 360 mg/day. The results showed good clinical efficiency in each of our six inpatients, with an important and significant improvement of scales scores. We noticed an early and significant action on mood without important sedative effect. The treatment has been well tolerated, without biological effects. Further studies are needed, but nimodipine could be an alternative treatment to the neuroleptics with a different type of action, less sedative and more specific on mood.

Tryptophanemia and tyrosinemia in adolescents with impulsive behavior.

Tryptophan (TRP) and tyrosine (TYR), respectively the circulating precursors of the central serotonergic (5-HT) and catecholamine systems, were measured in eight adolescents with impulsive behavior regardless of the exact type of disorder. The 6 week study period included weekly blood sampling and clinical evaluation. The ratios of TRP and TYR to large neutral amino acids (LNAA), which indicate the availability for the synthesis of neurotransmitters, were calculated. Comparison of results with eight hospitalized controls of the same age (12.5 to 18 years) revealed lower total TRP levels in four adolescent patients, a lower TRP/LNAA ratio in three adolescents, and a lower free TRP concentration in six adolescents with discretely enhanced albuminemia. A slight increase in TYR and the TYR/LNAA ratio was noted in nearly all of the adolescent patients. Despite the heterogeneity of individual biological results, the impulsive behavior subjects in this study seemed to present abnormalities in neurotransmitter precursors.

Cost of anxiety disorders: impact of comorbidity.

The aim of this study was to assess the relative impact of co-mobidity and of symptom severity on the costs of caring for patients with generalized anxiety disorders (GAD). One thousand and forty-two patients with GAD according to DSM III-R were observed by psychiatrists using a cross-sectional methodology. Demographic, clinical, therapeutic as well as health care utilization data were collected at a single point in time. Patients were stratified according to prevalence of co-morbidity. An economic analysis was performed based on a societal perspective. Hospitalizations and losses of productivity were the two major components of costs both in patients with and without co-morbidity. On the other hand costs of pharmaceuticals remain a marginal component of costs associated with GAD in the two groups. Controlling for confounding variables, the prevalence of health care utilisation was found to be significantly higher in patients with co-morbidity for hospitalization, laboratory tests, medications and absenteeism from work. Most of cost components were found to be significantly higher in patients with co-morbidity. The relative risk of health care utilization was higher in patients with co-morbidity, past history of anxiety, high level of anxiety as well as in older patients. Overall our findings suggest that both co-morbidity and symptom severity play a role in cost generation in GAD patients.

Influence of environmental factors on suicidal behavior.

The regional distribution of completed suicide was analyzed in 19 regions of France for the years 1975 and 1983. The regional distributions of environmental variables (ambient temperature, sunlight duration, and precipitation) and of sociological factors (social cohesion, socioeconomic status, status of women, and social support) were then correlated using Pearson coefficients, stepwise regression analysis, and partial correlations. Our main finding is that environmental factors such as ambient temperature may play a role in the regional distribution of completed suicide in France. Both the stepwise regression analysis and the controlled regression analysis revealed that, among all the variables studied (environmental and sociological), the main factors affecting the regional distribution of suicide were ambient temperature and sunlight duration. To our knowledge, this is the first detailed study demonstrating a clear relationship between environmental variables and suicidal behavior. The finding may be consistent with the recent description of forms of affective disorders occurring in relationship to environmental factors.