Case Report: Long-Acting Oral Cariprazine.

Introduction: Cariprazine is a third-generation antipsychotic, approved for the treatment of schizophrenia and bipolar disorder and used off-label for schizoaffective disorder and treatment-resistant depression. Cariprazine is a partial agonist at dopamine receptors D2 and D3 and serotonin receptor 5HT1A and an antagonist at serotonin receptors 5HT2B and 5HT2A. It is metabolized by CYP3A4 in desmetyl-cariprazine and didesmethyl-cariprazine, both active metabolites with a half-life of 1-2 days and 2-3 weeks, respectively. Case Report: Here we show the cases of 3 outpatients diagnosed with bipolar I disorder (two patients) and schizoaffective disorder (one patients) and characterized by low adherence to treatment, satisfactory cognitive and personal functioning and average disease severity to whom we administered cariprazine as a monotherapy, on a two-times a week schedule (i.e., every 72-96 h). We evaluated response to treatment and disease remission according to conventional definitions, using rating scales BPRS, PANSS and BDI-II. Two-times a week treatment was set either after a disease relapse (one patient), after a sustained remission obtained with daily administration of cariprazine (one patient) or since our first evaluation (one patient). After 4 weeks of treatment all three patients satisfied criteria for response to treatment and remission, a result that was sustained for 8 (in one patients) and 12 months (in other two patients) and still ongoing. Discussion: Reported results support our hypothesis that long half-lives of cariprazine and its metabolites provide an adequate therapeutic response with a two-times a week administration. In selected patients, cariprazine administered as a "oral long-acting" seems effective in treating acute episodes of illness and in sustaining remission, combining advantages of oral and long-acting injectable antipsychotics concerning therapeutic alliance.

Strucutural brain imaging at the onset of schizophrenia:What have we learned and what have we missed.

Over the past 50 years, the application of structural neuroimaging techniques to schizophrenia research has added relevant information about the pathophysiology of the disorder. Several lines of investigation gave strong evidence that schizophrenia is associated with multiple subtle brain abnormalities that involve both cerebral grey and white matter volumes and structure. The time of onset and longitudinal course of brain morphological abnormalities support the notion that brain pathology of schizophrenia has a neurodevelopmental component and a progressive course, although several confounders of brain changes should be carefully taken into account. Brain anomalies detected before and close to the onset of schizophrenia are likely to be unrelated to confounders of brain changes such as antipsychotic drug treatment, duration of illness or illicit substance abuse, i.e. they related to the pathological process of the disorder per se. Nonetheless, clinically useful diagnostic or prognostic biomarkers have not derived from neuroimaging studies and this is likely related to the neurobiological heterogeneity of the disorder. Thus, there is the compelling need to set new methodological standards for developing innovative hypothesis-driven studies to overcome what we have missed to date in neuroimaging research in schizophrenia.

Are Schizophrenic disorders with or without early cannabis use neurobiologically distinct disease entities? A meta-analysis of magnetic resonance imaging studies.

Cannabis use is considered an important risk factor for the development of psychotic illness and is associated with worse outcomes of the disorder. This study aimed to determine through a meta-analytic approach whether patients at the onset of schizophrenia with comorbid cannabis use (SCH CU+) show a different pattern of brain abnormalities as compared to patients with no comorbid cannabis use (SCH CU-). Ten Magnetic Resonance Imaging (MRI) studies were identified as suitable for analysis leading to the inclusion of n= 465 patients with schizophrenia (n= 227 SCH CU+ and n= 238 SCH CU-) and n= 366 healthy controls. Compared to healthy controls, both SCH CU+ and SCH CU- patients showed reduction of whole brain, total grey matter and hippocampal volumes. The direct comparison of SCH CU+ and SCH CU- patients, including up to 5 independent studies, did not demonstrate significant differences of brain volumes between the two groups even though total and regional grey matter volume deficits were more prominent in SCH CU+ patients. The available literature data indicate that, essentially, there is an overlap of brain abnormalities in SCH CU+ and SCH CU- patients at the onset of schizophrenia. The common vs specific trajectories of brain pathomorphology in SCH CU+ and SCH CU- patients are discussed.

Variation in brain structure volumes in schizophrenia: A commentary.

Recently, Kuo and Pogue-Geile (2019) quantitatively reviewed Magnetic Resonance Imaging (MRI) findings in patients with schizophrenia demonstrating, besides altered volume of several brain structures significantly greater structural variability in patients relative to controls as for intracranial, lateral and third ventricles volumes. We believe that additional points could be usefully included in the discussion of the conceptual meaning of these findings. In this commentary, first we highlight the role of potential confounding factors such as antipsychotic medication intake and duration of illness when interpreting MRI data in schizophrenia. Second, we discuss the finding of greater variability of cerebral structure volumes in the broader context of the pathophysiology and time course of brain abnormalities in the disease.

Feasibility and effectiveness of cognitive remediation in the treatment of borderline personality disorder.

Several studies have demonstrated that borderline personality disorder (BPD) is associated with neuropsychological deficits and there is evidence that the neurocognitive profile of patients with BPD may be related to the outcome of this disorder. The aim of this study was to investigate the feasibility and the effectiveness of a cognitive remediation intervention in patients with BPD. Thirty patients with a DSM-IV-TR diagnosis of BPD were assessed on clinical, neuropsychological and functional outcome measures at baseline and after 16 weeks of a computer-assisted cognitive remediation (CACR) intervention or treatment as usual (TAU). Patients who received CACR showed a greater improvement in working memory and psychosocial functioning measures than patients treated with TAU. Symptom severity was not significantly affected by CACR treatment. The findings of this pilot study suggest the feasibility and potential effectiveness on specific cognitive domains, but modest clinical usefulness of a computerised modality of cognitive remediation in the treatment of BPD.

Effects of cognitive remediation therapy on neurocognition and negative symptoms in schizophrenia: an Italian naturalistic study.

INTRODUCTION: Cognitive remediation therapy (CRT) has been reported to positively affect neurocognitive processes among patients with schizophrenia; however, the degree to which changes in cognition is linked to improved clinical symptoms, remains poorly understood. The current study aimed to investigate whether cognitive gains were associated to improvements in negative symptoms' severity in patients with schizophrenia living in two Italian psychiatric facilities. METHODS: Patients with a diagnosis of schizophrenia were consecutively assigned to CRT (n = 33) and compared with an historical control group (n = 28). Assessments were performed at baseline and post-treatment using a neuropsychological battery (Trail Making Test A and B, Self-Ordered Pointing Task, California Verbal Learning Test), along with clinical and functioning measures. RESULTS: Visual attention (TMT-A score change) was found as the only significant predictor of improvement in negative symptoms subscale of the Positive and Negative Syndrome Scale. Furthermore, a mediation path analysis confirmed that better performance in visual attention acts as mediator of the positive association between CRT intervention and lower post-treatment negative symptoms score. CONCLUSIONS: CRT can have a positive impact on a measure of visual attention in patients with schizophrenia and on negative symptoms reduction that is mediated by this significant intervention effect.

The Effect of Antipsychotic Treatment on Cortical Gray Matter Changes in Schizophrenia: Does the Class Matter? A Meta-analysis and Meta-regression of Longitudinal Magnetic Resonance Imaging Studies.

BACKGROUND: Deficits in cortical gray matter (GM) have been found in patients with schizophrenia, with evidence of progression over time. The aim of this study was to determine the role of potential moderators of such changes, in particular of the amount and type of antipsychotic medication intake. METHODS: Longitudinal magnetic resonance imaging studies comparing changes in the volume of cortical GM over time between patients with schizophrenia and healthy control subjects published between January 1, 1983, and March 31, 2014, were analyzed. Hedges' g was calculated for each study and volume changes from baseline to follow-up were analyzed. Meta-regression statistics were applied to investigate the role of potential moderators of the effect sizes. RESULTS: Eighteen studies involving 1155 patients with schizophrenia and 911 healthy control subjects were included. Over time, patients with schizophrenia showed a significantly higher loss of total cortical GM volume. This was related to cumulative antipsychotic intake during the interval between scans in the whole study sample. Subgroup meta-analyses of studies on patients treated with second-generation antipsychotics and first-generation antipsychotics revealed a different and contrasting moderating role of medication intake on cortical GM changes: more progressive GM loss correlated with higher mean daily antipsychotic intake in patients treated with at least one first-generation antipsychotic and less progressive GM loss with higher mean daily antipsychotic intake in patients treated only with second-generation antipsychotics. CONCLUSIONS: These findings add useful information to the controversial debate on the brain structural effects of antipsychotic medication and may have both clinical relevance and theoretical implications.

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.

Predictors of cognitive and functional improvement and normalization after cognitive remediation in patients with schizophrenia.

OBJECTIVE: Although the efficacy of cognitive remediation interventions has been demonstrated in several experimental studies on schizophrenia, few studies have investigated the predictors of response to such interventions. We were interested in determining what factors contribute to a positive outcome after cognitive rehabilitation and whether different factors are associated with different degrees of improvement in cognitive and real-world functioning in individual patients after cognitive remediation. METHODS: The study sample consisted of 56 patients with schizophrenia who had completed a 6-month cognitive remediation intervention and showed different cognitive and functional outcomes. Measures of cognitive and functional amelioration after cognitive remediation were analyzed in relation to patients' clinical, neuropsychological and functional variables at baseline using logistic regression analysis. RESULTS: Lower antipsychotic intake at baseline predicted cognitive improvement, whereas lower antipsychotic intake, severity of specific symptoms, and higher neurocognitive functioning (particularly executive functions and verbal memory) at baseline were associated with cognitive normalization after remediation treatment. Functional improvement was predicted by lower patient age and type of cognitive remediation intervention, whereas functional normalization was related to lower baseline antipsychotic intake and, at a trend level, to higher executive functioning and type of cognitive remediation intervention. CONCLUSION: Cognitive remediation could be more effective in younger, less disorganized, and cognitively less impaired patients, who take a smaller amount of antipsychotics. The predictive role of lower antipsychotic dosage on cognitive and functional outcome after remediation suggests either that patients with less severe illness could gain better advantage from cognitive remediation interventions or that high dose or complex antipsychotic therapy may limit the effectiveness of such interventions.

Efficacy and tolerability of asenapine for acute mania in bipolar I disorder: meta-analyses of randomized-controlled trials.

The aim of this study was to quantitatively review, using a meta-analytic approach, randomized-controlled trials analyzing the efficacy and safety profiles of asenapine in the treatment of bipolar disorder (BD). MEDLINE (1966 to August 2012) and EMBASE (1980 to August 2012) databases were systematically searched to identify relevant papers. Data from four randomized-controlled trials were analyzed. For continuous data (Young Mania Rating Scale, Clinical Global Impression Scale for Bipolar Disorder, and Montgomery-Asberg Depression Rating Scale scores), the Hedges g was adopted as a measure of the effect size; for dichotomous outcome measures (discontinuation and rates of adverse events), the risk ratio was calculated. In short-term trials, asenapine was found to be significantly superior to placebo in the treatment of manic symptoms of BD. There is also evidence of the positive effects of asenapine compared with placebo on depressive symptoms in mixed bipolar states. In the medium-term and long-term studies, asenapine showed comparable efficacy with the well-established comparator olanzapine in the treatment of manic and depressive symptoms of BD. Adverse events such as somnolence, weight gain, and extrapyramidal symptom, which have an impact on treatment adherence, are scarcely or moderately elicited by asenapine, which shows a better profile than olanzapine on metabolic parameters. On the basis of these results, asenapine can be considered as an effective and tolerable treatment for manic and mixed episodes of BD.

Interview-based assessment of cognition in schizophrenia: applicability of the Schizophrenia Cognition Rating Scale (SCoRS) in different phases of illness and settings of care.

INTRODUCTION: The Schizophrenia Cognition Rating Scale (SCoRS), an interview-based assessment of cognition, has proved to be a valid measure of cognitive performance in patients with schizophrenia. OBJECTIVE: The aims of this study were to analyze the validity of this scale in a naturalistic setting representative of the Italian system of psychiatric care, and to test whether the SCoRS could be appropriately used in different phases of illness and contexts of care. METHODS: Eighty-six patients with schizophrenia (DSM-IV-TR criteria) (N = 59 clinically stabilized patients; N = 27 recently hospitalized patients) were administered the SCoRS. The reliability of SCoRS was assessed and global ratings were correlated with neurocognitive, clinical, and psychosocial functioning measures. RESULTS: SCoRS inter-rater and test-retest reliability were high. In clinically stabilized patients, SCoRS global ratings were significantly correlated with composite scores of cognitive performance (global cognitive index: r = -0.570, P<0.001), symptoms (Positive and Negative Syndrome Scale (PANSS) total score: r = 0.602, P < 0.001), and psychosocial functioning (Global Assessment of Functioning (GAF): r = -0.532, P<0.001; Health of the Nation Outcome Scale (HoNOS): r = 0.433, P < 0.001). On the other hand, no such correlations were found in recently hospitalized patients. Correlations with neuropsychological and functional measures were less significant as the severity of the patients' symptoms, especially positive symptoms, increased. CONCLUSION: The SCoRS is a valid measure of cognitive performance and is related to psychosocial functioning, especially in clinically stable patients with schizophrenia. The usefulness of the SCoRS in patients recently admitted to hospital for an acute phase of illness is uncertain.

Cognitive remediation in schizophrenia: current status and future perspectives.

Objectives. This study is aimed to review the current scientific literature on cognitive remediation in schizophrenia. In particular, the main structured protocols of cognitive remediation developed for schizophrenia are presented and the main results reported in recent meta-analyses are summarized. Possible benefits of cognitive remediation in the early course of schizophrenia and in subjects at risk for psychosis are also discussed. Methods. Electronic search of the relevant studies which appeared in the PubMed database until April 2013 has been performed and all the meta-analyses and review articles on cognitive remediation in schizophrenia have been also taken into account. Results. Numerous intervention programs have been designed, applied, and evaluated, with the objective of improving cognition and social functioning in schizophrenia. Several quantitative reviews have established that cognitive remediation is effective in reducing cognitive deficits and in improving functional outcome of the disorder. Furthermore, the studies available support the usefulness of cognitive remediation when applied in the early course of schizophrenia and even in subjects at risk of the disease. Conclusions. Cognitive remediation is a promising approach to improve real-world functioning in schizophrenia and should be considered a key strategy for early intervention in the psychoses.

Factors related to different reasons for antipsychotic drug discontinuation in the treatment of schizophrenia: a naturalistic 18-month follow-up study.

In recent years, measurement of the effectiveness of antipsychotic therapy in schizophrenia has received increasing attention from clinicians and researchers. Several studies have used time to antipsychotic discontinuation for any reason as a global index of antipsychotic effectiveness because it reflects both the physician's and patient's judgment of drug efficacy and tolerability. In this study, we extend this approach by analyzing the rate of discontinuation for different reasons of antipsychotics administered to patients with schizophrenia in a naturalistic setting of care, and explore the determinants of such discontinuation. Ninety-nine patients with schizophrenia who received a first or second generation antipsychotic were followed for 18 months in the Italian outpatient community psychiatric system. We found discontinuation rates for different reasons to be variable and to be influenced by several factors not involving the type of pharmacologic therapy. Some of these factors, such as the frequency of visits to the care unit, underline the need to take into account the role of the care delivery system as potentially influencing the effectiveness of antipsychotics in the "real world".

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.

Cognitive remediation in the early course of schizophrenia: a critical review.

BACKGROUND: The aim of cognitive remediation is to target the cognitive impairments of patients with psychosis, including attentional deficits, memory problems, and limitations in planning and problem solving. It is hoped that by addressing these deficits, patients will be more able to take advantage of other interventions and will be more able to function in social and other domains. Many results in controlled trials of cognitive remediation in adult patients affected by schizophrenia have demonstrated its effectiveness on different cognitive domains and on patient's functioning. Some researchers speculate that deficits in cognition are more amenable to remediation during earlier phases of illness than when chronicity has developed. For these reasons cognitive rehabilitation should be a key component of early intervention programs, seeking to produce durable functional changes in the early course of schizophrenia. Although there is strong evidence that cognitive remediation is effective in adult schizophrenia, there is little evidence about its efficacy and long-term generalized effectiveness in the early course of the disease, and its possible application in the prodromal phase of the disease. PURPOSE OF REVIEW: The aim of this paper is to review the available literature on cognitive remediation in the prodromal phase and in the early course of schizophrenia. This review summarizes especially findings of cognitive changes induced in the early course or in the prodromal phases of schizophrenia by different remediation methods. Controlled studies of cognitive training are discussed in more detail. CONCLUSION: Few studies on the effects of cognitive training programs have been conducted in first episode or in early schizophrenia and only one study has been conducted in the prodromal phase of the disease. Although preliminary positive results have been achieved, more empirical research is needed to confirm the efficacy of cognitive remediation in the early course of schizophrenia, and future studies should address the issue of the usefulness of cognitive remediation in the prodromes of psychosis.

Effectiveness of different modalities of cognitive remediation on symptomatological, neuropsychological, and functional outcome domains in schizophrenia: a prospective study in a real-world setting.

OBJECTIVES: The efficacy of cognitive remediation interventions in schizophrenia has been demonstrated in several experimental studies. However, the effectiveness of such treatments in the usual setting of care of schizophrenia and a direct comparison of different modalities of interventions have not been systematically analyzed. The aim of the study was to assess the effectiveness of the cognitive subprograms of Integrated Psychological Therapy (IPT-cog) and of a computer-assisted cognitive remediation (CACR) method on symptomatological, neuropsychological and functional outcome measures in schizophrenia. METHODS: Ninety patients with schizophrenia were assigned to IPT-cog, CACR or usual rehabilitative interventions (REHAB) in a naturalistic setting of care. Clinical, neuropsychological, and functional outcome variables were assessed at baseline and after 24 weeks of treatment. RESULTS: Both the IPT-cog and CACR groups improved more than the comparison group with respect to all outcome variables. The more responsive cognitive domains were speed of processing and working memory. The effectiveness of the 2 remediation methods on the outcome dimensions considered was comparable. However, IPT-cog, but not CACR, was more effective than REHAB on speed of processing, and the CACR group had better outcome than both the REHAB and the IPT-cog groups when the Health of the Nation Outcome Scale was considered. Few correlations between neurocognitive and functional outcome changes were found. CONCLUSIONS: The study demonstrates the effectiveness, although nongeneralized, of IPT-cog and CACR in schizophrenia when applied within a psychiatric and psychosocial treatment regimen representative of the usual setting and modality of care, with no evident superiority of any of the methods, and indicates that the changes in functional outcome during treatment are modestly mediated by improvement in specific cognitive domains.