BDNF level in the rat prefrontal cortex increases following chronic but not acute treatment with duloxetine, a dual acting inhibitor of noradrenaline and serotonin re-uptake.

AIMS: Brain-Derived Neurotrophic Factor (BDNF) has a central role in neuronal survival, differentiation, and plasticity. The brain level of BDNF is changed by several mood stabilizers and antidepressant drugs acting on neurotransmitters such as noradrenaline and serotonin. We investigated the effects of acute and chronic treatment with Duloxetine, a new drug blocking the re-uptake of serotonin and noradrenaline (SNRI), on BDNF level in the prefrontal cortex, cerebrospinal fluid, plasma, and serum. METHODS: Wistar male rats were treated with acute (single treatment) and chronic oral administration (14 days) of different concentrations of Duloxetine (10, 30, and 100 mg/kg/day). At the end of the treatment periods, samples of blood, CSF and the prefrontal cortex were collected. BDNF levels were measured by ELISA. Levels of mature and precursor form of BDNF were measured by Western blot analysis. RESULTS: Animals treated with the Duloxetine at all concentrations and examined after 1 and 24 h (single treatment) did not reveal a significant change in the total BDNF level. In animals treated for 14 days with Duloxetine at 30 and 100 mg/kg, the total BDNF level increased significantly in the prefrontal cortex and CSF, but not in the plasma and serum. Using a specific antibody and Western blot we showed that the mature, but not the precursor, form of BDNF was significantly increased in the prefrontal cortex of rats treated for 14 days with Duloxetine at 30 mg/kg/day. CONCLUSIONS: Our results show a major finding that repeated, but not single, Duloxetine treatment increases the level of BDNF in the prefrontal cortex.

Plasma and serum brain-derived neurotrophic factor (BDNF) in depressed patients during 1 year of antidepressant treatments.

BACKGROUND: Brain-derived neurotrophic factor (BDNF) has been hypothesized to be involved in the neurobiology of major depression. The aim of this study was to assess the possible relationships between depressive symptoms and serum and/or plasma BDNF levels during 1 year of antidepressant treatment. METHODS: Plasma and serum BDNF levels were assayed in 15 drug-free depressed patients and in 15 healthy control subjects at baseline and the 1st, 3rd, 6th and 12th month of antidepressant treatment. RESULTS: At baseline, patients' serum and plasma BDNF levels were significantly lower (p<.001 and p=.004, respectively) than those found in healthy control subjects. However, while from the 1st month of treatment patients' plasma BDNF levels did not differ significantly from those observed in healthy control subjects, serum BDNF levels in patients remained significantly lower at all times. LIMITATIONS: The main limitations of the current study are represented by the small sample size and the high discontinuation rate. CONCLUSIONS: Untreated depressed patients showed reduced baseline serum and plasma BDNF levels, as compared with control subjects. The clinical improvement paralleled the normalization of plasma BDNF after 1 month of treatment, while, at every assessment time, patients' serum BDNF levels were lower than those of control subjects. This would suggest that serum BDNF might represent a non-specific trait marker of depression.

Epidemiology of life events: life events and psychiatric disorders in the Sesto Fiorentino study.

BACKGROUND: Although life events have been consistently reported as precipitating factors for most psychiatric disorders, there is no comprehensive investigation of the relationship between severe life events and psychiatric disorders in the general population. METHODS: This is a community-based study of psychiatric disorders among a cohort representative of adults in an Italian town. A total of 2,363 subjects out of 2,500 selected to be representative of the population living in Sesto Fiorentino, central Italy, were interviewed by their own general practitioner using the Mini International Neuropsychiatric Interview. Of the 613 subjects, 609 who resulted positive for any psychiatric disorders and 123 out of a random sample of 130 negatives were re-interviewed by the psychiatrists using the Florence Psychiatric Interview. The Florence Psychiatric Interview was used to explore each distinct psychiatric episode. Life events were recorded in detail by a specific interview. RESULTS: During the year prior to the onset of the first psychiatric disorder, 35.8% of cases suffered from at least a severe event, compared with 12.2% of non-cases during a comparable period (OR = 4.0, 95% CI = 2.3-7.1). The excess of life events occurred for almost all the diagnostic categories. The same results were reproduced even when only the 'independent' life events were considered. The distribution of the events through the 12 months taken into account showed an even distribution of events among non-cases, whereas there was a clear accumulation in the last 3 months prior to the onset of the pathology in the cases. CONCLUSIONS: Life stress is one of the main precipitating factors of psychopathology.

Presence of D4 dopamine receptors in human prefrontal cortex: a postmortem study.

OBJECTIVE: The aim of our study was to explore the presence and the distribution of D4 dopamine receptors in postmortem human prefrontal cortex, by means of the binding of [3H]YM-09151-2, an antagonist that has equal affinity for D2, D3 and D4 receptors. It was therefore necessary to devise a unique assay method in order to distinguish and detect the D4 component. METHOD: Frontal cortex samples were harvested postmortem, during autopsy sessions, from 5 subjects. In the first assay, tissue homogenates were incubated with increasing concentrations of [3H]YM-09151-2, whereas L-745870, which has a high affinity for D4 and a low affinity for D2/D3 receptors, was used as the displacer. In the second assay, raclopride, which has a high affinity for D2/D3 receptors and a low affinity for D4 receptors, was used to block D2/D3. The L-745870 (500 nM) was added to both assays in order to determine the nonspecific binding. RESULTS: Our experiments revealed the presence of specific and saturable binding of [3H]YM-09151-2. The blockade of D2 and D3 receptors with raclopride ensured that the D4 receptors were labeled. The mean maximum binding capacity was 88 +/- 25 fmol/mg protein, and the dissociation constant was 0.8 +/- 0.4 nM. DISCUSSION AND CONCLUSIONS: Our findings, although not conclusive, suggest that the density of D4 receptors is low in the human prefrontal cortex.

Health-related quality of life and functioning in remitted bipolar I outpatients.

The aim of this study was to characterize the health-related quality of life (HR-QOL) and functioning in 90 bipolar I remitted outpatients. According to Diagnostic and Statistical Manual of Mental Disorders IV remission specifiers, patients were categorized into 4 groups: group 1, fully remitted; group 2, less than 2 months remitted; group 3, with persisting manic symptoms; group 4, with persisting depressive symptoms. The severity of psychopathology was evaluated by using the Bech-Rafaelsen Mania-Melancholia Scale. The HR-QOL, functioning, and insight were assessed via the medical outcomes study 36-item short form, the global assessment of functioning scale, and the scale to assess unawareness of mental disorder, respectively. Fully remitted patients reported the highest scores in almost all domains of medical outcomes study 36-item short form, and had significantly higher scores on physical functioning, general health, social functioning, and mental health compared to patients with persisting depressive symptoms. Furthermore, patients with persisting manic symptoms reported significantly higher scores on general health, vitality and mental health than the group with persisting depressive symptoms. In contrast, the global assessment of functioning scale score differed among the 4 groups, with fully remitted patients reporting higher, although not statistically significant, scores than the other groups. Our data suggest that the persistence of depressive or manic symptoms seem to affect self-report measures of HR-QOL. An affectively biased cognition may explain the gap between patient's perception of functioning and estimated functional adjustment, as assessed by clinicians.

Presence of D4 dopamine receptors in human prefrontal cortex: a postmortem study

OBJECTIVE: The aim of our study was to explore the presence and the distribution of D4 dopamine receptors in postmortem human prefrontal cortex, by means of the binding of [³H]YM-09151-2, an antagonist that has equal affinity for D2, D3 and D4 receptors. It was therefore necessary to devise a unique assay method in order to distinguish and detect the D4 component. METHOD: Frontal cortex samples were harvested postmortem, during autopsy sessions, from 5 subjects. In the first assay, tissue homogenates were incubated with increasing concentrations of [³H]YM-09151-2, whereas L-745870, which has a high affinity for D4 and a low affinity for D2/D3 receptors, was used as the displacer. In the second assay, raclopride, which has a high affinity for D2/D3 receptors and a low affinity for D4 receptors, was used to block D2/D3. The L-745870 (500 nM) was added to both assays in order to determine the nonspecific binding. RESULTS: Our experiments revealed the presence of specific and saturable binding of [³H]YM-09151-2. The blockade of D2 and D3 receptors with raclopride ensured that the D4 receptors were labeled. The mean maximum binding capacity was 88 ± 25 fmol/mg protein, and the dissociation constant was 0.8 ± 0.4 nM. DISCUSSION AND CONCLUSIONS: Our findings, although not conclusive, suggest that the density of D4 receptors is low in the human prefrontal cortex.

OBJETIVO: O objetivo deste estudo foi quantificar a presença e a distribuição de receptores dopaminérgicos do tipo 4 (D4) no córtex cerebral humano em amostras post-mortem através do bloqueio com ³H-YM-09151-2 - um antagonista com afinidade equivalente pelos receptores D2, D3 e D4 - e do desenvolvimento de um método para a detecção específica do componente D4. MÉTODO: Foram obtidas amostras de córtex cerebral de cinco cadáveres. Em um primeiro ensaio, os homogeneizados de tecido cerebral foram incubados em concentrações crescentes de ³H-YM-09151-2, enquanto que o L-745,870, ligante que apresenta grande afinidade pelo receptor D4 e baixa afinidade por D2 e D3, foi utilizado como controle. Em um segundo ensaio, a racloprida, que apresenta alta afinidade por receptores D2 e D3, mas baixa afinidade por D4, foi usada para bloquear D2 e D3. O L-745,870 foi adicionado em ambos os ensaios para determinar o bloqueio não específico. RESULTADOS: Os resultados do experimento demonstraram a presença de um bloqueio específico e saturável com ³H-YM-09151-2. O bloqueio de receptores D2 e D3 com racloprida confirmou que apenas os receptores D4 livres foram avaliados. A Bmax (média ± DP) foi de 88 ± 25 fmol/mg de proteínas, enquanto que a Kd (média ± DP) foi de 0,8 ± 0,4 nM. DISCUSSÃO E CONCLUSÕES: Tais achados, ainda que não definitivamente conclusivos, sugerem a presença de uma baixa densidade de receptores D4 no córtex pré-frontal humano.

Lymphocyte subsets, cardiovascular measures and anxiety state before and after a professional examination.

Controversies exist regarding the impact of psychological stress on the functioning of the immune system in humans. The aim of the present study, therefore, was to evaluate whether the condition of a pre-exam stress may or not modify resting lymphocyte subsets, as well as blood pressure and heart rate. About 22 medical residents of both sexes not suffering from any medical or psychiatric disorder were included in the study. Anxiety levels were measured by means of the Hamilton rating scale for anxiety (HRSA) and anxiety traits by means of the panic-agoraphobic spectrum self-report (PAS-SR) version and the obsessive-compulsive spectrum self-report (OBS-SR) version. The results showed that systolic blood pressure and heart rate increased significantly just before sitting an examination (t(1)) in all subjects, as compared with a calm situation (t(2)), in parallel with the increase in the HRSA total score, while no significant difference was observed in lymphocyte subsets at the two assessment times. However, men had a higher number of CD4+ cells than women at t(1) and t(2), while women showed a higher heart rate at t(1). In addition, significant correlations between CD4+ lymphocyte count and heart rate at t(1) or HRSA at t(2) were detected. These findings indicate that the acute stress determined by sitting for examination provokes changes in autonomic nervous system parameters, such as blood pressure and heart rate, as well as in the subjective feeling of anxiety, as shown by the increased HRSA total scores, which were not paralleled by modifications of lymphocyte subsets. However, individual differences, related to both sex and personality traits yet to be identified, seem to have an impact in shaping the stress response.

The rabbit syndrome: state of the art.

INTRODUCTION: The rabbit syndrome (RS) is a rare movement disorder generally associated with prolonged use of antipsychotics and characterized by inwilling, rhythmic, fast and fine movements of oral and masticatory muscles along the vertical axis of the mouth. PREVALENCE: The prevalence of RS ranges between 1.5% and 4.4%; middle and elderly ages, the female gender, as well as past brain injuries are considered risk factors for its development. PATHOPHYSIOLOGY: Although a dysbalance of the cholinergic and dopaminergic neurotransmission in the basal ganglia seems to be involved in the pathophysiology of RS, its precise mechanisms need to be clarified as yet. RELATIONSHIPS WITH ANTIPSYCHOTICS: Fifty cases of RS have been published up-to-now: 34 and 10 occurred during treatments with typical and atypical antipsychotics, respectively, while 6 seemed unrelated to these drugs. DIFFERENTIAL DIAGNOSIS: The differential diagnosis between RS and tardive dyskinesias involving the mouth may be based mainly on the evidence that in these last conditions the movements of the mouth are less regular and slower and involve the tongue. Treatment strategy: The available data suggest that RS responds favourably to anticholinergic drugs and to the change of the antipsychotic.

A relationship between oxytocin and anxiety of romantic attachment.

The formation of social bonding is fundamental for several animals, including humans, for its relevant and obvious impact upon reproduction and, thus, survival of the species. Recent data would suggest that oxytocin might be one of the mediators of this process. Given the paucity of data on the possible involvement of oxytocin in human attachment, the present study was aimed to explore the possible relationships between the plasma levels of this neuropeptide and romantic attachment in healthy subjects. Forty-five healthy subjects who volunteered for the study, were included in the study. The romantic attachment was assessed using the Italian version of the so-called "Experiences in Close Relationships" (ECR), a self-report questionnaire for measuring this parameter in adults. The results showed that attachment anxiety and oxytocin are positively linked in romantic attachment to a statistically significant degree (r = 0.30, p = 0.04), that is, the higher the oxytocin levels the higher the score on the anxiety scale of the ECR. The authors suggest the hypothesis that this link represents one of the biological processes resulting in those rewarding emotions related to romantic attachment.

Insight in body dysmorphic disorder with and without comorbid obsessive-compulsive disorder.

INTRODUCTION: The aim of this study was to compare the level of insight in patients with body dysmorphic disorder (BDD) with and without comorbid obsessive-compulsive disorder (OCD), and to measure its possible relationships with clinical features. METHODS: Thirty outpatients affected by BDD, according to Diagnostic and Statistical Manual of Mental Disorder, Fourth Edition criteria, of whom 18 were also suffering from OCD, were included in the study. Clinical assessment was carried out by means of the Yale-Brown Obsessive-Compulsive Scale modified for BDD and a specially designed OCD Questionnaire. The level of insight was measured by means of the score at item 11 of the Yale-Brown Obsessive-Compulsive Scale modified for BDD. RESULTS: The insight resulted to be excellent in four cases, good in four, fair in five, poor in 15 and absent in two. Significant and positive correlations were observed between the level of insight and the following items: resistance to thoughts and to activities as well as to time spent on activities and control on activities related to the defect. The insight was significantly lower in patients affected by both BDD and OCD. CONCLUSION: The findings indicate that the majority of BDD patients in this study, and especially those with comorbid OCD, have a low degree of insight that is significantly correlated to symptoms specific of the disorder.

Binding of 3H-WIN-35,428 and 125I-RTI-121 to human platelet membranes.

The dopamine transporter (DAT) is a protein regulating dopamine concentration in the synaptic cleft through the re-uptake mechanism. The DAT is the main target of psychostimulants and seems to play a pivotal role in neuronal degeneration and different neuropsychiatric disorders involving the dopamine system. Exhaustive research, however, regarding the presence of this protein in human platelets is still inconclusive, although it is thought that it might provide a peripheral tool to serve as a mean of exploring the same structure present in the brain. Therefore, we assessed some binding assays in platelets derived from healthy human subjects by means of 3H-WIN 35,428, a compound which is considered a selective ligand for the labelling of this protein, and by means of 125I-RTI-121, another compound with high specificity for DAT. The results showed that the binding of 3H-WIN-35,428 was too low to enable the detection of any structure; the binding of 125I-RTI-121, on the other hand, revealed the presence of two binding sites with pharmacological profiles similar to that of the serotonin transporter (SERT). In conclusions, therefore, platelets would not seem to be a useful model for exploring the DAT, given the prevalence therein of the SERT and the difficulty of labelling the DAT with the currently available ligands.

Clinical significance of lifetime mood and panic-agoraphobic spectrum symptoms on quality of life of patients with rheumatoid arthritis.

BACKGROUND: Previous studies suggested that rheumatoid arthritis (RA) is associated with depressive and anxiety symptomatology. The well-being and functioning of patients with RA may be significantly influenced by subthreshold psychiatric comorbidity. Health-related quality of life (HRQoL) of patients with RA, compared with the Italian norms and patients with diabetes, was assessed by the influence of lifetime mood and panic-agoraphobic spectrum symptoms and demographic and clinical variables. METHODS: Ninety-two patients were consecutively recruited at the Department of Rheumatology at the University Hospital of Pisa, Italy. All patients met diagnostic criteria of RA according to the American College of Rheumatology. Health-related quality of life was measured using the Medical Outcomes Study 36-Item Short-Form Health Survey questionnaire (MOS SF-36). Mood and panic-agoraphobic spectra were assessed by two different structured self-report instruments: the Mood Spectrum (MOODS-SR) and the Panic-Agoraphobic Spectrum (PAS-SR), respectively. RESULTS: Patients with RA were compared, as regards the MOS SF-36 scale scores, with the Italian normative population and patients with diabetes. Compared with the Italian population, patients with RA showed significantly lower MOS SF-36 scale scores, except for role emotional. Moreover, patients with RA scored significantly lower on the role physical, bodily pain, and social functioning scales compared with patients with diabetes and higher on role emotional and mental health. A significant worsening of all MOS SF-36 scale scores was related to higher scores of the depressive domains of MOODS-SR, except for social functioning and bodily pain. A statistically significant negative association was also found between PAS-SR total score and the MOS SF-36 scales physical functioning, vitality, role emotional, and mental health. There were no statistically significant correlations between MOS SF-36 scales and the manic MOODS spectrum. In the multivariate models, the negative correlations between depressive MOODS, role emotional, and mental health were confirmed and the severity of arthritis showed a significant impact on all MOS SF-36 areas with the exception for social functioning; moreover, manic MOODS was associated with better general health. CONCLUSIONS: The present report shows that lifetime depressive spectrum symptoms negatively affects HRQoL of patients with RA and subthreshold mania improves the perception of general health. Diagnosis and appropriate clinical management of depression, including subthreshold symptoms, might enhance HRQoL in these patients.

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.

Predictors of response in a sample of treatment-resistant psychotic patients on clozapine.

This study aims at identifying potential predictors of clinical response and functional outcome in 101 neuroleptic-refractory patients with a DSM-III-R diagnosis of schizophrenia (N = 34), schizoaffective disorder (N = 30) or bipolar disorder with psychotic features (N = 37), naturalistically treated with clozapine over a 48-month period. The "clinical response" and "functional outcome" criteria were respectively defined a priori as: a reduction of at least 50 % in the Brief Psychiatric Rating Scale total score in one evaluation with respect to baseline; and a Global Assessment of Functioning Scale score of at least 50. Several clinical and socio-demographic variables were assessed at baseline and only the diagnosis of bipolar disorder was significantly related with the clinical response. Variables significantly related with the functional outcome were female gender, university education and early age at onset.

Impairment in visual and spatial perception in schizophrenia and delusional disorder.

The Judgment of Line Orientation Test, a visuospatial processing task, was administered to normal subjects, to schizophrenic patients and to patients with delusional disorder. Significantly better performance was seen in the normal subjects than in the schizophrenic and delusional patients. Delusional patients, in turn, showed better performance than the schizophrenic patients.

Cross-sectional similarities and differences between schizophrenia, schizoaffective disorder and mania or mixed mania with mood-incongruent psychotic features.

BACKGROUND: The cross-sectional clinical differentiation of schizophrenia or schizoaffective disorder from mood-incongruent psychotic mania or mixed mania is difficult, since pathognomonic symptoms are lacking in these conditions. AIMS OF THE STUDY: To compare a series of clinical variables related to mood and cognition in patient groups with DSM-III-R diagnosis of schizophrenia, schizoaffective disorder, mood-incongruent psychotic mania and mood-incongruent psychotic mixed mania. METHODS: One hundred and fifty-one consecutive patients were evaluated in the week prior to discharge by using the structured clinical interview for DSM-III-R-patient edition (SCID-P). Severity of psychopathology was assessed by the 18-item version of the brief psychiatric rating scale (BPRS) and negative symptoms by the scale for assessment of negative symptoms (SANS). Level of insight was assessed with the scale to assess unawareness of mental disorders (SUMD). RESULTS: There were no differences in rates of specific types of delusions and hallucinations between subjects with schizophrenia, schizoaffective disorder, psychotic mania and psychotic mixed mania. SANS factors scores were significantly higher in patients with schizophrenia than in the bipolar groups. Patients with mixed state scored significantly higher on depression and excitement compared to schizophrenia group and, to a lesser extent, to schizoaffective group. Subjects with schizophrenia showed highest scores on the SUMD indicating that they were much more compromised on the insight dimension than subjects with psychotic mania or mixed mania. CONCLUSION: Negative rather than affective symptomatology may be a useful construct to differentiate between schizophrenia or schizoaffective disorders from mood-incongruent psychotic mania or mixed mania.