The GRM7 gene, early response to risperidone, and schizophrenia: a genome-wide association study and a confirmatory pharmacogenetic analysis.

The search for biomarkers of response to antipsychotic medications is hindered by difficulties inherent in the topic or related to persistent methodological difficulties, such as high rates of anticipated discontinuation and consequent distortions in the imputation of missing data. Because early response to antipsychotics represents a sufficiently reliable index of the subsequent treatment response in patients with schizophrenia, we undertook a real-world, genome-wide association study (GWAS) with the aim of identifying genetic predictors of response to risperidone after 2 weeks in 86 patients with schizophrenia. Limited to the associations reaching significance in the GWAS, confirmatory analysis relative to risperidone response over 9 months was also designed involving 97 patients (European only) enroled in the CATIE (Clinical Antipsychotic Trials of Intervention Effectiveness) genetic substudy. The GWAS revealed a significant association (false discovery rate 0.02) of the single-nucleotide polymorphism rs2133450 inside the GRM7 gene with Emsley's positive domain derived from the positive and negative syndrome scale (PANSS). Patients with the rs2133450 CC genotype presented poorer improvement in the positive domain over 2 weeks, with odds ratios of 12.68 (95% CI, 3.51-45.76) and 6.95 (95% confidence interval (CI), 2.37-20.37) compared with patients with the AA and AC genotypes, respectively. Compared with A homozygotes, rs2133450 C homozygotes enroled in the CATIE-derived confirmatory analysis showed less improvement in Emsley's positive, excited and depression domains, positive and general PANSS subtypes, and total PANSS after 9 months of treatment with risperidone. The original GWAS and the CATIE-derived confirmatory analysis support the proposal that the rs2133450 may have translational relevance as a predictor of response to risperidone.

Social cognition in people with schizophrenia: a cluster-analytic approach.

BACKGROUND: The study aimed to subtype patients with schizophrenia on the basis of social cognition (SC), and to identify cut-offs that best discriminate among subtypes in 809 out-patients recruited in the context of the Italian Network for Research on Psychoses. METHOD: A two-step cluster analysis of The Awareness of Social Inference Test (TASIT), the Facial Emotion Identification Test and Mayer-Salovey-Caruso Emotional Intelligence Test scores was performed. Classification and regression tree analysis was used to identify the cut-offs of variables that best discriminated among clusters. RESULTS: We identified three clusters, characterized by unimpaired (42%), impaired (50.4%) and very impaired (7.5%) SC. Three theory-of-mind domains were more important for the cluster definition as compared with emotion perception and emotional intelligence. Patients more able to understand simple sarcasm (⩾14 for TASIT-SS) were very likely to belong to the unimpaired SC cluster. Compared with patients in the impaired SC cluster, those in the very impaired SC cluster performed significantly worse in lie scenes (TASIT-LI <10), but not in simple sarcasm. Moreover, functioning, neurocognition, disorganization and SC had a linear relationship across the three clusters, while positive symptoms were significantly lower in patients with unimpaired SC as compared with patients with impaired and very impaired SC. On the other hand, negative symptoms were highest in patients with impaired levels of SC. CONCLUSIONS: If replicated, the identification of such subtypes in clinical practice may help in tailoring rehabilitation efforts to the person's strengths to gain more benefit to the person.

Negative symptom severity at discharge from an index hospitalization and subsequent use of psychiatric care resources: A retrospective 1-year follow-up study on 450 patients with schizophrenia spectrum disorders.

Negative symptoms of schizophrenia have a great impact on patients' functioning and are among the most important contributors to subject's disability. However, few studies have assessed the role of type and severity of symptomatology of schizophrenia on the psychiatric care resource utilization. We investigated if the clinical profile of patients at discharge from an index hospitalization might be associated with a different use of psychiatric care resources in the subsequent 1-year period in a large population of patients with schizophrenia spectrum disorders. Clinical records of 450 patients with schizophrenia spectrum disorders admitted in an acute psychiatric inpatient service and subsequently followed in the outpatient services of the same Department were reviewed. Patients with more severe negative symptoms at discharge from hospital showed a higher number and duration of hospitalizations in the 1-year follow-up, as well as a higher number of rehabilitative residential admissions than patients with milder severity of negative symptoms. The same was true for patients with predominant negative symptoms. A global resource utilization index indicated a higher use of psychiatric resources in patients with higher severity of negative symptoms. In conclusion, showing moderate to severe negative symptoms versus positive symptoms at discharge from a hospitalization for an acute exacerbation of schizophrenia spectrum disorder does predict a higher use of psychiatric care resources. This underlines the importance of relieving negative symptoms even in the acute phase of treatment and the need to develop more effective treatments for this symptom dimension.

Long-acting risperidone improves negative symptoms in stable psychotic patients.

The aim of this paper was to evaluate the efficacy of risperidone long-acting injectable (RLAI) for reducing negative symptoms of schizophrenia in patients with predominantly negative symptoms at baseline. A subanalysis was performed on data from the 6-month, open-label Switch to Risperidone Microspheres trial. Patients with Positive and Negative Syndrome Scale (PANSS) negative subscale score > or = 21, which was higher than their PANSS positive subscale score, were included in this subanalysis. Improvement in negative symptoms was measured by assessing change in the PANSS negative subscale and a negative factor score. Additional outcome variables included measures in general functioning, quality of life and patient satisfaction. A total of 842 patients were eligible for inclusion in this subanalysis. Six months of treatment was completed by 631 (74.9%) patients. Forty-three (5.1%) patients discontinued treatment due to an adverse event. Negative symptoms were significantly reduced by 6.1 +/- 6.3 points for the PANSS negative score and 6.1 +/- 6.4 points for the negative factor score (P < 0.0001 for both). Significant improvements were also noted for total PANSS and other PANSS subscale scores, general functioning, quality of life and patient satisfaction (P < 0.0001). The most common treatment-emergent adverse events (>5%) were: anxiety (6.8% of patients), exacerbation of disease (6.2%) and insomnia (5.7%). Overall, RLAI was well tolerated and associated with significant reductions in movement disorder severity. The treatment resulted in a significant improvement in negative symptom severity and was well tolerated in patients with predominantly negative symptoms, who switched from a stable antipsychotic regimen

Long-term remission in schizophrenia and related psychoses with long-acting risperidone: results obtained in an open-label study with an observation period of 18 months.

OBJECTIVE: To monitor long-term symptomatic tolerability and remission in patients with stable but suboptimally treated psychoses after switching to risperidone long-acting injectable (RLAI). METHOD: This subgroup analysis of the Switch to Risperidone Microspheres (StoRMi) open-label trial followed up patients with psychoses who were converted to RLAI for a period of 18 months or until RLAI became commercially available in their country of residence. It included patients from seven European countries. Dosage adjustments were performed as clinically necessary. The efficacy endpoint was achieving and maintaining remission, defined as absent to mild core schizophrenia symptoms for > or = 6 months. A schizophrenia assessment was also completed and patients were monitored for the development of adverse events (AEs). Discontinuation rates were calculated based on Kaplan-Meier estimates where patients switching to commercial RLAI were used as censored observations. RESULTS: A total of 529 patients were followed for up to 18 months. At 18 months, the discontinuation rate was 55.7% based on Kaplan-Meier estimates. The median time to discontinuation was 15.7 months (95% CI (14.0; 17.5)). RLAI was generally well tolerated with most AEs mild-to-moderate in severity. 13% of patients discontinued treatment because of an AE. Body weight of patients increased by a mean A+/- SD of 1.0 A+/- 6.1 kg from treatment initiation to endpoint (p = 0.0001). Glucose-related AEs occurred in four patients (0.8%). Among those patients not meeting severity remission criteria at baseline, 44.8% were in remission at endpoint. Among those patients meeting severity criteria for remission at baseline, 84.2% were in remission at endpoint. A total of 93.7% of the patients who achieved or maintained remission at 6 months were in remission at endpoint. CONCLUSIONS: RLAI is safe during long-term treatment up to 18 months in adults requiring antipsychotics. Conversion to RLAI resulted in improved symptom control. Most patients achieved and maintained a sustained remission (> or = 6 months) after conversion to RLAI.

Deranged anterior pituitary responsiveness to hypothalamic hormones in depressed patients.

Abnormal anterior pituitary (AP) responsiveness to acute administration of thyrotropin-releasing hormone (TRH) and luteinizing hormone-follicle stimulating hormone-releasing hormone (LH-RH) was investigated in 14 patients (two men and 12 women) suffering from primary affective disorders. In ten, TRH, 500 microgram given intravenously, induced a rise in plasma growth hormone (GH) level, while in eight patients it induced a rise in plasma levels of FSH or LH or both. When LH-RH, 150 microgram was administered intravenously to ten patients, it induced a rise in plasma GH level in one patient and increased plasma prolactin level in three patients. Collectively, in only three of 14 patients was conventional AP responsiveness to hypothalamic neurohormones present. These findings demonstrate the existence of a profound derangement of AP responsiveness to hypothalamic neurohormones in depressed patients and suggest that a primary alteration in the physiologic links between the central nervous system and the AP may be at the origin of the neuroendocrine disturbance.

Direct transition to long-acting risperidone--analysis of long-term efficacy.

This report presents data from the extension phase of a 6-month trial that evaluated the efficacy of risperidone long-acting injectable (RLAI) in stable psychotic patients requiring a treatment change. Patients continued to receive RLAI every 2 weeks for a maximum of 12 months from study entry. Symptoms were assessed using the PANSS after 1, 3, 6, 9 and 12 months of treatment (or treatment endpoint). Remission of severity criteria were defined as < or =3 points in all PANSS items suggested by the Remission in Schizophrenia Working Group.715 patients (63% male) entered the extension phase and 508 completed the 12-month study. The mean PANSS total score at Day 0 was 74.9+/-22.7. This was significantly reduced after 1 month (67.7 +/-22.3, p< or =0.001), with continued improvements over the 12 months of the study until treatment endpoint (59.7+/-21.9). Significant improvements from Day 0 to endpoint were also seen in the scores for all PANSS subscales and symptom factors. The proportion of patients who met the PANSS severity criteria for remission increased from 29% at Day 0 to 60% at endpoint, and the proportion of patients who met these criteria for < or = 6 months increased from 24% at Month 6 to 45% at endpoint. Treatment with RLAI for up to 12 months provided significant and sustained improvements in symptom control in patients with schizophrenia. These improvements may help patients to achieve and remain in remission.

H(2) antagonist nizatidine may control olanzapine-associated weight gain in schizophrenic patients.

BACKGROUND: Olanzapine 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. METHODS: A patient with olanzapine temporally associated weight gain was treated with nizatidine as "add-on" therapy. RESULTS: Nizatidine 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. CONCLUSIONS: H(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.

3-Methoxy-4-hydroxyphenylglycol and primary depression: clinical and pharmacological considerations.

Pretherapeutic urinary excretion of 3-methoxy-4-hydroxyphenylglycol (MHPG) was studied in 25 primary depressed patients. The results indicate that: (i) There exists a wide variability among primary depressives with respect to MHPG excretion. (ii) Age of onset together with polarity of the disease may account for the nonhomogeneous division of the patients according to MHPG levels. (iii). The other variables considered, with the possible exception of motor activity, do not explain the dichotomy between high or normal and low MHPG levels, even though it is possible that they influence MHPG excretion to some extent, with the consequent possibility of errors in subclassification of the patients at the boundaries between the two groups. (iv) The correlation between motor retardation and low MHPG excretion is positive, but probably due to a frequent association between this motricity state and primary depression of bipolar early onset type. (v) Treatments with chlorimipramine and, to a lesser degree of specificity, with amitriptyline are particularly indicated in patients with normal or high MHPG. Some practical and theoretical implications deriving from these data are briefly discussed.

CT scan abnormalities and outcome of chronic schizophrenia.

The authors evaluated the relationship between brain morphological characteristics assessed by means of computerized tomography and the 2-year clinical and social outcomes of 18 patients with chronic schizophrenia. Cerebral structural abnormalities, especially cortical atrophy, were associated with a poorer outcome in several areas of clinical and social functioning.

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.

Cytokine profiles in drug-naive schizophrenic patients.

A large body of evidence concerning immunological abnormalities in schizophrenic patients seems to suggest a role of the immune system in the multifactorial pathogenesis of schizophrenia. We investigated the production of various cytokines [interleukin (IL)-2, IL-4, IL-10, interferon (INF)-gamma] in drug-free (n=26) and drug-naive (n=7) schizophrenic patients and in healthy controls (n=33). Production of IL-2 and INF-gamma was significantly higher (respectively P=0.021 and P=0.001) in patients than in controls. These findings provide further evidence that immunological abnormalities are present in some schizophrenic patients.

Platelet alpha 2-adrenoceptors in major depression: relationship with urinary 4-hydroxy-3-methoxyphenylglycol and age at onset.

Platelet alpha 2-adrenoceptor number and affinity were measured in 31 drug-free patients with major depressive illness utilizing 3H-clonidine as ligand. A significant negative correlation was found between number of alpha 2-adrenoceptors, baseline urinary 4-hydroxy-3-methoxyphenylglycol (MHPG) excretion, present age and age at onset of the disease. Kd did not correlate with any of these variables not with the Bmax of platelet alpha 2-adrenergic binding. Multiple regression analysis, with MHPG and age at onset as independent variables, explained variance for alpha 2-adrenoceptor density better than single regression (from 19% for MHPG and 30% for age at onset to 40%), with the addition of both these variables being significant.

Depressive disorders and personality variables in HIV positive and negative intravenous drug-users.

BACKGROUND: Only a few reports investigated the prevalence of depression in intravenous drug-users with HIV infection, including both asymptomatic and symptomatic subjects. In the same group, the association of depression and personality diagnoses was also poorly researched. METHODS: A consecutive sample of intravenous drug-users was collected from patients admitted to an infectious disease clinic, another random sample was taken from out-patients attending a methadone maintenance treatment program. Subjects were first screened with the Hospital Anxiety and Depression Scale, and then all positive subjects were evaluated with the Composite International Diagnostic Interview. Depression was diagnosed according to DSM-IIIR. In-patients were also given a structured personality inventory (Karolinska Psychodynamic Profile). RESULTS: HIV-positive patients had a high rate of depression (major depression 36.2%, dysthymic disorder 7.1%) when compared to HIV-negatives (15.7 and 3.9%, respectively). In-patients had the highest rate of depression, irrespective of HIV clinical staging. A personality disorder was diagnosed in 36% of the sample, but these subjects were no more significantly depressed. LIMITATIONS: Poor detection of depression by the admitting physician may have led to selective hospitalization of patients with both HIV and mood disorder. The composition of the sample may also be biased by the help-seeking behavior of HIV patients who are also depressed. CONCLUSION: Physicians treating AIDS patients should be alerted to the high rate of depression in clinical HIV illness, in order to identify and properly treat depression.

Quetiapine, clozapine, and olanzapine in the treatment of tardive dyskinesia induced by first-generation antipsychotics: a 124-week case report.

Our report of a patient with severe tardive dyskinesia (TD) who has been exposed to both typical antipsychotic and clozapine, olanzapine and quetiapine during a 124-week follow-up period supports the possible beneficial effect of atypical antipsychotics on pre-existing symptoms of TD. Persistently high AIMS scores during all the periods of treatment with typical antipsychotics contrast strongly with the drop in scores that occurs in strict chronological sequence after switching to both clozapine (45%), olanzapine (27.8%) and quetiapine (85%). Since the reversal to haloperidol from the three atypical agents was systemically associated with a return to high AIMS scores, it seems likely that the improvement noted with clozapine, olanzapine and quetiapine represents a temporary symptomatic effect rather than a sustained resolution of the disorder. The olanzapine-clozapine-quetiapine rank order of increasing effectiveness against TD symptoms suggests that this property, although shared by the atypical antipsychotics, is to some degree drug-specific. Patient- and/or drug-dependent mechanisms may be involved in this gradient of effect.

Combined measure of smooth pursuit eye movements and ventricle-brain ratio in schizophrenic disorders.

Smooth pursuit eye movements (SPEM) were examined in 67 schizophrenic patients and 101 control subjects. Our study confirms that eye tracking in schizophrenic patients is impaired compared to that in controls. The similar pattern of distribution of SPEM abnormalities in Italian patients as in ethnically different populations strengthens the hypothesis that these abnormalities may be a biological marker for schizophrenia. We also examined the relationship between SPEM abnormalities and the ventricle-brain ratio (VBR), which is also considered useful for differentiating schizophrenic subgroups. Our preliminary results indicate that there is an inverse correlation between abnormal SPEM performance and ventricular enlargement, suggesting that these abnormalities mark distinct subgroups of patients.

Alpha reactivity in schizophrenia and in schizophrenic spectrum disorders: demographic, clinical and hemispheric assessment.

Alpha EEG reactivity was assessed in a carefully diagnosed sample of 84 schizophrenic and schizophrenic spectrum disorder patients, both under resting conditions (eyes closed and eyes open) and during two spatial-geometric cognitive tasks. The influence of the subject's demographic (sex and age), clinical (diagnostic subtypes, disease course, CT scan characteristics) and neurophysiological (hemispheric recording and different cognitive tasks) characteristics on alpha peak reactivity was analyzed by means of multivariate analysis of variance. The results indicated a significant effect of type of illness on alpha EEG reactivity, patients with a diagnosis of undifferentiated and disorganized schizophrenia having the lowest alpha reactivity levels. None of the other variables considered had any contributing effect. The results are discussed in terms of orienting responses and hemispheric CNS organization in functional psychoses.

Variables associated with the hospitalization of psychiatric emergencies evaluated in the community.

We investigated hospitalization factors in acutely ill patients visited by psychiatrists at home. A series of 100 consecutive calls for psychiatric emergencies of a community mental health centre were investigated with a structured evaluation of psychiatric symptoms and aggressiveness (IEF, GAS, and VSAS). First order interactions were tested, and selected variables were tested with logistic regression analysis. Admission was significantly associated with GAS scores (low scores were found in 92.6% of admitted patients vs. 43.8% of patients not admitted), paranoid delusions (66.7 vs. 39.7%), and lack of social support (70.4 vs. 30.1%). Multivariate analysis confirmed a significant independent effect only for low GAS score and lack of social support. The study replicated some findings from research on hospitalization in emergency wards, while other factors, such as 'diagnosis' and 'suicide risk', were not significant.

Heterogeneity of major affective disorders. Biological and clinical evidence.

In this paper we summarize the results of our recent and present research focused on analyzing the correlations between neurochemical, pharmacological and clinical parameters in patients with Major Depression. There is evidence that: a) pretreatment urinary MHPG is a useful predictor for clinical response to tricyclic antidepressants and to long-term lithium treatment; b) urinary MHPG is positively correlated to the age at onset of the disease; c) previous responses to tricyclics and age at onset of affective illness are supplementary tools for predicting the effectiveness of lithium and antidepressant drugs; d) platelet alpha-2-adrenoceptor density is inversely correlated with both urinary MHPG and age at onset; e) cerebral ventricular size is positively correlated with urinary MHPG and age at onset and may discriminate between patients with different outcomes on lithium prophylaxis; f) low MHPG excretors are more likely to have suffered from stressful life events in early childhood than normal-to-high excretors. Taken together, these results lend strong support to the hypothesis that Major Affective Disorder is a heterogeneous illness and that inherently different subgroups of affective patients can be recognized.

Patterns of brain structural changes in first-contact, antipsychotic drug-naive patients with schizophrenia.

BACKGROUND AND PURPOSE: Previous studies have suggested that structural changes do occur in the brain of patients with schizophrenia compared with healthy control participants. However, findings from such studies are inconclusive, probably because of the different methodologic approaches, the clinical heterogeneity of patient samples, and also the fact that patients enrolled were treated with antipsychotic drugs. The aim of this study was to investigate brain GM volumes and intrinsic structural WM changes in first-contact, antipsychotic drug-naïve patients with schizophrenia. MATERIALS AND METHODS: A total of 43 first-contact, drug-naïve, patients with schizophrenia and 17 age-matched control participants were studied. All participants underwent T1-weighted MR imaging and DTI scans. Voxel-based morphometry and tract-based spatial statistics were used to compare GM volumes and WM DTI metrics between groups. MR imaging measures were correlated with the duration of the untreated psychosis and the clinical positive and negative symptoms. RESULTS: Compared with control participants, patients with schizophrenia showed smaller volumes of the temporal, parietal, and occipital GM, and a pattern of decreased mean diffusivity and increased fractional anisotropy in the brain stem and cerebellum bilaterally, interhemispheric and cortico-cortical connections bilaterally, and right anterior and posterior limb of the internal capsule. In patients, decreased mean diffusivity and increased fractional anisotropy in several brain regions were related to a longer duration of the untreated psychosis and the severity of positive symptoms. CONCLUSIONS: First-contact, drug-naïve, patients with schizophrenia present with volumetric and DTI changes, which correlated with their clinical features. This study increases our knowledge on the neural networks involved in the pathophysiologic mechanisms of schizophrenia.