Luis San

Polymorphisms of the 5-HT2C receptor and leptin genes are associated with antipsychotic drug-induced weight gain in Caucasian subjects with a first-episode psychosis.

Objectives Weight gain, leading to further morbidity and poor treatment adherence, is a common consequence of treatment with antipsychotic drugs. Two recent studies in the same cohort of Chinese Han subjects have shown that polymorphisms of the promoter regions of both the serotonin 5-hydroxytryptamine 2C (5-HT2C) receptor and the leptin genes, are associated with antipsychotic-induced weight gain over 10 weeks. We have investigated whether these effects remain true in a Caucasian population and following longer term treatment. Methods Seventy-three Spanish caucasian patients with a first-episode psychosis and initially drug-naive were genotyped for the 5-HT2C receptor −759C/T and leptin −2548A/G polymorphisms. Body mass index and plasma leptin levels were monitored after 6 weeks, 3 months and 9 months of antipsychotic treatment. Results Patients with the −759T variant allele showed significantly less weight gain than those without this allele. This effect held true in the smaller group of patients receiving olanzapine. The −2548 leptin polymorphism was not associated with short-term (6 week and 3 month) weight increases but did show significant association with 9-month antipsychotic-induced weight gain. The 5-HT2C −759 genotype was significantly associated with pre-treatment plasma leptin levels. Conclusions These findings confirm the importance of two genetic factors associated with long-term antipsychotic-induced weight increases in schizophrenia, and implicate a role for leptin in the 5-HT receptor-mediated weight regulation.

Agomelatine: A novel mechanism of antidepressant action involving the melatonergic and the serotonergic system

The clinical finding that depressive disorders are often associated with desynchronization of internal rhythms has encouraged the idea that resetting normal circadian rhythms may have antidepressant potential. Agomelatine, a naphthalene analog of melatonin, is both an agonist of human cloned melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Agomelatine combines zeitgeber (synchroniser of the circadian system) activity with neurotransmitter augmentation properties (enhances the levels of dopamine and noradrenaline in frontal cortex). The efficacy of agomelatine in treating depression has been shown in three short-term, pivotal, randomized, placebo-controlled studies. These studies have demonstrated agomelatine to be efficacious in Major Depressive Disorder at the standard dose of 25mg/day, with the possibility of increasing doses to 50mg/day in those patients with insufficient improvement. The number of adverse events during the treatment period was comparable to placebo. Four studies have shown the positive effect of agomelatine on sleep continuity and quality and shortening of sleep latency. Despite these promising data, further studies are needed to examine agomelatines efficacy over a longer treatment period.

Altered 5-HT2A binding sites and second messenger inositol trisphosphate (IP3) levels in hippocampus but not in frontal cortex from depressed suicide victims

The binding parameters of 5-HT(2A) and levels of its second messenger, 1,4,5-trisphosphate (IP(3)), were simultaneously studied in frontal cortex and hippocampus from the brains of 18 control subjects and 18 depressed suicide victims. All suicides met DSM-III-R criteria for depressive symptoms, suffered a violent death and had not taken any antidepressant drugs for at least 6 months prior to death. A significant decrease in the number of 5-HT(2A) binding sites (154+/-22 vs. 254+/-36 fmol/mg), together with a significantly lower apparent affinity constant (1.02+/- 0.08 vs. 1. 36+/-0.09 nM), was detected in hippocampus but not in frontal cortex from the depressed suicides compared to the control subjects. Furthermore, IP(3) concentrations were significantly increased in hippocampus (3.2+/-0.3 vs. 2.1+/-0.3 pmol/g) but not in frontal cortex (1.3+/-0.3 vs. 2.7+/-0.5 pmol/g) from the suicide victims. The reported results may indicate a significant hypersensitivity of the 5-HT(2A) postsynaptic receptor located in the hippocampus from depressed suicide victims, giving rise to an enhancement of its intracellular signaling system with higher IP(3) production.

Altered 5-HT2A and 5-HT4 Postsynaptic Receptors and Their Intracellular Signalling Systems IP3 and cAMP in Brains from Depressed Violent Suicide Victims

Serotonin 5-HT2A and 5-HT4 binding parameters and their second messengers 1,4,5-inositol triphosphate (IP3) and cyclic adenosyl monophosphate (cAMP) were studied in the frontal cortex, hippocampus, caudate nucleus and amygdala of 19 control subjects and 19 antidepressant-free, violent suicide victims. A significantly higher number of 5-HT4 receptors and higher second messenger cAMP concentrations were found in the frontal cortex and caudate nucleus of the depressed suicide victims as compared with the control group. Furthermore, significantly increased 5-HT2A binding sites and IP3 concentrations were noted in the caudate nucleus of the suicide victims, together with a significantly reduced number of 5-HT2A binding sites, higher binding affinity and increased IP3 concentrations in the hippocampus. No significant alterations in 5-HT4 and cAMP or in 5-HT2A and IP3 concentrations were observed in the amygdala. The caudate nucleus of depressed suicide victims seems to be the brain region with the highest alteration of the serotonergic system, and hence with the most diagnostic sensitivity. Further studies on suicidality and depression should focus on the functionality of the caudate nucleus.

Validation of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a naturalistic sample of 278 patients with acute psychosis and agitation in a psychiatric emergency room

BackgroundDespite the wide use of the Excited Component of the Positive and Negative Syndrome Scale (PANSS-EC) in a clinical setting to assess agitated patients, a validation study to evaluate its psychometric properties was missing.MethodsData from the observational NATURA study were used. This research describes trends in the use of treatments in patients with acute psychotic episodes and agitation seen in emergency departments. Exploratory principal component factor analysis was performed. Spearmans correlation and regression analyses (linear regression model) as well as equipercentile linking of Clinical Global Impression of Severity (CGI-S), Agitation and Calmness Evaluation Scale (ACES) and PANSS-EC items were conducted to examine the scales diagnostic validity. Furthermore, reliability (Cronbachs alpha) and responsiveness were evaluated.ResultsFactor analysis resulted in one factor being retained according to eigenvalue ≥1. At admission, the PANSS-EC and CGI-S were found to be linearly related, with an average increase of 3.4 points (p < 0.001) on the PANSS-EC for each additional CGI-S point. The PANSS-EC and ACES were found to be linearly and inversely related, with an average decrease of 5.5 points (p < 0.001) on the PANSS-EC for each additional point. The equipercentile method shows the poor sensitivity of the ACES scale. Cronbachs alpha was 0.86 and effect size was 1.44.ConclusionsThe factorial analyses confirm the unifactorial structure of the PANSS-EC subscale. The PANSS-EC showed a strong linear correlation with rating scales such as CGI-S and ACES. PANSS-EC has also shown an excellent capacity to detect real changes in agitated patients.

Recovery from schizophrenia: Results from a 1-year follow-up observational study of patients in symptomatic remission

OBJECTIVES This report presents the results of an observational empirical clinical investigation about the prevalence and correlates of a proposed definition of recovery from schizophrenia in outpatients in Spain. METHODS Of 1010 outpatients with schizophrenia (DSM-IV-TR), a subgroup of 452 patients in symptomatic remission (SR) was followed for 1 year. SR was defined according to Andreasens severity criteria based on the Scales for the Assessment of Positive (SAPS) and Negative (SANS) Symptoms. A Global Assessment of Functioning scale score of >80 was considered to be indicative of adequate functioning (AF). Correlates of recovery were identified by logistic regression. RESULTS At baseline, 103 (22.8%; N=452) patients fulfilled the recovery definition (SR + AF). After 1 year, 338 patients (89.9%; N=376) maintained SR. Among these, the proportion of patients in recovery increased to 27.1% (102 out of 376). Better premorbid adjustment (PA) and improved social cognition correlated with recovery at baseline. After 1 year, PA, duration of untreated psychosis (DUP), type of pharmacotherapy, attitudes toward medication, and variation of depressive symptoms and social cognition determined the likelihood of recovery. CONCLUSIONS The proportion of patients in recovery increased among those fulfilling SR criteria. After 1 year, in addition to known factors like shorter DUP and better PA, social cognitive abilities and depressive symptoms were found to correlate with recovery.

Assessment and management of agitation in psychiatry: Expert consensus

Abstract Background Psychomotor agitation is associated with different psychiatric conditions and represents an important issue in psychiatry. Current recommendations on agitation in psychiatry are not univocal. Actually, an improper assessment and management may result in unnecessary coercive or sedative treatments. A thorough and balanced review plus an expert consensus can guide assessment and treatment decisions. Methods An expert task force iteratively developed consensus using the Delphi method. Initial survey items were based on systematic review of the literature. Subsequent surveys included new, re-worded or re-rated items. Results Out of 2175 papers assessing psychomotor agitation, 124 were included in the review. Each component was assigned a level of evidence. Integrating the evidence and the experience of the task force members, a consensus was reached on 22 statements on this topic. Conclusions Recommendations on the assessment of agitation emphasise the importance of identifying any possible medical cause. For its management, experts agreed in considering verbal de-escalation and environmental modification techniques as first choice, considering physical restraint as a last resort strategy. Regarding pharmacological treatment, the “ideal” medication should calm without over-sedate. Generally, oral or inhaled formulations should be preferred over i.m. routes in mildly agitated patients. Intravenous treatments should be avoided.

Cross-cultural adaptation and validation of the Spanish version of the Calgary Depression Scale for Schizophrenia

BACKGROUND The Calgary Depression Scale for Schizophrenia (CDSS) is a valid tool to assess depression in schizophrenics and has been translated, adapted, and validated to be used in different non-English languages. Therefore, it may be predicted that a Spanish version of this scale will be also a valid instrument to assess symptoms of depression in patients with schizophrenia. OBJECTIVE We determined the validity of the Spanish version of the Calgary scale (CDSS-S). METHODS Outpatients and inpatients (n=93) diagnosed as having schizophrenia by DSM-IV criteria confirmed by SCID-IV interview were included. The Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale (HDRS-17 and HDRS-21 items), Montgomery-Asberg Depression Rating Scale (MADRS), Extrapyramidal Symptoms Rating Scale (ESRS), and Barnes Acathisia Rating Scale were administered by a first rater, whereas the CDSS-S was assessed by a second independent rater. RESULTS The internal consistency (Cronbachs alpha 0.83) and the interrater reliability (>0.73 intraclass correlation coefficient [ICC] for single items and 0.92 for total score) were good. The test-retest reliability was high (ICC of 0.89). The scale showed a good construct validity with statistically significant correlations with HDRS-17, HDRS-21, MADRS, and G6 item (depression) of PANSS. The CDSS showed no correlation with the positive subscale of PANSS and a weak correlation with the negative subscale, general psychopathology subscale, and total score of PANSS. A cut point of five showed 94.7% sensitivity, 86.5% specificity, and 70% and 98% positive and negative predictive values, respectively. CONCLUSIONS The Spanish version of CDSS is a valid instrument to assess depressive episodes for stabilized and acute patients with schizophrenia.

Remission in schizophrenia: Results from a 1-year follow-up observational study

OBJECTIVES This study used the Remission in Schizophrenia Working Group operational-severity criteria to, a) provide descriptive data on prevalence and stability of symptomatic remission, b) attempt a criterion (concurrent) validation of this measure of remission, and c) explore correlates of remission stability. METHODS From an unselected sample of 1010 stable outpatients with schizophrenia (DSM-IV-TR), a subgroup of 452 (44.8%) in symptomatic remission was followed for 1 year. Of these, 376 were re-evaluated in a research diagnostic assessment. In addition to relevant sociodemographic and clinical data, measures included symptoms, depression, functioning, social cognition, attitudes towards medication, and quality of life. Estimates of point prevalence are provided. Correlates of remission were identified by logistic regression. RESULTS Symptomatic remission at baseline correlated with better premorbid adjustment, better social cognition, good treatment compliance, younger age, the absence of comorbid substance abuse, current or past participation in psychotherapy, and a lack of past participation in rehabilitation. After 1 year, 338 out of the 376 (89.9%) patients re-evaluated were found again in remission. In this assessment, better premorbid adjustment, good treatment compliance, and improvement of depressive symptoms and social cognition during follow-up again correlated with remission. CONCLUSIONS The results of this study suggest that symptomatic remission (as defined above) has considerable criterion validity and is a realistic goal in the treatment of schizophrenia. Attaining and sustaining remission may warrant better clinical and functional outcomes for patients.

Antipsychotic Drug Treatment of Schizophrenic Patients with Substance Abuse Disorders

Background/Aim: In recent years, there has been a growing interest in developing adequate treatments for patients with a diagnosis of schizophrenia and a comorbid substance use disorder (SUD). In the present paper we aim to critically review published reports on the use of conventional and second-generation antipsychotics in the treatment of patients with schizophrenia and comorbid SUD, to provide clinicians with a clearer view of the pharmacological treatment of this highly prevalent dual diagnosis based upon the evidence arising from the scientific literature. Methods: A search of the relevant literature from Medline, PsycLIT and EMBASE databases, included in the Science Citation Index, and available up to November 2006 was conducted using the terms: ‘schizophrenia’, ‘substance use disorder’ and ‘antipsychotics’. Results: While research on the use of conventional antipsychotics has remained limited, the majority of studies suggest the effectiveness of second-generation antipsychotics, particularly clozapine, for patients with schizophrenia and a comorbid substance use disorder. Conclusion: In the absence of randomized controlled trials that could provide more reliable information, clinical decisions may need to rely on indirect data provided by the increasing number of case reports, open trials and retrospective studies showing a decrease in cigarette smoking, alcohol, cocaine or cannabis use and an improvement of overall psychiatric symptoms.