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Sono gradite proposte di collaborazione

 3 maggio 2017. Un largo studio sulla popolazione conferna l'efficacia antidepressiva della Ketamina, un farmaco che nei prossimi anni sarà prescrivibile come antidepressivo, con l'indicazione anche nei non responders agli attuali antidepressivi.

Population scale data reveals the antidepressant effects of ketamine and other therapeutics approved for non-psychiatric indications

Scientific Reports
 7, Article number: 1450   

l'intero articolo, open access, : https://www.nature.com/articles/s41598-017-01590-x

Un' altra ricerca conferma l'associazione tra schizofrenia e uso di Cannabis in adolescenza:


Human Molecular Genetics  11 aprile 2017

 BDNF overexpression prevents cognitive deficit elicited by adolescent cannabis exposure and host susceptibility interaction



Cannabis abuse in adolescence is associated with increased risk of psychotic disorders. Δ-9-tetrahydrocannabinol (THC) is the primary psychoactive component of cannabis. Disrupted-In-Schizophrenia-1 (DISC1) protein is a driver for major mental illness by influencing neurodevelopmental processes. Here, utilizing a unique mouse model based on host (DISC1) X environment (THC administration) interaction, we aimed at studying the pathobiological basis through which THC exposure elicits psychiatric manifestations. Wild-Type and dominant-negative-DISC1 (DN-DISC1) mice were injected with THC (10 mg/kg) or vehicle for 10 days during mid-adolescence-equivalent period. Behavioral tests were conducted to assess exploratory activity (open field test, light-dark box test) and cognitive function (novel object recognition test). Electrophysiological effect of THC was evaluated using acute hippocampal slices, and hippocampal cannabinoid receptor type 1 and brain-derived neurotrophic factor (BDNF) protein levels were measured. Our results indicate that THC exposure elicits deficits in exploratory activity and recognition memory, together with reduced short-term synaptic facilitation and loss of BDNF surge in the hippocampus of DN-DISC mice, but not in wild-type mice. Over-expression of BDNF in the hippocampus of THC-treated DN-DISC1 mice prevented the impairment in recognition memory. The results of this study imply that induction of BDNF following adolescence THC exposure may serve as a homeostatic response geared to maintain proper cognitive function against exogenous insult. The BDNF surge in response to THC is perturbed in the presence of mutant DISC1, suggesting DISC1 may be a useful probe to identify biological cascades involved in the neurochemical, electrophysiological, and behavioral effects of cannabis related psychiatric manifestations.

Questa ricerca su un nuovo recettore per la serotonina apre la ricerca per nuovi farmaci antidepressivi per i pazienti che non rispondono agli SSRI.

Molecular Psychiatry , (25 April 2017) | doi:10.1038/mp.2017.87

A novel 5HT3 receptor–IGF1 mechanism distinct from SSRI-induced antidepressant effects

M Kondo, Y Koyama, Y Nakamura and S Shimada

Depression is a common mental disorder affecting around 350 million people worldwide. Although selective serotonin reuptake inhibitors (SSRIs) are the most widely used antidepressants, a significant proportion of depressed patients do not achieve remission with SSRIs. In this study, we show that a serotonin type 3 receptor (5HT3R) agonist induces antidepressant effects as well as hippocampal neurogenesis independent of fluoxetine (a commonly used SSRI). Notably, our histological analysis reveals that 5HT3R and insulin-like growth factor 1 (IGF1) are expressed in the same neurons in the subgranular zone of the hippocampal dentate gyrus. Furthermore, our in vivo microdialysis analysis shows that 5HT3R regulates hippocampal extracellular IGF1 levels, and we also show that 5HT3R-dependent hippocampal neurogenesis is mediated by increased IGF1 levels. Altogether, our findings suggest a novel 5HT3R–IGF1 mechanism that is distinct from fluoxetine-induced responses and that provides a new therapeutic target for depression, especially bringing significant benefits for SSRI-resistant depressed patients.

The intellectual disability protein ​RAB39Bselectively regulates ​GluA2 trafficking to determine synaptic AMPAR composition

 Maria Lidia Mignogna, Maila Giannandrea, Antonia Gurgone, Francesca Fanelli, Francesco Raimondi, Lisa Mapelli, Silvia Bassani, Huaqiang Fang, Eelco Van Anken, Massimo Alessio, Maria Passafaro, Silvia Gatti, José A. Esteban, Richard HuganirPatrizia D’Adamo

Nature Communications  6,  Article number:  6504  doi:10.1038/ncomms7504 Received  26 March 2014  Accepted  03 February 2015  Published  18 March 2015

  Pubblicato in questi giorni, sulla prestigiosa rivista Nature Communications, il lavoro a firma dei ricercatori del Dulbecco Telethon Institute (DTI) e dell’IRCCS Ospedale San Raffaele, una delle 18 strutture di eccellenza del Gruppo Ospedaliero San Donato, coordinati da Patrizia D’Adamo, ricercatrice DTI e responsabile dell’Unità di Genetica molecolare del ritardo mentale. Gli studiosi hanno individuato il meccanismo con cui una proteina – RAB39B – scoperta qualche anno fa dallo stesso gruppo, causa un difetto di comunicazione tra le cellule nervose provocando disabilità intellettiva e autismo. La disabilità intellettiva(DI) è una malattia pediatrica con un’incidenza variabile nella popolazione dal 2 al 3%. La DI è caratterizzata da limitazioni nelle funzioni cognitive, sociali e comunicative come risultato di una mancata comunicazione delle sinapsi (i contatti tra una cellula nervosa e l’altra) del sistema nervoso centrale. Oltre a fattori ambientali, la DI è una delle caratteristiche cliniche di oltre 750 sindromi genetiche. Le più frequenti dipendono da difetti in geni localizzati sul cromosoma X umano, chiamate “disabilità intellettive associate a mutazioni di geni sul cromosoma X” (XLID). A oggi sono stati identificati 120 geni associati a XLID e la ricerca del loro ruolo nella DI ha portato a scoprire che la maggior parte di essi sono coinvolti nel funzionamento delle sinapsi e nel corretto sviluppo delle funzioni cognitive.  




Fumare marijuana produce danni vascolari come il fumo di sigaretta, come si evidenzia anche in questo recente poster:

  Brief Exposure to Marijuana Secondhand Smoke Impairs Vascular Endothelial Function

Chicago – American Hearth Association 2014 Poster

Authors Xiaoyin Wang, Ronak Derakhshandeh, Shilpa Narayan, Emmy Luu, Stephenie Le, Olivia M. Danforth, Hilda J. Rodriguez, Richard E. Sievers, Suzaynn F. Schick, Stanton A. Glantz, Matthew L. Springer, Univ of California, San Francisco, San Francisco, CA


Objectives: Despite general public awareness that tobacco secondhand smoke (SHS) is harmful, much of the public still regards marijuana SHS as benign. Because marijuana smoke and tobacco smoke are chemically and physically similar (other than nicotine and tetrahydrocannabinol (THC)), we tested this assumption by asking whether short exposure to marijuana SHS causes acute vascular endothelial dysfunction similar to that caused by tobacco SHS. Exposure to tobacco SHS impairs arterial flow-mediated dilation (FMD) in humans and rats. Methods: We used a rat model to test the effects of secondhand marijuana smoke on FMD. We exposed anesthetized rats to marijuana SHS using a modified cigarette smoking machine, and measured FMD three times: before 30-min exposure (“pre”), 10 min after end of exposure (“post10”), and 40 min after end of exposure (“post40”). FMD was measured by micro-ultrasound measurements of femoral artery diameter before and after transient (5 min) surgical ligation of the common iliac artery. Concentrations of respirable suspended particles <2.5 µm (RSP) fell during exposure; exposure conditions are denoted by starting concentrations. Results: Marijuana SHS starting at 667±62 µg/m3 RSP (n=8) caused FMD to fall from 7.5±0.94% (SEM) pre to 2.3±0.50% at post10 and 2.2±0.80 at post40 (P<0.01 for both post10 and post40 vs. pre, adjusted for multiple comparisons). SHS from placebo marijuana lacking THC starting at 671±49 µg/m3 RSP (n=7) similarly impaired FMD (9.9±1.4% pre, 4.3±0.64% post10 (p<0.01), 5.5±1.3% post40 (P<0.05)), confirming that impairment did not depend on the THC. In contrast, air in the exposure chamber (1.8±0.7 µg/m3 RSP; n=8) did not alter FMD (11.0±0.64% pre, 11.4±0.72% post10, 11.7±0.86% post40, P>0.70). Conclusions: Marijuana and tobacco SHS impair endothelial function similarly under comparable exposure conditions. Public exposure to SHS should be avoided whether the source is tobacco or marijuana.


Initial Severity of Schizophrenia and Efficacy of Antipsychotics

Participant-Level Meta-analysis of 6 Placebo-Controlled Studies   
Toshi A. Furukawa, MD, PhD
1,2; Stephen Z. Levine, PhD3; Shiro Tanaka, PhD4; Yair Goldberg, PhD5; Myrto Samara, MD6; John M. Davis, MD7; Andrea Cipriani, MD, PhD8,9; Stefan Leucht, MD6,9,10

   JAMA Psychiatry. Published online November 05, 2014


Importance  Antipsychotic drugs constitute the mainstay in the treatment of schizophrenia, and their efficacy is well established in hundreds of randomized clinical trials. However, it is not known whether they are effective or how effective they are across the wide range of baseline symptom severity.

Objective  To examine the influence of baseline severity of schizophrenia on the efficacy of antipsychotic drugs.

Design, Setting, and Participants  Meta-analysis of participant-level data from 3 pivotal randomized trials of acute schizophrenia (n = 611) and 3 pivotal trials in patients with predominantly negative symptoms of schizophrenia (n = 475).

Interventions  Olanzapine or risperidone vs placebo, and amisulpride vs placebo.

Main Outcomes and Measures  Change scores on the Positive and Negative Syndrome Scale (PANSS; score range, 30-210) and the Scale for the Assessment of Negative Symptoms (SANS; score range, 0-125) up to 6 weeks after baseline. The relationship between baseline and change scores for the drug and placebo groups was examined with 8 competing mixed-effects models for repeated measures.

Results  The best-fitting models showed that, for both types of patients, the interactions between baseline symptom severity and treatment were statistically significant (P < .01). The greater the baseline severity was, the greater the magnitude of the differences was between active treatment and placebo. In acute treatment, the mean differences in PANSS change scores were 9.5 points for patients who were mildly ill at baseline (baseline PANSS score of 58), 13.7 for moderately ill patients (baseline PANSS score of 75), 18.8 for markedly ill patients (baseline PANSS score of 95), and 24.0 for severely ill patients (baseline PANSS score of 116). In treatment of predominantly negative symptoms, the mean differences in SANS change scores were 1.7 for those who were moderately ill (baseline SANS score of 55), 5.7 for markedly ill patients (baseline SANS score of 70), and 9.7 for severely ill patients (baseline SANS score of 85).

Conclusions and Relevance  We can expect benefits of antipsychotic drugs for the full spectrum of patients likely to be treated for acute schizophrenia and for highly symptomatic patients with predominantly negative symptoms. Toward the mildest end of the spectrum, clinicians need to be aware that patients benefit less in terms of symptom improvement but may experience full adverse effects of antipsychotics. Clinicians also need to be aware that in addition to the treatment of active symptoms, which was the focus of this study, antipsychotics have another important action, namely to prevent relapses among patients in remission.


Possible contributions of skin pigmentation and vitamin D in a polyfactorial model of seasonal affective disorder

,  ,  , Michael G. Kimlin

Seasonal affective disorder (SAD) is a polyfactorial and polygenetic disorder that involves biological and psychological sub-mechanisms that differentially involve depression, seasonality, circadian rhythms, retinal sensitivity, iris pigmentation, sleep factors, and the neurotransmitters involved with these systems. Within the framework of the polyfactorial conceptualization of SAD, we review the possible contributions of vitamin D3 with respect to the aforementioned sub-mechanisms. We hypothesize that rather than functioning primarily as a proximal or direct sub-mechanism in the etiology of SAD, vitamin D likely functions in a more foundational and regulative role in potentiating the sub-mechanisms associated with the depressive and seasonality factors. There are several reasons for this position: 1. vitamin D levels fluctuate in the body seasonally, with a lag, in direct relation to seasonally-available sunlight; 2. lower vitamin D levels have been observed in depressed patients (as well as in patients with other psychiatric disorders) compared to controls; 3. vitamin D levels in the central nervous system affect the production of both serotonin and dopamine; and 4. vitamin D and vitamin D responsive elements are found throughout the midbrain regions and are especially concentrated in the hypothalamus, a region that encompasses the circadian timing systems and much of its neural circuitry. We also consider the variable of skin pigmentation as this may affect levels of vitamin D in the body. We hypothesize that people with darker skin pigmentation may experience greater risks for lower vitamin D levels that, especially following their migration to regions of higher latitude, could contribute to the emergence of SAD and other psychiatric and physical health problems.

Medical Hypotheses
Volume 83, Issue 5, Pages 517–525, November 2014


Identifying Autism from Neural Representations of Social Interactions: Neurocognitive Markers of Autism   Plos One 2 december 2014


Autism is a psychiatric/neurological condition in which alterations in social interaction (among other symptoms) are diagnosed by behavioral psychiatric methods. The main goal of this study was to determine how the neural representations and meanings of social concepts (such as to insult) are altered in autism. A second goal was to determine whether these alterations can serve as neurocognitive markers of autism. The approach is based on previous advances in fMRI analysis methods that permit (a) the identification of a concept, such as the thought of a physical object, from its fMRI pattern, and (b) the ability to assess the semantic content of a concept from its fMRI pattern. These factor analysis and machine learning methods were applied to the fMRI activation patterns of 17 adults with high-functioning autism and matched controls, scanned while thinking about 16 social interactions. One prominent neural representation factor that emerged (manifested mainly in posterior midline regions) was related to self-representation, but this factor was present only for the control participants, and was near-absent in the autism group. Moreover, machine learning algorithms classified individuals as autistic or control with 97% accuracy from their fMRI neurocognitive markers. The findings suggest that psychiatric alterations of thought can begin to be biologically understood by assessing the form and content of the altered thought’s underlying brain activation patterns.

 2013 Sep 14;382(9896):951-62. doi: 10.1016/S0140-6736(13)60733-3. Epub 2013 Jun 27.

Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis.


Department of Psychiatry and Psychotherapy, Technische Universität München, Klinikum rechts der Isar, Munich, Germany. stefan.leucht@lrz.tum.de

Erratum in

  • Lancet. 2013 Sep 14;382(9896):940.



The question of which antipsychotic drug should be preferred for the treatment of schizophrenia is controversial, and conventional pairwise meta-analyses cannot provide a hierarchy based on the randomised evidence. We aimed to integrate the available evidence to create hierarchies of the comparative efficacy, risk of all-cause discontinuation, and major side-effects of antipsychotic drugs.


We did a Bayesian-framework, multiple-treatments meta-analysis (which uses both direct and indirect comparisons) of randomised controlled trials to compare 15 antipsychotic drugs and placebo in the acute treatment of schizophrenia. We searched the Cochrane Schizophrenia Group's specialised register, Medline, Embase, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for reports published up to Sept 1, 2012. Search results were supplemented by reports from the US Food and Drug Administration website and by data requested from pharmaceutical companies. Blinded, randomised controlled trials of patients with schizophrenia or related disorders were eligible. We excluded trials done in patients with predominant negative symptoms, concomitant medical illness, or treatment resistance, and those done in stable patients. Data for seven outcomes were independently extracted by two reviewers. The primary outcome was efficacy, as measured by mean overall change in symptoms. We also examined all-cause discontinuation, weight gain, extrapyramidal side-effects, prolactin increase, QTc prolongation, and sedation.


We identified 212 suitable trials, with data for 43 049 participants. All drugs were significantly more effective than placebo. The standardised mean differences with 95% credible intervals were: clozapine 0·88, 0·73-1·03; amisulpride 0·66, 0·53-0·78; olanzapine 0·59, 0·53-0·65; risperidone 0·56, 0·50-0·63; paliperidone 0·50, 0·39-0·60; zotepine 0·49, 0·31-0·66; haloperidol 0·45, 0·39-0·51; quetiapine 0·44, 0·35-0·52; aripiprazole 0·43, 0·34-0·52; sertindole 0·39, 0·26-0·52; ziprasidone 0·39, 0·30-0·49; chlorpromazine 0·38, 0·23-0·54; asenapine 0·38, 0·25-0·51; lurasidone 0·33, 0·21-0·45; and iloperidone 0·33, 0·22-0·43. Odds ratios compared with placebo for all-cause discontinuation ranged from 0·43 for the best drug (amisulpride) to 0·80 for the worst drug (haloperidol); for extrapyramidal side-effects 0·30 (clozapine) to 4·76 (haloperidol); and for sedation 1·42 (amisulpride) to 8·82 (clozapine). Standardised mean differences compared with placebo for weight gain varied from -0·09 for the best drug (haloperidol) to -0·74 for the worst drug (olanzapine), for prolactin increase 0·22 (aripiprazole) to -1·30 (paliperidone), and for QTc prolongation 0·10 (lurasidone) to -0·90 (sertindole). Efficacy outcomes did not change substantially after removal of placebo or haloperidol groups, or when dose, percentage of withdrawals, extent of blinding, pharmaceutical industry sponsorship, study duration, chronicity, and year of publication were accounted for in meta-regressions and sensitivity analyses.


Antipsychotics differed substantially in side-effects, and small but robust differences were seen in efficacy. Our findings challenge the straightforward classification of antipsychotics into first-generation and second-generation groupings. Rather, hierarchies in the different domains should help clinicians to adapt the choice of antipsychotic drug to the needs of individual patients. These findings should be considered by mental health policy makers and in the revision of clinical practice guidelines.



Copyright © 2013 Elsevier Ltd. All rights reserved.




Ann Intern Med. 2012 Aug 14.

Antipsychotics in Adults With Schizophrenia: Comparative Effectiveness of First-Generation Versus Second-Generation Medications: A Systematic Review and Meta-analysis.

Hartling L, Abou-Setta AM, Dursun S, Mousavi SS, Pasichnyk D, Newton AS.



Debate continues about the comparative benefits and harms of first-generation antipsychotics (FGAs) and second-generation antipsychotics (SGAs) in treating schizophrenia.


To compare the effects of FGAs with those of SGAs in the treatment of adults aged 18 to 64 years with schizophrenia and related psychosis on illness symptoms, diabetes mellitus, mortality, tardive dyskinesia, and a major metabolic syndrome.


English-language studies from 10 electronic databases to March 2012, reference lists of relevant articles, and gray literature.


Randomized trials for efficacy and cohort studies at least 2 years in duration for adverse events.


Two independent reviewers extracted data from 114 studies involving 22 comparisons and graded the strength of evidence for primary outcomes as insufficient, low, moderate, or high using the Grading of Recommendations Assessment, Development and Evaluation approach.


Few differences of clinical importance were found for core illness symptoms; lack of precision in effect estimates precluded firm conclusions for many comparisons. Moderate-strength evidence showed a clinically important benefit of haloperidol over olanzapine for improving positive symptoms, but the benefit was scale-dependent: It was seen when the Scale for the Assessment of Positive Symptoms was used but not when the Positive and Negative Syndrome Scale (PANSS) was used. Moderate-strength evidence showed a clinically important benefit of olanzapine over haloperidol in improving negative symptoms when the PANSS and the Scale for the Assessment of Negative Symptoms were used. Low-strength evidence showed no difference in mortality for chlorpromazine verus clozapine or haloperidol versus aripiprazole, increased incidence of the metabolic syndrome for olanzapine versus haloperidol (risk differences, 2% and 22%), and higher incidence of tardive dyskinesia for chlorpromazine versus clozapine (risk differences, 5% and 9%). Evidence was insufficient to draw conclusions for diabetes mellitus.


All studies had high or unclear risk of bias. Length of study follow-up was often too brief to adequately measure adverse events. Medication comparisons, dosage, and outcome measurement were heterogenous for head-to-head comparisons. Selective patient populations limit generalizability.


Clear benefits of FGAs versus SGAs for treating schizophrenia remain inconclusive because of variation in assessing outcomes and lack of clinically important differences for most comparisons. The strength of evidence on safety for major medical events is low or insufficient.

PRIMARY FUNDING SOURCE:  Agency for Healthcare Research and Quality


I vantaggi degli antipsicotici di seconda generazione rispetto a quelli di prima nel trattamento dei pazienti affetti da schizofrenia restano incerti: un'ampia revisione con metanalisi, apparsa sugli Annals of internal medicine, non permette di trarre conclusioni date le diversità nella valutazione degli outcome e la scarsità di differenze clinicamente rilevanti negli studi di confronto. La ricerca ha messo a confronto gli effetti dei due gruppi di farmaci impiegati in soggetti schizofrenici adulti su sintomi di malattia, diabete, mortalità, discinesia tardiva e sindrome metabolica. In tutto sono stati inclusi nell'analisi 114 lavori, comprendenti 22 studi di confronto diretto. Si sono riscontrate poche differenze di rilevanza clinica nei sintomi fondamentali di malattia: la mancanza di precisione nella stima degli effetti ha impedito conclusioni definitive in molti confronti. Evidenze di grado moderato e forte hanno mostrato un beneficio superiore e clinicamente importante dell'aloperidolo rispetto all'olanzapina nel miglioramento dei sintomi positivi; l'effetto era però scala-dipendente: lo si notava se si usava la Scale for the assessment of positive symptoms, ma non lo si rilevava in caso di impiego della Positive and negative syndrome scale (Panss). Si sono trovate forti prove di un maggiore beneficio clinico con olanzapina a confronto dell'aloperidolo sotto il profilo della riduzione dei sintomi negativi usando la scala Panss e la Scale for the assessment of negative symptoms. Scarso invece il grado delle evidenze riguardanti una maggiore incidenza di sindrome metabolica con olanzapina vs aloperidolo e di discinesia con clorpromazina rispetto a clozapina, mentre non si è rilevata alcuna differenza di mortalità con l'uso di clorpromazina vs clozapina o di aloperidolo a confronto di aripiprazolo. Nessuna conclusione si è potuta trarre in riferimento al diabete mellito.





 The Cochrane Collaboration
Cochrane Reviews

Olanzapine versus other atypical antipsychotics for schizophrenia

This review examined the effects of olanzapine compared to other second generation antipsychotic drugs for schizophrenia. We identified 50 relevant studies with 9476 participants, comparing olanzapine with amisulpride, aripiprazole, clozapine, quetiapine, risperidone and ziprasidone. Comparisons of olanzapine with the second generation antipsychotic drugs sertindole or zotepine are currently not available. Olanzapine was somewhat more efficacious than aripiprazole, quetiapine, risperidone and ziprasidone, whereas there was no efficacy difference compared to amisulpride and clozapine. The main disadvantage of olanzapine was its higher weight gain and associated metabolic problems compared to all other second generation antipsychotic drugs, except for clozapine.

This is a Cochrane review abstract and plain language summary, prepared and maintained by The Cochrane Collaboration, currently published in The Cochrane Database of Systematic Reviews 2011 Issue 2, Copyright © 2011 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.. The full text of the review is available in The Cochrane Library (ISSN 1464-780X).
This record should be cited as: Komossa K, Rummel-Kluge C, Hunger H, Schmid F, Schwarz S, Duggan L, Kissling W, Leucht S. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD006654. DOI: 10.1002/14651858.CD006654.pub2
Editorial Group: Schizophrenia Group
This version first published online: March 17. 2010

J Clin Psychopharmacol. 2010 Oct;30(5):579-590.
Treatment Options for Bipolar Depression: A Systematic Review of Randomized, Controlled Trials.
Vieta E, Locklear J, Günther O, Ekman M, Miltenburger C, Chatterton ML, Aström M, Paulsson B.

From the *Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, Institut d'Investigacions Biomédiques August Pi i Sunyer, Centro de Investigación Biomédica en Red de Salud Mental, Barcelona, Spain; †AstraZeneca Pharmaceuticals LP, Wilmington, DE; ‡i3 Innovus, Berlin, Germany; §MLG Consulting Services, Inc, Chadds Ford, PA; ∥AstraZeneca R&D, Lund; and ¶AstraZeneca R&D, Södertälje, Sweden.
This meta-analysis examined the effectiveness of treatments of bipolar depression. Trials were identified using the MEDLINE, EMBASE, http://www.clinicaltrials.gov, and Cochrane databases (1993 to July 2008). The outcome measures included mean change in Montgomery-Åsberg Depression Rating Scale (MADRS) or Hamilton Depression Rating Scale (HAM-D) total scores, and rates of response and remission.Overall, 19 publications were included. Medications included quetiapine, lamotrigine, paroxetine, lithium, olanzapine, aripiprazole, phenelzine, and divalproex. The most trials were identified for quetiapine (5) and lamotrigine (6). Not all medications were associated with symptomatic improvement (significant reduction in MADRS/HAM-D total scores vs placebo), with lamotrigine, paroxetine, aripiprazole, and lithium not being different from placebo. Highest reductions in MADRS scores versus placebo were reported for the olanzapine-fluoxetine combination (1 trial: -6.6; 95% confidence interval [CI], -9.59 to -3.61; P = 0.000) and quetiapine monotherapy (5 trials: for 300 mg/d, -4.8; 95% CI, -6.18 to -3.49; P = 0.000; for 600 mg/d, -4.8; 95% CI, -6.22 to -3.28; P = 0.000), with quetiapine monotherapy also showing the highest reduction in HAM-D scores (4 trials: -4.0; 95% CI, -5.0 to -2.9; P = 0.000). All medications except paroxetine, lithium, aripiprazole, and phenelzine significantly improved the ratio of probabilities of response (overall rate, 1.31; 95% CI, 1.22-1.40) and remission (1.32; 95% CI, 1.20-1.45) versus placebo.Variability in efficacy exists between treatments of bipolar depression. Quetiapine and the olanzapine-fluoxetine combination showed the greatest symptomatic improvement. Efficacy considerations will need to be balanced against safety and tolerability of the individual agents.

Il Food  and Drug Administration (Agenzia per gli Alimenti e i Medicinali, abbreviato in FDA), l'ente governativo statunitense che si occupa della regolamentazione dei prodotti alimentari e farmaceutici, ha approvato l'estensione dell'uso della memantina  nelle forme moderate- avanzate dell'Alzheimer con dosaggio di 28 mg die in una unica somministrazione giornaliera.(Namenda XR). La notizia è stata data da Forest Laboratories Inc e Merz Pharmaceuticals GmbH il 21.06.2010.

J Clin Psychiatry. 2010 Jun;71(6):682-8.

Complementary and alternative medicine for major depressive disorder: a meta-analysis of patient characteristics, placebo-response rates, and treatment outcomes relative to standard antidepressants.
Freeman MP, Mischoulon D, Tedeschini E, Goodness T, Cohen LS, Fava M, Papakostas GI.

Perinatal and Reproductive Psychiatry Program, Massachusetts General Hospital, 185 Cambridge St, 2nd Floor, Boston, MA 02114, USA. [email protected]

Comment in:

J Clin Psychiatry. 2010 Jun;71(6):667-8.

OBJECTIVE: To compare patient characteristics, placebo-response rates, and outcome differences in active treatment compared to placebo in randomized controlled trials (RCTs) of complementary and alternative medicine (CAM) and standard antidepressants for major depressive disorder (MDD). DATA SOURCES: Eligible studies were first identified using searches of PubMed/MEDLINE, restricted to English, by cross-referencing the search term placebo with each of the antidepressants (those that had received letters of approval by the US, Canadian, or EU drug regulatory agencies for the treatment of MDD) and selected CAM agents. These searches were limited to articles published between January 1, 1980, and September 15, 2009 (inclusive). Reference lists from identified studies were also searched for studies eligible for inclusion. STUDY SELECTION: We selected RCTs for MDD that included validated diagnostic assessment and baseline/outcome measures of illness severity. Assessment was limited to widely used CAM agents most frequently studied in RCTs with pill placebo: St John's wort, omega-3 fatty acids, and S-adenosyl-L-methionine (SAMe). DATA SYNTHESIS: Of eligible publications, 173 reported results of 1 trial, and 5 included > 1 trial, representing a total of 185 RCTs. Patient variables, including illness severity, were similar across CAM and antidepressant RCTs, except for a higher proportion of women in CAM studies (P = .0003). Random-effects meta-analysis indicated that both antidepressant and CAM monotherapy resulted in superior response rates compared with placebo. Placebo-response rates were significantly lower for patients enrolled in CAM versus antidepressant RCTs (P = .002). Meta-regression analyses yielded no significant differences in the relative risk of prematurely discontinuing therapy due to any reason between active treatment and placebo for antidepressant and CAM RCTs, although discontinuation due to adverse events was higher in antidepressant RCTs compared to CAM RCTs (P = .007). CONCLUSIONS: Participants in CAM trials were more likely to be female and to have a lower placebo-response rate compared to those in standard antidepressant trials for MDD. Trials of standard antidepressants and CAM therapies were composed of patients with similar depression severity. 2010 Physicians Postgraduate Press, Inc.


J Clin Psychiatry. 2010 Jun;71(6):669-81.

Complementary and alternative medicine in major depressive disorder: the American Psychiatric Association Task Force report.
Freeman MP, Fava M, Lake J, Trivedi MH, Wisner KL, Mischoulon D.

Center for Women's Mental Health, Massachusetts General Hospital, Boston, MA 02114, USA. [email protected]

Comment in:

J Clin Psychiatry. 2010 Jun;71(6):667-8.

OBJECTIVE: To review selected complementary and alternative medicine (CAM) treatments for major depressive disorder (MDD). PARTICIPANTS: Authors of this report were invited participants in the American Psychiatric Association's Task Force on Complementary and Alternative Medicine. EVIDENCE: The group reviewed the literature on individual CAM treatments for MDD, methodological considerations, and future directions for CAM in psychiatry. Individual CAM treatments were reviewed with regard to efficacy in MDD, as well as risks and benefits. Literature searches included MEDLINE and PsycINFO reviews and manual reference searches; electronic searches were limited to English-language publications from 1965 to January 2010 (but manual searches were not restricted by language). Treatments were selected for this review on the basis of (1) published randomized controlled trials in MDD and (2) widespread use with important clinical safety or public health significance relevant to psychiatric practice. An action plan is presented based on needs pertaining to CAM and psychiatry. CONSENSUS PROCESS: Consensus was reached by group conferences. Written iterations were drafted and sent out among group members prior to discussion, resolution of any differences of interpretation of evidence, and final approval. CONCLUSIONS: A review of randomized controlled trials for commonly used CAM treatments such as omega-3 fatty acids, St John's wort (Hypericum), folate, S-adenosyl-l-methionine (SAMe), acupuncture, light therapy, exercise, and mindfulness psychotherapies revealed promising results. More rigorous and larger studies are recommended. Each CAM treatment must be evaluated separately in adequately powered controlled trials. At this time, several CAM treatments appear promising and deserve further study. The greatest risk of pursuing a CAM therapy is the possible delay of other well-established treatments. Clinical, research, and educational initiatives designed to focus on CAM in psychiatry are clearly warranted due to the widespread use of CAM therapies. 2010 Physicians Postgraduate Press, Inc.

Ann Gen Psychiatry. 2010 Jun 24;9(1):27. [Epub ahead of print]

A randomised, double-blind, placebo-controlled trial of tropisetron in patients with schizophrenia.
Shiina A, Shirayama Y, Niitsu T, Hashimoto T, Yoshida T, Hasegawa T, Haraguchi T, Kanahara N, Shiraishi T, Fujisaki M, Fukami G, Nakazato M, Iyo M, Hashimoto K.

ABSTRACT: BACKGROUND: Cognitive deficits in schizophrenia are associated with psychosocial deficits that are primarily responsible for the poor long-term outcome of this disease. Auditory sensory gating P50 deficits are correlated with neuropsychological deficits in attention, one of the principal cognitive disturbances in schizophrenia. Our studies suggest that the alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) agonist tropisetron might be a potential therapeutic drug for cognitive deficits in schizophrenia. Therefore, it is of particular interest to investigate the effects of tropisetron on the cognitive deficits in patients with schizophrenia. METHODS: A randomised, placebo-controlled trial of tropisetron in patients with schizophrenia was performed. A total of 40 patients with chronic schizophrenia who had taken risperidone (2 to 6 mg/day) were enrolled. Subjects were randomly assigned to a fixed titration of tropisetron (n = 20, 10 mg/day) or placebo (n = 20) in an 8-week double-blind trial. Auditory sensory gating P50 deficits and Quality of Life Scale (QLS), Cambridge Neuropsychological Test Automated Battery (CANTAB), and Positive and Negative Syndrome Scale (PANSS) scores were measured. RESULTS: In all, 33 patients completed the trial. Tropisetron was well tolerated. Administration of tropisetron, but not placebo, significantly improved auditory sensory gating P50 deficits in non-smoking patients with schizophrenia. The score on the rapid visual information processing (sustained visual attention) task of CANTAB was significantly improved by tropisetron treatment. Total and subscale scores of PANSS were not changed by this trial. QLS scores in the all patients, but not non-smoking patients, were significantly improved by tropisetron trial. CONCLUSIONS: This first randomised, double-blind, placebo-controlled trial supports the safety and efficacy of adjunctive tropisetron for treatment of cognitive deficits in schizophrenia.

J Neuroimaging. 2010 Jun 21. [Epub ahead of print]

Gray Matter Alterations in First-Admission Adolescents with Schizophrenia.
Henze R, Brunner R, Thiemann U, Parzer P, Richterich A, Essig M, Resch F, Stieltjes B.

From the Department of Child and Adolescent Psychiatry, Center for Psychosocial Medicine, University of Heidelberg, Germany (RH, RB, UT, PP, AR, FR); and Department of Radiology, German Cancer Research Center, Heidelberg, Germany (RH, ME, BS).

ABSTRACT BACKGROUND AND PURPOSE Imaging studies of patients with schizophrenia have described a variety of cerebral alterations. However, long-term medication and the chronicity of the disorder may have contributed substantially to these alterations. Studies examining patients in the early stages of the disorder reduce the possibility of such confounding factors but are rare. In light of this, the aim of the present study was to examine adolescents in the early stages of the disorder to observe primary structural brain abnormalities. METHODS Gray and white matter were measured in 13 adolescents with schizophrenia and 13 healthy controls matched for age, gender, handedness, and school type using voxel-based morphometry. RESULTS Subjects with schizophrenia displayed decreased gray matter in the cerebellar vermis, and alterations in the left putamen and in several parts of the visual system. CONCLUSIONS These findings support cerebellar involvement in the pathogenesis of schizophrenia, and the alterations observed in several parts of the visual system may provide insights into the nature of hallucinations and delusional interpretations.

Arch Gen Psychiatry. 2010 May;67(5):468-74.

Elevated brain monoamine oxidase A binding in the early postpartum period.
Sacher J, Wilson AA, Houle S, Rusjan P, Hassan S, Bloomfield PM, Stewart DE, Meyer JH.

Vivian M. Rakoff PET Centre, Centre for Addiction and Mental Health and Department of Psychiatry, University of Toronto, Toronto, Ontario M5T 1R8, Canada.

CONTEXT: The early postpartum period is a time of high risk for a major depressive episode (or postpartum depression), with a prevalence of 13%. During this time, there is a heightened vulnerability for low mood because postpartum blues is common. Severe postpartum blues can herald the onset of postpartum depression. The neurobiological mechanisms to explain postpartum blues and the high risk for the onset of postpartum depression in the first few weeks after delivery are unclear. Estrogen levels drop 100- to 1000-fold during the first 3 to 4 days postpartum, and changes in estrogen levels have an inverse relationship with monoamine oxidase A (MAO-A) density. However, MAO-A levels have never been measured in the early postpartum period. OBJECTIVE: To determine whether brain MAO-A binding is elevated in the early postpartum period. DESIGN: Case-control study. SETTING: Tertiary care academic psychiatric hospital in Toronto, Ontario, Canada. PARTICIPANTS: Fifteen healthy women who were 4 to 6 days postpartum and 15 healthy women who had not recently been postpartum underwent carbon 11-labeled harmine positron emission tomography scanning. All women were nonsmoking and medication free. MAIN OUTCOME MEASURE: MAO-A total distribution volume, an index of MAO-A density, was measured in prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain. RESULTS: MAO-A total distribution volume was significantly elevated (mean, 43%) throughout all analyzed brain regions during the early postpartum period. CONCLUSIONS: Elevated MAO-A levels in the early postpartum period can be interpreted as a marker of a monoamine-lowering process that contributes to the mood change of postpartum blues. Rather than a purely psychosocial model, we propose a neurobiological model of estrogen decline, followed by elevated MAO-A binding, low mood, and subsequently a period of high risk for major depressive episodes. Our model has important implications for preventing postpartum depression and for developing therapeutic strategies that target or compensate for elevated MAO-A levels during postpartum blues.



J Alzheimers Dis. 2009 Jul;17(3):661-80.
Caffeine reverses cognitive impairment and decreases brain amyloid-beta levels in aged Alzheimer's disease mice.

Arendash GW, Mori T, Cao C, Mamcarz M, Runfeldt M, Dickson A, Rezai-Zadeh K, Tane J, Citron BA, Lin X, Echeverria V, Potter H.

Department of Cell Biology, Florida Alzheimer's Disease Research Center, University of South Florida, Tampa, FL 33620, USA. [email protected]

Comment in:

* J Alzheimers Dis. 2009 Jul;17(3):699-700; discussion 701-2.


We have recently shown that Alzheimer's disease (AD) transgenic mice given a moderate level of caffeine intake (the human equivalent of 5 cups of coffee per day) are protected from development of otherwise certain cognitive impairment and have decreased hippocampal amyloid-beta (Abeta) levels due to suppression of both beta-secretase (BACE1) and presenilin 1 (PS1)/gamma-secretase expression. To determine if caffeine intake can have beneficial effects in "aged" APPsw mice already demonstrating cognitive impairment, we administered caffeine in the drinking water of 18-19 month old APPsw mice that were impaired in working memory. At 4-5 weeks into caffeine treatment, those impaired transgenic mice given caffeine (Tg/Caff) exhibited vastly superior working memory compared to the continuing impairment of control transgenic mice. In addition, Tg/Caff mice had substantially reduced Abeta deposition in hippocampus (decrease 40%) and entorhinal cortex (decrease 46%), as well as correlated decreases in brain soluble Abeta levels. Mechanistically, evidence is provided that caffeine suppression of BACE1 involves the cRaf-1/NFkappaB pathway. We also determined that caffeine concentrations within human physiological range effectively reduce active and total glycogen synthase kinase 3 levels in SweAPP N2a cells. Even with pre-existing and substantial Abeta burden, aged APPsw mice exhibited memory restoration and reversal of AD pathology, suggesting a treatment potential of caffeine in cases of established AD.



Schizophr Res. 2009 Dec;115(2-3):97-103. Epub 2009 Oct 9.

Effectiveness of antipsychotics in first-episode schizophrenia and schizophreniform disorder on response and remission: an open randomized clinical trial (EUFEST).
Boter H, Peuskens J, Libiger J, Fleischhacker WW, Davidson M, Galderisi S, Kahn RS; EUFEST study group.

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands. [email protected]

BACKGROUND: Predefined response and remission criteria may hold more clinical relevance than mean scores on rating scales. We compared the effectiveness of low doses of haloperidol and regular doses of second generation antipsychotics (SGAs) on >or=50% response and remission. METHODS: In an open randomized clinical trial in 14 countries, 498 unselected first-episode patients with schizophrenia were assigned to haloperidol (1-4 mg/d; n=103), amisulpride (200-800 mg/d; n=104), olanzapine (5-20mg/d; n=105), quetiapine (200-750 mg/d; n=104), or ziprasidone (40-160 mg/d; n=82). Primary outcomes were >or=50% response and remission within 12 months, as measured with the Positive and Negative Syndrome Scale. Analysis was by intention-to-treat. RESULTS: Within 12 months, the proportions of patients with >or=50% response were 37% for haloperidol, 67% for amisulpride, 67% for olanzapine, 46% for quetiapine, and 56% for ziprasidone. Comparisons with haloperidol showed a higher likelihood for >or=50% response with amisulpride (hazard ratio [HR] 2.27, [95% CI 1.51-3.42]), olanzapine (HR 2.07 [1.38-3.10]), and ziprasidone (HR 1.62 [1.02-2.56]). Within 12 months, the proportions of patients in remission were 17% for haloperidol, 40% for amisulpride, 41% for olanzapine, 24% for quetiapine, and 28% for ziprasidone. Comparisons with haloperidol showed a better chance for remission on amisulpride (HR 2.49, [95% CI 1.43-4.35]), olanzapine (HR 2.58 [1.48-4.48]), quetiapine (HR 1.96 [1.06-3.64]), and ziprasidone (HR 2.03 [1.07-3.87]). CONCLUSIONS: Substantial proportions of first-episode patients with schizophrenia showed clinically meaningful response and remission rates within 12 months. The proportions of response and remission were higher for most SGAs as compared to haloperidol.

Psychopharmacology Bulletin CME. 2009;41(2):35-49

Bipolar-I Patient Characteristics Associated With Differences in Antimanic Medication Prescribing
Alisa B. Busch, MD, MS ; Richard G. Frank, PhD ; Gary Sachs, MD ; Sharon-Lise T. Normand, PhD

Objective: Second-generation antipsychotics offer more choice in antimanic pharmacologic treatment. Unclear though is whether they are expanding antimanic treatment, replacing mood stabilizers, or if/which patient characteristics influence prescribing choices. We studied the association between patient characteristics and patient-reported antimanic medication use upon entry in the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).
Experimental Design: Observational study using STEP-BD baseline data from bipolar-I patients (N = 1,943) during years 2000-2004. Two logistic regression models (binomial and multinomial) were estimated to examine associations between patient characteristics and patient-reported drug use: 1) any anti-manic medication (antipsychotic or mood stabilizer), and 2) mood stabilizer, antipsychotic monotherapy, or neither.
Principal Observations: At study entry over 80% of participants reported receiving at least one antimanic medication; 73% a mood stabilizer specifically. In general, there was no association between study year and the odds of entering on antimanic medication. Measures of psychiatric severity or complexity were more likely to be associated with differences in the drugs used; co-occurring medical conditions were not. Depressed states were associated with similar odds of antipsychotic monotherapy as elevated or mixed states. Compared to whites, blacks had greater odds of entering on antipsychotic monotherapy relative to a mood stabilizer.
Conclusions: Despite increasing pharmacotherapy options, we found no evidence that over time more patients received antimanic medication. Not all prescribing differences were consistent with the medical literature. Also, blacks were more likely to receive antipsychotic monotherapy, even after adjusting for clinical characteristics. Future research examining provider characteristics that influence prescribing is needed.

Circ Arrhythm Electrophysiol. 2009 Oct 1;2(5):511-523

Latent Genetic Backgrounds and Molecular Pathogenesis in Drug-Induced Long-QT Syndrome.

Itoh H, Sakaguchi T, Ding WG, Watanabe E, Watanabe I, Nishio Y, Makiyama T, Ohno S, Akao M, Higashi Y, Zenda N, Kubota T, Mori C, Okajima K, Haruna T, Miyamoto A, Kawamura M, Ishida K, Nagaoka I, Oka Y, Nakazawa Y, Yao T, Jo H, Sugimoto Y, Ashihara T, Hayashi H, Ito M, Imoto K, Matsuura H, Horie M.
Department of Cardiovascular and Respiratory Medicine and the Department of Physiology, Shiga University of Medical Science, Shiga, Japan; the Department of Laboratory Medicine, Fujita Health University School of Medicine, Toyoake, Japan; the Division of Cardiology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan; the Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan; the Cardiovascular Division, Showa University Fujigaoka Hospital, Yokohama, Japan; the Division of Cardiology, Gifu University Graduate School of Medicine, Gifu, Japan; the Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Daisan Hospital, Tokyo, Japan; the Department of Cardiology, Hyogo Brain and Heart Center, Himeji, Japan; the Department of Cardiology, Kitano Hospital, Osaka, Japan; and the Department of Information Physiology, National Institute for Physiological Sciences, Okazaki, Japan.

BACKGROUND: Drugs with I(Kr)-blocking action cause secondary long-QT syndrome. Several cases have been associated with mutations of genes coding cardiac ion channels, but their frequency among patients affected by drug-induced long-QT syndrome (dLQTS) and the resultant molecular effects remain unknown. METHODS AND RESULTS: Genetic testing was carried out for long-QT syndrome-related genes in 20 subjects with dLQTS and 176 subjects with congenital long-QT syndrome (cLQTS); electrophysiological characteristics of dLQTS-associated mutations were analyzed using a heterologous expression system with Chinese hamster ovary cells together with a computer simulation model. The positive mutation rate in dLQTS was similar to cLQTS (dLQTS versus cLQTS, 8 of 20 [40%] versus 91 of 176 [52%] subjects, P=0.32). The incidence of mutations was higher in patients with torsades de pointes induced by nonantiarrhythmic drugs than by antiarrhythmic drugs (antiarrhythmic versus others, 3 of 14 [21%] versus 5 of 6 [83%] subjects, P<0.05). When reconstituted in Chinese hamster ovary cells, KCNQ1 and KCNH2 mutant channels showed complex gating defects without dominant negative effects or a relatively mild decreased current density. Drug sensitivity for mutant channels was similar to that of the wild-type channel. With the Luo-Rudy simulation model of action potentials, action potential durations of most mutant channels were between those of wild-type and cLQTS. CONCLUSIONS: dLQTS had a similar positive mutation rate compared with cLQTS, whereas the functional changes of these mutations identified in dLQTS were mild. When I(Kr)-blocking agents produce excessive QT prolongation (dLQTS), the underlying genetic background of the dLQTS subject should also be taken into consideration, as would be the case with cLQTS; dLQTS can be regarded as a latent form of long-QT syndrome.


Psychiatry Research Volume 169, Issue 2, Pages 124-131 (30 September 2009)
Comparative effectiveness of biomarkers and clinical indicators for predicting outcomes of SSRI treatment in Major Depressive Disorder: Results of the BRITE-MD study

Andrew F. Leuchterab, Ian A. Cookab, Lauren B. Marangellc, William S. Gilmerd, Karl S. Burgoynebe, Robert H. Howlandf, Madhukar H. Trivedig, Sidney Zisookh, Rakesh Jaini, James T. McCrackenb, Maurizio Favaj, Dan Iosifescuj, Scott Greenwaldk
Patients with Major Depressive Disorder (MDD) may not respond to antidepressants for 8 weeks or longer. A biomarker that predicted treatment effectiveness after only 1 week could be clinically useful. We examined a frontal quantitative electroencephalographic (QEEG) biomarker, the Antidepressant Treatment Response (ATR) index, as a predictor of response to escitalopram, and compared ATR with other putative predictors. Three hundred seventy-five subjects meeting DSM-IV criteria for MDD had a baseline QEEG study. After 1 week of treatment with escitalopram, 10 mg, a second QEEG was performed, and the ATR was calculated. Subjects then were randomly assigned to continue with escitalopram, 10 mg, or change to alternative treatments. Seventy-three evaluable subjects received escitalopram for a total of 49days. Response and remission rates were 52.1% and 38.4%, respectively. The ATR predicted both response and remission with 74% accuracy. Neither serum drug levels nor 5HTTLPR and 5HT2a genetic polymorphisms were significant predictors. Responders had larger decreases in Hamilton Depression Rating Scale (Ham-D17) scores at day 7 (P=0.005), but remitters did not. Clinician prediction based upon global impression of improvement at day 7 did not predict outcome. Logistic regression showed that the ATR and early Ham-D17 changes were additive predictors of response, but the ATR was the only significant predictor of remission. Future studies should replicate these results prior to clinical use.

The Lancet, Volume 374, Issue 9690, Pages 620 - 627, 22 August 2009

11-year follow-up of mortality in patients with schizophrenia: a population-based cohort study (FIN11 study)

J. Tiihonen , J. Lönnqvist K. Wahlbeck T. Klaukka MD et Al.

The introduction of second-generation antipsychotic drugs during the 1990s is widely believed to have adversely affected mortality of patients with schizophrenia. Our aim was to establish the long-term contribution of antipsychotic drugs to mortality in such patients.
Nationwide registers in Finland were used to compare the cause-specific mortality in 66 881 patients versus the total population (5·2 million) between 1996, and 2006, and to link these data with the use of antipsychotic drugs. We measured the all-cause mortality of patients with schizophrenia in outpatient care during current and cumulative exposure to any antipsychotic drug versus no use of these drugs, and exposure to the six most frequently used antipsychotic drugs compared with perphenazine use.
Although the proportional use of second-generation antipsychotic drugs rose from 13% to 64% during follow-up, the gap in life expectancy between patients with schizophrenia and the general population did not widen between 1996 (25 years), and 2006 (22·5 years). Compared with current use of perphenazine, the highest risk for overall mortality was recorded for quetiapine (adjusted hazard ratio [HR] 1·41, 95% CI 1·09—1·82), and the lowest risk for clozapine (0·74, 0·60—0·91; p=0·0045 for the difference between clozapine vs perphenazine, and p<0·0001 for all other antipsychotic drugs). Long-term cumulative exposure (7—11 years) to any antipsychotic treatment was associated with lower mortality than was no drug use (0·81, 0·77—0·84). In patients with one or more filled prescription for an antipsychotic drug, an inverse relation between mortality and duration of cumulative use was noted (HR for trend per exposure year 0·991; 0·985—0·997).
Long-term treatment with antipsychotic drugs is associated with lower mortality compared with no antipsychotic use. Second-generation drugs are a highly heterogeneous group, and clozapine seems to be associated with a substantially lower mortality than any other antipsychotics. Restrictions on the use of clozapine should be reassessed.
Annual EVO Financing (Special government subsidies from the Ministry of Health and Welfare, Finland).

Articoli correlati : Clozapine for schizophrenia: Life-threatening or life-saving treatment?   http://www.currentpsychiatry.com/article_pages.asp?AID=8165

CNS Drugs. 2009 Aug 1;23(8):649-59

The CATIE and CUtLASS studies in schizophrenia: results and implications for clinicians.
Naber D, Lambert M.

Department of Psychiatry and Psychotherapy, Centre for Psychosocial Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. [email protected]

Numerous double-blind studies have compared second-generation antipsychotics (SGAs) with first-generation antipsychotics (FGAs), with most finding better efficacy and tolerability for SGAs. However, these 'efficacy trials' were generally short term and included only highly selected patients. Mostly because of weight gain and other metabolic effects of the SGAs, as well as their high acquisition price, the debate on the (cost) effectiveness of the SGAs led to two pragmatic clinical trials with no sponsorship by industry. Both trials had broad inclusion criteria and long follow-up, and tried to mimic clinical routine: CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) and CUtLASS (Cost Utility of the Latest Antipsychotic drugs in Schizophrenia Study). 1493 patients participated in CATIE, an 18-month, double-blind trial comparing the SGAs olanzapine, quetiapine, risperidone and ziprasidone with the FGA perphenazine. If efficacy or tolerability was insufficient, patients were re-randomized to a medication other than the one they previously received. Improvement of psychopathology and of quality of life was only moderate. Overall, 74% of patients discontinued study medication before 18 months, and the median time to discontinuation was 4.6 months. Aside from olanzapine (time to discontinuation 9.2 months), the other SGAs did not differ from each other or from perphenazine. Except for adverse effects as a reason for discontinuation, differences between the SGAs and the FGA were minimal. In CUtLASS, a 12-month open-label trial, 277 patients were randomized to receive an FGA or a SGA. Again, efficacy was rather similar between the two groups, with only limited improvement of psychopathology and quality of life. The authors of both trials concluded that SGAs do not markedly differ from FGAs regarding compliance, quality of life and effectiveness. The methodological problems of both trials have been discussed extensively. Patients had psychotic symptoms that were moderate in severity and were at least partially treatment resistant. The marginal improvement observed indicated that this population might not be appropriate to detect differences between FGAs and SGAs. Specific issues of CATIE include the exclusion of patients with tardive dyskinesia in the perphenazine arm and the high discontinuation rate. In CUtLASS, the concept of including 13 different FGAs and four SGAs in the respective classes was problematic. It is of interest that the most widely prescribed drug was sulpiride--of the FGAs, this is probably the 'most atypical' drug. Aside from the finding that the advantages of the SGAs are not as strong as early trials and marketing suggested or promised, the trials do not provide much helpful information regarding everyday practice. For tardive dyskinesia, no conclusions at all can be drawn. Similarly, methodological problems inhibited the detection of the other major advantage of the SGAs, i.e. the improved subjective well-being/quality of life while receiving these agents. It is well known that patients' and doctors' perspectives differ markedly, and the Quality of Life Scale (QLS), an expert-rated scale used in both trials, might not be sensitive enough to detect the subjective advantages reported by the majority of patients in other trials. CATIE and CUtLASS suggest that SGAs do not live up to all the previous expectations. However, even if most of these advantages are debatable, the lower risk of tardive dyskinesia and the better subjective effects should be strong enough reasons to favour these drugs. There is no single antipsychotic that is best for every schizophrenia patient, as individual responses differ markedly. For successfully individualized treatment, a multitude of antipsychotic options are needed.

Farm Hosp. 2009 Jul 1;33(4):224-8

Mortality in patients with dementia treateds with atypical antipsychotics (olanzapine, quetiapine and ziprasidone)

Martínez Martínez L, Olivera Fernández MR, Piñeiro Corrales G.
Servicio de Farmacia, Complexo Hospitalario de Pontevedra, Pontevedra, España.

INTRODUCTION: The atypical antipsychotics (AA) quetiapine, olanzapine and ziprasidone are used to treat behavioural disorders associated with dementia. This indication does not appear on their technical sheet. The object of this study is to analyse the relationship of these treatments with mortality and other factors. METHOD: Retrospective study from March 2005 to July 2007 of AA treatments requested as compassionate use. We collected information on mortality, age, history of heart disease or cerebrovascular disease, and duration and number of concomitant treatments per patient. RESULTS: 289 patients were studied. Mortality was 31.1 %. A higher mortality rate was shown for patients with a history of heart disease and in those who used olanzapine. Quetiapine was the most commonly prescribed antipsychotic drug. CONCLUSIONS: The use of AA in the elderly could have risks that outweigh the benefi ts. When prescribing these drugs for at-risk patients, one should consider their safety warnings and the individual case of each patient. According to our data, olanzapine seems to be associated with a higher risk than quetiapine and ziprasidone.

Am J Psychiatry. 2009 Apr 15
Cognitive Effects of Antipsychotic Drugs in First-Episode Schizophrenia and Schizophreniform Disorder: A Randomized, Open-Label Clinical Trial (EUFEST).

Davidson M, Galderisi S, Weiser M, Werbeloff N, Fleischhacker WW, Keefe RS, Boter H, Keet IP, Prelipceanu D,Rybakowski JK, Libiger J, Hummer M, Dollfus S, López-Ibor JJ, Hranov LG, Gaebel W, Peuskens J, Lindefors N,Riechler-Rössler A, Kahn RS.

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. Method 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. Conclusions 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.

Michael Davidson, MD, del Sheba Medical Center, in Tel-Hashomer, Israel, e gli altri Autori hanno dichiarato che il vantaggio suggerito dagli studi precedenti riguardo l'attività maggiore dei nuovi antipsicotici sui sintomi cognitivi rispetto ai vecchi era legato all'uso di dosi eccessive di antipsicotici di prima generazione usati come paragone, con effetti negativi sulle performance motorie e la necessità di associare dei farmaci anticolinergici che a loro volta determinavano deficit cognitivi. Gli Autori pensano che siano necessari dei farmaci nuovi, con meccanismi di azione diversi, per curare i sintomi cognitivi.

J Clin Psychopharmacol. 2009 Apr;29(2):141-6.
Systematic overview of Cochrane reviews for anticholinergic effects of antipsychotic drugs.
Ozbilen M, Adams CE.
Newsam Centre, Seacroft Hospital, Leeds, United Kingdom. [email protected]

BACKGROUND: Despite much being written on the topic, there are few surveys investigating the prevalence of anticholinergic adverse effects of antipsychotic drugs. One study, however, used trial-derived data to calculate estimates. OBJECTIVES: To investigate the prevalence/incidence rates of anticholinergic effects as viewed from within relevant randomized trials. METHODS: Data were extracted from each relevant study included in Cochrane reviews. Data were checked, extracted, and simple frequencies, and 95% confidence intervals (CIs) were calculated. RESULTS: Many trials in relevant reviews reported no data on anticholinergic effects (estimate 40,000 participants). However, data were extracted from 177 studies within 54 reviews (N = 27,328 participants). Most data are short-term (<12 weeks). For blurred vision, the newer generations of drugs have rates of between 10% and 20% (eg, risperidone, n = 1460, 6 randomized controlled trials [RCTs], 11.9% prevalence; CI, 10-14; olanzapine, n = 1584; 4 RCTs, 12.2% prevalence; CI, 11-14). These estimates are similar to those of sulpiride (n = 186; 2 RCTs, 12.4%; CI, 8-18) and chlorpromazine (n = 294; 10 RCTs, 11.2%; CI, 8-15), less than trifluoperazine (n = 167; 8 RCTs, 31.1%; CI, 25-39), but considerably more than perphenazine (n = 410; 8 RCTs, 3.7%; CI, 2-6). Data are presented on a range of anticholinergic effects across different periods. CONCLUSIONS: Anticholinergic symptoms are common adverse effects associated with the use of all antipsychotic drugs, and newer-generation drugs are not clearly distinguishable from many older compounds. Adverse effect data should be more accessible.


J Psychopharmacol 2009; 23; 346 originally published online Mar 27, 2009;

GM Goodwin and Consensus Group of the British Association for Psychopharmacology from the British Association for Psychopharmacology

Evidence-based guidelines for treating bipolar disorder: revised second edition recommendations


L'articolo è liberamente scaricabile: http://jop.sagepub.com/cgi/reprint/23/4/346

 Cell. 2009 Mar 20;136(6):1017-31

Disrupted in schizophrenia 1 regulates neuronal progenitor proliferation via modulation of GSK3beta/beta-catenin signaling.

Mao Y, Ge X, Frank CL, Madison JM, Koehler AN, Doud MK, Tassa C, Berry EM, Soda T, Singh KK, Biechele T, Petryshen TL, Moon RT, Haggarty SJ, Tsai LH.
Howard Hughes Medical Institute, Cambridge, MA 02139, USA.

The Disrupted in Schizophrenia 1 (DISC1) gene is disrupted by a balanced chromosomal translocation (1; 11) (q42; q14.3) in a Scottish family with a high incidence of major depression, schizophrenia, and bipolar disorder. Subsequent studies provided indications that DISC1 plays a role in brain development. Here, we demonstrate that suppression of DISC1 expression reduces neural progenitor proliferation, leading to premature cell cycle exit and differentiation. Several lines of evidence suggest that DISC1 mediates this function by regulating GSK3beta. First, DISC1 inhibits GSK3beta activity through direct physical interaction, which reduces beta-catenin phosphorylation and stabilizes beta-catenin. Importantly, expression of stabilized beta-catenin overrides the impairment of progenitor proliferation caused by DISC1 loss of function. Furthermore, GSK3 inhibitors normalize progenitor proliferation and behavioral defects caused by DISC1 loss of function. Together, these results implicate DISC1 in GSK3beta/beta-catenin signaling pathways and provide a framework for understanding how alterations in this pathway may contribute to the etiology of psychiatric disorders.

Lancet. 2009 Feb 28;373(9665):746-58. (Review)

Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis.

Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C.

Department of Medicine and Public Health, Section of Psychiatry and Clinical Psychology, University of Verona, Italy; Department of Psychiatry, University of Oxford, UK.

BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression.
METHODS: We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis.
FINDINGS: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.
INTERPRETATION: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost.

Lancet. 2009 Jan 17;373(9659):234-9
Common genetic determinants of schizophrenia and bipolar disorder in Swedish families: a population-based study.
Lichtenstein P, Yip BH, Björk C, Pawitan Y, Cannon TD, Sullivan PF, Hultman CM.

Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.

BACKGROUND: Whether schizophrenia and bipolar disorder are the clinical outcomes of discrete or shared causative processes is much debated in psychiatry. We aimed to assess genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and their comorbidity. METHODS: We linked the multi-generation register, which contains information about all children and their parents in Sweden, and the hospital discharge register, which includes all public psychiatric inpatient admissions in Sweden. We identified 9 009 202 unique individuals in more than 2 million nuclear families between 1973 and 2004. Risks for schizophrenia, bipolar disorder, and their comorbidity were assessed for biological and adoptive parents, offspring, full-siblings and half-siblings of probands with one of the diseases. We used a multivariate generalised linear mixed model for analysis of genetic and environmental contributions to liability for schizophrenia, bipolar disorder, and the comorbidity. FINDINGS: First-degree relatives of probands with either schizophrenia (n=35 985) or bipolar disorder (n=40 487) were at increased risk of these disorders. Half-siblings had a significantly increased risk (schizophrenia: relative risk [RR] 3.6, 95% CI 2.3-5.5 for maternal half-siblings, and 2.7, 1.9-3.8 for paternal half-siblings; bipolar disorder: 4.5, 2.7-7.4 for maternal half-siblings, and 2.4, 1.4-4.1 for paternal half-siblings), but substantially lower than that of the full-siblings (schizophrenia: 9.0, 8.5-11.6; bipolar disorder: 7.9, 7.1-8.8). When relatives of probands with bipolar disorder were analysed, increased risks for schizophrenia existed for all relationships, including adopted children to biological parents with bipolar disorder. Heritability for schizophrenia and bipolar disorder was 64% and 59%, respectively. Shared environmental effects were small but substantial (schizophrenia: 4.5%, 4.4%-7.4%; bipolar disorder: 3.4%, 2.3%-6.2%) for both disorders. The comorbidity between disorders was mainly (63%) due to additive genetic effects common to both disorders. INTERPRETATION: Similar to molecular genetic studies, we showed evidence that schizophrenia and bipolar disorder partly share a common genetic cause. These results challenge the current nosological dichotomy between schizophrenia and bipolar disorder, and are consistent with a reappraisal of these disorders as distinct diagnostic entities.

N Engl J Med. 2009 Jan 15;360(3):225-35.
Atypical antipsychotic drugs and the risk of sudden cardiac death.

Ray WA, Chung CP, Murray KT, Hall K, Stein CM.
Division of Pharmacoepidemiology, Department of Preventive Medicine, Vanderbilt University School of Medicine, Nashville 37212, USA. [email protected]

BACKGROUND: Users of typical antipsychotic drugs have an increased risk of serious ventricular arrhythmias and sudden cardiac death. However, less is known regarding the cardiac safety of the atypical antipsychotic drugs, which have largely replaced the older agents in clinical practice. METHODS: We calculated the adjusted incidence of sudden cardiac death among current users of antipsychotic drugs in a retrospective cohort study of Medicaid enrollees in Tennessee. The primary analysis included 44,218 and 46,089 baseline users of single typical and atypical drugs, respectively, and 186,600 matched nonusers of antipsychotic drugs. To assess residual confounding related to factors associated with the use of antipsychotic drugs, we performed a secondary analysis of users of antipsychotic drugs who had no baseline diagnosis of schizophrenia or related psychoses and with whom nonusers were matched according to propensity score (i.e., the predicted probability that they would be users of antipsychotic drugs). RESULTS: Current users of typical and of atypical antipsychotic drugs had higher rates of sudden cardiac death than did nonusers of antipsychotic drugs, with adjusted incidence-rate ratios of 1.99 (95% confidence interval [CI], 1.68 to 2.34) and 2.26 (95% CI, 1.88 to 2.72), respectively. The incidence-rate ratio for users of atypical antipsychotic drugs as compared with users of typical antipsychotic drugs was 1.14 (95% CI, 0.93 to 1.39). Former users of antipsychotic drugs had no significantly increased risk (incidence-rate ratio, 1.13; 95% CI, 0.98 to 1.30). For both classes of drugs, the risk for current users increased significantly with an increasing dose. Among users of typical antipsychotic drugs, the incidence-rate ratios increased from 1.31 (95% CI, 0.97 to 1.77) for those taking low doses to 2.42 (95% CI, 1.91 to 3.06) for those taking high doses (P<0.001). Among users of atypical agents, the incidence-rate ratios increased from 1.59 (95% CI, 1 .03 to 2.46) for those taking low doses to 2.86 (95% CI, 2.25 to 3.65) for those taking high doses (P=0.01). The findings were similar in the cohort that was matched for propensity score. CONCLUSIONS: Current users of typical and of atypical antipsychotic drugs had a similar, dose-related increased risk of sudden cardiac death. 2009 Massachusetts Medical Society

CNS Drugs. 2009;23 Suppl 2:27-34.

Agomelatine: innovative pharmacological approach in depression.

Popoli M.

Center of Neuropharmacology, Department of Pharmacological Sciences, University of Milan, Milan, Italy. [email protected]

Currently available antidepressant agents such as tricyclic antidepressants (TCAs) act primarily through monoaminergic systems in the brain, and have proved to be suboptimal for the management of major depressive disorder (MDD). Such agents are also active at non-target receptor sites, contributing to the development of often serious adverse events. Even the newer selective serotonin reuptake inhibitors (SSRIs), which also act through monoaminergic systems, have suboptimal antidepressant efficacy, and the adverse events that do occur often negatively influence adherence. Although the pathophysiology of depression is not completely understood, it is increasingly recognized that monoamine deficiency/disruption is not the only pathway involved. Recognition that circadian rhythm desynchronization also plays a key role in mood disorders has led to the development of agomelatine, which is endowed with a novel mechanism of action distinct from that of currently available antidepressants. Agomelatine is an agonist of the melatonergic MT(1) and MT(2) receptors, as well as a 5-HT(2C) receptor antagonist. The antidepressant activity of agomelatine is proposed to stem from the synergy between these sets of receptors, which are key components of the circadian timing system. Agomelatine has shown antidepressant-like activity in a number of animal models of depression, such as the learned helplessness model, the chronic mild stress model, the forced swim test and the chronic psychosocial stress test. Moreover, agomelatine has been found to restore normal circadian rhythms in animal models of a disrupted circadian system, and has proved beneficial in an animal model of delayed sleep phase syndrome. Likewise, it has been shown to improve disturbed sleep-wake rhythms in depressed patients. Moreover, current pharmacological and clinical data strongly support the use of agomelatine in the management of MDD.


1: Cochrane Database Syst Rev. 2009 Jan 21;(1):CD000059.   Update of:Cochrane Database Syst Rev. 2000;(2):CD000059.

Clozapine versus typical neuroleptic medication for schizophrenia.

Essali A, Al-Haj Haasan N, Li C, Rathbone J.
27 Al Zahraw Street, Rawdad, Damascus, Syrian Arab Republic. [email protected]

BACKGROUND: Long-term drug treatment of schizophrenia with typical antipsychotics has limitations: 25 to 33% of patients have illnesses that are treatment-resistant. Clozapine is an antipsychotic drug, which is claimed to have superior efficacy and to cause fewer motor adverse effects than typical drugs for people with treatment-resistant illnesses. Clozapine carries a significant risk of serious blood disorders, which necessitates mandatory weekly blood monitoring at least during the first months of treatment. OBJECTIVES: To evaluate the effects of clozapine compared with typical antipsychotic drugs in people with schizophrenia. SEARCH STRATEGY: For the current update of this review (March 2006) we searched the Cochrane Schizophrenia Group Trials Register. SELECTION CRITERIA: All relevant randomised clinical trials (RCTs). DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated relative risks (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We calculated numbers needed to treat/harm (NNT/NNH) where appropriate. For continuous data, we calculated weighted mean differences (WMD) again based on a fixed-effect model. MAIN RESULTS: We have included 42 trials (3950 participants) in this review. Twenty-eight of the included studies are less than 13 weeks in duration, and, overall, trials were at significant risk of bias. We found no significant difference in the effects of clozapine and typical neuroleptic drugs for broad outcomes such as mortality, ability to work or suitability for discharge at the end of the study. Clinical improvements were seen more frequently in those taking clozapine (n=1119, 14 RCTs, RR 0.72 CI 0.7 to 0.8, NNT 6 CI 5 to 8). Also, participants given clozapine had fewer relapses than those on typical antipsychotic drugs (n=1303, RR 0.62 CI 0.5 to 0.8, NNT 21 CI 15 to 49). BPRS scores showed a greater reduction of symptoms in clozapine-treated patients, (n=1145, 16 RCTs, WMD -4.22 CI -5.4 to -3.1), although the data were heterogeneous (Chi(2) 0.0001, I(2) 66%). Short-term data from the SANS negative symptom scores favoured clozapine (n=196, 5 RCTs, WMD -5.92 CI -7.8 to -4.1). We found clozapine to be more acceptable in long-term treatment than conventional antipsychotic drugs (n=982, 16 RCTs, RR 0.60 CI 0.5 to 0.7, NNT 15 CI 12 to 20). Blood problems occurred more frequently in participants receiving clozapine (3.2%) compared with those given typical antipsychotics (0%) (n=1031, 13 RCTs, RR 7.09 CI 2.0 to 25.6). Clozapine participants experienced more drowsiness, hypersalivation, or temperature increase, than those given conventional neuroleptics. However, clozapine patients experienced fewer motor adverse effects (n=1433, 18 RCTs, RR 0.58 CI 0.5 to 0.7, NNT 5 CI 4 to 6).The clinical effects of clozapine were more pronounced in participants resistant to typical neuroleptics in terms of clinical improvement (n=370, 4 RCTs, RR 0.71 CI 0.6 to 0.8, NNT 4 CI 3 to 6) and symptom reduction. Thirty-four per cent of treatment-resistant participants had a clinical improvement with clozapine treatment. AUTHORS' CONCLUSIONS: Clozapine may be more effective in reducing symptoms of schizophrenia, producing clinically meaningful improvements and postponing relapse, than typical antipsychotic drugs - but data are weak and prone to bias. Participants were more satisfied with clozapine treatment than with typical neuroleptic treatment. The clinical effect of clozapine, however, is, at least in the short term, not reflected in measures of global functioning such as ability to leave the hospital and maintain an occupation. The short-term benefits of clozapine have to be weighed against the risk of adverse effects. Within the context of trials, the potentially dangerous white blood cell decline seems to be more frequent in children and adolescents and in the elderly than in young adults or people of middle-age.The existing trials have largely neglected to assess the views of participants and their families on clozapine. More community-based long-term randomised trials are needed to evaluate the efficacy of clozapine on global and social functioning as trials in special groups such as people with learning disabilities

I senatori Fabio Rizzi e Rossana Boldi (Lega Nord) hanno presentato il 24 marzo 2009 il Disegno di Legge n. 1423 di modifica della 180. Prescrizione psichiatrica obbligatoria, strutture di accertamento psichiatrico all’interno dei pronto soccorso, centri ospedalieri dedicati per la cura dei malati di depressione e trattamenti psichiatrici effettuabili anche presso strutture private accreditate rappresentano le principali novità.

Lancet. 2009 Jan 28. Cipriani A, Furukawa TA, Salanti G, et al. (Review)

Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. 

BACKGROUND: Conventional meta-analyses have shown inconsistent results for efficacy of second-generation antidepressants. We therefore did a multiple-treatments meta-analysis, which accounts for both direct and indirect comparisons, to assess the effects of 12 new-generation antidepressants on major depression.
METHODS: We systematically reviewed 117 randomised controlled trials (25 928 participants) from 1991 up to Nov 30, 2007, which compared any of the following antidepressants at therapeutic dose range for the acute treatment of unipolar major depression in adults: bupropion, citalopram, duloxetine, escitalopram, fluoxetine, fluvoxamine, milnacipran, mirtazapine, paroxetine, reboxetine, sertraline, and venlafaxine. The main outcomes were the proportion of patients who responded to or dropped out of the allocated treatment. Analysis was done on an intention-to-treat basis.
FINDINGS: Mirtazapine, escitalopram, venlafaxine, and sertraline were significantly more efficacious than duloxetine (odds ratios [OR] 1.39, 1.33, 1.30 and 1.27, respectively), fluoxetine (1.37, 1.32, 1.28, and 1.25, respectively), fluvoxamine (1.41, 1.35, 1.30, and 1.27, respectively), paroxetine (1.35, 1.30, 1.27, and 1.22, respectively), and reboxetine (2.03, 1.95, 1.89, and 1.85, respectively). Reboxetine was significantly less efficacious than all the other antidepressants tested. Escitalopram and sertraline showed the best profile of acceptability, leading to significantly fewer discontinuations than did duloxetine, fluvoxamine, paroxetine, reboxetine, and venlafaxine.
INTERPRETATION: Clinically important differences exist between commonly prescribed antidepressants for both efficacy and acceptability in favour of escitalopram and sertraline. Sertraline might be the best choice when starting treatment for moderate to severe major depression in adults because it has the most favourable balance between benefits, acceptability, and acquisition cost. FUNDING: None.

Bipolar Disord. 2008 Dec;10(8):957-68

Why antidepressants are not antidepressants: STEP-BD, STAR*D, and the return of neurotic depression.
Ghaemi SN.

Mood Disorders Program, Department of Psychiatry, Tufts Medical Center, 800 Washington Street, #1007, Boston, MA 02111, USA. [email protected]

The widely held clinical view of 'antidepressants' as highly effective and specific for the treatment of all types of depressive disorders is exaggerated. This sobering conclusion is supported by recent findings from the NIMH-sponsored STEP-BD and STAR*D projects. Antidepressants have limited short-term efficacy in unipolar depressive disorders and less in acute bipolar depression; their long-term prophylactic effectiveness in recurrent unipolar major depression remains uncertain, and is doubtful in recurrent bipolar depression. These limitations may, in part, reflect the excessively broad concept of major depression as well as unrealistic expectations of universal efficacy of drugs considered 'antidepressants.' Treatment-refractory depression may reflect failure to distinguish depressive conditions, particularly bipolar disorder, that are inherently less responsive to antidepressants. Antidepressants probably should be avoided in bipolar depression, mixed manic-depressive states, and in neurotic depression. Expectations of antidepressants for specific types of patients with symptoms of depression or anxiety require critical re-evaluation. A revival of the concept of neurotic depression would make it possible to identify patients with mild-to-moderate, chronic or episodic dysthymia and anxiety who are unlikely to benefit greatly from antidepressants. Diagnostic criteria for a revival of the concept of neurotic depression are proposed.

1:Lancet. 2008 Dec 4

Second-generation versus first-generation antipsychotic drugs for schizophrenia: a meta-analysis.

Leucht S, Corves C, Arbter D, Engel RR, Li C, Davis JM.

Department of Psychiatry and Psychotherapy, Technische Universität München, Munich, Germany.

BACKGROUND: Because of the debate about whether second-generation antipsychotic drugs are better than first-generation antipsychotic drugs, we did a meta-analysis of randomised controlled trials to compare the effects of these two types of drugs in patients with schizophrenia. METHODS: We compared nine second-generation antipsychotic drugs with first-generation drugs for overall efficacy (main outcome), positive, negative and depressive symptoms, relapse, quality of life, extrapyramidal side-effects, weight gain, and sedation. FINDINGS: We included 150 double-blind, mostly short-term, studies, with 21 533 participants. We excluded open studies because they systematically favoured second-generation drugs.
Four of these drugs were better than first-generation antipsychotic drugs for overall efficacy, with small to medium effect sizes (amisulpride -0.31 [95% CI -0.44 to -0.19, p<0.0001], clozapine -0.52 [-0.75 to -0.29, p<0.0001], olanzapine -0.28 [-0.38 to -0.18, p<0.0001], and risperidone -0.13 [-0.22 to -0.05, p=0.002]). The other second-generation drugs were not more efficacious than the first-generation drugs, even for negative symptoms. Therefore efficacy on negative symptoms cannot be a core component of atypicality. Second-generation antipsychotic drugs induced fewer extrapyramidal side-effects than did haloperidol (even at low doses). Only a few have been shown to induce fewer extrapyramidal side-effects than low-potency first-generation antipsychotic drugs. With the exception of aripiprazole and ziprasidone, second-generation antipsychotic drugs induced more weight gain, in various degrees, than did haloperidol but not than low-potency first-generation drugs. The second-generation drugs also differed in their sedating properties. We did not note any consistent effects of moderator variables, such as industry sponsorship, comparator dose, or prophylactic antiparkinsonian medication. INTERPRETATION: Second-generation antipsychotic drugs differ in many properties and are not a homogeneous class. This meta-analysis provides data for individualised treatment based on efficacy, side-effects, and cost. FUNDING: National Institute of Mental Health.


Am J Psychiatry. 2008 Apr;165(4):490-6.

Excessive brain volume loss over time in cannabis-using first-episode schizophrenia patients.

Rais M, Cahn W, Van Haren N, Schnack H, Caspers E, Hulshoff Pol H, Kahn R.
Department of Psychiatry, University Medical Center Utrecht, Heidelberglaan 100, 3584CX Utrecht, the Netherlands. [email protected]

OBJECTIVE: Cerebral gray matter volume reductions have been found to progress over time in schizophrenia, with larger decreases related to poorer outcome, which has also been associated with cannabis use in schizophrenia patients. Progressive gray matter changes in patients who use cannabis may be more extensive than in those who do not. METHOD: Patients with recent-onset schizophrenia (N=51) and matched healthy subjects (N=31) were included. For all subjects, magnetic resonance imaging scans were obtained at inclusion (T0) and at 5-year follow-up (T5). Nineteen patients used cannabis but no other illicit drugs; 32 patients did not use any drugs during the 5-year follow-up. At T5, clinical outcome was measured. Cumulative amount of antipsychotic medication during the interval was calculated. At T0 and T5, total brain, gray and white matter, and lateral and third ventricle volumes were measured. Univariate analysis of covariance and pairwise comparisons were performed. Result: Schizophrenia patients showed a larger gray matter volume decrease over time than healthy subjects. They also showed larger increases in lateral and third ventricle volumes than healthy subjects and patients who did not use cannabis during follow-up. This decrement was significantly more pronounced in the patients who continued to use cannabis. These differences could not be attributed to outcome or baseline characteristics. CONCLUSIONS: First-episode schizophrenia patients who use cannabis show a more pronounced brain volume reduction over a 5-year follow-up than patients with schizophrenia who do not use cannabis. These results may help explain some of the detrimental effects of cannabis use in schizophrenia.

Drug Saf. 2008;31(8):685-94.

Associations between venous thromboembolism and antipsychotics. A study of the WHO database of adverse drug reactions.
Hägg S, Bate A, Stahl M, Spigset O.
Division of Clinical Pharmacology, Linköping University Hospital, Linköping, Sweden. [email protected]

BACKGROUND: Concern has been raised about the occurrence of venous thromboembolism (VTE) during treatment with antipsychotics. However, to date, clozapine is the only antipsychotic agent for which recurring evidence supports an association with VTE. Therefore, the aim of this study was to investigate the association between antipsychotic drugs, including clozapine and VTE. STUDY DESIGN AND METHODS: Data mining of the WHO database of adverse drug reactions (ADRs) using Bayesian statistics is in routine use for early alerting to possible ADRs. An information component measure was used to investigate the association between antipsychotic drugs and VTE reactions in the database. RESULTS: A total of 754 suspected cases of VTE related to treatment with antipsychotics had been reported. After excluding cases related to clozapine, 379 cases remained. A robust association was found for the second-generation antipsychotics group but not for the high-potency, first-generation antipsychotics group or the low-potency first-generation antipsychotics group. The individual compounds with statistically significant associations were olanzapine, sertindole and zuclopenthixol. A time-dependent analysis showed that the associations were positive for these drugs in 2002, 2001 and 2003, respectively. Case analyses were undertaken after excluding ten suspected duplicate reports. Of the remaining 369 cases, 91 cases were associated with olanzapine, 9 with zuclopenthixol and 6 with sertindole. CONCLUSIONS: VTE was more often reported with the antipsychotic drugs olanzapine, sertindole and zuclopenthixol than with other drugs in the WHO database. Further studies are warranted to explain this disproportional reporting. Since the associations found were based on incomplete clinical data, the results should be considered as preliminary and interpreted cautiously.

Ddl riforma legge 180, tso a domicilio ed anche in strutture accreditate

Roma, 16. dic. (Adnkronos Salute) - Più fondi all'assistenza psichiatrica in Italia, obbligo per il medico di recarsi al domicilio del malato qualora quest'ultimo diserti agli appuntamenti fissati nell'ambito di un progetto terapeutico e non solo. I cosiddetti Tso - acronimo di trattamento sanitario obbligatorio - più lunghi e non più ad esclusivo appannaggio degli ospedali pubblici, ma realizzabili anche nelle strutture accreditate e, addirittura, a domicilio del paziente quando si presentino le condizioni per farlo. Sono questi i punti salienti di un disegno di legge del Pdl che prevede il 'restyling' della celeberrima legge Basaglia, il provvedimento che regola l'assistenza psichiatrica in Italia. E che, qualora dovesse essere disertata dalle Regioni una volta diventata legge, prevede il commissariamento ad acta per chi non si attiene alle nuove regole. La legge 180 "attende una riforma - spiega Carlo Ciccioli, primo firmatario del ddl e vice presidente della commissione Affari sociali della Camera, oggi in un incontro sul tema a Roma - che anche il premier Silvio Berlusconi, proprio ieri sera a cena, ha riconosciuto si debba fare". I firmatari del ddl sperano di "chiudere la partita entro il 2009", confidano in una "condivisione politica, che veda unita anche l'opposizione", ma non nascondono "di essere pronti anche allo strappo e alla decretazione d'urgenza qualora il provvedimento in sede parlamentare dovesse essere ostacolato dall'ostruzionismo ideologico". Intanto, per riformare la legge Basaglia, chiedono più soldi per l'assistenza psichiatrica, con una quota percentuale destinata alla causa che ammonti al 7% del Fondo sanitario nazionale, "anziché al 4-5% - spiega Ciccioli, che è anche uno psichiatra - come avviene oggi". Il che si traduce "in tre miliardi di euro in più, che costituirebbero intanto un inizio per cambiare le cose".Nel ddl il Tso passa dai 7 giorni attuali previsti dalla legge a ben 30. Ma può essere interrotto qualora non ci siano più le condizioni - da verificare ogni 7 giorni - per andare avanti con le terapie. Viene inoltre previsto, ed è questa una delle principali novità dal ddl, il trattamento sanitario prolungato (Tsop) senza consenso. "Il Tsop - spiega Ciccioli - ha una durata di sei mesi e può essere interrotto o ripetuto. Riguarda tutti quei pazienti che necessitano di cure obbligatorie per tempi protratti". E può essere fatto non solo nelle strutture pubbliche. "Il bacino si allarga - spiega il primo firmatario del ddl - alle strutture accreditate", tra queste "comunità terapeutiche, alloggi protetti con educatori, cooperative e strutture di semi-residenzialità". Nonché a casa del paziente, "mentre oggi si incorre in violazione di domicilio se cerchiamo di raggiungerli nelle loro abitazioni". Con questa riforma "non vogliamo restaurare i manicomi nè tantomeno rinnegare la legge 180 - ci tiene a precisare il vice presidente della Commissione Affari sociali di Montecitorio - ma andare oltre senza abbandonare i pazienti in strada o alle famiglie, determinando dei veri e propri manicomi domestici con familiari in ostaggio". "Confido nel gioco di squadra di Governo, Parlamento e addetti ai lavori - aggiunge il sottosegretario alla Salute Francesca Martini, che ha preso parte all'incontro capitolino - la riforma della 180 va fatta tutti insieme, dando vita ad un grosso dibattito che investa tutto il Paese".

(Il testo nella sezione legislazione)

Schizophr Res. 2008 Nov 20.

Results of phase 3 of the CATIE schizophrenia trial.

Stroup TS, Lieberman JA, McEvoy JP, Davis SM, Swartz MS, Keefe RS, Miller AL, Rosenheck RA, Hsiao JK; for the CATIE Investigators.
Department of Psychiatry, School of Medicine, University of North Carolina at Chapel Hill, United States.

OBJECTIVE: The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study examined the comparative effectiveness of antipsychotic treatments for individuals with chronic schizophrenia. Patients who had discontinued antipsychotic treatment in phases 1 and 2 were eligible for phase 3, in which they selected one of nine antipsychotic regimens with the help of their study doctor. We describe the characteristics of the patients who selected each treatment option and their outcomes. METHOD: Two hundred and seventy patients entered phase 3. The open-label treatment options were monotherapy with oral aripiprazole, clozapine, olanzapine, perphenazine, quetiapine, risperidone, ziprasidone, long-acting injectable fluphenazine decanoate, or a combination of any two of these treatments. RESULTS: Few patients selected fluphenazine decanoate (n=9) or perphenazine (n=4). Similar numbers selected each of the other options (range 33-41). Of the seven common choices, those who selected clozapine and combination antipsychotic treatment were the most symptomatic, and those who selected aripiprazole and ziprasidone had the highest body mass index. Symptoms improved for all groups, although the improvements were modest for the groups starting with relatively mild levels of symptoms. Side effect profiles of the medications varied considerably but medication discontinuations due to intolerability were rare (7% overall). CONCLUSIONS: Patients and their doctors made treatment selections based on clinical factors, including severity of symptoms, response to prior treatments, and physical health status. Fluphenazine decanoate was rarely used among those with evidence of treatment non-adherence and clozapine was underutilized for those with poor previous response. Combination antipsychotic treatment warrants further study.


Am J Psychiatry. 2008 Nov;165(11):1495.

Double-blind comparison of first- and second-generation antipsychotics in early-onset schizophrenia and schizo-affective disorder: findings from the treatment of early-onset schizophrenia spectrum disorders (TEOSS) study.

Sikich L, Frazier JA, McClellan J, Findling RL, Vitiello B, Ritz L, Ambler D, Puglia M, Maloney AE, Michael E, De Jong S, Slifka K, Noyes N, Hlastala S, Pierson L, McNamara NK, Delporto-Bedoya D, Anderson R, Hamer RM, Lieberman JA.

University of North Carolina at Chapel Hill, NC 27514, USA. [email protected]

OBJECTIVE: Atypical (second-generation) antipsychotics are considered standard treatment for children and adolescents with early-onset schizophrenia and schizoaffective disorder. However, the superiority of second-generation antipsychotics over first-generation antipsychotics has not been demonstrated. This study compared the efficacy and safety of two second-generation antipsychotics (olanzapine and risperidone) with a first-generation antipsychotic (molindone) in the treatment of early-onset schizophrenia and schizoaffective disorder. METHOD: This double-blind multisite trial randomly assigned pediatric patients with early-onset schizophrenia and schizoaffective disorder to treatment with either olanzapine (2.5-20 mg/day), risperidone (0.5-6 mg/day), or molindone (10-140 mg/day, plus 1 mg/day of benztropine) for 8 weeks. The primary outcome was response to treatment, defined as a Clinical Global Impression (CGI) improvement score of 1 or 2 and >or=20% reduction in Positive and Negative Syndrome Scale (PANSS) total score after 8 weeks of treatment. RESULTS: In total, 119 youth were randomly assigned to treatment. Of these subjects, 116 received at least one dose of treatment and thus were available for analysis. No significant differences were found among treatment groups in response rates (molindone: 50%; olanzapine: 34%; risperidone: 46%) or magnitude of symptom reduction. Olanzapine and risperidone were associated with significantly greater weight gain. Olanzapine showed the greatest risk of weight gain and significant increases in fasting cholesterol, low density lipoprotein, insulin, and liver transaminase levels. Molindone led to more self-reports of akathisia. CONCLUSIONS: Risperidone and olanzapine did not demonstrate superior efficacy over molindone for treating early-onset schizophrenia and schizoaffective disorder. Adverse effects were frequent but differed among medications. The results question the nearly exclusive use of second-generation antipsychotics to treat early-onset schizophrenia and schizoaffective disorder. The safety findings related to weight gain and metabolic problems raise important public health concerns, given the widespread use of second-generation antipsychotics in youth for nonpsychotic disorders.

Donna morta in psichiatria, Medici e infermieri accusati di omicidio colposo

Nove persone, fra cui il primario, una psichiatra, cinque infermieri e due ausiliari ospedalieri del reparto di psichiatria dell'ospedale civile di Sassari, sono state iscritte nel registro degli indagati per la morte di Maria Grazia Pavin, la donna morta dopo aver rifiutato l'amputazione di una mano e di un piede. L'accusa ipotizzata per tutti dal sostituto procuratore Maria Grazia Genoese è di omicidio colposo. L'inchiesta è stata aperta per accertare come sia potuto accadere che la donna di 41 anni (originaria di Varese ma residente a Laerru in provincia di Sassari) il 7 dicembre scorso sia rimasta ustionata nell'ottanta per cento del corpo, all'interno di un bagno del reparto di Psichiatria, in cui era ricoverata da qualche tempo. Il 26 dicembre scorso, dopo 18 giorni di agonia, il cuore di Maria Grazia Pavin si era fermato nel reparto di Rianimazione dell'ospedale civile Santissima Annunziata di Sassari. Pochi giorni prima davanti a tre magistrati la donna aveva negato il consenso ai medici che, per tentare di salvarle la vita, le avevano chiesto di poter effettuare un intervento di amputazione di una mano e di un piede. Ieri mattina al terzo piano del palazzo di Giustizia, nell'ufficio del sostituto procuratore, è stato conferito l'incarico per eseguire l'autopsia sul corpo della donna a Vindice Mingioni, primario del Servizio di Anatomia Patologica dell'Ospedale San Francesco di Nuoro. Ieri pomeriggio il medico ha eseguito l'esame autoptico nell'istituto di medicina legale di Sassari ma ha chiesto al magistrato 120 giorni di tempo per poter eseguire ulteriori esami istologici e altri accertamenti. Solo a quel punto, quando sul tavolo del magistrato arriverà la relazione del medico, si potrà avere più chiaro il quadro della situazione. Dopo l'autopsia il corpo della donna è stato restitutito alla famiglia. Questo pomeriggio alle ore 15, nella chiesa parrocchiale di Laerru, sarà celebrato il funerale.
Fonte: L'Unione Sarda, 31/12/2008

 Arch Intern Med. 2008 May 26;168(10):1090-6.

Antipsychotic therapy and short-term serious events in older adults with dementia.

Rochon PA, Normand SL, Gomes T, Gill SS, Anderson GM, Melo M, Sykora K, Lipscombe L, Bell CM, Gurwitz JH.
Department of Medicine, University of Toronto, Canada.

BACKGROUND: Antipsychotic therapy is widely used to treat behavioral problems in older adults with dementia. Cohort studies evaluating the safety of antipsychotic therapy generally focus on a single adverse event. We compared the rate of developing any serious event, a composite outcome defined as an event serious enough to lead to an acute care hospital admission or death within 30 days of initiating antipsychotic therapy, to better estimate the overall burden of short-term harm associated with these agents. METHODS: In this population-based, retrospective cohort study, we identified 20 682 matched older adults with dementia living in the community and 20 559 matched individuals living in a nursing home between April 1, 1997, and March 31, 2004. Propensity-based matching was used to balance differences between the drug exposure groups in each setting. To examine the effects of antipsychotic drug use on the composite outcome of any serious event we used a conditional logistic regression model. We also estimated adjusted odds ratios using models that included all covariates with a standard difference greater than 0.10. RESULTS: Relative to those who received no antipsychotic therapy, community-dwelling older adults newly dispensed an atypical antipsychotic therapy were 3.2 times more likely (95% confidence interval, 2.77-3.68) and those who received conventional antipsychotic therapy were 3.8 times more likely (95% confidence interval, 3.31-4.39) to develop any serious event during the 30 days of follow-up. The pattern of serious events was similar but less pronounced among older adults living in a nursing home. CONCLUSIONS: Serious events, as indicated by a hospital admission or death, are frequent following the short-term use of antipsychotic drugs in older adults with dementia. Antipsychotic drugs should be used with caution even when short-term therapy is being prescribed.


Neurology. 2008;71:1923-1924. Rebecca Bromley

Valproate for Epilepsy During Pregnancy May Increase Autism Risk

December 2, 2008 — New preliminary results suggest that women who take valproate while pregnant increase their child's risk of developing autism spectrum disorder (ASD). The findings add to previous reports suggesting a link between ASD following exposure to valproate in utero.

Br J Clin Pharmacol. 2008;65:695-705. Caroline Cassels

Paroxetine, Fluoxetine in Early Pregnancy Linked to Heart Defects in Offspring 

December 5, 2008 — Fluoxetine and paroxetine, 2 of the most commonly used selective serotonin reuptake inhibitors (SSRIs), have been linked to an increased risk for congenital cardiac abnormalities in the offspring of women who took these medications in early pregnancy, new research suggests


Roma 14/10/2008
Nicotina sembra mitigare sintomi schizofrenia


Un gruppo di ricercatori italiani che lavora in Usa ha scoperto che la nicotina può mitigare i sintomi della schizofrenia: infatti accende nei neuroni un neurotrasmettitore inibitorio, il GABA, che spegne i neuroni e potrebbe aiutare a controllare le allucinazioni tipiche della malattia. E’ quanto emerso in un lavoro su animali condotto da Alessandro Guidotti ed Erminio Costa del Dipartimento di Psichiatria del College of Medicine, University of Illinois e pubblicato sulla rivista dell’Accademia Americana delle Scienze ’PNAS’.
Somministrando a topolini per via sottocutanea della nicotina, i ricercatori si sono accorti che nei neuroni ’GABAergici’ della corteccia frontale, un importante circuito inibitorio del cervello che tiene a bada l’attività cerebrale, aumentano i livelli di neurotrasmettitore inibitorio GABA, di solito carente nei pazienti con schizofrenia.
Gli esperti hanno scoperto anche l’esatto meccanismo con cui la nicotina induce nel cervello la produzione di questo fattore inibitorio ed hanno visto che bloccando i recettori della nicotina l’effetto svanisce. Questa ricerca suggerisce quindi un motivo per cui molti pazienti schizofrenici fumano incessantemente sigarette, perché appunto la nicotina potrebbe dar loro effetti benefici sui sintomi della loro malattia.


Omicidio in psichiatria, Psichiatra e infermieri condannati a 1 anno e al risarcimento. Condannata anche l'Asl

UN MEDICO e due infermieri del reparto di psichiatria dell'ospedale di Passirana di Rho sono stati condannati a un anno di reclusione e al risarcimento dei danni per la morte di Paolo Bulgheroni, 23 anni, di Arese. La sentenza è stata emessa dopo oltre un anno di udienze davanti alla quinta sezione del Tribunale penale di Milano. Il fatto risale alla notte tra il 15 e il 16 gennaio 2003: il giovane aresino fu accoltellato da un suo vicino di letto, Giuseppe Campagna, di 81 anni, ricoverato erroneamente nella stessa stanza. Secondo l'accusa sostenuta dal Pm Maria Vittoria Mazza, il medico di guardia, al momento del ricovero dell'anziano omicida, avrebbe disposto la sistemazione del paziente nella stessa stanza di Paolo nonostante fosse a conoscenza dell'incompatibilità tra i due, a causa delle loro patologie; inoltre successivamente non avrebbe riferito ai medici le lamentele di entrambi e la necessità di separare i due pazienti. I due infermieri invece sono stati condannati in quanto, pur essendo addetti all'accoglienza dei pazienti e al controllo degli oggetti personali, non si sarebbero accorti che l'ottantunenne aveva un coltellino serramanico che successivamente ha usato per colpire il vicino di letto. La loro «negligenza, imprudenza e imperizia» li ha resi complici in concorso dell'omicidio colposo del ventitreenne aresino. I condannati dovranno risarcire 70.000 euro ai genitori e 15.000 euro a ciascuno dei quattro fratelli di Paolo Bulgheroni, che si sono costituiti parte civile con il patrocinio dell'avvocato milanese Massimo Bassi. Condannata anche l'azienda ospedaliera Salvini, mentre sono stati assolti il primario del reparto e altri tre infermieri. L'omicida, dichiarato incapace di intendere e volere, quindi non rinviato a giudizio, nel frattempo è deceduto. CON QUESTA sentenza si chiude una vicenda giudiziaria durata alcuni anni, non certo la ferita nella famiglia Bulgheroni. «È stata fatta giustizia: per questo esprimiamo la nostra soddisfazione - spiega la madre di Paolo, Giusy -. Certamente questa sentenza ha rievocato in noi il dolore per la perdita di nostro figlio». Poi aggiunge: «Paolo è ancora vivo grazie al progetto di solidarietà che stiamo sostenendo in Romania con l'aiuto di tantissimi amici aresini e non solo». La famiglia infatti ha trasformato il dolore per l'assurda morte del figlio in uno straordinario gesto di solidarietà: il ricordo di Paolo è vivo anche a Ciocanari, un piccolo villaggio a 15 chilometri da Bucarest, in Romania, nel «Villaggio dei ragazzi Fabio, Sergio e Guido», realizzato dalla Caritas locale, per accogliere, educare alla vita e formare al lavoro quei giovani che si trovano in stato di abbandono e marginalità sociale. Tra le iniziative che ricordano il 23enne aresino anche uno skatepark inaugurato a Garbagnate. (Fonte: Il Giorno) dicembre 2008



Di Giovanni Negri (“Il Sole 24 Ore” pag. 36 del 17/09/08)

È un diritto di rilevanza costituzionale anche quello di non curarsi. Ma il dissenso rispetto a terapie future deve essere manifestato in maniera «espressa, inequivoca, attuale e informata». Lo chiarisce la Corte di cassazione, intervenendo ancora una volta su uno dei temi caldi della discussione tra diritto e vita. La Corte, con la sentenza n. 23676 depositata il 15 settembre, è intervenuta decidendo sul caso di un testimone di Geova che, nonostante il rifiuto alla trasfusione, manifestato esclusivamente su un cartellino recante la scritta «niente sangue», era stato comunque sottoposto dai medici alla terapia.
La sentenza parte da quello che appare ai giudici un elemento ormai acquisito al nostro ordinamento, quello della libertà di rifiutare le cure anche quando ci si espone al rischio di perdere la vita. Tanto più in materia di trasfusione, sottolinea la Corte, richiamando le conclusioni in materia della dottrina, dove il conflitto tra due beni, entrambi tutelati sul piano costituzionale, della salute e della libertà di coscienza non può essere risolto in maniera automatica a favore del primo.
Il problema diventa allora quello del «non consenso» e delle sue modalità di manifestazione, sia sul piano cronologico sia su quello formale. È su questo aspetto che i giudizi si soffermano, chiarendo che il dissenso deve «esprimere una volontà non astrattamente ipotetica, ma concretamente accertata; un'intenzione non meramente programmatica ma affatto specifica; una cognizione dei fatti non soltanto "ideologica", ma frutto di informazioni specifiche in ordine alla propria situazione sanitaria; un giudizio e non una "precomprensione" ». In definitiva, ciò che preme alla Corte è il fatto che il dissenso sia manifesto solo dopo che l'interessato si è formato una rappresentazione veritiera e attuale delle proprie condizioni di salute, prendendo consapevolezza della diversa gravità cui si espone.
È vero, ammette la pronuncia, che il testimone di Geova aveva al collo un cartellino con la scritta «Niente sangue », ma non si tratta di un elemento decisivo alla luce dell'interpretazione giuridica data dalla Corte. A fronte di un'indicazione sommaria, infatti, peserebbe sul medico l'onere di ricostruire, magari in condizioni di emergenza, la reale volontà del paziente. Un compito insostenibile, puntualizza la sentenza.
Del resto, la posizione assunta costituisce il logico contraltare dell'impossibilità di un consenso preventivo a un trattamento sanitario in assenza di una completa informazione sulle caratteristiche della terapia. È in questa prospettiva che la necessità di un dissenso informato viene compromessa quando il paziente non è cosciente, perchè, sottolinea ancora la Cassazione, una cosa è un generico diniego a un trattamento in condizioni di piena salute, altra cosa è la sua riaffermazione in una situazione di pericolo di vita. Venendo al caso di un paziente, a rischio della vita e dalle forti convinzioni religiose, come nel caso preso in esame dalla Corte, non è che la sue condizioni di incoscienza determinino per forza la sua soggezione a una cura che potrebbe essergli sgradita. Emerge invece l'esigenza che a manifestare il dissenso al trattamento (alla trasfusione) sia lo stesso paziente magari – precisa la Corte – con una dichiarazione condotta con sè dalla quale emerga senza equivoci la sua volontà di impedire la terapia anche in pericolo di vita, oppure un soggetto diverso, indicato dal paziente, che, dimostrato il proprio potere rappresentativo, confermi il dissenso dopo avere ricevuto dai medici tutte le informazioni necessarie.


Cassazione. I malati pericolosi che lo rifiutano, devono essere obbligati a curarsi
 Associazione Italiana Psichiatri - Webmaster (09 2008)
Ci sono alcune inesattezze nell'articolo apparso su Repubblica dal titolo “Nessuno può far curare un malato che lo rifiuta".
Non è vero che la legge non può far curare un malato che lo rifiuta: lo dice la Costituzione, il Codice Penale e lo ribadiscono alcune recenti sentenze di Cassazione. L'equivoco nasce dalla confusione del Codice Penale con la Legge Quadro 180 che di pericolosità sociale non parla: il concetto di pericolosità sociale, infatti, non è mai stato abolito dal Codice Penale.
Sono sempre più numerose le sentenze di condanna di medici, infermieri, operatori di strutture sanitarie, che non hanno messo in atto tutte le procedure (non il solo Tso) al fine di scongiurare eventi lesivi per il paziente (suicidio) e per terzi (aggressioni, omicidi).
La sentenza del Tribunale di Bologna del 27/01/06, in merito al paziente che accoltellò e uccise un operatore sanitario, recentemente confermata in Cassazione, è chiara:
“Il medico deve mettere in atto la cura appropriata al fine di scongiurare, dal punto di vista eziologico, le condizioni positive dell'evento lesivo per il paziente e per terzi, e, allo stesso tempo, di attivare le condizioni impeditive del medesimo, approntando un sistema di cautele e precauzioni idoneo a scongiurare il verificarsi di eventi dannosi o pericolosi all’accrescersi dei rischi” .
Inoltre, nel 2000, la Corte di Cassazione Penale, (decisione Cass. pen. Sez.IV 13-09-2000, n. 9638), ha introdotto il principio, (confermato dalla Cassazione Penale, Sezione IV, Sentenza n. 9739 del 11/03/2005), in base al quale, la cosiddetta “posizione di garanzia” essendo “espressione dell'obbligo di solidarietà costituzionalmente imposto ex art. 2 e 32 cost, nei confronti dei pazienti, la cui salute devono tutelare contro qualsivoglia pericolo che ne minacci l'integrità” vincola “ex lege” tutti gli operatori di una struttura sanitaria, medici e paramedici.


Cassazione. Paziente psichiatrico uccide vicino di camera, infermieri condannati per omicidio colposo

Sussiste il reato di omicidio colposo in capo agli infermieri di un ospedale per non avere prestato, nella loro qualità, idonea vigilanza durante le ore notturne sui pazienti ricoverati ed in particolare sull’autore dell’aggressione mortale in danno del vicino di camera. Agli infermieri non era stato contestato di avere agito con imperizia, non essendo tenuti ad una diagnosi che è estranea alla loro competenza, ma di avere agito con negligenza, perchè se è vero che l'insorgenza della psicosi acuta dissociativa è improvvisa, la imprevedibilità di tale stato riguarda le persone sane, non i soggetti affetti da disturbi di tipo psichico, che palesano irrequietezza. - Cassazione Penale – Sezione IV, Sent. n. 8611 del 27/02/2008 (Avv. Ennio Grassini – www.dirittosanitario.net )

Paziente si lancia dalla finestra di un ospedale, Sanitari condannati per omesso controllo

ROMA -Corte d’Appello, Sezione prima civile - In ordine alla imprevedibilità di un atto autolesionistico, non può non tenersi conto, che nel caso di specie era pacificamente noto al personale di servizio trattarsi di persona da ricoverare presso il centro di igiene mentale, dunque di malato di mente, che era stato infatti collocato, in barella, dinanzi alla porta dello psichiatra, in attesa di essere visitato; allora, anche se si trattava di soggetto apparentemente calmo e tranquillo, prudenza avrebbe voluto che lo si tenesse sotto maggiore controllo, essendo in ogni caso una persona disturbata di mente, in condizioni ancora tutte da verificare - vista l'accertata necessità di ricovero - non certo da lasciare incustodita come un qualunque alto traumatizzato in forma lieve. [Avv. Ennio Grassini – www.dirittosanitario.net]

Porte Aperte in SPDC PDF Stampa E-mail


Il convegno del 6 giugno 2008 tenutosi a Mantova , è stato l' occasione per riflettere sull' importanza del lavoro infermieristico rispetto all' obbiettivo di operare senza pratiche di restrizione. Le Porte Aperte in SPDC a Mantova sono nate nel ' 78 e dal ' 91 i mezzi di contenzione meccanica non sono più utilizzati. Rete180 in questo convegno ha dato il suo contributo intervistando Alice Banfi autrice del romanzo " Tanto scappo lo stesso " , facendo sentire la  Voce della propria esperienza, forte e diretta, così come le Voci  di infermieri e  pazienti che hanno vissuto questo percorso pionieristico applicato in poche realtà psichiatriche....Buon Ascolto !!!

Ascolta Interviste:   Antonella SPDC    Fabio SPDC    Mariano SPDC     Salomoni SPDC





 Maggio 2008.

Pubblicato, sul sito del ministero della salute, il libro bianco sui principi fondamentali del Servizio sanitario. (Dalla presentazione del Ministro: ....Si tratta di un testo che è rivolto, innanzitutto, agli operatori del settore, che vi potranno rintracciare il tessuto connettivo e l'"anima" di un Servizio nazionale che, seppur non esente da difetti gestionali e da difficoltà dell'operare quotidiano, poggia su alti e saldi fondamenti teoretici. Ma la lettura del documento potrà essere di grande interesse anche per il cittadino che voglia riflettere sulla complessità della organizzazione dei servizi sanitari e sui principi su cui si basa l'erogazione delle prestazioni di cui egli fruisce, per poter interagire in modo sempre più consapevole con le istituzioni della sanità, continuando a rivendicare i suoi giusti diritti e al tempo stesso facendosi coinvolgere, responsabilmente, nelle azioni necessarie a individuare e superare i problemi che si frappongono alla loro piena attuazione"...)

                                                                                         Treatment-resistant depression: critique of current approaches.

Wijeratne C, Sachdev P.

School of Psychiatry, University of New South Wales, Kensington, New South Wales, Australia. [email protected]

The aim of the present study was to critically appraise current conceptual approaches; demographic, neurobiological and clinical correlates; and management strategies of treatment-resistant depression (TRD), especially in light of recent research findings. To this end, a review of the relevant English-language literature was undertaken using Medline, Embase and Psychinfo. TRD has been defined in conceptually restrictive terms as symptomatic non-response to physical therapies alone, with little systematic study of aetiology made. It is likely that a range of sociodemographic (such as higher socioeconomic status), genetic (such as variation in functional monoamine polymorphisms) and clinical variables (such as signal hyperintensities seen on structural neuroimaging scans) are responsible for non-response in individuals. There is insufficient evidence to suggest that TRD is associated with specific subtypes of depression, physical comorbidity, personality or chronicity. The large-scale Sequenced Treatment Alternatives to Relieve Depression (STAR*D) and other studies have suggested that a structured psychotherapy such as cognitive behaviour therapy may be as effective as medication in initial drug non-responders. Also conventional alternatives such as the use of older antidepressant classes, pharmacological augmentation or electroconvulsive therapy in established cases of TRD are not as effective as traditionally thought. There is insufficient preliminary evidence to make formal recommendations about the use of novel brain stimulation techniques in TRD. TRD should be re-defined as the failure to reach symptomatic and functional remission after adequate treatment with physical and psychological therapies. Treatment resistance may be more usefully conceived within the context of well-defined cohorts such as patients with specific subtypes of depression. Although neurobiological markers such as gene polymorphisms, which are potentially predictive of medication tolerance and efficacy, may be used in the future, it is likely that sociocultural variables such as beliefs about depression, and evidence-based treatments for it, will also determine treatment resistance.

PMID: 18696279 [PubMed - in process]

PLOS Medicine
Published: February 26, 2008
                                                                             Initial Severity and Antidepressant Benefits: A Meta-Analysis of Data Submitted to the Food and Drug Administration

Irving Kirsch1*, Brett J. Deacon2, Tania B. Huedo-Medina3, Alan Scoboria4, Thomas J. Moore5, Blair T. Johnson3

1 Department of Psychology, University of Hull, Hull, United Kingdom, 2 University of Wyoming, Laramie, Wyoming, United States of America, 3 Center for Health, Intervention, and Prevention, University of Connecticut, Storrs, Connecticut, United States of America, 4 Department of Psychology, University of Windsor, Windsor, Ontario, Canada, 5 Institute for Safe Medication Practices, Huntingdon Valley, Pennsylvania, United States of America


Secondo questa metanalisi recentemente pubblicata in Gran Bretagna, e liberamente accessibile grazie alla politica open access della Rivista Plos Medicine, gli antidepressivi vanno considerati quasi come placebo nella terapia della depressione.
Irving Kirsch, del dipartimento di Psicologia dell'Università di Hull  (Hull Gran Bretagna) con  un gruppo di specialisti  ha osservato i risultati di 47 studi - noti e riservati, cui hanno avuto accesso grazie alla legge sulla libertà di informazione della FDA , sugli effetti di alcuni antidepressivi (fluoxetina , venlafaxina   paroxetina , nefazodone).
E i risultati, dicono gli studiosi sulla rivista PloS Medicine, parlano chiaro: i farmaci non sono più efficaci dei placebo nei casi leggeri e per la maggior parte dei casi gravi di depressione. Nei casi più gravi, in cui un effetto c'é, la differenza nei progressi ha più a che vedere con una minore reazione dei pazienti ai placebo, che non a una reazione positiva agli antidepressivi.

Download dell'articolo completo: http://medicine.plosjournals.org/perlserv/?request=get-document&doi=10.1371%2Fjournal.pmed.0050045&ct=1

Corte di Cassazione - Penale

Falsa attestazione in assenza di visita

Il certificato rilasciato dal medico è destinato a provare la verità di fatti morbosi a qualsiasi terzo interessato e presuppone necessariamente, anche se implicitamente, che il medico stesso abbia proceduto direttamente all'accertamento della malattia mediante visita del paziente. Per conseguenza risponde di falso ideologico il medico che attesti una malattia senza aver compiuto la visita, anche se di essa non abbia fatto esplicita menzione nel certificato.
Integra il reato di falsità ideologica commessa dal p.u. in atto pubblico (art. 479 cod. pen.) - e non quello di falsità ideologica commessa dal p.u. in certificati o autorizzazioni amministrative (art. 480 cod. pen.) - la condotta del medico di base che rediga una proposta di trattamento sanitario obbligatorio nei confronti di un paziente del quale attesti falsamente l'alterazione psichica, senza sottoporlo a visita, considerato che il provvedimento che dispone il t.s.o. di un infermo di mente è adottato dal sindaco su proposta motivata di un medico, convalidata da un altro medico della struttura sanitaria pubblica, che si inserisce nell'attività della P.A. disciplinata dalla legge n. 180 del 1978 quale atto di impulso di natura costrittiva (derivando da esso l'obbligatoria soggezione del paziente ad ulteriori visite) di un procedimento amministrativo. (

Alzheimer: VBM predice il tasso di declino

La valutazione dell'atrofia regionale tramite VBM (Voxel-based morphometry (1)) può essere utilizzata per prevedere il tasso di declino nei pazienti con lieve morbo di Alzheimer. Una migliore conoscenza dei fattori che possono predire la gravità della progressione della malattia può avere importanti implicazioni per l'assistenza al paziente, per lo sviluppo degli studi clinici con nuovi agenti terapeutici e per la salute pubblica. La VBM, più della neuropsicologia, è in grado di rilevare un futuro rapido declino cognitivo e differenziare due stadi adiacenti della malattia, anche in un piccolo campione di pazienti con morbo di Alzheimer. L'atrofia parieto-occipitale mediale è un buon marcatore prognostico per questa malattia. Il recente sviluppo di potenti strumenti per l'acquisizione e l'analisi delle immagini ha arricchito in modo drammatico la possibilità di andare a fondo nella neurobiologia del morbo di Alzheimer, ma non bisogna sovrastimare le possibilità dell'armamentario disponibile. Si sta attualmente raccogliendo una gran quantità di dati prospettici da tutto il mondo che nei prossimi anni consentirà di evidenziare più accuratamente la storia naturale nella neurobiologia del morbo di Alzheimer, e di raffinare gli strumenti per le previsioni individuali. (Neurology 2008; 70: 2194-5 e 2201-11)


FDA Approves Aripiprazole as Adjunctive to Lithium or Valproate in Adults With Bipolar 1 Disorder

TOKYO and PRINCETON, NJ -- May 9, 2008 -- The US Food and Drug Administration (FDA) has approved aripiprazole (Abilify) as an adjunctive therapy to either lithium or valproate for the acute treatment of manic and mixed episodes associated with bipolar 1 disorder with or without psychotic features in adults. Aripiprazole has been approved as monotherapy for the treatment of manic and mixed episodes associated with bipolar 1 disorder with or without psychotic features in adults since September 2004.

In addition to this new indication, the FDA also approved a new recommended starting and target dose of 15 mg daily for aripiprazole monotherapy in the treatment of bipolar 1 disorder in adults.

                                                                   Tarenflurbil Elicits Sustained Responses in Treating Alzheimer's Disease: Presented at AGS
By Crina Frincu-Mallos, PhD

WASHINGTON, DC -- May 9, 2008 -- Treatment with tarenflurbil, a novel selective amyloid beta-42-lowering agent, results in improvement or no decline in cognitive function over a 2-year period in patients with mild Alzheimer's disease, according to a post hoc analysis.

Tarenflurbil was evaluated in 207 patients with mild Alzheimer's disease in a multicenter, randomised, double-blind, placebo-controlled, phase 2 trial conducted at 31 sites in Canada and the United Kingdom.

Lead author Kenton H. Zavitz, PhD, Senior Director of Clinical Affairs, Myriad Pharmaceuticals, Inc., Salt Lake City, Utah, presented the results in a poster session here on May 2 at the 2008 Annual Scientific Meeting of the American Geriatrics Society (AGS). The results also were published online on April 30 in Lancet Neurology

Psychiatr Serv 59:500-506, May 2008
doi: 10.1176/appi.ps.59.5.500
© 2008 American Psychiatric Association

What CATIE Found: Results From the Schizophrenia Trial

Marvin S. Swartz, M.D., T. Scott Stroup, M.D., M.P.H., Joseph P. McEvoy, M.D., Sonia M. Davis, Dr.P.H., Robert A. Rosenheck, M.D., Richard S. E. Keefe, Ph.D., John K. Hsiao, M.D. and Jeffrey A. Lieberman, M.D.

The authors provide an overview of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) sponsored by the National Institute of Mental Health. CATIE was designed to compare a proxy first-generation antipsychotic, perphenazine, to several newer drugs. In phase 1 of the trial, consenting patients were randomly assigned to receive olanzapine, perphenazine, quetiapine, risperidone, or ziprasidone for up to 18 months on a double-blind basis. Patients with tardive dyskinesia were excluded from being randomly assigned to perphenazine and were assigned to one of the four second-generation antipsychotics in phase 1A. Clozapine was included in phase 2 of the study. Overall, olanzapine had the longest time to discontinuation in phase 1, but it was associated with significant weight and metabolic concerns. Perphenazine was not significantly different in overall effectiveness, compared with quetiapine, risperidone, and ziprasidone. Also, perphenazine was found to be the most cost-effective drug. Clozapine was confirmed as the most effective drug for individuals with a poor symptom response to previous antipsychotic drug trials, although clozapine was also associated with troublesome adverse effects. There were no differences in neurocognitive or psychosocial functioning in response to medications. Subsequent randomizations suggest that a poor response to an initial medication may mean that a different medication will be more effective or better tolerated. Although the CATIE results are controversial, they are broadly consistent with most previous antipsychotic drug trials and meta-analyses; however, the results may not generalize well to patients at high risk of tardive dyskinesia. Patient characteristics and clinical circumstances affected drug effectiveness; these patient factors are important in making treatment choices

Accordo, ai sensi dell'articolo 9 del decreto legislativo 28 agosto 1997, n. 281, sul documento concernente «Linee di indirizzo nazionali per la salute mentale». (Repertorio atti n. 43/CU del 20 marzo 2008). (GU n. 102 del 2-5-2008  - Suppl. Ordinario n.111)

 Pubblicato il 4-1-2008 sul Bolletino Ufficiale della Regione Calabria - Parte III - n. 1 il DECRETO n. 21269 del 17 dicembre 2007  

Registro provvisorio delle Strutture Sanitarie pubbliche

Pubblicate dal Ministero della Salute le linee guida "Gli interventi precoci nella schizofrenia " (ottobre 2007)


                                                                      Conferenza Stato Regioni 1 agosto 2007: riordino del sistema di Formazione continua in Medicina


In data 1 agosto 2007 è stato siglato l'accordo Stato–Regioni concernente il "Riordino del sistema di Formazione continua in Medicina".
Nell'accordo è riportato, tra l'altro, che ogni operatore sanitario deve acquisire 150 crediti formativi nel triennio 2008-2010 secondo la seguente ripartizione:
  • 50 crediti/anno (minimo 30 e massimo 70 per anno) per un totale di 150 nel triennio 2008-2010.
In particolare, dei 150 crediti formativi del triennio 2008-2010, almeno 90 dovranno essere "nuovi" crediti, mentre fino a 60 potranno derivare dal riconoscimento di crediti formativi acquisiti negli anni della sperimentazione a partire dall'anno 2004 fino all'anno 2007.
Le misure legate agli incentivi e/o alle sanzioni che interverranno in ordine all'acquisizione dei crediti formativi saranno adottate e rese note a seguito di un confronto con i soggetti interessati (parti sociali, organizzazioni di categoria, ecc.).
Per l'anno 2007 è confermato il debito formativo per gli operatori sanitari fissato in n. 30 (trenta) crediti formativi
E' prorogato il vigente programma sperimentale di educazione continua in medicina fino e non oltre il 31 dicembre 2007

Am J Cardiol. 2007 Apr 15;99(8):1134-6.

Relation of depression to coronary endothelial function.

Yang EH, Lerman S, Lennon RJ, Simari RD, Lerman LO, Lerman A.
Center of Coronary Physiology and Imaging, Division of Cardiovascular Diseases, Mayo College of Medicine, Rochester, Minnesota, USA.

The purpose of this study was to determine the association between depression and coronary endothelial function and cardiac risk factors in men and women without obstructive coronary artery disease. Patients with no significant coronary artery disease who underwent invasive coronary endothelial function assessment with acetylcholine were studied. Men and women were divided into 2 groups: those with depression and those without. Endothelial function and risk factor profiles were compared between the 2 groups. Seven hundred fifty-nine patients were studied, 603 (79%) without depression and 156 (21%) with depression. Patients with depression were more likely to be women (71% vs 60%, p = 0.02), have greater body mass indexes (29.9 +/- 6.7 vs 28.2 +/- 5.9 kg/m(2), p = 0.002), and be diabetic (12% vs 6%, p = 0.02). Depressed patients also had higher levels of C-reactive protein (0.35 vs 0.30 mg/dl, p = 0.02). There was no difference in the change in coronary blood flow or diameter in response to acetylcholine between the 2 groups in men and women. In conclusion, the results of this study demonstrate that depression is not associated with coronary endothelial dysfunction in men and women without significant coronary artery disease. It is, however, associated with a cluster of cardiac risk factors that are linked to the progression of atherosclerotic disease.

Pubblicate sul BURC (1 marzo 2007) le  Linee guida per la tutela della salute mentale. (DELIBERAZIONE DELLA GIUNTA REGIONALE CALABRIA 19 febbraio 2007, n. 105)

                                                                       Rispetto delle indicazioni in scheda tecnica dei medicinali anche in ospedale


Legge n. 296 del 27.12.06, Gazzetta Ufficiale n. 299 del 27.12.06 - Suppl. Ordinario n. 244

Il comma 796, lettera z), delle legge finanziaria 2007 ritorna sulla problematica dell'impiego di un medicinale in difformità da quanto riportato in scheda tecnica, problematica già affrontata dal legislatore del 1998.

Questa volta il legislatore si rivolge principalmente, ma non esclusivamente, al medico dipendente di strutture sanitarie, stabilendo che la deroga prevista dal comma 2 dell'articolo 3 della legge 94/98 (1) "non è applicabile al ricorso a terapie farmacologiche a carico del Servizio sanitario nazionale, che, nell'ambito dei presidi ospedalieri o di altre strutture e interventi sanitari, assuma carattere diffuso e sistematico e si configuri, al di fuori delle condizioni di autorizzazione all'immissione in commercio, quale alternativa terapeutica rivolta a pazienti portatori di patologie per le quali risultino autorizzati farmaci recanti specifica indicazione al trattamento."

Il provvedimento continua, inoltre: "Il ricorso a tali terapie è consentito solo nell'ambito delle sperimentazioni cliniche dei medicinali di cui al decreto legislativo 24 giugno 2003, n. 211, e successive modificazioni".

Sono previste pure sanzioni e le regioni devono provvedere "ad adottare entro il 28 febbraio 2007 disposizioni per le aziende sanitarie locali, per le aziende ospedaliere, per le aziende ospedaliere universitarie e per gli Istituti di ricovero e cura a carattere scientifico volte alla individuazione dei responsabili dei procedimenti applicativi delle disposizioni di cui alla presente lettera, anche sotto il profilo della responsabilità amministrativa per danno erariale."

In altre parole vengono espressamente dichiarate illecite e sanzionabili certe diffuse abitudini di alcuni Centri Ospedalieri, dove le terapie off-label diventano consolidata abitudine

(1) In singoli casi il medico può, sotto la sua diretta responsabilità e previa informazione del paziente e acquisizione del consenso dello stesso, impiegare un medicinale prodotto industrialmente per un'indicazione o una via di somministrazione o una modalità di somministrazione o di utilizzazione diversa da quella autorizzata, ovvero riconosciuta agli effetti dell'applicazione dell'articolo 1, comma 4, del decreto-legge 21 ottobre 1996, n. 536, convertito dalla legge 23 dicembre 1996, n. 648, qualora il medico stesso ritenga, in base a dati documentabili, che il paziente non possa essere utilmente trattato con medicinali per i quali sia già approvata quella indicazione terapeutica o quella via o modalità di somministrazione e purchè tale impiego sia noto e conforme a lavori apparsi su pubblicazioni scientifiche accreditate in campo internazionale

                                                                                     Iperdosaggio “fuori scheda tecnica”? E’ omicidio colposo

Prescrivere farmaci in dosaggio superiore a quanto indicato introduce un fattore di rischio che, se concretizzato, puo’ configurare l’ omicidio colposo.
Un neurologo aveva in cura una paziente affetta, da molto tempo, da una grave sindrome depressiva con un cocktail di farmaci somministrati a dosaggi superiori a quelli indicati. Essendosi verificato il decesso della paziente, gli accertamenti giudiziali effettuati evidenziavano tale superdosaggio farmacologico, e confermavano che tale circostanza era da ritenere connessa al decesso con nesso di causalita’. Il medico veniva condannato per omicidio colposo sia in primo grado che in appello; la condanna e’ poi stata confermata anche in Cassazione (Sentenza n. 840/2007) “per non aver seguito un corretto dosaggio dei farmaci somministrati alla paziente provocando così un accumulo dei principi attivi contenuti nei medesimi farmaci da cui derivavano gravi alterazioni patologiche che cagionavano il decesso". Il sanitario quindi, avendo violato il divieto di somministrare le terapie in dosaggi superiori a quelli previsti e senza tener conto della pericolosità dei
fattori di accumulo" aveva introdotto nel quadro clinico della paziente un fattore di rischio poi effettivamente concretizzatosi.

Tratto da: Scienza e Professione febbraio 2008  www.scienzaeprofessione.it che si ringrazia per la politica di libera diffusione editoriale.

Arch Gen Psychiatry. 2007 Jan;64(1):65-72. Related Articles, Links

Cost-effectiveness of systematic depression treatment among people with diabetes mellitus.

Simon GE, Katon WJ, Lin EH, Rutter C, Manning WG, Von Korff M, Ciechanowski P, Ludman EJ, Young BA.

Center for Health Studies, Group Health Cooperative, Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, WA 98101, USA. [email protected]

CONTEXT: Depression co-occurring with diabetes mellitus is associated with higher health services costs, suggesting that more effective depression treatment might reduce use of other medical services. OBJECTIVE: To evaluate the incremental cost and cost-effectiveness of a systematic depression treatment program among outpatients with diabetes. DESIGN: Randomized controlled trial comparing systematic depression treatment program with care as usual. SETTING: Primary care clinics of group-model prepaid health plan. PATIENTS: A 2-stage screening process identified 329 adults with diabetes and current depressive disorder. INTERVENTION: Specialized nurses delivered a 12-month, stepped-care depression treatment program beginning with either problem-solving treatment psychotherapy or a structured antidepressant pharmacotherapy program. Subsequent treatment (combining psychotherapy and medication, adjustments to medication, and specialty referral) was adjusted according to clinical response. MAIN OUTCOME MEASURES: Depressive symptoms were assessed by blinded telephone assessments at 3, 6, 12, and 24 months. Health service costs were assessed using health plan accounting records. RESULTS: Over 24 months, patients assigned to the intervention accumulated a mean of 61 additional days free of depression (95% confidence interval [CI], 11 to 82 days) and had outpatient health services costs that averaged $314 less (95% CI, $1007 less to $379 more) compared with patients continuing in usual care. When an additional day free of depression is valued at $10, the net economic benefit of the intervention is $952 per patient treated (95% CI, $244 to $1660). CONCLUSIONS: For adults with diabetes, systematic depression treatment significantly increases time free of depression and appears to have significant economic benefits from the health plan perspective. Depression screening and systematic depression treatment should become routine components of diabetes care.

da: Il Sole 24 Ore Sanità, nr.17 3-9 maggio 2005

Psichiatra: dovere di custodia solo col Tso

La IV Sezione penale della Cassazione, con una sentenza depositata il 12 aprile, ritorna sul tema delicato della responsabilità del medico psichiatra, non oggetto di frequente disamina. La vicenda riguarda il suicidio di un paziente ricoverato in ospedale in regime di trattamento sanitario obbligatorio (Tso): dopo aver già tentato di uccidersi, il malato si era impiccato nel bagno, dove si era recato senza alcun controllo, portando con sé le lenzuola con cui aveva costruito una corda rudimentale. Anche per il fatto che il paziente aveva preannunciato i suoi propositi e persino il tempo della loro attuazione con missive ai familiari (consegnate ai sanitari), il medico responsabile del reparto e quello di turno la notte dell’accadimento erano stati incriminati per omicidio colposo, addebitando loro di aver omesso precise, vincolanti e rigide disposizioni agli infermieri sulla necessità di esercitare un ininterrotto controllo sulla parte offesa. La Corte d’appello, dopo la sentenza assolutoria di primo grado, affermava la responsabilità dei medici, ritenendo fondato il rimprovero di colpa. Gli imputati, infatti, ben conoscevano la condizione clinica del paziente, sia perché era stato già sottoposto a trattamento terapeutico presso lo stesso servizio, sia perché era nota l’anamnesi recente, con i precedenti tentativi di suicidio, resa palese dagli scritti e dallo stesso testamento, sicché erano consapevoli della ingravescenza della depressione e dell’altissima probabilità di reiterazione di un insano gesto. Aggiungeva il giudice di appello che la particolare gravità della depressione doveva comportare l’eliminazione o comunque il controllo degli strumenti idonei a tentare il suicidio, spiegando che se fossero state impartite prescrizioni puntuali e personalizzate, l’evento lesivo non si sarebbe verificato, perché gli infermieri non solo avrebbero controllato che il paziente non portasse con sé nel bagno oggetti idonei per il gesto autolesivo, ma avrebbero esercitato attenta vigilanza, restando vicino alla porta non chiusa del locale e così percependo rumori incompatibili con quelli della soddisfazione delle esigenze fisiologiche. La Cassazione ha registrato l’ormai avvenuta prescrizione del reato, ma ha affrontato comunque le doglianze dei sanitari ricorrenti ai fini del concorrente e perdurante aspetto della loro responsabilità civile, enunciando, tra l’altro, quattro principi di diritto (si veda la tabella), la cui valenza oltrepassa lo specifico caso. In particolare, va richiamata l’attenzione sul secondo dei principi indicati, poiché sembra disporsi in modo difforme rispetto a precedente decisione, in analoga materia, della Cassazione (quarta sezione, sentenza n. 10430, depositata il 4 marzo 2004). Allora la Cassazione ritenne corretta l’affermazione della responsabilità di un medico psichiatra per il suicidio di una paziente non sottoposta a Tso e affetta da sindrome depressiva (autrice di vari tentativi di suicidio), postulando l’esistenza di un dovere di protezione della incolumità fisica e naturalmente della vita dell’inferma da parte del sanitario che l’aveva in cura. Questi avrebbe dovuto comunque adottare delle cautele (se non poteva ricorrere alla coercizione, non essendovi regime di Tso) a tutela della paziente, attesa la sua pericolosità autolesiva, essendo comunque portatore di un dovere di custodia e di vigilanza nei suoi confronti.

Gianfranco Iadecola

I princìpi fissati dalla Suprema Corte

1) Nei confronti di un infermo dimente soggetto a Tso esiste la posizione di garanzia dei medici della struttura, i quali, proprio perché si tratta di un trattamento non volontario ma obbligatorio (da adottarsi quando esistano alterazioni psichiche tali da richiedere urgenti interventi terapeutici che non vengano accettati dal malato), possono adottare misure limitative della libertà personale a tutela del paziente stesso (e, in via riflessa, eventualmente, dei terzi), e tale tutela, a fronte di una situazione di gravità estrema e di mancata collaborazione del soggetto che non aderisca a un trattamento volontario, non può non effettuarsi che attraverso la custodia del soggetto, e se del caso attraverso la contenzione.

2) Se, viceversa, la persona, in stato di grave compromissione psichica, accetta di sottoporsi a un trattamento volontario, non è suscettibile di coercizione, «né conseguentemente può sorgere un obbligo di custodia nei confronti di un soggetto al quale nulla può essere imposto».

3) La libertà di cura, peraltro, se può significare ripudio delle cure per lasciarsi morire, non significa anche libertà di compiere atti positivi per morire, non spiegandosi altrimenti la possibilità di Tso in presenza di gravi tendenze suicidiarie. Né potrebbe parlarsi di assoluta irrilevanza penale del fatto di suicidio sul rilievo che il relativo tentativo non è punito, «in quanto, a prescindere dall’espressa previsione come reato dell’istigazione al suicidio (art. 580 Cp) e dell’omicidio del consenziente (art. 579 Cp), può confluire in uno stesso evento materiale, quale la morte del soggetto, il reato di omicidio, doloso o colposo a seconda dell’elemento psichico che assista il comportamento di un terzo che cooperi alla realizzazione dell’evento».

4) Di un evento come quello occorso non può muoversi addebito nei confronti del medico di guardia (di turno) al momento del suo verificarsi, non competendo al medesimo, bensì al sanitario di guardia che aveva effettuato l’accettazione del paziente, la prescrizione di trattamenti terapeutici e di prevenzione personalizzati.

(Sentenza Cassazione IV Sez.(12/04/2005): “Nei confronti di un infermo di mente soggetto a TSO esiste la posizione di garanzia dei medici della struttura, i quali, proprio perché si tratta di un trattamento non volontario ma obbligatorio, possono adottare misure limitative della libertà personale a tutela del paziente stesso e tale tutela, a fronte di una situazione di gravità estrema e di mancata collaborazione del soggetto che non aderisca a un trattamento volontario, non può non effettuarsi che attraverso la custodia del soggetto, e se del caso attraverso la contenzione”.



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