Emilio Sacchetti

Brain morphology in schizophrenia: a 2- to 5-year CT scan follow-up study

In order to investigate whether structural brain changes in schizophrenia are static or progress in time, 17 schizophrenic patients were examined by computed tomography (CT) between 2 and 5 years after the initial scan. There was no change in cerebral ventricular size or degree of cortical atrophy over this period. The stability of CT scan measures of cerebral atrophy in individual schizophrenic patients confirms the hypothesis of the early appearance of structural brain abnormalities in schizophrenia as formulated in previous cross‐sectional studies. Furthermore, the pathological process responsible for the CT finding of cortical or central atrophy does not seem to progress nor to reverse itself in young schizophrenic patients.

Brain structural abnormalities at the onset of schizophrenia and bipolar disorder: a meta-analysis of controlled magnetic resonance imaging studies.

A number of structural brain imaging studies and meta-analytic reviews have shown that multiple subtle brain abnormalities are consistently found in schizophrenia and bipolar disorder. Several studies suggest that schizophrenia and affective psychoses share a largely common pattern of brain abnormalities. Aim of the present study was to compare, by means of a meta-analytic approach, brain structural abnormalities, as detected by Magnetic Resonance Imaging (MRI), found at the onset of schizophrenia and bipolar disorder in order to address the question of the specificity of brain abnormalities across diagnostic groups. Forty-five studies were identified as suitable for analysis. In both schizophrenic and bipolar patients significant overall effect sizes were demonstrated for intracranial, whole brain, total grey and white matter volume reduction as well as for an increase of lateral ventricular volume at disease onset. Thus, the available literature data strongly indicate that some brain abnormalities are already present in first-episode schizophrenia or bipolar disorder and that there is a significant overlap of brain abnormalities in affective and non-affective psychotic disorders at the onset of the disease. However, whole grey matter volume deficits and lateral ventricular enlargement appear to be more prominent in first-episode schizophrenia whereas white matter volume reduction seems more prominent in bipolar disorder. The common vs specific trajectories of brain pathomorphology in schizophrenia and bipolar disorder are discussed.

Reduced fractional anisotropy of corpus callosum in first-contact, antipsychotic drug-naive patients with schizophrenia

BACKGROUNDnCorpus callosum is the most important commissure of the brain and therefore represents a first-choice candidate to challenge hypotheses of disrupted inter-hemispheric connectivity and white matter pathology in patients with schizophrenia. Recent studies on diffusion tensor imaging (DTI) of corpus callosum yielded promising but equivocal evidence of reduced fractional anisotropy (FA) in schizophrenia patients who were, for the most part, chronic cases on medication for a lengthy period of time. To exclude potentially confounding effects of the course of the disorder and its treatment, we compared callosal FA of first-contact, antipsychotic drug-naive schizophrenia patients (n=21) and healthy controls (n=21).nnnMETHODSnSplenium and genu FA were obtained by two independent observers utilizing large, rectangular, tractography-guided regions of interest outlined on directional color-coded maps. Inter-observer agreement on FA was evaluated by means of the Bland and Altman and the Passing and Bablok procedures together with an estimate of the intra-class correlation coefficient.nnnRESULTSnStrong inter-observer agreement of FA values emerged from each of the three statistical approaches utilized. ANCOVA showed a significant effect on FA for the interaction between patient-control membership and callosal region (F=5.354; p=0.026); post hoc multiple comparisons demonstrated that, when compared to the controls, the patients had lower mean FA values (p=0.005) in the splenium but not in the genu and that this difference tended to be more evident in males (p=0.090).nnnCONCLUSIONSnLowered mean FA values in the splenium of first-contact, antipsychotic drug-naive patients with respect to healthy controls strongly support the hypothesis that processes operant at least since the earliest phases of the disorder and independent from exposition to antipsychotic drugs contribute to reduced anisotropy in schizophrenia.

Cerebrovascular Accidents in Elderly People Treated with Antipsychotic Drugs: A Systematic Review

After 2002, an association between stroke and antipsychotic use was reported in clinical trials and large database studies. This review considers previous quantitative reviews, newly published clinical trials, and recent observational cohort and case-control studies, and focuses on the clinical significance of the risk for stroke, the difference between typical and atypical antipsychotics, the possible at-risk patient profile and the timing of stroke after exposure. A search of MEDLINE covering the period from 1966 to June 2009 was carried out using selected keywords. Inclusion criteria were (i) quantitative reviews on stroke and antipsychotics; (ii) double-blind, placebo-controlled clinical trials involving patients with dementia treated with antipsychotics; and (iii) observational database cohort studies and observational case-control studies investigating the association between stroke and antipsychotics. Clinical trials were excluded if they were single-blind or if patients were affected by dementia and/or other neurological illnesses.Four reviews with aggregate data, 2 meta-analyses, 13 randomized, double-blind, controlled trials, 7 observational cohort studies and 4 observational case-control studies were selected and analysed. The incidence of cerebrovascular accidents (CVAs) was found to be very low in aggregate reviews and meta-analyses (2–4%). When the number collected was sufficiently high, or different drug treatments were grouped together, the higher rate in subjects exposed to antipsychotics was statistically significant. Inspection of other randomized controlled clinical trials, not included in aggregate reviews and meta-analyses, reported similar rates of CVAs. The majority of observational cohort studies compared typical and atypical antipsychotics and no significant class differences were found. A comparison with non-users was carried out in some cohort studies. In case-control studies, the probability of CVAs in users compared with non-users was in the range of 1.3- to 2-fold greater. Preliminary data also indicate that the highest risk of stroke is related to the first weeks of treatment, and a risk profile for stroke is emerging, such as older age, cognitive impairment and vascular illness. Different pathophysiological pathways may be involved, ranging from the facilitation of thrombosis, pre-existing cardiovascular factors, sedation and a common diathesis for stroke of dementia, schizophrenia and affective illness.Before prescribing an antipsychotic, clinicians should weigh all the risk factors for a given patient and consider not only the indications as provided by the regulatory agencies, but also the overall effectiveness of typical and atypical antipsychotics.

β-endorphin and β-lipotropin plasma levels in chronic schizophrenia, primary affective disorders and secondary affective disorders

Abstract Plasma levels of β-endorphin (β-EP), β-lipotropin (β-LPH) and ACTH were assayed in 15 chronic schizophrenics, nine patients with primary affective disorders (PAD) and seven patients with secondary affective disorders (SAD). Patients received no therapy for 10 days prior to study. All subjects were studied once; eight schizophrenics were studied again after 10 days of Haloperidol therapy, at a dose of 0.1 mg/kg body weight. β-LPH levels were significantly higher in the schizophrenics without hallucinations and in the PAD and SAD patients in comparison to the controls; β-EP levels were higher in the schizophrenics and SAD patients compared to the controls; and ACTH concentrations were significantly lower in the SAD than in the PAD patients. Haloperidol therapy failed to induce significant changes in β-LPH, β-EP or ACTH plasma levels. Statistical evaluation by multiple linear regression confirmed the significant positive correlations among β-LPH, β-EP and ACTH in the controls, schizophrenics with hallucinations, and PAD and SAD patients, while inverse correlations between β-LPH and the other two peptides were found in the schizophrenics without hallucinations. The same analysis revealed that, while in the PAD patients equimolar amounts of the three peptides occurred, the SAD patients were characterized by ACTH/β-LPH and ACTH/β-EP molar ratios of 0.5. Although these results are preliminary, they seem to indicate that β-LPH, β-EP and ACTH secretion patterns in chronic schizophrenia, PAD and SAD may help in revealing specific groups of patients with different biochemical substrates.

H2 antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients

BACKGROUNDnOlanzapine is temporally associated, in a number of patients with schizophrenia, with weight gain. H(2) antagonists, like nizatidine, have been shown to control appetite in overweight patients.nnnMETHODSnA patient with olanzapine temporally associated weight gain was treated with nizatidine as add-on therapy.nnnRESULTSnNizatidine treatment was associated with good control and subsequent reduction of weight after 4 to 5 weeks of therapy in a patient with repetitive episodes of weight gain during olanzapine treatment. Olanzapine was otherwise well tolerated and effective in controlling psychopathology.nnnCONCLUSIONSnH(2) antagonist treatment with olanzapine may be a valid medical strategy in preventing and/or reducing weight gain in patients with schizophrenia. Controlled studies are recommended to confirm this observation.

Ziprasidone vs clozapine in schizophrenia patients refractory to multiple antipsychotic treatments: the MOZART study.

This 18-week, randomized, flexible-dose, double-blind, double-dummy trial evaluated ziprasidone as an alternative to clozapine in treatment-refractory schizophrenia patients. Patients had a DSM-IV diagnosis of schizophrenia, a history of resistance and/or intolerance to at least three acute cycles with different antipsychotics given at therapeutic doses, PANSS score >or=80, and CGI-S score >or=4. Patients were randomized to ziprasidone (80-160 mg/day, n=73) or clozapine (250-600 mg/day, n=74). On the primary ITT-LOCF analysis, baseline-to-endpoint decreases in PANSS total scores were similar in the ziprasidone (-25.0+/-22.0, 95% CI -30.2 to -19.8) and clozapine (-24.5+/-22.5, 95% CI -29.7 to -19.2) groups. A progressive and significant reduction from baseline in PANSS total score was observed from day 11 in both study arms. There were also significant improvements on PANSS subscales, CGI-S, CG-I, CDSS, and GAF, without between-drug differences. The two treatment groups had similar rates of early discontinuations due to AEs. AEs were mostly of similar mild-moderate severity in the two groups. There were also no detrimental effects on prolactin, renal and liver function, hematology, and cardiovascular parameters. However, ziprasidone but not clozapine showed a significant reduction of SAS and AIMS scores. Moreover, when compared with clozapine, ziprasidone also had a more favorable metabolic profile, with significant endpoint differences in weight, fasting glucose, total cholesterol, LDL cholesterol, and triglycerides. In conclusion, this trial indicates that both ziprasidone and clozapine, having comparable efficacy coupled with satisfactory general safety and tolerability, may be regarded as valuable options for the short-term treatment of difficult-to-treat schizophrenia patients with a history of multiple resistance and/or intolerance to antipsychotics. The more favorable metabolic profile of ziprasidone may represent an added value that could guide clinicians, at least in the presence of patients at high risk for metabolic disorders.

G308A tumor necrosis factor alpha functional polymorphism and schizophrenia risk : Meta-analysis plus association study

Research on -G308A functional polymorphism in the tumor necrosis factor alpha (TNFalpha) gene as a susceptibility factor for schizophrenia has provided contrasting results in different populations. Therefore we conducted a meta-analysis of the published case-control association studies and a replication study in a large sample. Meta-analyses (total sample: 2512 cases versus 3223 controls) showed that the AA genotype was weakly associated with schizophrenia susceptibility in Caucasoids (Odd Ratio OR=1.65, 95% CI=1.00-2.71 Z=1.98 p=0.05). The replication case-control association study (323 DSM-IV-TR schizophrenia patients and 346 controls) showed that the A allele conferred an increased susceptibility for schizophrenia only in males (OR=1.73, 95% CI=1.07-2.79, p=0.025), and the association became more specific when only patients of the paranoid subtype were compared to the controls (relative risk ratio=3.09, 95% CI=1.28-7.47, p=0.012). The presence of the A allele was also associated with a later age at onset of schizophrenia in the whole sample (F(1,291)=7.094, p=0.008). Our results confirm that TNFalpha A allele could have an effect on vulnerability to schizophrenia but further studies revaluating the role of gender and diagnostic subtypes are necessary to confirm these findings.

Cortical atrophy in schizophrenia prevalence and associated features

The degree of cortical atrophy as revealed by computed tomographic scans was assessed in 124 patients meeting the DSM III criteria for schizophrenia and in 45 age- and sex-matched healthy controls. 21 patients, i.e., 33% of the entire sample, showed moderate to severe atrophy. The presence of atrophy was not associated with such variables as patients age, age at onset and duration of illness, diagnostic subtype of schizophrenia, family history of schizophrenia in first degree relatives, history of suicidal behavior, I.Q., employment status, clinical outcome on neuroleptic treatment and HLA antigens distribution. The only variables found to be associated with atrophy were: male sex and cerebral ventricular enlargement. The significance of the CT finding of cortical atrophy in schizophrenia is discussed in the light of these results.

Lithium in drinking water and suicide prevention: a review of the evidence.

Suicide is a serious public health problem worldwide, and many nations are committed to developing prevention programmes to reduce the incidence of suicide. To date, several strategies have been proposed for suicide prevention, both at the population and at the individual level, some of which may be pharmacological. In particular, a substantial amount of data show that lithium significantly reduces mortality in patients with mood disorders. Initiating from this evidence, some recent studies have investigated whether a relationship might exist between levels of lithium in drinking water and mortality rates for suicide in the general population. We have systematically reviewed all the articles published on this issue to date. The available literature indicates that higher lithium levels in drinking water may be associated with reduced risk of suicide in the general population.