Cariprazine in Three Special Different Areas: A Real-World Experience.

Cariprazine is an antipsychotic medication which received approval from the US Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Furthermore, although to a more limited extent, cariprazine also exhibits partial agonism at the level of 5-HT1A receptors, thus exerting an antidepressant effect in addition to the antipsychotic effect. The most commonly encountered adverse events are extrapyramidal symptoms and akathisia. Short-term weight gain appears infrequently. Cariprazine is not associated with any clinically meaningful alterations in metabolic variables, prolactin, or ECG QT interval. Cariprazine is also approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Clinical trials of cariprazine are ongoing in patients with acute bipolar I depression and as adjunctive treatment to antidepressant therapy in patients with major depressive disorder. In this article, we present some significant clinical cases regarding the use of cariprazine, with the hope that our experience can provide insight or suggestions to be used in clinical practice.

Regulation of gene transcription in bipolar disorders: Role of DNA methylation in the relationship between prodynorphin and brain derived neurotrophic factor.

Bipolar Disorder (BD) is a prevalent and disabling condition, determined by gene-environment interactions, possibly mediated by epigenetic mechanisms. The present study aimed at investigating the transcriptional regulation of BD selected target genes by DNA methylation in peripheral blood mononuclear cells of patients with a DSM-5 diagnosis of type I (BD-I) and type II (BD-II) Bipolar Disorders (n=99), as well as of healthy controls (CT, n=42). The analysis of gene expression revealed prodynorphin (PDYN) mRNA levels significantly reduced in subjects with BD-II but not in those with BD-I, when compared to CT. Other target genes (i.e. catechol-O-methyltransferase (COMT), glutamate decarboxylase (GAD67), serotonin transporter (SERT) mRNA levels remained unaltered. Consistently, an increase in DNA methylation at PDYN gene promoter was observed in BD-II patients vs CT. After stratifying data on the basis of pharmacotherapy, patients on mood-stabilizers (i.e., lithium and anticonvulsants) were found to have lower DNA methylation at PDYN gene promoter. A significantly positive correlation in promoter DNA methylation was observed in all subjects between PDYN and brain derived neurotrophic factor (BDNF), whose methylation status had been previously found altered in BD. Moreover, among key genes relevant for DNA methylation establishment here analysed, an up-regulation of DNA Methyl Transferases 3b (DNMT3b) and of the methyl binding protein MeCP2 (methyl CpG binding protein 2) mRNA levels was also observed again just in BD-II subjects. A clear selective role of DNA methylation involvement in BD-II is shown here, further supporting a role for BDNF and its possible interaction with PDYN. These data might be relevant in the pathophysiology of BD, both in relation to BDNF and for the improvement of available treatments and development of novel ones that modulate epigenetic signatures.

Italian patients with more recent onset of Major Depressive Disorder have a shorter duration of untreated illness.

BACKGROUND: Previous investigation on the duration of untreated illness (DUI) in patients with Major Depressive Disorder (MDD) revealed a different latency to first antidepressant treatment, with adverse consequences in terms of outcome for individuals with a longer DUI. Recent reports, moreover, documented a reduced DUI, as observed with the passage of time, in patients with different psychiatric disorders. Hence, the present study was aimed to assess DUI and related variables in a sample of Italian patients with MDD as well as to investigate potential differences in subjects with onset before and after 2000. METHODS: An overall sample of 188 patients with MDD was assessed through a specific questionnaire investigating DUI and other variables related to the psychopathological onset and latency to first antidepressant treatment, after dividing them in two different subgroups on the basis of their epoch of onset. RESULTS: The whole sample showed a mean DUI of approximately 4.5 years, with patients with more recent onset showing a significantly shorter latency to treatment compared with the other group (27.1±42.6 vs 75.8±105.2 months, P<.05). Other significant differences emerged between the two subgroups, in terms of rates of onset-related stressful events and benzodiazepine prescription, respectively, higher and lower in patients with more recent onset. CONCLUSIONS: Our findings indicate a significant DUI reduction in MDD patients whose onset occurred after vs before 2000, along with other relevant differences in terms of onset-related correlates and first pharmacotherapy. Further studies with larger samples are warranted to confirm the present findings in Italy and other countries.

Access and latency to first antipsychotic treatment in Italian patients with schizophrenia and other schizophrenic spectrum disorders across different epochs.

BACKGROUND: The duration of untreated illness (DUI) is a measure to express the latency to first psychopharmacological treatment: it differs among psychiatric disorders, being influenced by several illness-intrinsic and environmental factors. The present study aimed to assess differences in DUI and related variables in patients with schizophrenia (SKZ) versus other schizophrenic spectrum disorders (SSDs) across different epochs. METHODS: 101 SKZ or SSD patients were assessed with respect to DUI and related variables through clinical interview and questionnaire. RESULTS: Patients with SKZ showed earlier ages of onset, first diagnosis and first antipsychotic treatment compared with patients with other SSDs (F = 11.02, p < 0.001; F = 12.68, p < 0.001; F = 13.74, p < 0.001, respectively) who showed an earlier access to benzodiazepines than SKZ patients (F = 6.547; p < 0.05). Dividing the total sample by the epoch of onset (before 1978; between 1978-2000; after 2000) showed a significantly later age of onset in patients with onset within the two most recent epochs (F = 7.46; p < 0.001) and a reduced DUI across epochs (from 144 to 41 to 20 months, on average; F = 11.78, p < 0.001). CONCLUSION: Schizophrenic patients showed earlier onset and longer DUI compared with patients with other SSDs. Data on the total sample showed a later age of onset and a reduced DUI across epochs.

Use of asenapine as add-on therapy in the treatment of bipolar disorder: a comprehensive review and case series.

INTRODUCTION: Several randomized controlled trials (RCTs), conducted in schizophrenic and bipolar patients, have documented the efficacy and tolerability of asenapine as monotherapy both for short- and long-term treatment. However, evidence on its augmentative use is more limited and related to the manic/mixed phase of bipolar disorder (BD). AREAS COVERED: The present article reviews augmentative asenapine efficacy and safety/tolerability in the treatment of BD. It also includes some original cases of bipolar patients treated with add-on asenapine in the short- and long-term. EXPERT OPINION: To date, only a single RCT with manic/mixed patients with partial response to mood-stabilizer monotherapy supports the efficacy and safety/tolerability of augmentative asenapine to lithium/valproate, both in acute and long-term treatment. Additionally, two case reports confirm the overall effectiveness of augmentative asenapine to clozapine and valproate. Our case series, consisting of 4 bipolar patients treated with adjunctive asenapine to mood stabilizers and atypical antipsychotics - with treatment duration ranging from 1 to 14 months - provided clinical results that are consistent with literature data. Taken as a whole, available evidence seems to support the efficacy and safety of adjunctive asenapine in bipolar patients, though additional studies with active comparators are requested to confirm the current body of evidence.

Neuroimaging procedures and related acquisitions in bipolar disorder: state of the art.

Bipolar disorder (BD) is a chronic and disabling mood disorder, with significant suicide rates among psychiatric disorders. Although the pathophysiological bases of BD have not been fully elucidated yet, over the last two decades, neuroimaging research has documented specific neuroanatomic and functional abnormalities in bipolar patients. The present review was aimed to provide an updated and comprehensive overview about currently available evidence on main structural and functional alterations documented in BD by neuroimaging procedures, through a Medline research. Among the structural alterations, the most consistent ones seem to be at the level of frontal, temporal and insular cortices, amygdala and basal ganglia, having been ventriculomegaly reported as well. Magnetic resonance spectroscopy findings showed, in turn, biochemical alterations in several neurotransmitter systems. Functional neuroimaging data are quite heterogeneous with positron emission tomography and single photon emission computed tomography studies showing phase-specific abnormalities of blood flow and glucose metabolism, as well as modifications of serotonin transporter density and binding. Functional magnetic resonance imaging data documented impaired neural networks involved in emotional regulation, including anterior limbic, ventral and dorsal prefrontal regions. Taken as a whole, neuroimaging data are strongly advancing the understanding of the neural bases of BD as described in the present review.

Selective DNA methylation of BDNF promoter in bipolar disorder: differences among patients with BDI and BDII.

The etiology of bipolar disorder (BD) is still poorly understood, involving genetic and epigenetic mechanisms as well as environmental contributions. This study aimed to investigate the degree of DNA methylation at the promoter region of the brain-derived neurotrophic factor (BDNF) gene, as one of the candidate genes associated with major psychoses, in peripheral blood mononuclear cells isolated from 94 patients with BD (BD I=49, BD II=45) and 52 healthy controls. A significant BDNF gene expression downregulation was observed in BD II 0.53±0.11%; P<0.05), but not in BD I (1.13±0.19%) patients compared with controls (CONT: 1±0.2%). Consistently, an hypermethylation of the BDNF promoter region was specifically found in BD II patients (CONT: 24.0±2.1%; BDI: 20.4±1.7%; BDII: 33.3±3.5%, P<0.05). Of note, higher levels of DNA methylation were observed in BD subjects on pharmacological treatment with mood stabilizers plus antidepressants (34.6±4.2%, predominantly BD II) compared with those exclusively on mood-stabilizing agents (21.7±1.8%; P<0.01, predominantly BD I). Moreover, among the different pharmacological therapies, lithium (20.1±3.8%, P<0.05) and valproate (23.6±2.9%, P<0.05) were associated with a significant reduction of DNA methylation compared with other drugs (35.6±4.6%). Present findings suggest selective changes in DNA methylation of BDNF promoter in subjects with BD type II and highlight the importance of epigenetic factors in mediating the onset and/or susceptibility to BD, providing new insight into the mechanisms of gene expression. Moreover, they shed light on possible mechanisms of action of mood-stabilizing compounds vs antidepressants in the treatment of BD, pointing out that BDNF regulation might be a key target for their effects.