Combination therapy as a potential risk factor for the development of type 2 diabetes in patients with schizophrenia: the GOMAP study.

BACKGROUND: Schizophrenia (SCZ) is associated with increased risk of type 2 diabetes (T2D). The potential diabetogenic effect of concomitant application of psychotropic treatment classes in patients with SCZ has not yet been evaluated. The overarching goal of the Genetic Overlap between Metabolic and Psychiatric disease (GOMAP) study is to assess the effect of pharmacological, anthropometric, lifestyle and clinical measurements, helping elucidate the mechanisms underlying the aetiology of T2D. METHODS: The GOMAP case-control study (Genetic Overlap between Metabolic and Psychiatric disease) includes hospitalized patients with SCZ, some of whom have T2D. We enrolled 1653 patients with SCZ; 611 with T2D and 1042 patients without T2D. This is the first study of SCZ and T2D comorbidity at this scale in the Greek population. We retrieved detailed information on first- and second-generation antipsychotics (FGA, SGA), antidepressants and mood stabilizers, applied as monotherapy, 2-drug combination, or as 3- or more drug combination. We assessed the effects of psychotropic medication, body mass index, duration of schizophrenia, number of hospitalizations and physical activity on risk of T2D. Using logistic regression, we calculated crude and adjusted odds ratios (OR) to identify associations between demographic factors and the psychiatric medications. RESULTS: Patients with SCZ on a combination of at least three different classes of psychiatric drugs had a higher risk of T2D [OR 1.81 (95% CI 1.22-2.69); p = 0.003] compared to FGA alone therapy, after adjustment for age, BMI, sex, duration of SCZ and number of hospitalizations. We did not find evidence for an association of SGA use or the combination of drugs belonging to two different classes of psychiatric medications with increased risk of T2D [1.27 (0.84-1.93), p = 0.259 and 0.98 (0.71-1.35), p = 0.885, respectively] compared to FGA use. CONCLUSIONS: We find an increased risk of T2D in patients with SCZ who take a combination of at least three different psychotropic medication classes compared to patients whose medication consists only of one or two classes of drugs.

Psychometric evaluation of the Fatigue Severity Scale in patients with major depression.

PURPOSE: This study aimed to investigate the psychometric properties of the Fatigue Severity Scale (FSS), a widely used unidimensional fatigue measure, in patients with major depression. METHODS: Subjects included were 72 patients with major depressive disorder, diagnosed with the DSM-IV based M.I.N.I. 5.0.0., without comorbid fatigue-associated conditions and Hamilton Depression Rating Scale (HDRS) scores ≥ 17 as well as 40 sex- and age-matched healthy controls. The FSS was administered to patients on two time points separated by a 1-week interval and to controls. The vitality subscale of the 36-item Short Form Health Survey (SF-36vit) and a visual analogue fatigue scale (VASF) were also administered. RESULTS: A total of 79.2% of patients vs. 15% of controls were fatigue cases according to the M.I.N.I. fatigue/energy loss item. The distribution of FSS scores was negatively skewed in the patient group, demonstrating a ceiling effect. The FSS presented satisfactory test-retest reliability (intraclass correlation coefficient 0.993), internal consistency (Cronbach's α coefficient 0.947), concurrent validity (correlations with SF-36vit, VASF and HDRS were -0.52, 0.73 and 0.32, respectively) and discriminative validity between patients and controls. Factor analysis demonstrated a unidimensional structure. The optimal FSS cutoff score for clinically significant fatigue was 5.4 against the presence of fatigue/energy loss according to the M.I.N.I. as a 'gold standard'. CONCLUSION: When administered to patients with major depression, the FSS was shown to have satisfactory psychometric properties with the exception of a ceiling effect, which may pose limitations to its use in this population.

The Fatigue Questionnaire: Standardization in patients with major depression.

Fatigue measures have not been specifically standardized in depressed patients. This study aimed to investigate the reliability and validity of the 14-item Fatigue Questionnaire (FQ), a widely used multidimensional fatigue measure, in patients with major depression without comorbid fatigue-associated conditions. Subjects included were 81 patients with Major Depressive Disorder and Hamilton Depression Rating Scale (HDRS) scores > or = 15 without conditions associated with prominent fatigue and 40 sex- and age-matched healthy controls. The vitality subscale of the 36-item Short-Form Health Survey (SF-36vit) and a visual analogue fatigue scale (VASF) served as standards of reference for reported fatigue. The FQ presented satisfactory internal consistency (Cronbach's alpha coefficient 0.924), test-retest reliability (intraclass correlation coefficient 0.978), discriminant validity (between patients and controls) and concurrent validity (correlations with the SF-36vit and the VASF were -0.469 and 0.477, respectively). Factor analysis showed a two-factor structure (physical and mental fatigue), i.e. a structure similar to the one originally proposed. However, items 3 ('sleepiness'), 4 ('difficulty starting things') and 14 ('loss of interest') did not load on the factor expected. With these items removed, the derived 11-item version of the scale was shown to be a 'purer' measure of fatigue in depressed patients, independent of the severity of depression and comorbid sleepiness.

Chromatin alterations in leukocytes of first-episode schizophrenic patients.

Studies of peripheral blood leukocytes of schizophrenic patients have shown in electron microscopy (EM) that decondensation of the chromatin constitutes a biological marker indicating increased genomic expression. Since this increase depends on chromatin relaxation by dissociation of lysine-rich histone H1 from nucleosomes, with exposure of arginine residues of core histones, the ratio of arginine to lysine residues in each nucleus represents a reliable measure of activation. Lysine- and arginine-rich proteins are demonstrable in light microscopy (LM), differentially, as yellow and black, respectively, with the ammoniacal silver reaction (ASR). Application of ASR on leukocyte pellets before they are dehydrated and embedded in epoxy resins gives reliable results in semithin sections. In thin sections the ASR method localizes only the amino acid arginine by forming deposits of electron-opaque particles, visualized in the EM. Leukocytes of 12 first-episode schizophrenic patients and 5 controls were used. Light micrographs of the semithin sections were inserted in a personal computer. The percentage of lysine and arginine was measured in 300 nuclei per subject. Morphometry showed that lymphocytes of schizophrenic patients have increased ratios of arginine to lysine, compared to controls, indicating activation; neutrophils of the patients have even a higher ratio, indicating an abnormal condition of the genome. Chromatin conformational changes are also evident by phosphotungstic acid hematoxylin (PTAH) block staining, which reveals condensed chromatin as an electron-lucent area in the nuclei, and decondensed chromatin as an electron-dense area. Because decondensed chromatin is a biological marker of schizophrenia, the efficacy of these methods to demonstrate this particular state offers a tool for early diagnosis, since first-episode schizophrenic patients have a better prognosis when treatment is started promptly, at the beginning of the disease.

The delusional misidentification syndromes: strange, fascinating, and instructive.

The delusional misidentification syndromes (Capgras' syndrome, Frégoli syndrome, intermetamorphosis syndrome, syndrome of subjective doubles) are rare psychopathologic phenomena that occur primarily in the setting of schizophrenic illness, affective disorder, and organic illness. They are grouped together because they often co-occur and interchange, and their basic theme is the concept of the double (sosie). They are distinguished as hypoidentifications (Capgras' syndrome) and hyperidentifications (the other three syndromes). In this review, we present the basic hypotheses that have been put forward to explain these syndromes and propose that the appearance of these syndromes must alert physicians to investigate the existence of possible organic contributions.

Sleep disturbances in relation to fatigue in major depression.

OBJECTIVE: This study aimed to investigate the independent correlations of subjective sleep disturbances (insomnia and daytime sleepiness) with the severity of fatigue in patients with major depression. METHODS: Eighty-one currently depressed patients (70 females and 11 males), aged between 23 and 65 years, with a DSM-IV diagnosis of major depressive disorder were studied. Patients with physical diseases or other conditions associated with prominent fatigue were excluded. The 17-item Hamilton Depression Rating Scale (HDRS), the Athens Insomnia Scale (AIS), and the Epworth Sleepiness Scale (ESS) were used for the cross-sectional assessment of the severity of depression, insomnia, and sleepiness, respectively. Severity of fatigue was measured with the Fatigue Severity Scale (FSS). Pearson's and Spearman's coefficients were used in bivariate correlations between FSS score and the independent variables (age, gender, inpatient/outpatient status, HDRS score, AIS total score, AIS individual item scores, and ESS score). A stepwise multiple regression analysis was then performed, with FSS score as the dependent variable. RESULTS: The severity of fatigue was significantly correlated with female sex, HDRS score, AIS total score, awakenings during the night (AIS item 2), compromised sleep quality (AIS item 5), and ESS score. Sleep quality (AIS item 5) and daytime sleepiness (ESS) were the only significant predictors of the severity of fatigue in the multiple regression analysis. CONCLUSIONS: Both sleep quality and daytime sleepiness correlate independently with fatigue severity, as measured with the FSS, in patients with major depression. The FSS does not appear to be a 'pure' measure of fatigue in depressed patients, a finding with potential implications for the choice of appropriate fatigue measures in this population.

Isotretinoin and psychopathology: a review.

Isotretinoin, a synthetic oral retinoid that is used against severe nodulocystic acne, has been associated with various psychiatric side effects such as depression, suicidality and psychotic symptoms. A great number of reports on its effects have been published since its introduction into the market. However, a causal relationship has not been established and the link between isotretinoin use and psychiatric events remains controversial. The present paper reviews the available evidence regarding the association of isotretinoin and psychiatric side effects. All published material reporting psychiatric side effects following isotretinoin treatment, including case reports, case series, reports from adverse drug event reporting systems, prospective surveys and retrospective case-control studies, are presented. In addition, the neurobiology of the retinoids and possible biological mechanisms that may lead to psychopathology are described.

Association of physical and social anhedonia with depression in the acute phase of schizophrenia.

BACKGROUND/AIMS: Researchers have shown interest in the association between anhedonia and depression in schizophrenia. The aim of the current study was to investigate the relationship between physical and social anhedonia with depression in a sample of inpatients with schizophrenia in the acute phase of their illness. METHODS: Sixty-two patients with acute schizophrenia consecutively admitted at the Eginition Hospital, Department of Psychiatry, University of Athens were assessed using the revised Physical Anhedonia Scale, the revised Social Anhedonia Scale and the Calgary Depression Scale for Schizophrenia. RESULTS: The Calgary Depression Scale for Schizophrenia score correlated with both physical anhedonia and social anhedonia ratings. The revised Social Anhedonia Scale score significantly correlated to self-depreciation, guilty ideas of reference, pathological guilt, early wakening, suicidality and observed depression. The revised Physical Anhedonia Scale score significantly correlated with depressive mood, self-depreciation, pathological guilt and observed depression. Self-depreciation, pathological guilt and observed depression were correlated with both social and physical anhedonia. CONCLUSION: Depression in schizophrenia and anhedonia may overlap, and it could therefore be difficult to clinically differentiate them, especially in acute schizophrenia patients.

Practical issues with amisulpride in the management of patients with schizophrenia.

Amisulpride is an atypical antipsychotic with a significantly greater effect size than first-generation, typical antipsychotics, and efficacy at least similar to that of olanzapine and risperidone in large-scale clinical trials in schizophrenia. Amisulpride provides greater improvement in positive and negative symptoms of schizophrenia, a better long-term outcome than typical antipsychotics, and distinct tolerability advantages over typical antipsychotics, which are reported to cause extrapyramidal symptoms (EPS) in 20-50% of patients. In addition, amisulpride is associated with significantly less weight gain than olanzapine and risperidone, does not increase body mass index, and favourably influences lipid profiles. In many patients with schizophrenia, adverse events impair adherence to treatment, and switching from typical or atypical antipsychotic therapy to amisulpride may be clinically appropriate. Observational drug-utilization studies suggest that many physicians switch to amisulpride because of fewer EPS and/or less weight gain and improved patient adherence. Cross-tapering (over 4 weeks), rather than abrupt cessation of pre-switch treatment, is preferred. Amisulpride has a low risk of drug-drug interactions, and, during cross-tapering, patients can remain on concurrent treatments (e.g. anticholinergics and antiparkinsonian agents) until the effective dosage has been reached. An appropriate amisulpride starting dose is 800 mg/day for patients with acute psychotic exacerbations, 400-800 mg/day for patients with predominantly positive symptoms, and 100-300 mg/day for predominantly negative symptoms. Amisulpride may be particularly suitable for clozapine-augmentation therapy in patients with refractory schizophrenia. Indeed, amisulpride is more effective than quetiapine as augmentation therapy in patients partially responsive to clozapine, and several prospective open-label studies and case series have reported promising results for amisulpride/clozapine combination therapy. In three prospective studies, addition of amisulpride 200-800 mg/day to clozapine significantly reduced mean scores on the Brief Psychiatric Rating Scale (BPRS) total (-33% to -35%), Clinical Global Impression (CGI)-Severity scale (-31%), Positive and Negative Syndrome Scale total (-22%), and Scale for the Assessment of Negative Symptoms (-34%). The proportion of responders (CGI score > or =3 or BPRS improvement >20%) was 71-86%. Retrospective case-series analyses have also reported improved psychopathological state, reduced adverse events, and lower clozapine dosage requirement with use of this combination. The pharmacological and clinical profiles of amisulpride suggest that this agent is a viable clinical option when a change of antipsychotic therapy is required in patients with schizophrenia because of lack of efficacy, adverse events and poor adherence to treatment, or for augmentation of clozapine in treatment-resistant illness.

Early psychosis intervention outpatient service of the 1st Psychiatric University Clinic in Athens: 3 Years of experience.

To present the 3-year experience of the early intervention in psychosis (EIP) service implementation of the 1st Psychiatric University Clinic in Athens. An overview of: (1) the purpose of our service, (2) the referral network, (3) the selection criteria, (4) the diagnostic procedures, (5) the therapeutic interventions and (6) the research activities. The service was established in 2012 and developed gradually aiming to provide information, early detection, treatment and support to people aged 15 to 40 years with psychotic manifestations, who are either at increased risk of developing psychosis (at-risk mental state [ARMS]) or with first episode psychosis (FEP). In order to assess individuals with ARMS, we used the comprehensive assessment of at-risk mental states interview and the Social and Occupational Functioning Assessment Scale The duration of untreated psychosis was estimated by using the Nottingham Onset Schedule. So far we have had 65 referrals, of which 26 were ARMS and 17 FEP. Based on the individual needs, they were offered psychotherapeutic and/or pharmacological treatment. After 3 years, the rate of transition to psychosis was 19.2% and the rate of psychosis relapse was 11.7%. The implementation of our service has had positive results, enabling young people with early psychosis to receive prompt and effective care. The rates of transition to psychosis are the first to be published from a Greek EIP service. Further development of our referral network and inter-hospital collaboration will allow us to address the needs of a wider part of the population.

Evidence for genetic contribution to the increased risk of type 2 diabetes in schizophrenia.

The epidemiologic link between schizophrenia (SCZ) and type 2 diabetes (T2D) remains poorly understood. Here, we investigate the presence and extent of a shared genetic background between SCZ and T2D using genome-wide approaches. We performed a genome-wide association study (GWAS) and polygenic risk score analysis in a Greek sample collection (GOMAP) comprising three patient groups: SCZ only (n = 924), T2D only (n = 822), comorbid SCZ and T2D (n = 505); samples from two separate Greek cohorts were used as population-based controls (n = 1,125). We used genome-wide summary statistics from two large-scale GWAS of SCZ and T2D from the PGC and DIAGRAM consortia, respectively, to perform genetic overlap analyses, including a regional colocalisation test. We show for the first time that patients with comorbid SCZ and T2D have a higher genetic predisposition to both disorders compared to controls. We identify five genomic regions with evidence of colocalising SCZ and T2D signals, three of which contain known loci for both diseases. We also observe a significant excess of shared association signals between SCZ and T2D at nine out of ten investigated p value thresholds. Finally, we identify 29 genes associated with both T2D and SCZ, several of which have been implicated in biological processes relevant to these disorders. Together our results demonstrate that the observed comorbidity between SCZ and T2D is at least in part due to shared genetic mechanisms.

Refractory psychosis and prominent cognitive deficits in a patient with mega-cisterna magna.

We present a case of refractory psychosis with prominent cognitive deficits in a patient with 'mega-cisterna magna', a congenital defect within the 'Dandy-Walker Complex' continuum. The 21-year-old female had a 3-year history of refractory psychotic symptoms despite adequate antipsychotic treatment. CT and MRI scans disclosed 'mega-cisterna magna'. Thorough neuropsychological testing recorded extensive deficits. Treatment with amisulpride 1200 mg/day resulted in a 30% decrease in PANSS score within 2 months. Then galantamine 8 mg/day was added and PANSS score decreased further by 27% within 2 weeks. Cognitive and social functioning was overall much improved. The effect was sustained in a 24 months follow-up. It is postulated that even a less extended cerebellar lesion, such as mega-cisterna magna, can be associated with psychosis, and in some cases with treatment refractoriness or cognitive dysfunction. Adjuvant galantamine may improve cognitive and psychosocial functioning in these patients.

Evaluating the glucose raising effect of established loci via a genetic risk score.

Recent genome-wide association studies have identified several single nucleotide polymorphisms (SNPs) associated with glucose levels. We tested the hypothesis here whether the cumulative effect of glucose raising SNPs, assessed via a score, is associated with glucose levels. A total of 1,434 participants of Greek descent from the THISEAS study and 1,160 participants form the GOMAP study were included in this analysis. We developed a genetic risk score (GRS), based on the known glucose-raising loci, in order to investigate the cumulative effect of known glucose loci on glucose levels. In the THISEAS study, the GRS score was significantly associated with increased glucose levels (mmol/L) (ß ± SE: 0.024 ± 0.004, P = 8.27e-07). The effect of the genetic risk score was also significant in the GOMAP study (ß ± SE: 0.011 ± 0.005, P = 0.031). In the meta-analysis of the two studies both scores were significantly associated with higher glucose levels GRS: ß ± SE: 0.019 ± 0.003, P = 1.41e-09. Also, variants at the SLC30A8, PROX1, MTNR1B, ADRA2A, G6PC2, LPIN3 loci indicated nominal evidence for association with glucose levels (p < 0.05). We replicate associations of the established glucose raising variants in the Greek population and confirm directional consistency of effects (binomial sign test p = 6.96e-05). We also demonstrate that the cumulative effect of the established glucose loci yielded a significant association with increasing glucose levels.

Concurrent administration of clozapine and electroconvulsive therapy in clozapine-resistant schizophrenia.

OBJECTIVE: The aim of this article is to critically review all published studies regarding the efficacy and safety of the concurrent administration of clozapine (CLZ) and electroconvulsive therapy (ECT) in CLZ-resistant schizophrenic or schizoaffective patients. METHOD: A MEDLINE search from January 1980 to July 2005 was conducted. RESULTS: One open-label trial and 6 case studies were located, comprising 21 schizophrenic and 1 schizo affective patients (12 men and 10 women) with a mean age of 41.9 years. The duration and dosage of CLZ monotherapy before ECT were reported at least 12 weeks and 300 mg/d, respectively, in 10 patients (45.4%). Plasma CLZ levels before ECT were assessed in 12 patients (54.5%), in which only 7 (31.8%) were reported to be higher than 350 ng/mL. The CLZ dosage during ECT ranged from 200 to 900 mg/d (mean, 518.2 +/- 203.3 mg/d). The number of ECT sessions ranged from 2 to 20 (mean, 11.5 +/- 5.4). Application of electrodes was unilateral in 7 patients, bilateral in 10 patients, and mixed in 2 patients. Sixteen patients (72.7%) showed marked improvement whereas 6 patients (27.3%) had moderate, minimal, or no improvement. No predictors of outcome could be isolated. Side effects reported by 5 patients (22.7%) were nausea, tachycardia, hypertension, memory problems, and confusion. Ten patients (45.4%) relapsed during follow-up. Substantial improvement persisted beyond 4 months in only 5 patients (22.7%). CONCLUSION: Preliminary evidence exists for the safety and short-term efficacy of the concurrent administration of CLZ and ECT in CLZ-resistant schizophrenic or schizoaffective patients.

Physical anhedonia in the acute phase of schizophrenia.

BACKGROUND: The aim of the current study is to investigate the relationship between physical anhedonia and psychopathological parameters, pharmacological parameters or motor side-effects in a sample of inpatients with schizophrenia in an acute episode of their illness. METHOD: Eighty one patients with schizophrenia, consecutively admitted, with an acute episode of their illness, at the Eginition Hospital, Department of Psychiatry, University of Athens, during a one-year period were investigated regarding possible relationships between physical anhedonia, social-demographic data and clinical parameters as well as motor side-effects, induced by antipsychotic agents. All patients were assessed using the Chapman Revised Physical Anhedonia Scale (RPAS), the Positive and Negative Syndrome Scale (PANSS), the Rating Scale for Extrapyramidal Side-Effects (EPSE), the Barnes Akathisia Rating Scale (BARS) and the Abnormal Involuntary Movement Scale (AIMS). Simple cross tabulations were initially employed. Subsequently, multiple regression analysis was performed. RESULTS: Both positive and negative symptoms were associated with physical anhedonia. A positive association between physical anhedonia and the non-paranoid sub-category of schizophrenia was also proved. CONCLUSION: According to these results, it seems that in the acute phase of schizophrenia, physical anhedonia may be a contributing factor to patient's psychopathology.

Suicide in Greece 1992-2012: A time-series analysis.

BACKGROUND AND AIMS: Since 2008, Greece has entered a long period of economic crisis with adverse effects on various aspects of daily life. In this frame, it is quite important to examine the suicide trends in Greece. METHOD: Our analysis covered the period 1992-2012. 2012 was the last year for which official suicide data were available. The inclusion of data for pre-crisis period enabled us to assess trends in suicide preceding the economic crisis, starting in 2008. Trends in sex- and age-adjusted standardized suicide rates (SSR) were analyzed using joinpoint regression. RESULTS: Total SSR presented statistically significant annual decrease of 0.89% (95% confidence interval (CI): -1.7, -0.1) during the period 1992-2008. After 2009, the trend in total SSR increased statistically significant annual increase (12.48%; 95% CI: 0.3%, 26.1%). SSR in males presented an initial period of modest annual decrease (-0.84%; 95% CI: -1.6%, -0.1%), during the period 1992-2008. After 2009, an annual increase by 9.25% (95% CI: 2.7%, 16.3%) was revealed. No change in female SSR trend was observed during the studied period. CONCLUSION: According to the results of this study, there is clear evidence of an increase in the overall SSR and male SSR in Greece during the period of the current financial crisis.

Case studies of adjunctive agents in clozapine-resistant schizophrenic patients.

Approximately 40%-70% of neuroleptic-resistant schizophrenic patients are nonresponders even to clozapine. Several clozapine augmentation strategies have come into clinical practice, although often without evidence-based support. This study aims to critically review all the reported case studies regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. All published case studies examining the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic patients were searched for in the MEDLINE database from January 1980 to February 2004. Case studies regarding ECT as a clozapine augmentation strategy were not included in our study. All the included papers were critically reviewed and examined against a set of clinical and pharmacological parameters, outcome measures, and reported side effects. Fifteen case studies regarding the efficacy and safety of sulpiride, risperidone, olanzapine, lithium, lamotrigine, fluvoxamine, and bromocriptine as clozapine adjuncts were found. A total of 33 schizophrenic or schizoaffective patients were included. Of the 15 studies, 8 were associated with risperidone. The duration and dosage of previous clozapine monotherapy was adequate for 16 patients. Plasma clozapine level was assessed for only 7 patients. Outcome measures were used for only 11 patients. The outcome was positive in 13 studies. Combined treatments were generally well tolerated, and side effects never resulted in discontinuation of treatment. Most case studies favor the use of risperidone as an adjunctive agent in clozapine-resistant schizophrenic or schizoaffective patients. However, small numbers of patients and other methodological shortcomings limit the impact of evidence provided.

Randomized controlled augmentation trials in clozapine-resistant schizophrenic patients: a critical review.

Approximately 40-70% of treatment-resistant schizophrenic patients fail to benefit from clozapine monotherapy or are partial responders. During the last years several clozapine adjunctive agents have come into clinical practice. This study aims to critically review all published randomized, double-blind, placebo-controlled clinical trials (RCTs) regarding the efficacy and safety of adjunctive agents in clozapine-resistant schizophrenic or schizoaffective patients. A MEDLINE search for RCTs on clozapine adjunctive agents published from January 1980 to February 2004 was conducted. All identified papers were critically reviewed and examined against several methodological features as well as clinical and pharmacological parameters. Eleven trials including 270 patients, partial or non-responders to clozapine, assessed the efficacy of sulpiride, lithium, lamotrigine, fluoxetine, glycine, d-serine, d-cycloserine and ethyl-eicosapentanoate (E-EPA) as clozapine adjuncts. There were eight parallel-group and three crossover trials. The inclusion criteria varied widely. The duration as well as the dosage of clozapine monotherapy were reported adequate in only one trial. Plasma clozapine levels were assessed in only three trials. Main side-effects reported were hypersalivation, sedation, diarrhea, nausea, hyperprolactinaemia. The outcome favored clozapine augmentation with sulpiride, lamotrigine and E-EPA. Lithium was shown to benefit only schizoaffective patients. However, the methodological shortcomings of trials analyzed limit the impact of evidence provided.

Olanzapine-associated neuroleptic malignant syndrome.

Neuroleptic malignant syndrome (NMS) is an uncommon but serious idiosyncratic reaction associated with antipsychotic medication. The purpose of this study was to reveal and analyze the clinical characteristics of the reported cases of NMS in patients given the novel antipsychotic olanzapine. A MEDLINE search related to olanzapine-induced NMS cases reported in the international literature was conducted. All cases were critically reviewed and examined against three different sets of NMS diagnostic criteria (DSM-IV, Addonizio, Levenson). The authors identified 17 cases of possible NMS associated with olanzapine. Ten of the reported NMS cases were definitely NMS meeting all three sets of criteria and three cases were probable NMS meeting two sets of criteria. Most of the patients exhibited a full-blown NMS. There were four definite NMS cases associated with olanzapine monotherapy. Three of them had concurrent serious physical illnesses and one had a previous NMS episode. Olanzapine can cause NMS, mainly in susceptible or predisposed patients.

Toxic interaction between risperidone and clozapine: a case report.

Although atypical antipsychotics have generally a decreased risk of neurotoxicity, there are reports regarding various neurotoxic or idiosyncratic reactions including neuroleptic malignant syndrome (NMS). The authors present here the toxic interaction between risperidone (RIS) and clozapine (CLZ) in a first-episode schizophrenic patient. A 20-year-old man suffering from first-episode schizophrenia--catatonic subtype, developed a neurotoxic syndrome, which has been characterized as a mild form of NMS, after CLZ (100 mg/day) was added to a regimen of RIS (16 mg/day). The NMS symptomatology subsided only by drug discontinuation and supportive care. Later, CLZ monotherapy restarted without further complications. This case report shows that neurotoxic syndromes, even NMS, may occur during combination therapy with RIS and CLZ.