Optimal duration of risperidone or olanzapine adjunctive therapy to mood stabilizer following remission of a manic episode: A CANMAT randomized double-blind trial.

Atypical antipsychotic adjunctive therapy to lithium or valproate is effective in treating acute mania. Although continuation of atypical antipsychotic adjunctive therapy after mania remission reduces relapse of mood episodes, the optimal duration is unknown. As many atypical antipsychotics cause weight gain and metabolic syndrome, they should not be continued unless the benefits outweigh the risks. This 52-week double-blind placebo-controlled trial recruited patients with bipolar I disorder (n=159) who recently remitted from a manic episode during treatment with risperidone or olanzapine adjunctive therapy to lithium or valproate. Patients were randomized to one of three conditions: discontinuation of risperidone or olanzapine and substitution with placebo at (i) entry ('0-weeks' group) or (ii) at 24 weeks after entry ('24-weeks' group) or (iii) continuation of risperidone or olanzapine for the full duration of the study ('52-weeks' group). The primary outcome measure was time to relapse of any mood episode. Compared with the 0-weeks group, the time to any mood episode was significantly longer in the 24-weeks group (hazard ratio (HR) 0.53; 95% confidence interval (CI): 0.33, 0.86) and nearly so in the 52-weeks group (HR: 0.63; 95% CI: 0.39, 1.02). The relapse rate was similar in the 52-weeks group compared with the 24-weeks group (HR: 1.18; 95% CI: 0.71, 1.99); however, sub-group analysis showed discordant results between the two antipsychotics (HR: 0.48, 95% CI: 0.17; 1.32 olanzapine patients; HR: 1.85, 95% CI: 1.00, 3.41 risperidone patients). Average weight gain was 3.2 kg in the 52-weeks group compared with a weight loss of 0.2 kg in the 0-weeks and 0.1 kg in the 24-weeks groups. These findings suggest that risperidone or olanzapine adjunctive therapy for 24 weeks is beneficial but continuation of risperidone beyond this period does not reduce the risk of relapse. Whether continuation of olanzapine beyond this period reduces relapse risk remains unclear but the potential benefit needs to be weighed against an increased risk of weight gain.

Cholecystokinin: Corelease with dopamine from nigrostriatal neurons in the cat.

Halothane-anaesthetized cats were implanted with push-pull cannulae to demonstrate the in vivo release of cholecystokinin-like immunoreactivity (CCK-LI) in the substantia nigra and the ipsilateral caudate nucleus. The spontaneous and the calcium-dependent potassium-evoked release of CCK-LI were observed in both structures. In addition, the local application of tetrodotoxin (10-6 M) reduced the spontaneous release of the peptide. 6-OHDA lesions made in the substantia nigra pars compacta led to a complete destruction of nigrostriatal dopaminergic neurons. CCK-LI levels were not affected in the caudate nucleus but were reduced substantially in the substantia nigra. The activation of dopaminergic cells induced by the nigral application of alpha-methyl-para-tyrosine (10-4 M) stimulated the release of CCK-LI and dopamine in the ipsilateral caudate nucleus, whilst opposite effects were seen in the substantia nigra. Similar results were obtained when dopaminergic transmission was blocked in the caudate nucleus suggesting that the evoked release of CCK-LI by the alpha-methyl-para-tyrosine treatment originates from dopaminergic nerve terminals and not from other CCK-LI containing fibres in response to released dopamine. Dopamine (10-7 M) as well as the D1 agonist SKF 38393 (10-5 M) stimulated CCK-LI release when applied into the caudate nucleus while the D2 agonist, LY 171555 (10-6 M) slightly reduced peptide release. The local application of cholecystokinin-8 sulfate (CCK-8S) (10-8 M, for 30 min) into the substantia nigra pars compacta increased the firing rate of dopaminergic cells and stimulated the release of newly synthesized 3H-dopamine from dendrites and nerve terminals. These results suggest, but do not definitively prove, that, in the cat, CCK-LI and dopamine are coreleased from nigrostriatal mixed dopaminergic/CCK-LI neurons and that CCK-LI released from dendrites is, like dopamine, involved in the regulation of the activity of these cells.

Corpus callosum agenesis and psychosis in Andermann syndrome.

Recent illustrations by cerebral magnetic resonance imaging of anomalies of the corpus callosum in schizophrenics have kindled renewed interest in this association. We studied 62 patients affected by the Andermann syndrome, a polymalformative familial syndrome combining frequent congenital corpus callosum agenesis, mental retardation, psychotic episodes, peripheral neuropathy, and some dysmorphic features. Twenty of 62 patients presenting with psychosis were compared with 20 nonpsychotic patients matched according to sex and age. The psychotic patients presented an atypical psychosis as defined by the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, beginning in postadolescence. No significant relationship was observed between corpus callosum agenesis and psychosis. However, a significant association between posterior fossa atrophy and psychosis was established in our study. Although there are limitations in using cross-sectional data for this purpose, the findings suggest an association between cerebellar anomalies and schizophrenialike syndrome and rule out an implication of developmental callosal defects in such psychiatric disorders.

In vivo presynaptic control of dopamine release in the cat caudate nucleus--II. Facilitatory or inhibitory influence of L-glutamate.

The local effects of various concentrations of L-glutamate (from 10(-8) M up to 10(-3) M) on the release of [3H]dopamine synthesized continuously from [3H]tyrosine were examined in the caudate nucleus of halothane-anaesthetized cats implanted with push-pull cannulae. When used at a concentration of 10(-8) M or 10(-7) M, L-glutamate stimulated the release of [3H]dopamine from nerve terminals of the nigrostriatal dopamine neurons. This effect was still observed in the presence of tetrodotoxin (5 X 10(-7) M) but it was antagonized by 2-amino 6-trifluoromethoxy benzothiazole (PK 26124) (10(-5) M), an antagonist dopamine nerve terminals. While no significant change in the release of [3H]dopamine was observed with 10(-6) M L-glutamate, higher concentrations (from 10(-5) M to 10(-3) M) of the amino acid produced a long-lasting reduction in the [3H]transmitter release. This latter effect was also antagonized by PK 26124 (10(-5) M) but, unlike that observed with 10(-8) M L-glutamate, it did not persist in the presence of tetrodotoxin (5 X 10(-7) M). On the contrary, a marked stimulation of the release of [3H]dopamine was seen in the presence of this neurotoxin. The reduction in the release of [3H]dopamine produced by 10(-4) M L-glutamate was also antagonized by bicuculline (10(-5) M) and moreover a marked stimulation of [3H]dopamine release took place in the presence of this gamma-aminobutyric acid (GABA) antagonist. Therefore, high concentrations of L-glutamate exerted an inhibitory presynaptic control on [3H]dopamine release which seemed to be indirect and mediated partly by GABAergic neurons. Since a sustained reduction in the spontaneous release of [3H]dopamine was seen in the presence of PK 26124, the corticostriatal glutamatergic neurons appeared to exert a tonic facilitatory presynaptic influence on dopamine release. This effect was important since it represented 40% of the tetrodotoxin-sensitive release of the [3H]transmitter. The direct (stimulatory) and indirect (inhibitory) presynaptic controls on dopamine release mediated by corticostriatal glutamatergic fibres are discussed in light of previous findings and of the anatomical organization of the caudate nucleus.

Substance P and neurokinin A regulate by different mechanisms dopamine release from dendrites and nerve terminals of the nigrostriatal dopaminergic neurons.

Numerous striatal neurons innervating the substantia nigra contain substance P and/or neurokinin A. In contrast to substance P or neurokinin A, little neurokinin B is found in the substantia nigra. This led us to compare the effects of nigral application of these tachykinins on the release of dopamine from dendrites and nerve terminals of nigrostriatal dopaminergic neurons. Experiments were made in halothane-anesthetized cats implanted with one push-pull cannula in the substantia nigra and another in the ipsilateral caudate nucleus [3H]Tyrosine was delivered continuously to each push-pull cannula and the release of newly synthesized [3H]dopamine measured in the superfusate. Unlike substance P or neurokinin A, neurokinin B (10(-8) M) applied for 30 min into the pars compacta of the substantia nigra was without effect on the release of [3H]dopamine from nerve terminals or dendrites. When either substance P (10(-8) M) or neurokinin A (10(-8) M) was applied into the pars compacta, the release of [3H]dopamine from nerve terminals was enhanced. While neurokinin A also stimulated the dendritic release of [3H]dopamine, this was reduced by substance P. At a lower concentration (10(-9) M), neurokinin A induced similar effects to those observed at 10(-8) M whereas substance P (10(-9) M) stimulated moderately [3H]dopamine release from nerve terminals but did not affect the dendritic release of the [3H]amine. When superfused into the pars reticulata, substance P (10(-8) M) still stimulated [3H]dopamine release from nerve terminals but not from dendrites while neurokinin A (10(-8) M) was without effect either in the caudate nucleus or the substantia nigra. Additional experiments were made to determine whether or not substance P (10(-8) M) or neurokinin A (10(-8) M) act directly on nigral dopaminergic neurons when applied into the pars compacta. The effects of substance P on [3H]dopamine release from nerve terminals and dendrites were prevented when 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M), an antagonist of glutamatergic transmission, was applied continuously into the caudate nucleus. In contrast, the stimulatory effects of neurokinin A on [3H]dopamine release from nerve terminals and dendrites were insensitive to 2-amino-6-trifluoromethoxy benzothiazole (10(-5) M). These results suggest that neurokinin A, but not substance P, acts directly on dopaminergic cells. In the light of previous observations, we propose that the effects of substance P on dopaminergic transmission are mediated by a nigro-thalamo-cortico-striatal loop.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical psychomotor retardation and attention in depression.

The importance of the cognitive component in depressive clinical psychomotor retardation is well-recognized, but the underlying information-processing dysfunction has not been precisely investigated. Thirty unmedicated major depressives were concurrently assessed using the Depressive Retardation Rating Scale (DRRS) and an attentional battery in order to evaluate selective and divided attention. Results were analysed following dimensional and categorical approaches. The depressive episode intensity and the associated anxiety did not correlate with any of the attentional variables. However, significant correlations were observed between the DRRS score and every attentional task. Results of the categorical analysis contrasting attentional performances of depressives with and without clinical psychomotor retardation argued for the existence of a link between psychomotor retardation and a global attentional deficit. This study attests to the value of clinical psychomotor retardation as a predictor of cognitive deficits in depressed patients.

SSRIs in anxious-agitated depression: a post-hoc analysis of 279 patients.

A post-hoc analysis of nine controlled antidepressant trials examined the intensity of the initial anxiety and agitation of depressed patients improved by SSRIs compared with depressed patients improved by norepinephrine (NE) reuptake inhibitors, mixed NE/serotonin reuptake inhibitors and placebo. We report that SSRI responders were more anxious-agitated than NE reuptake inhibitor responders, suggesting a preferential efficacy of SSRIs in agitated depression.

Are there differential effects of fluoxetine in retarded/blunted affect versus agitated/anxious depressives? A clinical study.

BACKGROUND: Clinical selectivity of antidepressants with pharmacological specificity still remains under debate. METHOD: In the open trial presented below, the effects of fluoxetine, a selective serotonin re-uptake inhibitor (SSRI), were compared across two groups of depressive inpatients contrasted on their symptomatological expression (agitated/anxious versus retarded/blunted affect). Sixteen patients (8 in each groups) were included in the 4-weeks treatment period and submitted to a weekly-based evaluation. Global depression, retardation, emotional blunting, agitation, anxiety and mood profile were assessed. RESULTS: Significant improvements of the HDRS and MADRS scores were observed in both groups. Although no group x treatment interaction was found on the global scores of depression, a differential effect according to the group was observed on anxiety, agitation, irritability and emotional lability. DISCUSSION: These preliminary results support the hypothesis that the effect of fluoxetine on positive clinical dimensions could lead to a differential effect in patients with agitation/anxiety when compared with patients with retardation/blunted affect.

[Essential arterial hypertension and quality of life. Comparative crossed double-blind study of labetalol and captopril]. / Hypertension artérielle essentielle et qualité de vie. Essai comparatif en double-insu croisé du labétatol et du captopril.

The purpose of this multicenter randomised, double-blind and cross-over study was to compare the antihypertensive effects of labetalol (L) and captopril (C) in 42 moderate hypertensive patients (mean age: 52 years). The drugs were given during two 4-weeks periods at the end of which the systolic (SBP) and diastolic blood pressures (DBP) were measured at rest in supine and standing positions. The assessment of the quality of life was realized with 4 scales completed by the practitioner [anxiety, depression, well-being, visual analog scale (VAS)] and 4 scales of auto-assessment completed by the patient [2 VAS, well-being, sub-scale of pleasure]. At the end of the first treatment's period (D28), both drugs had decreased significantly supine SBP and DBP (p less than 0.001), standing DBP (L = p less than 0.01; C = p less than 0.05), while only L lowered supine SBP (p less than 0.01). The cross-over analysis was unable to conclude, due to the number of patients and a significant interaction which reduced its power. Thus the effect of the first treatment's period seemed to influence the efficacy of the second one. The percentages of patients with a controlled BP were respectively: after 4 weeks of treatment, L = 61 p. 100 vs C = 42 p. 100 and at the end of study (D56), L = 67 p. 100 vs C = 64 p. 100.(ABSTRACT TRUNCATED AT 250 WORDS)

[Blood pressure control and quality of life: a comparative multicenter double-blind and cross-over trial of labetalol and captopril]. / Contrôle tensionnel et qualité de vie: essai multicentrique comparatif en double-aveugle et croisé du labétalol et du captopril.

The purpose of this multicenter randomised, double-blind and cross-over study was to compare the antihypertensive effects of labetalol (L) and captopril (C) in 42 moderate hypertensive patients (mean age: 52 years). The drugs were given during two 4-weeks periods at the end of which the systolic (SBP) and diastolic blood pressures (DBP) were measured at rest in supine and standing positions. The assessment of the quality of life was realized with 4 scales completed by the practitioner [anxiety, depression, well-being, visual analog scale (VAS)] and 4 scales of auto-assessment completed by the patient [2 VAS, well-being, sub-scale of pleasure]. At the end of the first treatment's period (D28), both drugs had decreased significantly supine SBP and DBP (p less than 0.001), standing DBP (L = p less than 0.01; C = p less than 0.05), while only L lowered supine SBP (p less than 0.01). The cross-over analysis was unable to conclude, due to the number of patients and a significant interaction which reduced its power. Thus the effect of the first treatment's period seemed to influence the efficacy of the second one. The percentages of patients with a controlled BP were respectively: after 4 weeks of treatment, L = 61 p. 100 vs C = 42 p. 100 and at the end of study (D56), L = 67 p. 100 vs C = 64 p. 100. The cross-over analysis didn't show any difference between the effects of L and C on the quality of life.(ABSTRACT TRUNCATED AT 250 WORDS)

[Perphenazine enanthate. Results of a 1-year open multicenter study]. / Enanthate de perphénazine. Résultats d'une étude ouverte multicentrique d'un an.

The results of a one-year, open multicenter trial of perphenazine enanthate, a sustained-release neuroleptic drug, are reported. 240 patients (62% suffering from schizophrenia) were included in the study and 144 were followed during the 12-month period. The usual adverse reactions associated with sustained-release neuroleptic drugs were observed. Total and partial BPRS ratings showed that improvement (expressed as a percentage) after 12 months' treatment was similar for systematized chronic delusions, paranoid schizophrenia and hebephrenia. However, the onset of therapeutic activity was different in these three groups of patients. Maximum therapeutic activity, as defined by the BPRS rating, was obtained within 4 months in chronic delusions whereas schizophrenia improved more progressively. Such patients therefore require prolonged treatment before the therapeutic activity of a sustained-release neuroleptic drug can be assessed.

Early onset of lithium-associated hypothyroidism.

In general practice, psychiatrists are confronted with the difficulty of structuring a rational design for the early detection of hypothyroidism. To determine the period during which a patient receiving lithium is most at risk of developing hypothyroidism, a retrospective study was conducted on the records of 154 patients at two general hospital lithium clinics from January 1980 to August 1991. Forty-two cases of hypothyroidism (clinical hypothyroidism and/or abnormally elevated levels of TSH) were detected. A significant difference was found between the onset of hypothyroidism and age (older patients developed more thyroid dysfunction), but no significant differences were found between thyroid abnormality and sex or diagnostic category and menopausal status, although trends were observed for the two former variables. This longitudinal study is the first to describe an outline of thyroid functioning in terms of the duration of treatment. Lithium-associated hypothyroidism develops most often during the first two years. Of the 42 cases of hypothyroidism, 16 were diagnosed within six months (38%), 23 within the first year (55%), and 31 two years (74%). Since thyroid functioning is an important parameter in the course of affective disorders, its close and frequent monitoring is mandatory during the first two years of treatment.

[Pathological gambling: literature revue]. / Le jeu pathologique: une revue de la littérature.

This paper summarizes the current literature on pathological gambling. Interest in gambling has been present in every society but treated as an object of sociopolitical or literary interest. It is only from the beginning of this century that psychiatry began to look at pathological gambling, first with Freud and his writing on Dostoïevsky then with other theories like the learning theory, studies on substance dependence, the links with affective syndromes and the psychobiological studies. These studies are presented and discussed. Finally, the authors offer some guidelines for an approach to a pathological gambler.

[Involvement of the basal ganglia in obsessive compulsive disorder: a review]. / Implication des noyaux gris centraux dans le trouble obsessionnel-compulsif: une revue.

This article reviews the main clinical indicators linking the basal nuclei to obsessive compulsive disorder (OCD). Various pathologies associated with lesions of the basal nuclei are examined, followed by a review of neuropharmacological, brain imaging and psychosurgical studies. Once the role of the neostriatum in ritualistic behaviours has been clarified, the symptoms of OCD are interpreted based on the hypothesis of a lesion of the striato-orbito-frontal loop.