Benedetta Grancini

Age at onset in patients with bipolar i and II disorder : A comparison of large sample studies

BACKGROUND Bipolar Disorder (BD) is a leading cause of disability worldwide and factors contributing to its burden include chronic relapsing course, comorbidity, suicide risk, and early age at onset (AAO). In particular, recent investigation has shown that BD onset may occur earlier than previously believed, even though whether BDI and II are different in such regard is still debated. Reduced samples may, moreover, limit the confidence in the published studies, with geographic issues, in turn, representing potentially conditioning factors. The present review was aimed to select and analyze large sample studies comparing AAO in BDI vs II patients. METHODS A PubMed literature search was performed, considering English-written articles published up to December 2015, comparing AAO in BDI vs II patients with sample size≥100 subjects per group. RESULTS Seventeen studies were considered suitable for revision, with 8 studies reporting statistically significant differences and 9 not. Among studies reporting statistically significant differences, mostly conducted in Europe, 6 showed an earlier AAO in BDI, while 2 in BDII subjects. LIMITATIONS Only studies with large samples included, considering AAO as a continuous variable, and providing a comparison between the bipolar subtypes. CONCLUSIONS Our findings suggest that AAO per se does not seem to reliably differentiate BDI from BDII patients and that such variable should likely be investigated in the context of other clinical characteristics, in order to assess its overall influence over BD course. Geographic factors may, in turn, play a potential role with future investigation warranted to further explore this specific issue.

Reduced duration of untreated illness over time in patients with schizophrenia spectrum, mood and anxiety disorders.

Psychiatric disorders represent highly impairing conditions, often underdiagnosed and undertreated, with a conspicuous duration of untreated illness (DUI). Given that social and cultural factors influence the DUI and assuming that progress in diagnosis and treatment determines a reduced latency to pharmacotherapy, we assessed and compared DUI and related variables in a large sample of psychiatric patients (n = 562) whose onset occurred within three different a priori‐defined epochs.

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

&NA; 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. HighlightsSelective target genes expression alterations in BDRole of DNA methylation in mediating PDYN mRNA level changes in BDCorrelation between PDYN and BDNF epigenetic mark in BD

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

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.

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

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.

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.

Cannabis-Induced Psychosis

The association between mental illness and drug abuse is complex and has been investigated by a wide scientific literature. Such comorbidity has a negative impact on both persistence and severity of illness. Nonetheless, a causal relationship still needs to be univocally defined, and the sole chronological criterion is not sufficient to determine a cause-effect relationship.

Ten-year outcome of vagus nerve stimulation-implanted patients with treatment-resistant depression: Two italian cases

Over the last 15 years, vagus nerve stimulation (VNS) has been used as an augmentative therapeutic intervention in patients with treatment-resistant depression (TRD), whether with a lifetime diagnosis of major depressive disorder or bipolar disorder. From being a potentially effective treatment in the acute phase of TRD, recently published treatment guidelines seemed to converge on the indication that VNS’s greatest benefit may be seen mostly beyond the short term. However, with the exception of a recent multicenter American report, very few studies have assessed the long-term efficacy of VNS in TRD patients. Herein, we present the cases of two Italian patients with TRD, with 10-year VNS follow-up evaluation. Both patients were found to benefit from augmentative VNS, and the latency of their stimulation response, tolerability, associated pharmacological treatment, number and duration of recurrences, and overall level of functioning are described and discussed. Further reports with larger samples are needed to support the long-term efficacy and tolerability of VNS in TRD patients, particularly beyond 5 years of follow-up.

Benzodiazepine ingestion as a way to die by suicide and related safety: the case of an elderly patient

Benzodiazepines (BDZs) are widespread psychotropic compounds, often prescribed as first-line symptomatic option by general practitioners in patients with different psychiatric disorders. Sometimes, however, they contribute to delay the administration of the first appropriate psychopharmacological treatment, thus leading to a longer duration of untreated illness in patients with depressive and anxiety disorders. The well-established pros of BDZs use in clinical practice include efficacy, rapidity of action, versatility, and safety. Among the cons, BDZs can provoke cognitive side-effects, asthenia, and misuse/abuse. Although their overall safety has been traditionally viewed as one of their greatest strengths, BDZs massive ingestion for suicidal purposes may pose, in some cases, serious life-threatening conditions, as described in the present case report. Hence, particular attention needs to be paid in prescribing these compounds to special populations, such as elderly patients. Among these, their prescription should be limited to the short-term and particularly monitored in case of risk factors, as they may be unsafe in case of overdose.

Augmentative repetitive Transcranial Magnetic Stimulation in the acute treatment of Major Depressive Episode with poor drug-response: a comparative study between different protocols of high and low frequency stimulation

Introduction: Transcranial Magnetic Stimulatio (rTMS) is a noninvasive brain stimulation technique which mechanism of action consists in the application of a non-invasive electrical stimulation to the dorsolateral prefrontal cortex (DLPFC) by means of magnetic pulses generated by a special coil [1]. RTMS has been approved by the FDA in 2008 for the treatment of patients with current depressive episode who failed to respond to at least one antidepressant treatment [2]. The aim of the present study was to assess and compare the efficacy and tolerability of different protocols of augmentative rTMS in poor responders with current Major Depressive Episode (MDE) in the context of unipolar or bipolar disorder. Methods: Thirty-three patients were recruited in a 4-week blind rater rTMS trial and randomized to the following 3 groups of stimulation, according to international guidelines [3]: right DLPFC, 1HZ, 110% of the motor threshold (MT), 420 stimuli/day; right DLPFC, continuous,1HZ,110% MT, 900 stimuli/day; left DLPFC 10 Hz, 80% MT, 750 stimuli/day. Results: 29 patients completed the treamtnet, showing a significant reduction of the HAM-D, MADRS and CGI-S overall scores (t¼8.1, p<0.001; t¼8.6, p<0.001; t¼4.6, p<0.001, respectively). No statistically significant differences between the 3 protocols were observed in terms of efficacy and tolerability, as well as between high and low frequency when grouping the two low frequency protocols vs the high frequency one. No statistically significant differences were found between unipolar and bipolar depression. Mild and transient side-effects were reported by 24% of the sample. One hypomanic switch was reported causing one of the four dropouts. Conclusions: rTMS appeared to be an effective and well tolerated strategy for the acute treatment of unipolar and bipolar poorresponse depression, with no significant differences between the three protocols of stimulation, nor between high and low frequency.