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This 4-week, double-blind, randomized study was undertaken to determine the dose-response relationship of amisulpride in 319 patients with acute exacerbation of schizophrenia. Fixed doses of amisulpride (400, 800 and 1200 mg/day) and haloperidol (16 mg/day) were compared to amisulpride, 100 mg/day, as a potentially subtherapeutic dose. Efficacy data (BPRS total score and PANSS positive subscale) in the amisulpride groups generated a bell-shaped dose-response curve, with 400 mg/day and 800 mg/day being the most effective treatments for positive symptoms. Parkinsonism did not increase significantly between baseline and endpoint with amisulpride 400, 800 and 1200 mg/day compared to the amisulpride 100 mg/day group, whereas the difference was significant for haloperidol (P

SummaryThe effects of acute tryptophan depletion were investigated in 20 healthy volunteers. Ten of them received a balanced amino acid solution and 10 a tryptophan-free solution. The fall in tryptophan levels induced by the oral administration of a mixture tryptophan-free of L-amino acids was - 77% for free tryptophan and - 81% for total tryptophan. Before treatment, there were intergroup differences affecting alertness parameters (critical flicker threshold, recognition reaction time), plasma levels of prolactin and baseline performance in the proofreading correction test. In the tryptophan-depleted group, the number of errors reported during the unpleasant sound signal was increased (+ 48%) after treatment, whereas the number of errors fell (— 15%) in the group receiving the tryptophan supplement. Conversely the levels of prolactin were correlated with those of serum tryptophan. Few subjective effects were reported.

BackgroundThe efficacy of low doses of certain neuroleptics in improving negative symptoms is still controversial. This study assessed the efficacy of amisulpride, a benzamide which increases dopaminergic transmission at low doses via presynaptic dopamine receptor blockade, on negative symptoms of schizophrenia.MethodThe study was designed as a parallel-group, double-blind, placebo-controlled trial. Patients had to fulfil DSM–III criteria for schizophrenia, Andreasen's criteria for negative schizophrenia, and to have a total score of at least 75 on the SANS; those treated with neuroleptics or antidepressants underwent a six-week placebo wash-out. One hundred and four in-patients were randomly assigned to amisulpride 100 mg/d, amisulpride 300 mg/d, or placebo for six weeks; 85 patients completed the study.ResultsBoth amisulpride doses were significantly more effective than placebo on the primary evaluation criterion (SANS total score, MANOVAP< 0.02). No significant changes were found in positive symptoms or in extrapyramidal symptoms.ConclusionsNegative symptoms can be improved by low doses of amisulpride, favouring the hypothesis of dopaminergic hypofunction as one of the causes of negative symptoms.

The present study provides evidence that, in mice subjected to the forced swimming test, the anti-immobility effect of the tricyclic antidepressants, desipramine and impramine (16–32 mg/kg) was antagonized by the acute co-administration of a benzodiazepine, diazepam (0.25–2 mg/kg) and lorazepam (0.125 mg/kg). This effect cannot be accounted for by variations in plasma and/or brain levels of each compound since brain and plasma concentrations of desipramine and plasma levels of diazepam and desmethyldiazepam, measured immediately after the swimming test, were not significantly modified by the co-administration. Diazepam (2 mg/kg) also counteracted the reduction of time spent immobile induced by the MAO inhibitors, toloxatone (256 mg/kg) and selegiline (4 mg/kg) and the 5-HT1A receptor agonist, 8-OH-DPAT (1 mg/kg), but not by the psychostimulant, caffeine (32 mg/kg). The sedative neuroleptic, thioridazine (4 mg/kg) was also found to reverse the anti-immobility effect of desipramine whereas the non-benzodiazepine anxiolytics, alpidem (8 mg/kg) and buspirone (0.5 mg/kg) did not. These results indicate that the observed interactions were unlikely to be accounted for by a reduction of the stressful aspect of the situation whereas the participation of some motor or sedative component could not be totally ruled out.

SummaryThe dopaminergic agonist apomorphine hydrochloride (0.1, 0.2 and 0.4 mg s.c.) compared to placebo in a double-blind, latin square design induced yawing in population of 8 healthy volunteers. Yawning was the only behavioral effect observed and was not dose-related, as all the 3 doses were equipotent. Yawning was maximum between 10 and 20 min post-injection and did not last longer than 20 min. Compared to the data in the literature, 0.1 mg is the lowest dose described as inducing yawning in man. Further studies using doses lower than 0.1 mg would be required to determine the highest inactive dose in order to use apomorphine-induced yawning as an index of CNS dopaminergic receptor sensitivity.

SummaryThe target for the efficacy of energizing neuroleptics on negative symptoms in schizophrenic patients may be the schizophrenic illness itself, or the existence ol a subgroup of negative symptoms. We searched for a non-psychotic population presenting a negative syndrome. A group of patients complaining of loss of interest, anhedonia, anergia, fatigue but with no painful mood, who did not meet the criteria for primary depression (Feighner 1972) and who had never presented psychotic symptoms seemed appropriate to answer this question. We Present here the results of a double-blind therapeutic trial in 93 outpatients, comparing the effects of 2 dosages of amisulpride, a neuroleptic of the benzamide substitute group, with a placebo. In these non-psychotic subjects, the 50 mg daily dose produced a significantly greater improvement in the negative syndrome than the placebo, and a non-significant intermediary improvement with the dose of 100 mg. The encouraging results must nevertheless be interpreted witli prudence, and confirmed by further studies due to the high number of drop-outs in the 50 mg group. This resuit indicates a transnosological effect of energizing neuroleptics on negative symptoms.

SummaryIn a double-blind cross-over study realized in 8 healthy volunteers, a bolus injection of yohimbine (0.15 mg/kg) followed by an infusion (0.0025 mg/kg/min) induced a raise of blood pressure without affecting selfratings. Total dose was 0.3 mg/kg. One subject out of 8 experienced a severe anxiety episode under yohimbine and dropped out.

RésuméL’activité d’un système de neurotransmetteurs dépend à la fois de la quantité de neuromédiateur présent dans la fente synaptique et de la réactivité de l’ensemble récepteur-post récepteur. Dans le cadre de l’hypothèse noradrénergique des états dépressifs, la majorité des études ont eu pour objectif de mettre en évidence une diminution de libération de noradrénaline, et peu d’études se sont intéressées à la réactivité des récepteurs adrénergiques. Une hypersensibilité pourrait exister, réactionnelle à une diminution de noradrénaline présente dans la fente synaptique ; une hyposensibilité chez certains patients pourrait expliquer un hypofonctionnement noradrénergique tout autant qu’une diminution de libération de la noradrénaline. Par ailleurs, l’effet thérapeutique des antidépresseurs semble être en relation avec la stimulation des récepteurs bêta-adréneigiques centraux. L’effet thérapeutique des antidépresseurs pourrait donc varier selon la réactivité initiale de ces récepteurs avant traitement.En l’absence de modèle de mesure de la réactivité des récepteurs bêta-adrénergiques centraux, l’étude de la dose d’isoprénaline nécessaire pour augmenter de 20 battements par minute la fréquence cardiaque (DE20), a été utilisée ici comme index de réactivité des systèmes bêta-adrénergiques. Chez des malades déprimés sans traitement antidépresseur, la DE20 est significativement augmentée indiquant une hyporéactivité du système bêta-adrénergique cardiaque. Cette modification est plus importante chez les déprimés endogènes. Cette hyporéactivité semble ne pas pouvoir être expliquée par l’âge.Ces résultats sont compatibles avec ceux de la littérature, indiquant une diminution du nombre de récepteurs bêta-adrénergiques au niveau des lymphocytes, ou une diminution de la production d’adénosine monophosphate cyclique induite par l’isoprénaline au niveau des lymphocytes.Après traitement antidépresseur (un mois) cette hyporéactivité est significativement accrue. Ces résultats chez l’homme sont compatibles avec ceux de pharmacologie expérimentale, indiquant une diminution du nombre de récepteurs bêta centraux après administration chronique d’antidépresseurs.

SummaryAs emphasized by Lecrubier in 1980, the major finding of the last thirty years of classical neuroleptic use in schizophrenia is not that they are antischizophrenic or antipsychotic agents, but that they act on positive symptoms whatever the cause. There is now a widely accepted attribution of this kind of therapeutic property to the post-synaptic dopaminergic blockade induced by most of the neuroleptics when administered at high doses. On the other hand, during the last decade, various authors have reported clear evidence for a disinhibitory action of some neuroleptics when used at low doses. From a clinical point of view, the literature on the therapeutic action of low doses of neuroleptics seems quite controversial. In order to assess the exact determinants for clinical activity of neuroleptics (such as patient type, selected substances, administered doses) two series of independent controlled studies were conducted.First series of studies: active drugs at low and high doses in schizophrenic patients(Tables 1 to 6)The first study was designed to assess the change of negative symptoms under low doses of neuroleptics. Sixty-two patients meeting the DSM III criteria of schizophrenia (subtypes: disorganized, catatonic or residual) were randomly assigned after a three-week washout period to six weeks’ treatment with either amisulpride (50 to 300 mg/day) or fluphenazine (2 to 12 mg/day), administered in keeping with a flexible dosage schedule. All patients had to meet the Andreasen criteria for negative symptoms (at least two of the following components had to be checked as present: anhedonia, alogia, affective flattening, avolition-apathy, attentional impairment). None of the patients presented one of the positive components to a marked degree: hallucinations, delusions, bizarre behavior, positive formal thought disorders. The evolution of symptomatology was assessed by means of the Brief Psychiatric Rating Scale (B.P.R.S.) and an ad hoc defective symptoms scale (D.S.A.S.), the sensitivity and reliability of which was previously tested in our department. The results show that the two groups (amisulpride versus fluphenazine) were initially highly comparable. Negative symptoms were severe, as evidenced by the D.S.A.S. scores, and by the presence of three items of the A6 criterion of the DSM III. The final global clinical assessment and the final D.S.A.S. scores both showed a significant improvement, with no statistically significant difference between the two treatments. Nevertheless, the scores of the “anergia” and “anxiety-depression” factors of the B.P.R.S. showed a significantly greater improvement in the amisulpride group.The second study, complementary to the first, aimed to check the efficacy of high doses of amisulpride on the productive symptoms of schizophrenia. In this case, only the B.P.R.S. was used due to the good correlation of this scale with the global severity of the positive symptomatology. After three weeks of treatment, consisting either of amisulpride at a high, flexible dosage (800 to 1200 mg/day) or of haloperidol (20 to 30 mg/day), each of the two groups of twenty patients showed a significant improvement. In particular, the “thought disorders” factor of the B.P.R.S. (which unfortunately does not correspond exactly to the “formal thought disorder” component of the Andreasen positive symptoms scale - S.A.P.S.) was greatly improved in both groups. Evolution of the other symptoms was however identical in the two groups.Second series of studies: active drugs versus placebo in schizophrenia(Figures 1 to 6)As we know, dopaminergic blocking agents are able to induce negative symptomatology. Consequently, to separate the secondary syndrome from the true deficit, a longer washout period than that previously described has to be imposed. On the other hand, the longitudinal course of schizophrenia must be taken into account for correct interpretation of changes in symptomatology; for example, patients with negative symptoms may abruptly present productive episodes, in particular during the neuroleptic withdrawal period. For optimal control of these two variables (natural history of the disease, the blunting effect of neuroleptics), 90 patients presenting either or both subtypes of schizophrenia were selected and included in a two-step, double-blind, controlled study. Patients with negative symptoms underwent a six-week washout period, after which they were treated either with low doses of amisulpride (100 or 300 mg/day) or a placebo. Patients with initial positive symptoms received mandatory high doses of amisulpride. According to the protocol, negative patients presenting productive symptoms during the washout period were to be systematically assigned to the highdose group. First results concerning 38 patients with a predominant negative symptomatology are presented here. A very clear improvement can be shown both for the SANS global mean score and for the sum of global ratings in the groups treated with low doses of amisulpride compared to the placebo group. The scores of the alogia, blunted affect and attentional impairment subscales decrease dramatically as well with the active drug.

SummaryIn a preliminary study the effect of tyramine, used as eye-drops, was assessed in two different ethnical groups composed of healthy volunteers: 6 Africans and 6 Caucasians.Tyramine-induced mydriasis in the Caucasian group was 5 times greater than in the African group.Similar differences had already been observed for indirect sympathominetic amines (ephedrine and cocaine) used as mydriatics, as well as for the effects of alpha 1 blocking drugs on the vascular system.Very few data are available in the literature concerning the CNS effects of drugs modulating the alpha adrenergic receptors.

Summary— This study evaluated the effects of acute doses of zopiclone (7.5 mg), triazolam (0.25 mg) and placebo on memory and psychomotor performance of 12 normal volunteers. The subjects received both drugs in a repeated measure, double-blind Latin square design. The tests (CFF, CRT, DSST, memory assessments) were performed before and 2 and 6 hr after treatment. Zopiclone and triazolam induced an anterograde amnesia affecting short-term and long-term memory which lasted less than 6 hr. No retrograde amnesia was observed. Two hr after drug intake of both hypnotics psychomotor performances were significantly altered compared with placebo. The subjects also felt more drowsy, dizzy, clumsy and tired, and less alert and energetic 2 hr after zopiclone and triazolam compared to placebo. There was no difference between the effects of the two hypnotics at the doses studied.