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Objectives: Clozapine (CLZ) is prescribed to (relatively) treatment-resistant patients with schizophrenia spectrum disorders. Currently, it is unknown what factors predict response to CLZ. Therefore, we performed meta-analyses to identify predictors of CLZ response, hence aiming to facilitate timely and efficient prescribing of CLZ., Methods: A systematic search was performed in 'Pubmed' and 'Embase' until 1 January 2019. Articles were eligible if they provided data on predictors of CLZ response measured demographic and clinical factors at baseline or biochemical factors at follow-up in schizophrenia spectrum disorder patients., Results: A total of 34 articles, total number of participants = 9386; N unique = 2094, were eligible. Factors significantly associated with better CLZ response were: lower age, lower PANSS negative score and paranoid schizophrenia subtype., Conclusion: The results of our meta-analyses suggest that three baseline demographic and clinical features are associated with better clozapine response, i.e. relatively young age, few negative symptoms and paranoid schizophrenia subtype. These variables may be taken into account by clinicians who consider treating a specific patient with CLZ., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objective: Antipsychotic-induced weight gain (AiWG) is a debilitating adverse effect of most antipsychotics. First-episode psychosis patients are particularly vulnerable to the detrimental consequences of AiWG. Amisulpride has good efficacy and tolerability. We here aimed to identify the phenotypic factors associated with amisulpride-induced weight gain in first-episode psychosis patients., Method: Data were collected from the Optimization of Treatment and Management of Schizophrenia in Europe trial. Multivariable regression models with various phenotypic variables (N = 305) were performed with absolute AiWG and clinically relevant AiWG (≥7% AiWG) as outcomes., Results: Four weeks of amisulpride treatment increased body weight from 69.7 to 72.4 kg (P < 0.001). In the regression model of absolute AiWG, unemployment (β = 0.94, P = 0.016), younger age (β = -0.07, P = 0.031) and absence of current comorbid major depression disorder (β = -1.61, P = 0.034) were positively associated with absolute AiWG. In the regression model of clinically relevant AiWG, unemployment (OR = 2.83, P = 0.001), schizophreniform disorder (OR = 2.00, P = 0.025) and low baseline weight (OR = 0.97, P = 0.032) increased the likelihood of clinically relevant AiWG., Conclusions: Clinicians prescribing amisulpride should consider the relatively high susceptibility to AiWG in unemployed first-episode patients with psychosis, in particular young subjects with a diagnosis of schizophreniform disorder. We advise to carefully monitor these patients and, when needed, implement weight-reducing strategies., (© 2019 The Authors. Acta Psychiatrica Scandinavica published by John Wiley & Sons Ltd.)

Conventional antipsychotic medication is ineffective in around a third of patients with schizophrenia, and the nature of the therapeutic response is unpredictable. We investigated whether response to antipsychotics is related to brain glutamate levels prior to treatment. Proton magnetic resonance spectroscopy was used to measure glutamate levels (Glu/Cr) in the anterior cingulate cortex (ACC) and in the thalamus in antipsychotic-naive or minimally medicated patients with first episode psychosis (FEP, n = 71) and healthy volunteers (n = 60), at three sites. Following scanning, patients were treated with amisulpride for 4 weeks (n = 65), then 1 H-MRS was repeated (n = 46). Remission status was defined in terms of Positive and Negative Syndrome Scale for Schizophrenia (PANSS) scores. Higher levels of Glu/Cr in the ACC were associated with more severe symptoms at presentation and a lower likelihood of being in remission at 4 weeks (P < 0.05). There were longitudinal reductions in Glu/Cr in both the ACC and thalamus over the treatment period (P < 0.05), but these changes were not associated with the therapeutic response. There were no differences in baseline Glu/Cr between patients and controls. These results extend previous evidence linking higher levels of ACC glutamate with a poor antipsychotic response by showing that the association is evident before the initiation of treatment.

Objective: No consensus exists on whether clozapine should be prescribed in early stages of psychosis. This systematic review and meta-analysis therefore focus on the use of clozapine as first-line or second-line treatment in non-treatment-resistant patients., Methods: Articles were eligible if they investigated clozapine compared to another antipsychotic as a first- or second-line treatment in non-treatment-resistant schizophrenia spectrum disorders (SCZ) patients and provided data on treatment response. We performed random-effects meta-analyses., Results: Fifteen articles were eligible for the systematic review (N = 314 subjects on clozapine and N = 800 on other antipsychotics). Our meta-analysis comparing clozapine to a miscellaneous group of antipsychotics revealed a significant benefit of clozapine (Hedges' g = 0.220, P = 0.026, 95% CI = 0.026-0.414), with no evidence of heterogeneity. In addition, a sensitivity analysis revealed a significant benefit of clozapine over risperidone (Hedges' g = 0.274, P = 0.030, 95% CI = 0.027-0.521)., Conclusion: The few eligible trials on this topic suggest that clozapine may be more effective than other antipsychotics when used as first- or second-line treatment. Only large clinical trials may comprehensively probe disease stage-dependent superiority of clozapine and investigate overall tolerability., (© 2018 The Authors Acta Psychiatrica Scandinavica Published by John Wiley & Sons Ltd.)

Recent literature hints that outcomes of clinical trials in medicine are selectively reported. If applicable to psychotic disorders, such bias would jeopardize the reliability of randomized clinical trials (RCTs) investigating antipsychotics and thus their extrapolation to clinical practice. We therefore comprehensively examined outcome reporting bias in RCTs of antipsychotic drugs by a systematic review of prespecified outcomes on ClinicalTrials.gov records of RCTs investigating antipsychotic drugs in schizophrenia and schizoaffective disorder between 1 January 2006 and 31 December 2013. These outcomes were compared with outcomes published in scientific journals. Our primary outcome measure was concordance between prespecified and published outcomes; secondary outcome measures included outcome modifications on ClinicalTrials.gov after trial inception and the effects of funding source and directionality of results on record adherence. Of the 48 RCTs, 85% did not fully adhere to the prespecified outcomes. Discrepancies between prespecified and published outcomes were found in 23% of RCTs for primary outcomes, whereas 81% of RCTs had at least one secondary outcome non-reported, newly introduced, or changed to a primary outcome in the respective publication. In total, 14% of primary and 44% of secondary prespecified outcomes were modified after trial initiation. Neither funding source (P=0.60) nor directionality of the RCT results (P=0.10) impacted ClinicalTrials.gov record adherence. Finally, the number of published safety endpoints (N=335) exceeded the number of prespecified safety outcomes by 5.5 fold. We conclude that RCTs investigating antipsychotic drugs suffer from substantial outcome reporting bias and offer suggestions to both monitor and limit such bias in the future.

Clozapine is one of the most effective atypical antipsychotic drugs prescribed to patients with treatment-resistant schizophrenia. Approximately 1% of patients experience potential life-threatening adverse effects in the form of agranulocytosis, greatly hindering its applicability in clinical practice. The etiology of clozapine-induced agranulocytosis (CIA) remains unclear, but is thought to be a heritable trait. We reviewed the genetic studies of CIA published thus far. One recurrent finding from early candidate gene study to more recent genome-wide analysis is that of the involvement of human leukocyte antigen locus. We conclude that CIA is most likely a complex, polygenic trait, which may hamper efforts to the development of a genetic predictor test with clinical relevance. To decipher the genetic architecture of CIA, it is necessary to apply more rigorous standards of phenotyping and study much larger sample sizes.

Phase 1 of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study enrolled a sample of 1493 chronic schizophrenia patients. The European First Episode Schizophrenia Trial (EUFEST) enrolled 498 patients. We have combined these two samples to study the effects of hostility on study discontinuation as well as to examine correlates and predictors of hostility. Individual data from 1154 patients with complete data were used for analyses. Survival analysis demonstrated that higher hostility was associated with earlier all-cause treatment discontinuation. Furthermore, regression analysis indicated that increased hostility was associated with more severe positive symptoms, lower adherence to pharmacological treatment, younger age, impaired insight, and more drug or alcohol consumption. The clinical implications of the results point to the importance of establishing therapeutic alliance while managing patient's symptoms of hostility with antipsychotics such as olanzapine combined with psychosocial interventions to improve insight and reduce substance use., (Copyright © 2015 Elsevier Masson SAS. All rights reserved.)

Although antipsychotics are widely prescribed, their effect of on improving poor illness insight in schizophrenia has seldom been investigated and therefore remains uncertain. This paper examines the effects of low dose haloperidol, amisulpride, olanzapine, quetiapine, and ziprasidone on insight in first-episode schizophrenia, schizoaffective disorder, or schizophreniform disorder. The effects of five antipsychotic drugs in first episode psychosis on insight were compared in a large scale open randomized controlled trial conducted in 14 European countries: the European First-Episode Schizophrenia Trial (EUFEST). Patients with at least minimal impairments in insight were included in the present study (n=455). Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS), administered at baseline and at 1, 3, 6, 9, and 12 months after randomization. The use of antipsychotics was associated with clear improvements in insight over and above improvements in other symptoms. This effect was most pronounced in the first three months of treatment, with quetiapine being significantly less effective than other drugs. Effects of spontaneous improvement cannot be ruled out due to the lack of a placebo control group, although such a large spontaneous improvement of insight would seem unlikely., (Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.)

It is evident that once psychosis is present in patients with schizophrenia, the underlying biological process of the illness has already been ongoing for many years. At the time of diagnosis, patients with schizophrenia show decreased mean intracranial volume (ICV) as compared with healthy subjects. Since ICV is driven by brain growth, which reaches its maximum size at approximately 13 years of age, this finding suggests that brain development in patients with schizophrenia is stunted before that age. The smaller brain volume is expressed as decrements in both grey and white matter. After diagnosis, it is mainly the grey matter loss that progresses over time whereas white matter deficits are stable or may even improve over the course of the illness. To understand the possible causes of the brain changes in the first phase of schizophrenia, evidence from treatment studies, postmortem and neuroimaging investigations together with animal experiments needs to be incorporated. These data suggest that the pathophysiology of schizophrenia is multifactorial. Increased striatal dopamine synthesis is already evident before the time of diagnosis, starting during the at-risk mental state, and increases during the onset of frank psychosis. Cognitive impairment and negative symptoms may, in turn, result from other abnormalities, such as NMDA receptor hypofunction and low-grade inflammation of the brain. The latter two dysfunctions probably antedate increased dopamine synthesis by many years, reflecting the much earlier presence of cognitive and social dysfunction. Although correction of the hyperdopaminergic state with antipsychotic agents is generally effective in patients with a first-episode psychosis, the effects of treatments to correct NMDA receptor hypofunction or low-grade inflammation are (so far) rather modest at best. Improved efficacy of these interventions can be expected when they are applied at the onset of cognitive and social dysfunction, rather than at the onset of psychosis.

There is ample evidence that the acute stress response is altered in schizophrenia and bipolar disorder. However, it is not clear whether such changes are related to the illness, a genetic vulnerability, or is the result of medication that is used in the majority of these patients. Therefore, we investigated determinants of the acute endocrine and autonomic stress response in healthy controls (n=48), euthymic BD1 patients (n=49) and unaffected siblings of BD1 patients (n=27). All participants completed a validated psychosocial stress task, the Trier Social Stress Test for Groups (TSST-G). Saliva levels of alpha-amylase and cortisol were measured before, during, and after exposure to stress. Compared to controls, we found a significantly blunted cortisol stress response in BD1 patients. Conversely, BD1 patients displayed exaggerated alpha-amylase levels in response to stress. Antipsychotic use was a significant contributing factor to the blunted cortisol stress response in BD1 patients. Unaffected BD1 siblings displayed similar stress-induced cortisol and alpha-amylase levels as controls, suggesting that familial risk for BD1 did not have a large effect on the functionality of the stress system. In conclusion, this study shows that euthymic BD1 patients have a substantially blunted endocrine stress response but an exaggerated autonomic stress response and that the endocrine stress response differences can be largely contributed to antipsychotic use rather than constitute a specific BD1 phenotype or vulnerability., (Copyright © 2014 Elsevier B.V. and ECNP. All rights reserved.)

Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol (CBD) may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD. In this targeted literature review we performed a search for English articles using Medline and EMBASE. Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention. Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment., (© 2013 Published by Elsevier B.V. and ECNP.)

There is convincing evidence that schizophrenia is characterised by progressive brain volume changes during the course of the illness. In a large longitudinal study it was shown that different age-related trajectories of brain tissue loss are present in patients compared to healthy subjects, suggesting that brain maturation that occurs in the third and fourth decade of life is abnormal in schizophrenia. However, studies show that medication intake and cannabis use are important confounding factors when interpreting brain volume (change) abnormalities. Indeed, continues use of cannabis, but not cigarette smoking, is associated to a more pronounced loss of grey matter in the anterior cingulated and the prefrontal cortex. Atypical antipsychotics have been found to be related to smaller decreases in tissue loss. Moreover, independent of antipsychotic medication intake, the brain volume abnormalities appear associated to the outcome of the illness., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Introduction: Head-to-head comparisons of antipsychotics have predominantly included patients with chronic conditions. The aim of the present study was to compare the efficacy and tolerability of ziprasidone and olanzapine in patients with recent-onset schizophrenia., Methods: The study was an 8-week, double-blind, parallel-group, randomized, controlled multicenter trial (NCT00145444). Seventy-six patients with schizophreniform disorder, schizophrenia or schizoaffective disorder (diagnosis < 5 y), and a maximum lifetime antipsychotic treatment < 16 weeks participated in the study. Efficacy of ziprasidone (80-160 mg/d) and olanzapine 10-20 mg was measured using the Positive and Negative Syndrome Scale (PANSS), the Clinical Global Impression (CGI) Scale, the Calgary Depression Scale for Schizophrenia (CDSS), and the Heinrich Quality of Life Scale (HQLS); tolerability assessments included laboratory assessments, body weight, and electroencephalogram., Results: Olanzapine (n = 34) and ziprasidone (n = 39) showed equal efficacy as measured by the PANSS, CDSS, CGI, and HQLS. However, mean weight gain was significantly higher in the olanzapine group (6.8 vs 0.1 kg, P < .001). Ziprasidone was associated with decreasing levels of triglycerides, cholesterol, and transaminases, while these parameters increased in the olanzapine group (all P values < .05). There were no significant differences in fasting glucose and prolactin levels or in cardiac or sexual side effects. Patients on ziprasidone used biperiden for extrapyramidal side effects more frequently (P < .05)., Discussion: The results of this study indicate that ziprasidone and olanzapine have comparable therapeutic efficacy but differ in their side effect profile. However, there is a risk of a type II error with this sample size. Clinically significant weight gain and laboratory abnormalities appear early after initiating treatment and are more prominent with olanzapine, while more patients on ziprasidone received anticholinergic drugs to treat extrapyramidal symptoms.

Few studies have assessed the comparative efficacy and safety of atypical and typical antipsychotic medications in patients within their first episode of psychosis. This study examined the effectiveness of the atypical antipsychotic olanzapine and the typical antipsychotic haloperidol in patients experiencing their first episode of a schizophrenia-related psychotic disorder over a 2-year treatment period. Two hundred and sixty-three patients were randomized to olanzapine or haloperidol in a doubleblind, multisite, international 2-year study. Clinical symptoms and side effects were assessed at baseline and longitudinally following randomization for the duration of the study. Olanzapine and haloperidol treatment were both associated with substantial and comparable reductions in symptom severity (the primary outcome measure) over the course of the study. However, the treatment groups differed on two secondary efficacy measures. Patients were less likely to discontinue treatment with olanzapine than with haloperidol: mean time (in days) in the study was significantly greater for those treated with olanzapine compared to haloperidol (322.09 vs. 230.38, p<0.0085). Moreover, remission rates were greater in patients treated with olanzapine as compared to those treated with haloperidol (57.25% vs. 43.94%, p<0.036). While extrapyramidal side effects were greater in those treated with haloperidol, weight gain, cholesterol level and liver function values were greater in patients treated with olanzapine. The data from this study suggest some clinical benefits for olanzapine as compared to haloperidol in first episode patients, which must be weighed against those adverse effects that are more likely with olanzapine.

Amino acids play a role in neurotransmitter availability in the central nervous system, in that e.g. the synthesis of brain serotonin depends on the concentration of its precursor tryptophan. Disturbances in amino acid metabolism have been implicated in the pathophysiology of schizophrenia.In the present study the effect of a 14 week treatment with atypical antipsychotics on the plasma levels of amino acids was investigated in patients with schizophrenia and compared to normal controls.Non-responders (< or =20% decrease in BPRS at endpoint) demonstrated lower baseline values of methionine as compared to good responders (> or =50% decrease in BPRS at endpoint; p<.05) and controls (p<.01). The ratio between tryptophan and the other large neutral amino acids (Trp/LNAA ratio) in poor-responders (<40%) decreased during treatment as compared to responders (> or =40%; p<.05). It is concluded that poor or non-response to atypical antipsychotics may be associated with an impaired synthesis of serotonin in the central nervous system.

In the present study, including 66 schizophrenic patients and 73 healthy controls, the effect of atypical antipsychotic treatment over a period of 14 weeks on psychotic symptoms and plasma levels of glutamate and monoaminergic metabolites was investigated. Treatment induced a modest reduction of psychotic symptoms in 42% of the patients (response criterion: Brief Psychiatric Rating Scale [BPRS] decrease >/=40%). Poor response was associated with severity of psychopathology, age and duration of disease. Glutamate at baseline was significantly higher in patients as compared to controls (p<0.01). During treatment, a significant further increase of glutamate, not related to response, was observed. Glutamate levels correlated significantly with negative symptom scores at baseline and weeks 3, 6 and 14 (p<0.05). At baseline, serotonin (5-HT) in plasma and 5-HT in platelets were significantly lower in the poor responders as compared to controls (p<0.05) and increased significantly during treatment (p<0.05). In the responders, treatment coincided with a decrease of 5-HT parameters. No differences in plasma levels of HVA, 5-HIAA and their ratio were observed between controls and response groups. The results of this study suggest an effect of atypical antipsychotics on glutamatergic neurotransmission and an association between lower pretreatment peripheral 5-HT parameters and response.

The mechanism of action of both typical antipsychotics and the atypical antipsychotic, clozapine, may be related to the (changing) interaction of dopamine and serotonin in schizophrenia. This study examined the effect of olanzapine in schizophrenic patients on cerebrospinal fluid (CSF) metabolites of dopamine (homovanillic acid, HVA) and serotonin (5-hydroxyindoleacetic acid, 5-HIAA). Twenty-three male schizophrenic patients, who were drug-free for at least 2 weeks (mean drug-free period of 35 days +/- 43; median 16 days), underwent a lumbar puncture (LP). Patients were subsequently treated with olanzapine 10 mg/day for 6 weeks, after which the LP was repeated. CSF was assayed for HVA and 5-HIAA concentrations. Psychiatric symptoms were rated once a week. Olanzapine significantly increased HVA concentrations and the HVA/5-HIAA ratio while 5-HIAA concentrations were not altered. These changes did not significantly correlate with treatment response. A negative correlation was found between HVA concentrations and negative symptoms after olanzapine treatment. In conclusion, olanzapine treatment increases HVA concentrations and the HVA/5-HIAA ratio in CSF of schizophrenic patients, but these changes are unrelated to its clinical efficacy.

Atypical antipsychotics have been hypothesized to be more effective than classical antipsychotics in the treatment of hostility and aggression, due to their characteristic pharmacological profile, involving serotonergic as well as dopaminergic systems. In the present quantitative review the published evidence regarding the effects of risperidone on hostility and aggression in schizophrenia is evaluated. Meta-analysis of seven controlled trials revealed significant differences between risperidone and classical antipsychotics and between risperidone and placebo, although the effect size was small. Additional analyses in which only methodological rigorous studies were included showed highly significant differences (risperidone versus classical antipsychotics) and the effect size approached the 'medium' range. We conclude that risperidone is superior to classical antipsychotics and placebo in the treatment of hostility and aggression in schizophrenia. Neuropharmacological mechanisms that might account for this effect are discussed, and directions for future research are outlined.

Objective: Studies have found that caudate volume increased after treatment with typical antipsychotics in patients with schizophrenia but decreased after treatment was changed to clozapine. In the current study the authors examined whether this volume decrease was related to clinical improvement., Method: Twenty-eight patients with schizophrenia who had not responded to treatment with typical antipsychotics were included in the study; 22 completed the study. Caudate volume was assessed by using magnetic resonance imaging during treatment with typical antipsychotics and after 24 weeks and 52 weeks of clozapine treatment. Symptoms were assessed just before clozapine treatment and once a month thereafter., Results: Clozapine treatment resulted in a significant reduction in left caudate volume in patients who responded to the drug but not in patients who did not respond to clozapine at 52 weeks of treatment. Overall, the degree of reduction in left caudate volume was significantly related to the extent of improvement in positive and general symptoms but not in negative symptoms., Conclusions: These findings suggest that the caudate nucleus plays a role in the positive and general symptoms of schizophrenia.

Typical antipsychotics have been reported to enlarge the caudate nucleus in schizophrenic patients. The atypical antipsychotic, clozapine, is associated with a decrease in caudate size in patients previously treated with typical antipsychotics. The present study investigates whether a change in caudate volume after switching from treatment with typical antipsychotics to treatment with clozapine is related to improvement in symptoms or tardive dyskinesia (TD). Twenty-six schizophrenic patients participated in this open study. Caudate nucleus volume and TD were assessed before discontinuing typical antipsychotics and after 24 weeks of treatment with clozapine. After discontinuing typical antipsychotics, symptoms were assessed in a 3 days drug-free period and subsequently once a month. Treatment with clozapine resulted in a decrease in caudate volume, improvement in symptoms and amelioration of TD. However, no difference in caudate volume changes was found between responders and non-responders to clozapine and no correlations were found between caudate volume changes and reduction of TD. In conclusion, this study replicates earlier findings that clozapine decreases caudate volume in patients previously treated with typical antipsychotics and suggests that this effect is unrelated to treatment response or to amelioration of TD.

In recent years several new antipsychotics have come to market in the Netherlands (i.e. risperidone, olanzapine and quetiapine). These compounds are called atypical for their lack of the extrapyramidal side effects typical of older antipsychotics. Clozapine, which was developed earlier, is also an atypical antipsychotic drug. The new antipsychotics have proven to be more effective than the old ones in reducing the negative symptoms and in improving the cognitive deficits of schizophrenia. Moreover, they indeed induce less extrapyramidal side effects than the older antipsychotics. Head-to-head comparisons of the atypical antipsychotics are sparse. Studies comparing low-dose regimens of the typical antipsychotics with the atypical drugs as well as relapse prevention studies are needed before it can be decided whether the atypical drugs can replace the older compounds.

A hypofunction of the glutamatergic system and NMDA receptors in schizophrenia has been hypothesized. Therefore, stimulation of these receptors could be of benefit to patients with schizophrenia. D-cycloserine has been used for this purpose. This study reports the effects of 100 mg D-cycloserine, when added to typical antipsychotics in chronic schizophrenic patients exhibiting prominent negative symptoms, using a placebo-controlled, double-blind, parallel, design. D-cycloserine slightly worsened psychotic symptoms and general psychopathology as compared to placebo. D-cycloserine failed to change negative symptoms and had no effect on extrapyramidal symptoms. The exacerbation of schizophrenic symptoms may be explained by the antagonistic effects of this dose of D-cycloserine at the glycine recognition site of the NMDA receptor due to competition with the endogenous agonist glycine. Another explanation for the increase in psychopathology may be an interaction with the effects of antipsychotics on NMDA mediated neurotransmission. Thus, D-cycloserine in this study did not ameliorate schizophrenic symptoms. However, the fact that they actually worsened suggests that NMDA systems may be involved in the pathogenesis of schizophrenia. Further placebo-controlled studies with lower dosages of D-cycloserine, preferably in drug-free patients, are necessary to evaluate if D-cycloserine is of use for the treatment of patients with schizophrenia.

D-Cycloserine, a partial agonist of the glycine recognition site of the N-methyl-D-aspartate (NMDA) receptor, may serve as a probe for human cerebral NMDA receptor function. Since NMDA receptors are involved in neuroendocrine secretion, changes in pituitary secretion in response to D-cycloserine administration could serve as a model for NMDA receptor activity. The effects of an oral dose of 500 mg D-cycloserine were assessed in a neuroendocrine challenge paradigm in 20 healthy male volunteers, using a double-blind, randomized placebo-controlled crossover design. Luteinizing hormone (LH) and cortisol secretion was studied, since preclinical studies indicate that these hormones increase in response to NMDA receptor stimulation. Furthermore, plasma homovanillic acid (HVA) secretion was studied, as NMDA receptors are suggested to be involved in the regulation of dopaminergic neurotransmission. D-cycloserine was readily absorbed and did not induce side-effects or changes in vital signs and mood scores. D-Cycloserine stimulated LH secretion and induced a significant rise of the area under the plasma concentration time curve of LH. D-Cycloserine did not stimulate cortisol or plasma HVA secretion. These neuroendocrine effects suggest that D-cycloserine may be used to assess human NMDA receptor function in cerebral disorders, such as schizophrenia.

Objective: The authors examined the association between three lifetime medication variables (cumulative amount of neuroleptics, number of interruptions in neuroleptic treatment, cumulative amount of anticholinergics) and the occurrence and severity of tardive dyskinesia., Method: The study was conducted in the only psychiatric hospital of a well-defined catchment area (the Netherlands Antilles). For all patients who had a history of taking neuroleptics for at least 3 months and were currently using neuroleptics (N = 133, mean age = 51.5 years), the presence and severity of tardive dyskinesia were measured with the Abnormal Involuntary Movement Scale., Results: Of the three lifetime medication variables, only the number of neuroleptic interruptions was significantly related to tardive dyskinesia. The risk of tardive dyskinesia was three times as great for patients with more than two neuroleptic interruptions as for patients with two or fewer interruptions., Conclusions: This finding supports the schizophrenia protocol of long-term neuroleptic treatment rather than targeted or intermittent neuroleptic treatment.

A prevalence study of extrapyramidal syndromes was conducted among all psychiatric inpatients of the Netherlands Antilles (n = 194; mean age 53.1). The Netherlands Antilles are very suitable for epidemiological research as it is a well-defined catchment area with only one psychiatric hospital and a health care system based on western principles. In this mainly chronic population, the prevalence was measured of tardive dystonia, tardive dyskinesia, parkinsonism and akathisia using respectively the Fahn-Marsden rating scale, the Abnormal Involuntary Movement Scale, the Unified Parkinson Disease Rating Scale and the Barnes Akathisia Rating Scale. The prevalence numbers were for tardive dystonia 13.4%, tardive dyskinesia 39.7%, parkinsonism 36.1%, akathisia 9.3% and pseudoakathisia 12.9%. The most important conclusions were: (1) The prevalence of tardive dystonia was higher than reported in most other studies and (2) extrapyramidal syndromes are very common in this predominantly Negroid population, with three out of four patients suffering of one or more extrapyramidal syndromes.

Baseline symptom severity, early reduction in symptom severity, initial subjective response to neuroleptic treatment, the degree of brain atrophy, and early changes in pHVA levels appear to predict treatment outcome in schizophrenic patients. Computerized EEG results, neuropsychological and neurophysiologic tests, and baseline pHVA concentrations require further examination. Only a limited proportion of variance in treatment response, however, could be explained by either of the nine predictors alone or combined. Therefore, further research is necessary to discover yet unidentified determinants of treatment response. Future studies should test the validity and reliability of these five promising predictors in large groups of male and female patients, employ high standards for assessment reliability of clinical parameters, and use absolute rating scores on psychopathology as well as functional scales for the definition of good and poor treatment response. Furthermore, the statistical approach for data analysis should take in consideration the need for appropriate corrections when multiple correlations are performed and should test the extent to which these predictors are interdependent.

Neuroleptic medication was abruptly discontinued in 24 male chronic schizophrenic patients who were subdivided on the basis of their history of illness into Kraepelinian (n = 8) and non-Kraepelinian (n = 16) subgroups. These patients were kept drug free for 6 weeks and then returned to treatment with haloperidol, 20 mg/day. Half of the non-Kraepelinian patients developed exacerbations of their symptoms, which quickly resolved when they were returned to medication, while none of the Kraepelinian patients showed a worsening of symptomatology. On-medication clinical severity failed to predict risk for exacerbation, with severity of exacerbation predicting the amount of improvement when returned to medication. The Kraepelinian patients were found to be much less variable than the non-Kraepelinian patients in their symptoms during both medication manipulations, suggesting that medication truly has a negligible effect on them.

Changes in plasma levels of the dopamine metabolite homovanillic acid have been reported to correlate with changes in the severity of schizophrenic symptoms during neuroleptic administration and after neuroleptic discontinuation. This study examined the effects of discontinuation of neuroleptic treatment on plasma homovanillic acid levels in 23 patients with chronic schizophrenia. It was hypothesized that clinical decompensation would be associated with increased plasma homovanillic acid levels. Plasma homovanillic acid was measured during administration of neuroleptic medication and during a subsequent 6-week drug-free period. Nine patients decompensated during the drug-free period and 14 patients did not. Following drug discontinuation, plasma homovanillic acid concentrations were higher in schizophrenic patients who decompensated than in those who did not. Furthermore, peak plasma homovanillic acid elevation after discontinuation of neuroleptic medication was significantly correlated with peak Brief Psychiatric Rating Scale increase. The data suggest that, in some schizophrenic patients, symptomatic decompensation after discontinuation of neuroleptic treatment is associated with increases in dopamine turnover.

In rats, the beta-endorphin fragment, 6-17 (des-enkephalin-gamma-endorphin, DE gamma E), dose-dependently antagonized the reduction of the rate of locomotion and rearing induced by small doses of apomorphine. Structure-activity studies revealed that the active moiety of gamma-endorphin fragments with respect to counteracting apomorphine-induced behavioural changes resides in the fragment 6-17. The influence of DE gamma E appeared to be specific for dopamine systems mediating apomorphine-induced hypomotility, since DE gamma E hardly affected apomorphine-induced stereotypy and amphetamine-induced behavioural changes. These data suggest that DE gamma E acts as a dopamine antagonist selectively, on those dopamine receptor systems which are stimulated by small doses of apomorphine and which may be located presynaptically. In contrast to acute treatment, administration of DE gamma E for 4 days resulted in an enhancement of apomorphine-induced hypomotility. Thus, the receptor systems involved in these effects of apomorphine may become supersensitive upon (sub)chronic treatment with DE gamma E. The significance of the present findings are discussed in relation to the neuroleptic-like and antipsychotic action of gamma-type endorphins.

Objective Based on the role of the superior temporal gyrus ( STG) in auditory processing, language comprehension and self-monitoring, this study aimed to investigate the relationship between STG cortical thickness and positive symptom severity in schizophrenia. Method This prospective meta-analysis includes data from 1987 individuals with schizophrenia collected at seventeen centres around the world that contribute to the ENIGMA Schizophrenia Working Group. STG thickness measures were extracted from T1-weighted brain scans using FreeSurfer. The study performed a meta-analysis of effect sizes across sites generated by a model predicting left or right STG thickness with a positive symptom severity score (harmonized SAPS or PANSS-positive scores), while controlling for age, sex and site. Secondary models investigated relationships between antipsychotic medication, duration of illness, overall illness severity, handedness and STG thickness. Results Positive symptom severity was negatively related to STG thickness in both hemispheres (left: βstd = −0.052; P = 0.021; right: βstd = −0.073; P = 0.001) when statistically controlling for age, sex and site. This effect remained stable in models including duration of illness, antipsychotic medication or handedness. Conclusion Our findings further underline the important role of the STG in hallmark symptoms in schizophrenia. These findings can assist in advancing insight into symptom-relevant pathophysiological mechanisms in schizophrenia. [ABSTRACT FROM AUTHOR]

BackgroundHyperprolactinemia is frequent in patients with schizophrenic psychoses. It is usually regarded as an adverse effect of antipsychotics but has recently also been shown in patients without antipsychotic medication. Our objective was to test whether hyperprolactinemia occurs in antipsychotic-naive first-episode patients (FEPs).MethodIn the framework of the European First Episode Schizophrenia Trial (EUFEST), 249 out of 498 FEPs were eligible for this study, of whom 74 were antipsychotic naive. All patients were investigated regarding their serum prolactin levels with immunoassays standardized against the 3rd International Reference Standard 84/500.ResultsTwenty-nine (39%) of the 74 antipsychotic-naive patients showed hyperprolactinemia not explained by any other reason, 11 (50%) of 22 women and 18 (35%) of 52 men.ConclusionsHyperprolactinemia may be present in patients with schizophrenic psychoses independent of antipsychotic medication. It might be stress induced. As enhanced prolactin can increase dopamine release through a feedback mechanism, this could contribute to explaining how stress can trigger the outbreak of psychosis. [ABSTRACT FROM PUBLISHER]

Tardive tongue dyskinesia is often under-diagnosed or misdiagnosed. Instrument measurement of lingual force variability may be a valid and reliable method for assessing tardive tongue dyskinesia. Instrument measurement of lingual force variability was compared to the clinical level of tardive tongue dyskinesia and total body dyskinesia as measured by the Abnormal Involuntary Movement Scale (AIMS) in 35 subjects: 23 patients with a psychiatric disorder using antipsychotics, of which 11 were with and 12 were without tardive tongue dyskinesia, and 12 age- and gender-matched healthy controls. Lingual force variability correlated with tardive tongue dyskinesia (Spearman r = 0.56; p < 0.01) and with total dyskinesia ( r = 0.47; p = 0.02); there was no association with age, antipsychotic dose, or psychiatric diagnosis. Instrument test-retest reliability corresponded with an ICC of 0.85 p < 0.0001. Instrument measurement of lingual force variability is a valid and reliable method for assessing tardive tongue dyskinesia. [ABSTRACT FROM AUTHOR]