Cristina Dobrea

Misdiagnosis, duration of untreated illness (DUI) and outcome in bipolar patients with psychotic symptoms: A naturalistic study.

BACKGROUND A number of data show the negative role of duration of untreated illness (DUI) on outcome in mood disorders, but no investigation has been carried out about the impact of this variable in bipolar disorder (BD) with psychotic symptoms. Clinical experience shows that many bipolar patients with psychotic symptoms receive other diagnoses and often are chronically treated with first generation antipsychotics, with the effect to reduce duration of untreated psychosis/untreated episode with psychotic symptoms (DUP), but not DUI. Purpose of the study was to define the rate of misdiagnosis and the impact of DUP/DUI on outcome of bipolar patients with psychotic symptoms. METHOD Clinical information (DUP, DUI, first received diagnosis) about bipolar outpatients with psychotic symptoms (N=240) were extrapolated through a retrospective review of the clinical charts, Lombardy database and, if necessary, through clinical interviews with patients and their relatives. Outcome measures included psychiatric and substance abuse comorbidity, occupational status, Global Assessment of Functioning (GAF), number of hospitalizations and of suicidal attempts, number of depressive/manic recurrences. Patients were divided in two groups according to the DUP (1 year) and DUI (8 years) median, and the groups were compared through analyses of variance (ANOVAs) for continuous variables or χ(2) tests for dichotomous ones. Multivariate analysis of variance (MANOVA) with duration of illness as covariate was then performed to eliminate the effect of this variable. Finally, binary logistic regressions were performed considering age at onset, DUI, DUP as independent variables and outcome variables as dependent ones (presence of hospitalizations/suicidal attempts, GAF scores<50, occupational status). RESULTS Most of patients (61.5%) received a first diagnosis different from BD with the most frequent DSM-diagnosis being delusional disorder (17.9%). Patients with longer DUP were not different in outcome measures with respect to patients with shorter DUP. Patients with a DUI >8 years presented higher number of hospitalizations (F=6.04, p=0.015), higher number of manic recurrences (F=5.25, p=0.023), higher number of depressive recurrences (F=7.13, p=0.008) and lower GAF scores (F=17.74, p<0.001). Statistical significance persisted for number of hospitalizations (p<0.001) and GAF scores (p=0.003) after MANOVA. Finally binary logistic regression showed that a longer DUI was predictive of GAF scores<50 (F=17.74, p<0.001). DISCUSSION More than half of bipolar patients with psychotic symptoms receive a different diagnosis at first contact with psychiatric services. DUI (but not DUP) is a predictor of outcome in bipolar patients with psychotic symptoms. This indicates that an early diagnosis and proper treatment with a mood stabilizer (or an atypical antipsychotic with mood stabilizing effects) may improve long-term outcome of these patients. In the light of the naturalistic design of the present paper, these results have to be considered as preliminary and have to be confirmed by prospective controlled studies.

Mood stabilizers for patients with bipolar disorder: the state of the art

Bipolar disorder (BD) is a prevalent and disabling condition, often comorbid with other medical and psychiatric conditions and frequently misdiagnosed. International treatment guidelines for BD recommend the use of mood stabilizers – either in monotherapy or in association – as the gold standard in both acute and long-term therapy. Commonly used in the clinical practice of BD, mood stabilizers have represented an evolving field over the last few years. The concept of stabilization, in fact, has been stressed as the ultimate objective of the treatment of BD, given the chronic and recurrent nature of the illness, which accounts for its significant levels of impairment and disability. To date, different compounds are included within the broad class of mood stabilizers, with lithium, anticonvulsants and, more recently, atypical antipsychotics being the most representative agents. This article is aimed at providing an updated review of the available literature in relation to the role of mood stabilizers in BD, with particular emphasis on their mechanism of action, main clinical aspects and specific use in the different phases of BD treatment, according to the most recently published international treatment guidelines.

Augmentative transcranial direct current stimulation (tDCS) in poor responder depressed patients: a follow-up study.

OBJECTIVES Transcranial direct current stimulation (tDCS) is a non-invasive neurostimulation technique that has received increasing interest in the area of mood disorders over the last several years. While acute, double-blind, sham-controlled studies have already reported positive findings in terms of efficacy and safety for tDCS, follow-up data are lacking. This need prompted the present follow-up study, which assesses post-acute effects of tDCS (no maintenance stimulation was performed), in the mid-term, in a sample of major depressives. METHODS After completing an acute, open trial of tDCS, 23 outpatients with either major depressive disorder or bipolar disorder entered a naturalistic follow-up (T1) with clinical evaluations at one week (T2), 1 month (T3), and 3 months (T4). A quantitative analysis of Hamilton Depression Rating Scale (HAM-D), Montgomery-Asberg Depression Rating Scale (MADRS), and Young Mania Rating Scale (YMRS) total scores, through repeated measures analysis of variance (ANOVA) (T1-T4) and paired t-test for comparing specific time points (T1-T2, T2-T3, and T3-T4), was performed. In addition, a qualitative analysis on the basis of treatment response and remission (HAM-D) was performed. RESULTS Even though a progressive reduction of follow-up completers was observed from T2 to T4 (95.6% at T2, 65.2% at T3, and 47.8% at T4), the antidepressant effects of acute tDCS persisted over 3 months in almost half of the sample. Of note, no post-acute side effects emerged during the follow-up observation. The most frequent causes of drop-out from this study included major modifications in therapeutic regimen (30%) and poor adherence to follow-up visits (17%). CONCLUSIONS In this mid-term, open, follow-up study, tDCS showed mixed results. Further controlled studies are urgently needed to assess its effects beyond the acute phase.

Altered prefrontal cortex activity during working memory task in Bipolar Disorder: A functional Magnetic Resonance Imaging study in euthymic bipolar I and II patients

BACKGROUND Working memory (WM) deficits are among the most frequently impaired cognitive domains in patients with Bipolar Disorder (BD), being considered promising cognitive endophenotype of the disorder. However, the related neurobiological correlates still deserve further investigation. The present study was aimed to explore whether dorsolateral prefrontal cortex (DLPFC) activity during WM processing was abnormal in euthymic bipolar patients and may represent a potential trait-related phenotype associated with the disorder. METHODS Using 3 Tesla functional Magnetic Resonance Imaging (3T fMRI), we studied 28 euthymic bipolar patients (15 BDI and 13 BDII), and 27 healthy controls (HCs), matched for a series of socio-demographic variables, while performing the N-back task for WM assessment. RESULTS We found that euthymic bipolar patients showed increased right middle frontal gyrus engagement compared with HCs (FWE-corrected p = 1 × 10(-3)), regardless of WM load, and in spite of similar WM behavioral performance between groups. In particular, BDI patients had greater BOLD signal change compared to HCs (post-hoc Tukey HSD, p = 1 × 10(-3)), while BDII patients expressed an intermediate pattern of activation between BDI patients and HCs. No other significant effects were detected in the corrected whole-brain analysis. LIMITATIONS Sample size, cross-sectional assessment and potential influence of some clinical variables. CONCLUSIONS Results provide direct evidence of a primary physiological abnormality in DLPFC function in BDI and II, even in the absence of behavioral differences with HCs. Such exaggerated fMRI response suggests inefficient WM processing in prefrontal circuitry, and further studies are warranted to investigate whether the dysfunction is related to the genetic risk for the disorder.

Tolerability and use in co-administration of pregabalin in affective patients: a 6-month prospective naturalistic study

Objective: The aims of the present study were to investigate the main demographic and clinical characteristics, comorbidity patterns, use in association and tolerability of pregabalin in a sample of patients with affective disorders, and to compare demographic and clinical variables of the groups divided, according to the treatment pregabalin was associated with. Methods: One hundred and fourteen consecutive outpatients, with anxiety and/or depressive disorders with or without comorbidity, were started on pregabalin, assessed and interviewed and their demographic data, associated therapy, tolerability and side effects collected over an observational period of 6 months. Results: The most frequent primary diagnoses were mood disorders (49.1%) and generalized anxiety disorder (21.9%). The most commonly associated treatments were antidepressants (66.7%) and mood stabilizers (15.8%). The most frequent side effects were sedation (3.4%), dizziness (0.9%), nausea (0.9%), diarrhea (0.9%), cough (0.9%) and peripheral edema (0.9%). When patients were divided according to the co-treatments, subgroups differed in terms of prescription of benzodiazepines (χ2 = 15.25, df = 6, p = 0.013, phi = 0.37), with the most frequent use of these molecules in patients co-treated with tricyclic antidepressants and minor use in the selective serotonin reuptake inhibitors group. Conclusions: Differences in the co-administration of benzodiazepines might suggest a stronger anxiolytic effect when pregabalin is combined with specific psychotropic drugs (e.g., SSRIs).

Augmentative Asenapine in a Recurrent Manic Catatonic Patient with Partial Response to Clozapine

Catatonia is a severe but treatable neuropsychiatric syndrome known since the middle of the nineteenth century. It has been considered for a long time as a subtype of schizophrenia, even though this association occurs only in 10% of cases. In contrast, it is frequently observed in bipolar patients. First-line treatment consists of benzodiazepines, while in case of resistance electroconvulsive therapy (ECT) and clozapine have shown positive results. In addition, recent studies reported the efficacy of some atypical antipsychotics. The present case shows the clinical response to augmentative asenapine in a catatonic manic patient with a partial response to clozapine.

Italian Bipolar II vs I patients have better individual functioning, in spite of overall similar illness severity

Introduction Bipolar disorders (BDs) comprise different variants of chronic, comorbid, and disabling conditions, with relevant suicide and suicide attempt rates. The hypothesis that BD types I (BDI) and II (BDII) represent more and less severe forms of illness, respectively, has been increasingly questioned over recent years, justifying additional investigation to better characterize related sociodemographic and clinical profiles. METHODS A sample of 217 outpatients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR)-described BD (141 BDI, 76 BDII), without a current syndromal mood episode, was recruited, and sociodemographic and clinical characteristics of BDI and II patients were compared. RESULTS BDII patients had significantly more favorable sociodemographics, in relation to occupational stability, cohabitation, and marital status. However, BDII compared with BDI patients had significantly longer duration of untreated illness, more frequent lifetime anxiety disorders comorbidity, longer most recent episode duration, higher rate of depressive first/most recent episode, and more current antidepressant use. In contrast, BDI compared with BDII patients had significantly more severe illness in terms of earlier age at onset; higher rate of elevated first/most recent episode, lifetime hospitalizations, and involuntary commitments; lower Global Assessment of Functioning score; and more current antipsychotic use. BDI and II patients had similar duration of illness, psychiatric family history, lifetime number of suicide attempts, current subthreshold symptoms, history of stressful life events, and overall psychiatric/medical comorbidity. CONCLUSION BDII compared with BDI patients had more favorable sociodemographic features, but a mixture of specific unfavorable illness characteristics, confirming that BDII is not just a milder form of BD and requires further investigation in the field.

Factors characterizing access and latency to first pharmacological treatment in Italian patients with schizophrenia, mood, and anxiety spectrum disorders

Latency to first pharmacological treatment [duration of untreated illness (DUI)] in psychiatric disorders can be measured in years, with differences across diagnostic areas and relevant consequences in terms of socio-occupational functioning and outcome. Within the psychopathological onset of a specific disorder, many factors influence access and latency to first pharmacotherapy and the present study aimed to investigate such factors, through an ad-hoc developed questionnaire, in a sample of 538 patients with diagnoses of schizophrenia-spectrum disorder (SZ), mood disorder (MD), and anxiety disorder (AD). Patients with SZs showed earlier ages at onset, first diagnosis and treatment, as well as shorter DUI compared with other patients (43.17 months vs. 58.64 and 80.43 months in MD and AD; F=3.813, P=0.02). Patients with MD and AD reported more frequently onset-related stressful events, benzodiazepines as first treatment, and autonomous help seeking compared with patients with SZs. In terms of first therapist, psychiatrist referral accounted for 43.6% of the cases, progressively decreasing from SZ to MD and AD (57.6, 41.8, and 38.3%, respectively). The opposite phenomenon was observed for nonpsychiatrist clinician referrals, whereas psychologist referrals remained constant. The present findings confirm the presence of a relevant DUI in a large sample of Italian patients with different psychiatric disorders (5 years, on average), pointing out specific differences, in terms of treatment access and latency, between psychotic and affective patients. Such aspects are relevant for detection of at-risk patients and implement early intervention programs.

Efficacy, tolerability, compliance, and quality of life of patients with mood disorders switched from Quetiapine immediate release to extended release

The present study aimed to assess switch from immediate-release (IR) to extended-release (XR) Quetiapine in terms of efficacy, tolerability, compliance, and quality of life in a sample of patients with mood disorders. Thirty patients, 10 with major depressive disorder and 20 with bipolar disorder, with residual depressive symptoms, who had switched from Quetiapine IR (mean 365 mg/day) to XR (mean 373 mg/day), were recruited and evaluated using different psychometric scales, administered at T0 (switch), T1, and T2 (1 and 6 weeks after the switch, respectively). A significant reduction from T0 to T2 of the total scores on the Hamilton Depression Rating Scale (t=2.15; P=0.04), Hamilton Anxiety Scale (t=3.04; P=0.006), and Clinical Global Impression-Severity Item (t=2.8; P=0.01) was found. No differences were found in terms of compliance and quality of life. The switch was well tolerated by 2/3 of patients. Most reported side effects were early/central insomnia with day drowsiness (16.7%), increased appetite and weight (8.4%), mild asthenia (4.2%), and constipation (4.2%), which, in two cases, led to switch interruption. Strategies to relieve side effects, including gradual cross-switch, improved switch feasibility. Switch from Quetiapine IR to XR seems to be associated with clinical improvement in major depressives with residual symptoms, although some patients may report side effects because of the different pharmacokinetics.

Structural and metabolic differentiation between bipolar disorder with psychosis and substance-induced psychosis: An integrated MRI/PET study

BACKGROUND Bipolar disorder (BD) may be characterized by the presence of psychotic symptoms and comorbid substance abuse. In this context, structural and metabolic dysfunctions have been reported in both BD with psychosis and addiction, separately. In this study, we aimed at identifying neural substrates differentiating psychotic BD, with or without substance abuse, versus substance-induced psychosis (SIP) by coupling, for the first time, magnetic resonance imaging (MRI) and positron emission tomography (PET). METHODS Twenty-seven BD type I psychotic patients with (n=10) or without (n=17) substance abuse, 16 SIP patients and 54 healthy controls were enrolled in this study. 3T MRI and 18-FDG-PET scanning were acquired. RESULTS Gray matter (GM) volume and cerebral metabolism reductions in temporal cortices were observed in all patients compared to healthy controls. Moreover, a distinct pattern of fronto-limbic alterations were found in patients with substance abuse. Specifically, BD patients with substance abuse showed volume reductions in ventrolateral prefrontal cortex, anterior cingulate, insula and thalamus, whereas SIP patients in dorsolateral prefrontal cortex and posterior cingulate. Common alterations in cerebellum, parahippocampus and posterior cingulate were found in both BD with substance abuse and SIP. Finally, a unique pattern of GM volumes reduction, with concomitant increased of striatal metabolism, were observed in SIP patients. CONCLUSIONS These findings contribute to shed light on the identification of common and distinct neural markers associated with bipolar psychosis and substance abuse. Future longitudinal studies should explore the effect of single substances of abuse in patients at the first-episode of BD and substance-induced psychosis.