Search for peripheral biomarkers in patients affected by acutely psychotic bipolar disorder: a proteomic approach.

Data on neurobiological mechanisms underlying mood disorders are elusive; the aetiology of such states is multifactorial, including genetic predisposition and environmental factors. Diagnosis is currently being made only on an interview-based methodology. Biological markers, which could improve the current classification, and in perspective, stratify patients on a biological basis into more homogeneous clinically distinct subgroups, are highly needed. We describe here a comparative proteomic analysis of peripheral lymphocytes from patients affected by acute psychotic bipolar disorder (PBD) (n = 15), major depressive episode (MDE) with no personal or family history of psychosis (n = 11), and a group of demographically matched healthy controls (HC) (n = 15). All patients were evaluated by means of Structured Clinical Interview for DSM-IV-Patient version (SCID-I-P), Positive and Negative Symptoms Scale (PANSS), Young Mania Rating Scale (YMRS), Hamilton Anxiety Rating Scale (HAM-A) and Hamilton Depression Rating Scale (HAM-D-17) questionnaires. Blood lymphocytes were obtained by gradient separation, and 2-DE was carried out on protein extracts. Significant differences in protein patterns among the three groups were observed. Thirty-six protein spots were found to be differentially expressed in patients compared to controls, which collapsed into 25 different proteins after mass spectrometry identification. Twenty-one of these proteins failed to discriminate between PBD and MDE, suggesting common signatures for these disorders. Nevertheless, after the western blot validation only two of the remaining proteins, namely LIM and SH3 domain protein1, and short-chain specific acyl-CoA dehydrogenase mitochondrial protein, resulted in being significantly upregulated in PBD samples suggesting additional mechanisms that could be associated with the psychotic features of bipolar disorder.

Catatonia and neuroleptic malignant syndrome: two disorders on a same spectrum? Four case reports.

We present the history of four bipolar patients who developed neuroleptic malignant syndrome (NMS) after antipsychotic treatment, focusing on the relationship between NMS and catatonia. In all cases, the administration of antipsychotics has been suspended as soon as fever and autonomic disturbances occurred. A supportive therapy was initiated to stabilize general conditions, then every patient started electroconvulsive therapy (ECT) in combination with benzodiazepines (BDZ). The risk of complications was reduced by the quick adoption of supportive care, whereas the combination of ECT and BDZ was effective in resolving the clinical picture. These cases may provide further support to the hypothesis that catatonia and NMS are disorders pertaining to the same spectrum of illness because the onset or exacerbation of catatonic symptoms coincided with the administration of antipsychotics. Our experience confirms the efficacy and safety of ECT in combination with BDZ as treatment of NMS and residual catatonia.

[Catatonia and neuroleptic malignant syndrome: two disorders on a same spectrum? Three case reports]. / Catatonia e sindrome maligna da neurolettici: condizioni cliniche diverse di uno stesso spettro? Descrizione di tre casi.

AIM: The authors present the cases of three bipolar patients who developed Neuroleptic Malignant Syndrome (NMS) after antipsychotic treatment, both typical and atypical, focusing on relationship between NMS and catatonia. METHODS: In all three cases, administration of antipsychotics has been stopped at once, when fever and autonomic disturbances occurred. A supportive therapy (including rehydration, electrolyte restoration and blood pressure aids, together with antipyretics, antibiotics and anticoagulants) was prescribed in order to stabilize general conditions. Every patient started then Electroconvulsive Therapy (ECT) in combination with benzodiazepines. RESULTS: High risk of complications and lethal outcome, associated with NMS, were successfully reduced by the tempestive adoption of a supportive care, while combination between ECT and BDZ was effective in resolution of clinical picture. DISCUSSIONS; These cases may provide further evidences about hypothesis of catatonia and NMS as disorders on the same spectrum. In one patient, NMS occurred overlapping with a previous catatonic state, while two others exhibited catatonic features after resolution of NMS. However, catatonic symptoms arose or worsened with administration of antipsychotics, supporting hypothesis of neuroleptic-induced catatonia as a step of progressive development of NMS. Our experience also confirms efficacy and safety of ECT in combination with BDZ as treatment of NMS and residual catatonia.

Platelet uptake of GABA and glutamate in patients with bipolar disorder.

OBJECTIVES: Gamma aminobutyric acid (GABA) and glutamate (Glu) are the major neurotransmitters of the human central nervous system, and their actions are determined by specific transporters. Several studies suggest that GABA- and Glu-uptake mechanisms are modified in patients with bipolar disorder (BD). We explored the functionality of the GABA and Glu transporters in three groups of patients with BD, each with a different polarity of index episode (manic, depressive, or euthymic) at the time of blood draw. METHODS: Forty patients with a diagnosis of BD, according to DSM-IV-TR criteria, and 15 healthy subjects were enrolled in the study. GABA and Glu uptake were evaluated in freshly prepared platelets using [(3) H]GABA or [(3) H]glutamate. RESULTS: Compared to controls, GABA uptake was significantly increased in patients with depressive episodes and significantly decreased in subjects with manic episodes. Glu uptake was significantly increased in patients with index manic episodes and in euthymic patients compared to healthy controls. Moreover, a positive correlation was found between GABA platelet uptake and Hamilton Depression Rating Scale scores and between Glu platelet uptake and Young Mania Rating Scale scores in patients with manic episodes. CONCLUSIONS: We found a relationship between GABA- and Glu-uptake levels and the polarity of episodes in patients with BD. Our data suggest that the functionality of both GABA and Glu transporters could represent a useful neurobiological marker to characterize the real polarity of an index episode of illness in patients with BD.

Artificial neural networks in the outcome prediction of adjustable gastric banding in obese women.

BACKGROUND: Obesity is unanimously regarded as a global epidemic and a major contributing factor to the development of many common illnesses. Laparoscopic Adjustable Gastric Banding (LAGB) is one of the most popular surgical approaches worldwide. Yet, substantial variability in the results and significant rate of failure can be expected, and it is still debated which categories of patients are better suited to this type of bariatric procedure. The aim of this study was to build a statistical model based on both psychological and physical data to predict weight loss in obese patients treated by LAGB, and to provide a valuable instrument for the selection of patients that may benefit from this procedure. METHODOLOGY/PRINCIPAL FINDINGS: The study population consisted of 172 obese women, with a mean ± SD presurgical and postsurgical Body Mass Index (BMI) of 42.5 ± 5.1 and 32.4 ± 4.8 kg/m(2), respectively. Subjects were administered the comprehensive test of psychopathology Minnesota Multiphasic Personality Inventory-2 (MMPI-2). Main goal of the study was to use presurgical data to predict individual therapeutical outcome in terms of Excess Weight Loss (EWL) after 2 years. Multiple linear regression analysis using the MMPI-2 scores, BMI and age was performed to determine the variables that best predicted the EWL. Based on the selected variables including age, and 3 psychometric scales, Artificial Neural Networks (ANNs) were employed to improve the goodness of prediction. Linear and non linear models were compared in their classification and prediction tasks: non linear model resulted to be better at data fitting (36% vs. 10% variance explained, respectively) and provided more reliable parameters for accuracy and mis-classification rates (70% and 30% vs. 66% and 34%, respectively). CONCLUSIONS/SIGNIFICANCE: ANN models can be successfully applied for prediction of weight loss in obese women treated by LAGB. This approach may constitute a valuable tool for selection of the best candidates for surgery, taking advantage of an integrated multidisciplinary approach.

Augmentation of clozapine with aripiprazole in severe psychotic bipolar and schizoaffective disorders: a pilot study.

AIM: To evaluate the efficacy and safety of the augmentation of clozapine with aripiprazole in patients with treatment-resistant schizoaffective and psychotic bipolar disorders in a retrospective manner. Pharmacodynamic and pharmacokinetic interactions between the two drugs were also investigated. PATIENTS: Three men and 4 women (median age 36 and 40 years, respectively) who had mean scores at BPRS and CGI-Severity of 59.1+/-12.0 and 5.4+/-0.5, respectively, were treated with clozapine (mean dose 292.9+/-220.7 mg/day). Patients received an adjunctive treatment with aripiprazole (mean dose 6.8 +/- 3.7 mg/day). Clozapine, norclozapine and aripiprazole plasma levels were measured by means of a high performance liquid chromatograpy with UV detection. RESULTS: Total scores at BPRS decreased significantly (from 59.1+/-12.0 to 51.1+/-15.6, p=0.007) after aripirazole augmentation. In particular, the factors "thought disorder" (from 10.4+/-4.4 to 9.0+/-4.5, p=.047) and "anergia" (from 10.0+/-2.7 to 8.0+/-2.4, p=.018) significantly improved. Concomitant administration of aripiprazole and clozapine did not result in an increase in side effects over the period of treatment. Dose-normalized plasma levels of both clozapine and norclozapine and the clozapine/norclozapine metabolic ratio in all patients did not vary as well. CONCLUSION: The augmentation of clozapine with aripirazole was safe and effective in severe psychotic schizoaffective and bipolar disorders which failed to respond to atypical antipsychotics. A possible pharmacokinetic interaction between clozapine and aripiprazole does not account for the improved clinical benefit obtained after aripiprazole augmentation.

Comparative response to electroconvulsive therapy in medication-resistant bipolar I patients with depression and mixed state.

OBJECTIVES: We compared the response with electroconvulsive therapy (ECT) of bipolar I patients resistant to pharmacological treatment, who presented depression or mixed state (MS). METHODS: Ninety-six bipolar I patients according to the Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition were included in the study (46 with major depressive episode and 50 with MS). Bilateral ECT was delivered using a brief pulse stimulator Mecta 5000Q (Mecta Corp, Lake Oswego, Ore) on a twice-a-week schedule. The patients were evaluated before ECT (baseline) and a week after the ECT course (final score), using the Hamilton Rating Scale for Depression (HAM-D), Mania Rating Scale, Brief Psychiatric Rating Scale (BPRS), and Clinical Global Improvement (CGI). RESULTS: Global response rate (CGI

The psychotic spectrum: a community-based study.

Over the last years, there has been an increasing awareness and knowledge about bipolar spectrum disorders. However, descriptive data on bipolar I disorder with psychotic features (BPI-p) in comparison with schizophrenia (SCH) and schizoaffective disorder (SA) in mental health community services are scanty in the literature. We conducted a study with the aim of assessing the prevalence, clinical characteristics and levels of functioning of SCH, SA and BPI-p in a random sample of patients with psychotic symptoms recruited in nine departments of mental health. Patients with a psychotic disorder according to their treating clinicians were assessed using the SCID and a series of questionnaires to evaluate their psychopathology and level of functioning. Patients who received a DSM-IV diagnosis of SA (N=55), SCH (N=82), or BPI-p (N=60) represented the final sample. The three diagnostic groups showed similar demographic characteristics. Independently from the diagnosis, all patients had a long duration of illness and a persistent course. Uni-variate group comparisons showed that, as compared to SCH patients, BPI-p and SA patients did better in several measures of functioning and differed in frequency of psychotic symptoms. However, a multinomial logistic regression model in which only significantly different variables were entered showed similar levels of functioning in the three groups of patients. The three groups' scores did not significantly differ on instruments that assessed dimensionally psychotic and affective symptoms during the previous month.

Mutation analysis of oxytocin gene in individuals with adult separation anxiety.

Individuals with a diagnosis of adult separation anxiety (ASAD) have extreme anxiety about separations, actual or imagined, from major attachment figures. ASAD might represent a psychological/behavioral model for research probably involving a dysregulation of those neurobiological mechanisms of attachment, in particular central oxytocin (OT), described in numerous animal studies. As experimental strategy, we chose the nucleotidic sequencing of the human OT gene of patients with ASAD to evaluate whether OT mutations were related to potential alteration of its production. With this aim, mutation scanning of proximal promoter and untranslated and coding regions of the OT gene was carried out in 36 patients with ASAD, 14 patients without ASAD, and 26 controls. No mutations were found in promoter and coding regions of the OT gene in our population. One rare 3'UTR single nucleotide variant (rs17339677) and one intron 2 molecular variant (rs34097556), which showed a high frequency, were evidenced. There was no significant difference in the genotype distribution of this intron 2 polymorphism between patients and healthy individuals. Further research is needed to investigate the association between ASAD and OT peptide and receptor polymorphisms.

Substance use in severe mental illness: self-medication and vulnerability factors.

The aim of this article is to examine the onset and clinical correlates of substance use in patients with psychotic disorders. One hundred and eight inpatients and outpatients with DSM-IV psychotic disorders were evaluated with the SCI-SUBS, an instrument designed to explore the spectrum of substance use and its clinical correlates. Comparisons were made between subjects with (n=47) and without (n=61) a DSM-IV diagnosis of substance use disorder (SUD). In patients with an early onset of psychosis (<17 years), the onset of SUD was subsequent. Patients with SUD had higher substance sensitivity, higher sensation-seeking traits and were more likely to self-medicate than patients without SUD. The reasons for self-medication endorsed by patients with SUD included relieving depression, achieving or maintaining euphoria, improving self-confidence and social abilities. Our results, based on a cross-sectional study, suggest that early onset of psychosis, substance sensitivity and sensation-seeking traits represent vulnerability factors for SUD. The relationships between SUD and psychosis should be examined systematically and clarified in longitudinal studies.

Bipolar disorder in late life: clinical characteristics in a sample of older adults admitted for manic episode.

BACKGROUND: Although manic episodes in older adults are not rare, little published data exist on late-life manic episodes. Resistance to treatment and concomitant neurological lesions are frequent correlates of elderly mania. The aim of this study was to investigate the prevalence of hospitalizations due to mania in patients older than 64 years through a period of 5 years in an Italian public psychiatric ward. Moreover, we aimed at describing clinical presentation of elderly manic episodes. METHODS: A retrospective chart review was conducted in order to describe clinical presentation of 20 elderly patients hospitalized for manic episode; moreover, we compared age at onset, the presence of family history for mood disorders, psychosis and irritability between the elderly group and a matched group of 20 younger manic inpatients. RESULTS: Seven percent of the whole inpatient elderly people suffered from mania. Half of those patients had a mood disorder age at onset after 50 years and 5 patients were at their first manic episode. Geriatric- and adulthood mania showed similar clinical presentation but younger people had more frequently a mood disorders family history. CONCLUSION: Half of our older manic inpatients consisted of "classic" bipolar patients with an extension of clinical manifestations into later life; the other half of our sample was heterogeneous, even though it was not possible to identify clearly which patients may have had vascular lesions related to the onset of mania.

Patterns of structural MRI abnormalities in deficit and nondeficit schizophrenia.

Negative symptoms of schizophrenia have generally been found in association with ventricular enlargement and prefrontal abnormalities. These relationships, however, have not been observed consistently, most probably because negative symptoms are heterogeneous and result from different pathophysiological mechanisms. The concept of deficit schizophrenia (DS) was introduced by Carpenter et al to identify a clinically homogeneous subgroup of patients characterized by the presence of primary and enduring negative symptoms. Findings of brain structural abnormalities reported by magnetic resonance imaging (MRI) studies focusing on DS have been mixed. The present study included 34 patients with DS, 32 with nondeficit schizophrenia (NDS), and 31 healthy comparison subjects, providing the largest set of MRI findings in DS published so far. The Schedule for the Deficit Syndrome was used to categorize patients as DS or NDS patients. The 2 patient groups were matched on age and gender and did not differ on clinical variables, except for higher scores on the negative dimension and more impaired interpersonal relationships in DS than in NDS subjects. Lateral ventricles were larger in NDS than in control subjects but were not enlarged in patients with DS. The cingulate gyri volume was smaller in NDS but not in DS patients as compared with healthy subjects. Both groups had smaller dorsolateral prefrontal cortex and temporal lobes than healthy subjects, but DS patients had significantly less right temporal lobe volume as compared with NDS patients. These findings do not support the hypothesis that DS is the extreme end of a severity continuum within schizophrenia.

The spectrum of substance abuse in bipolar disorder: reasons for use, sensation seeking and substance sensitivity.

OBJECTIVES: To examine the spectrum of alcohol and substance abuse, including reasons for use, in patients with bipolar I disorder, compared with patients with substance use disorder and healthy controls, with a specific focus on the relationship between substance use, substance sensitivity, other comorbid psychiatric symptoms and traits related to sensation seeking. METHODS: This study included 104 patients with bipolar I disorder (BPD I), of whom 57 (54.8%) met DSM-IV criteria for lifetime alcohol or substance use disorder (BPD + SUD), 35 patients with substance use disorder (SUD) and no psychiatric disorder and 50 healthy controls. Assessments included the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID) and the Structured Clinical Interview for the Spectrum of Substance Use (SCI-SUBS). RESULTS: Patients with BPD + SUD and SUD had significantly higher scores on the SCI-SUBS domains of self-medication, substance sensitivity and sensation seeking compared with patients with BPD and healthy controls. Reasons for substance use did not differ between patients with BPD + SUD and patients with SUD. Those most frequently cited were: improving mood; relieving tension; alleviating boredom; achieving/maintaining euphoria; and increasing energy. CONCLUSIONS: Recourse to substances is associated with increased mood and anxiety symptoms, substance sensitivity, and sensation seeking among patients with BPD + SUD and SUD. Substance sensitivity and sensation seeking traits should be investigated in all patients with BPD as possible factors associated with a development of SUD, in order to warn patients of the specific risks related to improper use of medications and substances.

Gender differences in bipolar disorder type 1: a 48-week prospective follow-up of 72 patients treated in an Italian tertiary care center.

To explore gender differences in bipolar I disorder, we compared the longitudinal treatment outcome and baseline demographic and clinical characteristics of 27 male and 45 female adult subjects who were treated for an acute affective episode and longitudinally followed for a period of up to 48 weeks. Females were more likely to report a history of suicidal gestures and a comorbid panic disorder; males were more likely to present with a comorbid obsessive-compulsive disorder, and there was a trend for a more frequent history of alcohol or substance abuse. No significant differences were found between the genders for the time to remission from the index episode, number of recurrences, and time spent with any clinical or subclinical mood symptom during the 48 weeks of maintenance treatment. Although differences may exist between bipolar I male and female subjects, prospective course does not seem to reveal differences in a 48-week period, at least when similar treatment strategies are adopted.

Effects of an educational intervention on weight gain in patients treated with antipsychotics.

BACKGROUND: Increasing numbers of reports have raised concerns about significant increases in weight and adiposity over both short- and long-term treatment in patients treated with antipsychotics (APs). The management of overweight and obesity in patients treated with APs has included pharmacological interventions, dietary suggestions, and behavioral strategies. Nevertheless, current evidence does not support the use of pharmacological management of this specific type of obesity, and only a limited number of studies have been published regarding prevention and treatment of weight gain with other strategies. OBJECTIVE: The aim of this study was to evaluate the effectiveness of an educational intervention (EI) that combines low-calorie diet with increased physical activity to prevent and treat weight gain in patients treated with APs. METHOD: Data were from 53 subjects whose body mass index (BMI) had increased by more than 7% after starting an AP therapy and who consented to participate in a 12-week educational intervention study aimed at preventing further weight gain and, when possible, at inducing a weight loss. Weight and BMI were measured at baseline (at each of the monthly follow-up visits) and at study completion 12 weeks from entry in the study. RESULTS: Twenty-six patients completed the 12-week program. Completers showed a significant mean body weight decrease of 3.15 kg, with a mean BMI reduction of 1.2 (kg/m) at the end of the 3-month period. CONCLUSIONS: Educational intervention can be an important tool for the management of weight increase in patients treated with APs. A larger prospective and controlled study is now needed to confirm our findings.

Upregulation of A2A adenosine receptors in platelets from patients affected by bipolar disorders under treatment with typical antipsychotics.

Antipsychotic drugs, potent dopamine receptor antagonists, are commonly used in the treatment of psychotic and affective illness. The discovery of antagonistic interactions between A2A adenosine receptors (ARs) and D2 dopamine receptors (DRs) in the central nervous system suggests that the adenosine system may be involved in the pathogenesis of psychiatric and neurological disorders. In the present study, we demonstrated for the first time that human platelets co-express A2A ARs and D2 DRs assembled into an heteromeric complexes. We also investigated the effects of chronic treatment with either typical or atypical antipsychotics on A2A AR binding parameters and receptors responsiveness in human platelets from patients affected by bipolar disorder. Chronic administration of typical antipsychotics induced a significant upregulation of A2A AR binding sites. Since no effects on A2A AR were obtained following "in vitro" platelet treatment with a typical antipsychotic (haloperidol), we could exclude a direct effect of the drug on A2A AR at the peripheral level. Moreover, typical antipsychotics induced a significant increase in the agonist potency to mediate A2A AR-G protein coupling. On the contrary, chronic treatment with atypical antipsychotics did not induce any significant alterations in A2A AR equilibrium binding parameters and receptor responsiveness suggesting that typical but not atypical antipsychotic drugs induced a selective modification of A2A AR binding parameters in human platelets. These results are in accordance with the literature data describing the selective A2A AR upregulation induced by typical antipsychotics in human striatum suggesting platelets as a peripheral model of the interactions between adenosine and dopamine system occurring in the central nervous system.

The spectrum of substance use in mood and anxiety disorders.

This study evaluates the prevalence of threshold and subthreshold use of substances among patients with psychiatric disorders and 2 comparison groups. Participants were outpatients and inpatients with mood and anxiety disorders, subjects with opiate dependence, and a comparison group of individuals not undergoing treatment for psychiatric disorders. Assessments included the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition , Axis I Disorders, an interview exploring the spectrum of substance use (Structured Clinical Interview for the Spectrum of Substance Use), and a self-report instrument exploring the spectrum of 5 psychiatric disorders (General 5-Spectrum Measure). The overall frequency of substance use disorder (SUD) and that of subthreshold use were 46% and 8% in patients with bipolar disorder, 4% and 26% in those with panic disorder, 8% and 26% in those with obsessive-compulsive disorder, and 6% and 10% in the control group, respectively ( Idouble dagger 2 = 51.6, P < .001). Inspection of standardized residuals indicated that alcohol use disorder and SUD were significantly ( P < .05) more frequent in subjects with bipolar disorder than among those with obsessive-compulsive disorder or panic disorder. The latter showed a significantly higher subthreshold use of substances than control subjects. The pattern of motivations for use varied according to the psychiatric disorder. Our results suggest that the well-established relationship between SUDs and psychiatric disorders might be the end point of a process that starts from increased proneness to substance use, which first leads to self-medication and then may eventually develop into substance abuse or dependence, among subjects with psychiatric symptoms.