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"Early detection Of schizophrenia, why and who to contact? Schizophrenia usually occurs in late adolescence or early adulthood but is generally preceded by a prodromal phase or by a "high risk mental state" which corresponds to the onset of the disease. Early detection of symptoms and rapid specialized intervention begin at this stage. Medical intervention at this stage aims to influence the course of the disease and to limit the transition to a first-episode psychosis (FEP). Patients with FEP will require initiation of antipsychotic treatment. A long delay before antipsychotic treatment initiation will negatively impact the short and long term outcomes: more severe symptoms, worse treatment response and less global functioning. Early detection of schizophrenia involves general practitioners who will be firstly solicited by patients and their families. Patient should then be addressed without any delay to specialized psychiatric teams.", Competing Interests: "A. Vandevelde déclare n’avoir aucun lien d’intérêts.S. Dollfus déclare des liens durables avec MedAvante-ProPhase et VeraSci, des liens ponctuels avec Roche, Takeda et Gedeon Richter, et avoir été prise en charge lors de congrès par Janssen, Lundbeck et Otsuka."

The fronto-striato-thalamic circuitry is a key network in patients with schizophrenia (SZPs). We use diffusion tensor imaging (DTI) to investigate the integrity of white matter (WM) pathways involved in this network in SZPs relative to healthy controls (HCs). We also evaluate the differential impact of chronic exposure to clozapine as well as other atypical and typical antipsychotics. 63 HCs and 41 SZPs were included. Of the SZPs, 16 were treated with clozapine (SZPsC), 17 with atypical antipsychotics (SZPsA), and 8 with typical antipsychotics (SZPsT). Three tracts were reconstructed in the left hemisphere using tractography: one fronto-subcortical tract, one prefronto-subcortical tract, and one prefronto-frontal tract. Diffusion parameters were individually extracted in each tract. SZPs exhibited lower integrity in both the fronto-subcortical and prefronto-subcortical tracts relative to HCs, and SZPsT showed altered integrity compared to SZPsC. There were no WM integrity differences in the prefronto-frontal tract between SZP groups or between SZPs and HCs. SZPs exhibit structural connectivity abnormalities in the prefronto-fronto-subcortical network that are specifically and differentially impacted by the type of antipsychotic treatment. Additional studies are needed to separate the contributions of clozapine-mediated neuroprotection, neurotoxicity related to typical antipsychotics, and the illness itself to observed differences., (Copyright © 2018. Published by Elsevier B.V.)

Objective: Cognitive impairment, manifested as mild to moderate deviations from psychometric norms, is present in many but not all schizophrenia patients. The purpose of the present study was to compare the effect of haloperidol with that of second-generation antipsychotic drugs on the cognitive performance of patients with schizophreniform disorder or first-episode schizophrenia., Methods: Subjects were 498 patients with schizophreniform disorder or first-episode schizophrenia who were randomly assigned to open-label haloperidol (1 to 4 mg/day [N=103]), amisulpride (200 to 800 mg/day [N=104]), olanzapine (5 to 20 mg/day [N=105]), quetiapine (200 to 750 mg/day [N=104]), or ziprasidone (40 to 160 mg/day [N=82]). The Rey Auditory Verbal Learning Test, Trail Making Test Part A and Part B, WAIS Digit Symbol Test, and Purdue Pegboard Test were administered at baseline and the 6-month follow-up evaluation., Results: Compared with scores at baseline, composite cognitive test scores improved for all five treatment groups at the 6-month follow-up evaluation. However, there were no overall differences among the treatment groups. In addition, there was a weak correlation between the degree of cognitive improvement and changes in Positive and Negative Syndrome Scale scores., Conclusion: Treatment with antipsychotic medication is associated with moderate improvement in the cognitive test performance of patients who have schizophreniform disorder or who are in their first episode of schizophrenia. The magnitude of improvement does not differ between treatment with haloperidol and treatment with second-generation antipsychotics. Moreover, cognitive improvement is weakly related to symptom change.

Among new-generation antipsychotics, quetiapine was found to be associated with a partial 'normalization' of reduced functional activation in prefrontal and temporal areas and studies conducted by our group found a clinical improvement in negative symptoms in addition to restoration of frontal activation in schizophrenia patients with blunted affect after treatment with quetiapine. Here we investigated the parallelism between improved clinical symptoms and grey mater density (GMD) changes in the frontal region after quetiapine treatment in 15 schizophrenia patients. We hypothesize that improvement in clinical symptoms will be associated with change in GMD in prefrontal regions of interest. By using voxel-based morphometry, paired t-test random-effect analysis showed a significant increase in GMD bilaterally in the inferior frontal cortex/orbitofrontal gyrus and anterior cingulate cortex after 5.5 months of treatment with quetiapine. This GMD increase was associated with a significant improvement in negative symptoms. When GMD was correlated with psychiatric assessment scores, there was a negative correlation between GMD in the anterior cingulate cortex and the Rating Scale for Emotional Blunting score (r=-665, P=0.008) and between the orbitofrontal gyrus and the total Positive and Negative Syndrome Scale negative score (r=-764, P=0.001). Results suggest that increased GMD in some frontal regions are associated with an improvement of negative symptoms. Although not unique to quetiapine, it would be reasonable to attribute the GMD changes in the study to treatment.

Background: Second-generation antipsychotic drugs were introduced over a decade ago for the treatment of schizophrenia; however, their purported clinical effectiveness compared with first-generation antipsychotic drugs is still debated. We aimed to compare the effectiveness of second-generation antipsychotic drugs with that of a low dose of haloperidol, in first-episode schizophrenia., Methods: We did an open randomised controlled trial of haloperidol versus second-generation antipsychotic drugs in 50 sites, in 14 countries. Eligible patients were aged 18-40 years, and met diagnostic criteria for schizophrenia, schizophreniform disorder, or schizoaffective disorder. 498 patients were randomly assigned by a web-based online system to haloperidol (1-4 mg per day; n=103), amisulpride (200-800 mg per day; n=104), olanzapine (5-20 mg per day; n=105), quetiapine (200-750 mg per day; n=104), or ziprasidone (40-160 mg per day; n=82); follow-up was at 1 year. The primary outcome measure was all-cause treatment discontinuation. Patients and their treating physicians were not blinded to the assigned treatment. Analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN68736636., Findings: The number of patients who discontinued treatment for any cause within 12 months was 63 (Kaplan-Meier estimate 72%) for haloperidol, 32 (40%) for amisulpride, 30 (33%) for olanzapine, 51 (53%) for quetiapine, and 31 (45%) for ziprasidone. Comparisons with haloperidol showed lower risks for any-cause discontinuation with amisulpride (hazard ratio [HR] 0.37, [95% CI 0.24-0.57]), olanzapine (HR 0.28 [0.18-0.43]), quetiapine (HR 0.52 [0.35-0.76]), and ziprasidone (HR 0.51 [0.32-0.81]). However, symptom reductions were virtually the same in all the groups, at around 60%., Interpretation: This pragmatic trial suggests that clinically meaningful antipsychotic treatment of first-episode of schizophrenia is achievable, for at least 1 year. However, we cannot conclude that second-generation drugs are more efficacious than is haloperidol, since discontinuation rates are not necessarily consistent with symptomatic improvement.

Aim: The World Health Organization has defined quality of life as "the perception of an individual, his/her place in life, in the context of the culture and the system of values in which he/she lives and in relation to his/her objectives, expectations, standards and concerns". The quality of life of the schizophrenic patients has been largely studied for the evaluation of their medical, social and therapeutic needs. The impact of neuroleptics, in particular atypical neuroleptics, on the subjective quality of life of these patients remains to be specified. The aim of this study was to compare the subjective quality of life of schizophrenic patients treated with classical neuroleptics (CN) or atypical neuroleptics (AN)., Methods: One hundred patients meeting DSM IV criteria for the diagnosis of schizophrenia (American Psychiatric Association, 1994) were included in the study. Sixty-four schizophrenic patients were treated with CN and thirty-six with AN. The symptomatology of the patients was assessed using the Positive And Negative Syndrome Scale, (PANSS, Kay et al., 1987) and the Schedule for the Deficit Syndrome (SDS, Kirkpatrick et al., 1989). The extra-pyramidal symptoms were assessed using the Extrapyramidal Symptom Rating Scale (Chouinard et al., 1980). The Subjective quality of life was studied using the Lehman Quality of Life Interview (QOLI, Lehman, 1988) translated and validated in France., Results: The patients treated by CN did not differ from the patients treated by AN in terms of severity of the positive and negative symptoms. The patients treated with AN presented significantly less extrapyramidal side effects than the patients treated with CN. No significant difference in terms of quality of life was found between both groups of patients., Conclusion: The kind of neuroleptic (CN vs AC) does not seem to influence the quality of subjective life of schizophrenic patients.

Objective: To compare the efficacy of two atypical antipsychotic drugs, olanzapine and risperidone, in schizophrenic patients with post-psychotic depression., Results: A clinically significant decrease of MADRS scores occurred in patients treated with both drugs for 8 weeks., Conclusion: Atypical antipsychotic drugs may be particularly appropriate when treating schizophrenic patients with depression.

The atypical antipsychotic zotepine was compared to haloperidol in 126 patients suffering from acute exacerbation of schizophrenia (DSM-III-R) in a randomized, double-blind study. After 8-weeks, 150 to 300 mg zotepine improved scores on the Brief Psychiatric Rating Scale (BPRS) more than 10 to 20 mg haloperidol (-17.03 versus -13.45; 95%CI for zotepine-haloperidol -9.34/2.04). BPRS subscores and Clinical Global impressions (CGI) Severity and improvement subscales showed comparable gains, but scores on the Scale for the Assessment of Negative Symptoms (SANS) improved significantly more with zotepine (-23.82) than haloperidol (-15.15; P < .05; 95%CI for zotepine haloperidol -18.03/-0.18). Adverse events were reported by 71 percent of zotepine and 78 percent of haloperidol patients. Extrapyramidal side effect (EPMS) scores decreased with zotepine (-0.34) but increased with haloperidol (+2.32; P < .05). Seven haloperidol patients reported akathisia but no zotepine patients did (p < .05). Uric acid reductions (which appear to have no clinical consequence) and transient raised liver enzymes were recorded with zotepine. Weight increased on zotepine (2.32 kg; P < .001) and a small increase in pulse rate occurred (P < .05). Both drugs were effective in reducing positive symptoms of schizophrenia; zotepine was significantly more effective against negative symptoms and reduced EPMS.

Since the Bleuler's early writings, studies in schizophrenia have often shown a frequent occurrence of depression in the context of schizophrenia and also its implications for the morbidity and mortality of schizophrenic patients. The wide variability in the prevalence of depression (between 7 to 70% in post-psychotic period) is due in part to the difficulty in clearly separating depressive symptoms from akinesia induced by neuroleptic or negative symptoms and to the lack of a valid assessment of depressive symptoms in schizophrenic patients. Under these conditions, a better understanding of depressive symptomatology in schizophrenia seems to be necessary to go further in this area of research with clinical and therapeutical purposes. The "Echelle de Ralentissement Dépressif" (ERD, Widlöcher, 1983) was studied in a sample of 53 schizophrenic patients to determinate whether ERD composed of three subscores (motor, ideic and subjective) could be able to evaluate the subjective depressive symptomatology and whether its measure would be independent of negative symptoms or akinesia. Pearson's correlations and correlations with variables partialled out were used to compare ERD to Montgomery and Asberg Depression Rating Scale (MADRS, 1979) and to establish their relationship with Positive And Negative Syndrome Scale (PANSS< Kay, 1987) and an Extrapyramidal Symptom Rating Scale (ESRS, Chouinard & Ross-Chouinard, 1980). Fifty three in or outpatients (35 males and 18 females, mean age +/- standard deviation = 38.26 +/- 9.82) were evaluated in a stable condition (i.e., when the psychotic symptomatology and the neuroleptic treatment have been stabilized since 4 weeks). According to DESM III-R criteria, 49 patients met the diagnosis of schizophrenia (2 schizoaffective disorders and 2 schizophreniform disorders).(ABSTRACT TRUNCATED AT 250 WORDS)

In infantile autism, the serotoninergic (5-HT) hypothesis is corroborated by biological dosages and therapeutic effects of fenfluramine which decrease blood serotonin. However other drugs, such as dopaminergic agonists or antagonists, have therapeutic effects. Therefore, we tested the hypothesis that two dopaminergic (DA) drugs have a similar 5-HT effect underlying the therapeutic efficiency. We evaluated in a randomized, double-blind and cross-over study, the effects of a DA agonist (bromocriptine) and a DA antagonist (amisulpride) on platelet 5-HT in infantile autism. The prolactinemia, reflecting the DA action, has been also measured. Nine children, aged from 4 to 13 years, according to the DSM III for infantile autism, received either drug in a random order during four weeks with an in-between placebo period of six weeks. The dosages of platelet 5-HT and serum prolactin were carried out at the beginning and at the end of every phase of treatment (active or placebo) with radioenzymology and radioimmunoassay methods respectively. The principal results on serum prolactin show neither order x treatment interaction, nor order effect but a significant treatment effect (p < 0.01): amisulpride increases serum prolactin whereas bromocriptine decreases according to the usual data. About platelet 5-HT, there is neither order x treatment interaction, nor treatment effect but a significant order effect (p < 0.01). Both drugs increase platelet 5-HT in the first phase of treatment. This order effect could be explained by a remanent effect of amisulpride after 6 wash-out weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

From the study of Kane et al. (1988), devoted to clozapine, a critical analysis of criteria of assessments about studies in treatment of resistant schizophrenic patients was drawn up. Therefore, among the inclusion criteria, the authors strengthen the necessity of a very long past neuroleptic treatment (beyond six months) before diagnosing a resistance, the "drug-free improvers" characterized by improvement when patients had been treated by a placebo, the necessity of a very long placebo wash-out (beyond six weeks), and the improvement by a second treatment after a first ineffective treatment. Moreover, the doses of neuroleptics opposed to clozapine are often too high leading to adverse effects and so decreasing the positive benefits. For instance, the dose of chlorpromazine is often increased to 1,800 mg/day whereas the doses required should be only 600 mg/day in equivalence to 500 mg/day of clozapine. Lastly, the scales more specific of the symptomatology of schizophrenia such as SANS-SAPS or PANSS should be used in the clinical trials whereas until now, all the studies were made by standard and global evaluations with BPRS, CPRS and AMDP.

An alteration of dopaminergic (DA) function much more complex than simple hyperactivity has been evoked in infantile autism. We therefore compared the clinical efficacy of a DA antagonist (amisulpride) and a DA agonist (bromocriptine) in a randomized, double-blind, crossover trial in 9 children with autism, likely severely mentally retarded. Amisulpride acts preferentially on specific autistic symptoms whereas bromocriptine acts more on motor hyperactivity and attention symptoms. These findings raise the specificity of these two drugs which appear to act preferentially on some target symptoms and are consistent with some clinical and pharmacological observations showing a sedative effect with low doses of DA agonists and a stimulant effect with low doses of DA antagonists such as the benzamides.

Feasible and ideal methodological conditions lacking, we have tried an evaluation concerning the efficacy of neuroleptics upon the course of schizophrenia by comparing the evolution of homogeneous studies before and since the neuroleptic period. On the short term, neuroleptics are significantly more effective than the placebo upon schizophrenic symptoms and prevent the relapses in an noteworthy manner. On the long term, the evolution is significantly better for follow-up studies treated by neuroleptics (60% of patients improved) than for the non-treated follow-up studies i.e. before neuroleptic period (27.5% of patients improved). The time of the follow-up has an effect on the course of schizophrenia. Before neuroleptic periods, the schizophrenic process beyond 6 to 10 years was either stabilized or worsened. On the contrary, since the neuroleptic period, the number of improvements continued to increase after 12 years time (79.5% of patients improved for the follow-up beyond 12 years time versus 60% under 12 years). These improvements include paranoid and hebephrenic forms. On the contrary, catatonic forms had decreased very much since the utilization of neuroleptics (they moved from 18 to 28% before neuroleptic periods to 2% after the beginning of utilization of neuroleptics). If neuroleptics have undeniable action upon the schizophrenic symptomatology, they also act, on the long term, upon the social course of schizophrenia (30% of social remission before neuroleptic period versus 50% since neuroleptic period).

Five years ago, Goldberg claimed that negative symptoms of schizophrenia do respond to neuroleptics. This apparent discovery is, in fact, a very common way of thinking for European schools of psychiatry, specially the French one guided by Delay and Deniker. Initially focused on reserpine and some alerting phenothiazines such as thioproperazine, this opinion has been extended to benzamides in the 1970s. The analysis of the publications devoted to this point indicates that several drugs are actually considered as potent disinhibitors (i.e. active on negative symptoms of schizophrenia): Phenothiazines: As shown in the controlled studies by Itil (1971), Poirier-Littré (1988), fluphenazine and pipotiazine improve the BPRS anergia factor and the SANS score. Butyrophenones: The first description of the "imipramine like" effect of trifluperidol by Janssen (1959) initiated the studies by Gallant (1960), Fox (1963). They compared trifluperidol at low doses versus haloperidol and chlorpromazine at medium and high doses, BPRS anergia factor improved only at low doses. Diphenylbutylpiperidines (DPBP): Meltzer's review (1986) concluded to the efficacy of such drugs on negative symptoms appearing as a specific biochemical relationship effect. A definite analysis about doses leads to a very different interpretation: DPBP low doses and only low doses improved negative symptoms as much as some low doses of phenothiazines. On the opposite, DPBP, phenothiazines and butyrophenones high doses are inefficient.(ABSTRACT TRUNCATED AT 250 WORDS)

Biological treatments of schizophrenia primarily consist of neuroleptics. These drugs can be prescribed in a relatively standardized manner (chlorpromazine equivalent), but neuroleptics will be less than effective on the type of schizophrenia with negative symptoms. Treatment can also be performed by utilizing the bipolarity of some drugs, and it is only with these drugs that resistant schizophrenia can be mobilized. Consideration is also given to other biological treatments and new prospects in chemotherapy.

The biochemical effects of neuroleptic drugs are reviewed step by step. The necessity to go beyond such a didactic way is highlighted considering two points; on the one hand neuroleptic drugs do affect more than one neurotransmitter system and on the other hand monoaminergic and peptidergic system exert reciprocal influences. From this point of view the consequences of the biochemical effects of neuroleptic drugs remain a wide open road for clinical pharmacology.

Abstract: This article is an update on the prescription of antipsychotics during a first psychotic episode (FPE). It demonstrates the interest and the importance of starting antipsychotics as soon as possible when psychotic symptoms emerge. It reviews the recommended doses, the duration of treatment and particularly the type of antipsychotics (first or second generation). If second generation antipsychotics (SGA) are recommended in the treatment of FPE, in Canada for instance, short and long term comparative studies have not shown their superiority on treatment of psychotic symptoms compared to the first generation antipsychotics (FGA). However, several studies agree on the fact that FPE patient treated with SGA maintains his/her treatment for a longer time and has a lesser risk of relapse associated with lesser neurological side effects. Nevertheless, other side effects, such as weight gain, of secondary generation antipsychotics counterbalance the neurological side effects of FGA. Consequently, whatever the type of antipsychotics, the practitioner must consider the particularity of the patient taking into account the attempted efficacy, the safety, the personal and familial antecedents and the patient''s subjective feeling about the drug: antipsychotic drugs have to be associated with a global therapeutic approach. [Copyright &y& Elsevier]

Abstract: Background: Recently, repetitive Transcranial Magnetic Stimulation (rTMS) has been introduced as an alternative treatment for auditory hallucinations in schizophrenic patients that fail to respond to antipsychotics. Until now, application of rTMS has been at low frequency, and most commonly applied to the left temporoparietal cortex. This 6-month follow-up pilot study was performed to demonstrate the efficacy of high frequency rTMS guided by anatomical and functional Magnetic Resonance Imaging (MRI). Methods: Eleven patients with schizophrenia (DSM-IV) were treated with high frequency (20 Hz) rTMS delivered over 2 days; they were then followed for 6 months. The target area was identified by fMRI as the highest activation cluster along the posterior part of the left superior temporal sulcus from the BOLD signal of each subject during a language task. Results: A significant reduction in global severity and frequency of auditory hallucinations between baseline and post-treatment day 12 was observed. Auditory hallucinations were entirely relieved at 6-month follow-up in 2 patients. The treatment was well tolerated in all patients. Conclusions: This is the first study reporting successful treatment of auditory hallucinations with 20 Hz rTMS. The efficacy at short term, the strength of the clinical response, the persistence of therapeutic effect over a 6-month follow-up, the safety profile, and the short duration of treatment present a considerable therapeutic gain compared to low frequency rTMS. [Copyright &y& Elsevier]