Naturalistic 6-month antidepressants follow-up in patients with fibromyalgia: impact on somatic and mood spectrum symptoms.

OBJECTIVES: Literature shows high rates of comorbidity between fibromyalgia (FM) and mood disorders, especially major depressive disorder (MMD), reported in more than half of the cases. Consistently, patients with FM also present high rates of mood spectrum symptoms, despite scant data are still available on the relationship with antidepressant treatment outcomes. The present study was aimed at exploring the clinical outcome of patients with FM-MDD comorbidity naturalistically treated with antidepressant drugs, besides the relationships between mood spectrum symptoms and the treatment response. METHODS: A total sample of 40 patients with FM and MDD, who started a treatment with an antidepressant drug, was recruited at the Rheumatology Unit of the University of Pisa, Italy. Patients were evaluated at baseline and after 1 (T1) and 6 months (T2) of the treatment with an antidepressant drug. Assessments included: the Mood Spectrum-Self Report (MOODS-SR) for mood spectrum symptoms, the Short Form Health Survey (SF-36) for the global functioning and the Clinical Global Impression (CGI) for the clinical severity and improvement. All instruments were administered at baseline and the SF-36 and CGI were repeated at T1 and T2. RESULTS: Twenty-eight (70%) patients reported an improvement at the CGI at T2. At T1 and T2 the CGI item-1 and most of the SF-36 domain scores significantly improved with respect to the T0, with the exception of the "role physical" and "role emotional" subscales. Improved patients reported higher scores in the energy depressive MOODS-SR domain. Furthermore, correlations emerged between several MOODS-SR domains and the CGI or SF-36 subscales scores at T0. CONCLUSIONS: Our results corroborate previous findings on the role of antidepressant drugs in the management not only of MDD symptoms, but also of the painful component of FM. FM patients should be investigated for Mood Spectrum symptomatology considering its prominent role on the manifestations of the disorder and treatment outcome.

Adult Autism Subthreshold spectrum correlates to Post-traumatic Stress Disorder spectrum in patients with fibromyalgia.

OBJECTIVES: Fibromyalgia (FM) is an increasingly prevalent disorder that usually shows a chronic course and a disappointing therapeutic response in which psychiatric features seem to play a relevant role. Most recently, the relationship between FM and Post-traumatic Stress Disorder (PTSD) has gained interest since several studies demonstrated a higher rate of PTSD, both full blown and partial, and Post-traumatic Stress spectrum symptoms. While the relationship between higher burden of autistic symptoms and PTSD is reported in literature, the relationship between FM and autism spectrum symptoms is still unexplored. In this study we investigated both post-traumatic and autistic spectrum in a sample of FM patients with the aim of exploring the relationships between these dimensions. METHODS: One hundred and nineteen patients with FM, diagnosed according the American College of Rheumatology 2010 criteria, were consecutively enrolled at the Unit of Rheumatology, University of Pisa, Italy. Assessments included: the Trauma And Loss Spectrum-Self Report (TALS-SR), for the post-traumatic stress spectrum symptomatology, the Adult Autism Subthreshold spectrum (AdAS spectrum) for the assessment of subthreshold autism spectrum. The scores reported to AdAS (total and per domain) by the entire sample and subgroups with PTSD diagnosis, partial PTSD and no PTSD were compared in order to detect a relation between Autistic Traits (ATs) and post-traumatic spectrum in this clinical sample. RESULTS: Our results show that FM patients with PTSD report an AdAS total score significantly higher than those reported by patients without PTSD. Moreover, through an examination of the correlation between AdAS spectrum and TALS-SR scores, significant correlations between the total score of the two instruments has emerged. The correlation resulted to be particularly significant between TALS-SR scores and non-verbal communication domain of the AdAS and between hyper-hypo reactivity to sensory input domain and several TALS-SR domains. CONCLUSIONS: These results highlight the clinical relevance of autistic traits in FM patients with PTSD. In this regard, we may claim a potential role of abnormal processing of sensory input and deficits in non-verbal communication in explaining this association.

Effect of Valproate and Antidepressant Drugs on Clozapine Metabolism in Patients With Psychotic Mood Disorders.

BACKGROUND: The aim of the present study was to appraise retrospectively the influence of valproate (VPA) and antidepressants (ADs) on the steady-state plasma concentrations of clozapine (CLZ), the prototype of various second-generation antipsychotics, norclozapine (NCLZ, its main metabolite), and their ratio (NCLZ:CLZ). METHODS: Sixty-seven psychotic patients with a prevalent diagnosis of bipolar disorder were studied. We then analyzed data altogether and subdivided them into 4 groups, according to pharmacological treatments: #1 CLZ (n = 21), #2 CLZ plus ADs (n = 13), #3 CLZ plus VPA (n = 16), and #4 CLZ plus ADs plus VPA (n = 17). RESULTS: First, significant positive between CLZ and NCLZ plasma levels (in nanograms/milliliter) and the drug daily dosages (in milligrams/kilogram of body weight) (n = 67) were observed (Spearman: rCLZ = 0.49; rNCLZ = 0.61; P < 0.001). We then normalized by given doses CLZ and NCLZ plasma levels, natural log transformed them, and performed analysis of variance factor analyses followed by pairwise comparisons, performed on the 4 groups and the 3 CLZ parameters. We identified significant drug effects on (1) CLZ plasma levels, significantly higher in group #2 versus group #1, and (2) NCLZ:CLZ ratio, lower in group #2 versus groups #1 and #3. Significant drug × gender interactions were observed in group #3, showing higher NCLZ levels and NCLZ:CLZ ratios in men compared with women. CONCLUSIONS: Despite its inherent limitations, this observational study confirms the significant increase in plasma CLZ concentrations and reduction in NCLZ:CLZ ratio when this drug was coadministered with ADs (group #2), an effect apparently counteracted by VPA (group #4). The drug × gender interactions in patients taking both CLZ and VPA (group #3) warrant further prospective study.

The impact of mood, anxiety, and sleep disorders on fibromyalgia.

INTRODUCTION: Several studies carried out mainly in North America revealed high rates of mood, anxiety and sleep disorders in patients with fibromyalgia (FM), while the information in other countries is scant. Therefore, we aimed at investigating the prevalence and the impact of such conditions on the health-related quality of life (HRQoL) and the severity of pain in a sample of Italian FM patients. METHODS: One-hundred and sixty-seven women suffering from primary FM were consecutively enrolled. Psychiatric diagnoses were made by means of DSM-IV criteria. The HRQoL and the severity of pain were measured through the Medical Outcomes Study 36-item Short-Form Health Survey (MOS-SF-36) and the FM Impact Questionnaire (FIQ). RESULTS: Fibromyalgia patients showed a high rate (80.8%) of lifetime and/or current comorbidity with mood and anxiety disorders. Patients with psychiatric comorbidity resulted significantly more impaired on the Mental Component Summary score of the MOS-SF-36 and showed a higher FIQ total score than those suffering from FM only. The severity of pain was associated with current psychiatric comorbidity. Patients with current mood disorders showed significantly lower Mental and Physical Component Summary scores of the MOS-SF-36 and higher FIQ total scores than those with current anxiety disorders or those without psychiatric comorbidity. Finally, patients with sleep disorders reported a lower HRQoL than those with a normal sleep, and specifically those with difficulty in falling in sleep had higher severity of pain. CONCLUSION: Psychiatric comorbidity, in particular with mood disorders, provokes a significant impairment of the HRQoL and, when current, a higher severity of pain in FM patients.

Complicated grief and suicidality: the impact of subthreshold mood symptoms.

UNLABELLED: IntroductionThe aim of the present study was to explore the relationship between subthreshold mood symptoms and suicidality in patients with complicated grief (CG). METHODS: Fifty patients with CG were included in the study and evaluated by the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition Axis-I disorders, the Inventory of Complicated Grief, and the Mood Spectrum Self Report (MOODS-SR) lifetime version, to evaluate the subthreshold mood symptoms. RESULTS: Twenty-eight patients (56%) reported lifetime suicidal ideation and 11 patients (22%) reported suicide attempts. Subthreshold depressive and rhythmicity/vegetative functions items of the MOODS-SR were significantly associated with increased suicidal ideation and attempts, while subthreshold manic items were associated with suicidal ideation only. Relationships were confirmed after controlling for Axis-I disorders comorbidity. CONCLUSION: The results of the present study suggest the usefulness of exploring lifetime subthreshold mood symptoms in CG patients, in order to promptly identify those who may be more prone to suicidality.

Lifetime manic-hypomanic symptoms in post-traumatic stress disorder: relationship with the 18 kDa mitochondrial translocator protein density.

Initially explored in military settings, post-traumatic stress disorder (PTSD) has shown increasing prevalence in the general population. The high comorbidity rates between bipolar disorder (BD) and PTSD have raised the issue of whether some characteristics of BD could represent risk factors for PTSD. In combat-related PTSD, the 18 kDa mitochondrial translocator protein (TSPO), essential for steroid synthesis, was found to be decreased. Aims of the present study were: 1) the assessment of the TSPO mitochondrial density in lymphomonocytes from civilian patients with non-combat-related PTSD, without current or lifetime Axis I mood comorbidity, versus controls; 2) the exploration of the correlations between TSPO density and the presence of comorbid manic/hypomanic lifetime spectrum symptoms. Assessments included the Structured Clinical Interview for DSM-IV (SCID), the Impact of Event Scale (IES), and the lifetime Mood Spectrum Self-Report (MOODS-SR). Blood samples were processed to assess TSPO binding parameters in lymphomonocyte mitochondrial membranes. PTSD patients showed a significant decrease in TSPO density, without changes in mitochondrial citrate synthase activity. Further, TSPO density correlated with the number of lifetime manic/hypomanic spectrum symptoms. For the first time, TSPO density was found to be decreased in non-war-related PTSD and such decreases correlated with comorbid manic/hypomanic spectrum symptoms, indicating a possible role of sub-threshold bipolar comorbidity in PTSD-related neurobiological dysregulation.

Sexual dysfunctions and suicidality in patients with bipolar disorder and unipolar depression.

INTRODUCTION: Impairment in sexual function is frequent and underestimated in patients with mental disorders, particularly in those with mood disorders. Few studies have examined the relationship between sexual dysfunctions and the clinical characteristics of mood disorders. AIM: The aim of the present study was to explore the frequency of sexual dysfunctions in patients with bipolar I disorder (BD) and unipolar depression (UD) with respect to control subjects, as well as their relationship with suicidality. MAIN OUTCOME MEASURES: Assessments included: the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (SCID-I/P), the 24-item Brief Psychiatric Rating Scale and the Mood Spectrum Self-Report, a questionnaire exploring lifetime mood spectrum symptomatology including symptoms of sexual functioning and suicidality. METHODS: A consecutive sample of 142 patients (60 BD and 82 UD) and a comparison group of 101 control subjects were recruited in a multicenter study involving 11 academic departments of psychiatry. RESULTS: Lifetime impairment in the sexual response cycle, including desire, excitement, and ability to achieve orgasm, was significantly more common in patients with mood disorders compared with control subjects. Increase in sexual activity and promiscuity were significantly more common in patients with BD vs. the other two groups. Lifetime dysfunctions in all three phases of the sexual response cycle explored were significantly associated with lifetime suicide attempts in patients with BD and with thoughts of death in patients with UD. In BD patients, the lifetime presence of periods with frequent changes of sexual partners was significantly associated with thoughts of death. CONCLUSIONS: Our findings suggest the importance of assessing sexual dysfunctions in patients with either BD or UD, as they may be clinically helpful in identifying phenotypes of mood disorders characterized by high suicidality.

Lifetime subthreshold mania is related to suicidality in posttraumatic stress disorder.

INTRODUCTION: Although the association between mood disorders, and particularly bipolar disorders, comorbidity and suicidality in posttraumatic (PTSD) patients is well established, less information is available on the impact of subsyndromal mood symptoms. The aim of the present study was, thus, to explore the frequency and relationship between subthreshold mood symptoms, assessed by a specific and validated questionnaire, and suicidality in PTSD patients. METHOD: Sixty-five PTSD outpatients without bipolar disorders and 65 healthy control subjects were asked to complete the Mood Spectrum-SR-Lifetime Version (MOODS-SR), a questionnaire exploring the presence of subthreshold affective symptoms. Logistic regression models were used to analyze the relationships between suicidality, explored by six items of the MOODS-SR combined and dichotomized to denote the presence or absence of suicidal ideations/plans and/or attempts, and the number of manic/hypomanic or depressive symptoms. RESULTS: Statistically significant and positive associations were found between the presence of manic/hypomanic and depressive symptoms and the likelihood of suicidal ideation or attempts. CONCLUSION: Besides depressive, even subthreshold manic/hypomanic features seem to be associated with higher suicidality in PTSD patients.

Validity and reliability of the Structured Clinical Interview for the Trauma and Loss Spectrum (SCI-TALS).

BACKGROUND: DSM-IV identifies three stress response disorders (acute stress (ASD), post-traumatic stress (PTSD) and adjustment disorders (AD)) that derive from specific life events. An additional condition of complicated grief (CG), well described in the literature, is triggered by bereavement. METHODS: This paper reports on the reliability and validity of the Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS) developed to assess the spectrum of stress response. The instrument is based on a spectrum model that emphasizes soft signs, low-grade symptoms, subthreshold syndromes, as well as temperamental and personality traits comprising clinical and subsyndromal manifestations. Study participants, enrolled at 6 Italian Departments of Psychiatry, included consecutive patients with PTSD (N = 48), CG (N = 44), and controls (N = 48). RESULTS: We showed good reliability and validity of the SCI-TALS. Domain scores were significantly higher in participants with PTSD or CG compared to controls. There were high correlations between specific SCI-TALS domains and corresponding scores on established measures of similar constructs. Participants endorsing grief and loss events reported similar scores on all instruments, except those with CG who scored significantly higher on the domain of grief reactions. CONCLUSION: These results support the existence of a specific grief-related condition and the proposal that different forms of stress response have similar manifestations.

Comorbidity with axis I anxiety disorders in remitted psychotic patients 1 year after hospitalization.

INTRODUCTION: Comorbid anxiety disorders are frequently encountered in psychoses and mainly assessed during the hospitalization. METHODS: Comorbidity was investigated in 98 patients with schizophrenia, schizoaffective, or bipolar disorder, previously hospitalized for psychotic symptoms. Assessments, including Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Brief Psychiatric Rating Scale, and Clinical Global Impressions Scale, were performed during hospitalization (t0) and subsequently in a phase of remission (t1). Comorbidity was assessed at t1 only. RESULTS: One or more comorbid anxiety diagnoses were made in 46 (46.9%) patients. Of these, 15 (32.6%) received multiple anxiety diagnoses, while 31 (67.4%) single anxiety diagnoses. Schizophrenic patients had a rate of social anxiety disorder (SAD) higher (P<.05) than the others. Patients assessed with panic disorder or with obsessive-compulsive disorder at t1 showed significantly greater severity of illness at t0; patients with SAD demonstrated greater severity at t1. No significant differences in the rates of individual anxiety disorders were found in patients treated with typical or atypical antipsychotics or with both. CONCLUSION: Anxiety disorders, particularly obsessive-compulsive disorder, panic disorder and SAD, seem to be frequently comorbid in remitted psychotic patients; SAD would be more prevalent in schizophrenia and might negatively impact the course of the illness.

Association between thyroid autoimmunity and fibromyalgic disease severity.

Our objectives were to investigate thyroid abnormalities and autoimmunity in 120 patients affected by fibromyalgia (FM) and to study their relationships with clinical data and symptoms. Thyroid assessment by means of antithyroglobulin antibodies, antithyroid peroxidase antibodies, free triiodo-thyronine, free thyroxine, and thyroid stimulating hormone analyses was carried out. The clinical parameters "Fibromyalgia Impact Questionnaire", pain, tender points, fatigue, and other symptoms, and the presence of depression or anxiety disorders were evaluated. The basal thyroid hormone levels of FM patients were in the normal range, while 41% of the patients had at least one thyroid antibody. Patients with thyroid autoimmunity showed a higher percentage of dry eyes, burning, or pain with urination, allodynia, blurred vision, and sore throat. Correlations found between thyroid autoimmunity and age or with the presence of depression or anxiety disorders were not significant. However, in the cohort of post-menopausal patients, the frequency of thyroid autoimmunity was higher with respect to pre-menopausal patients. In conclusion, autoimmune thyroiditis is present in an elevated percentage of FM patients, and it has been associated with the presence of typical symptoms of the disease.

Newer antipsychotics and the rabbit syndrome.

BACKGROUND: Rabbit syndrome is a movement disorder that is associated with long-term exposure to neuroleptic medications. Of particular interest and importance is the risk of rabbit syndrome with exposure to the newer atypical antipsychotics. Our recent experience with such a case brought to light the importance of exploring this risk. METHODS: MEDLINE and PubMed (1972-2006) databases were searched for English language articles using the keywords rabbit syndrome, tardive dyskinesia, antipsychotic, extrapyramidal symptoms and side effects. A recent case study is used to expand upon the literature available on newer antipsychotics and rabbit syndrome. RESULTS: We reviewed papers that addressed the following aspects of rabbit syndrome 1) the clinical manifestations 2) prevalence and risk factors, 3) etiopathogenesis 4) older antipsychotics and rabbit syndrome 5) newer antipsychotics, 6) treatment options. Moreover, we report a case of RS in a 50 year old white female, diagnosed with bipolar I disorder, that, after the discontinuation of risperidone, developed involuntary movements of the mouth that were fine, rhythmic and rapid, along the vertical axis, and without involvement of the tongue. After the re-introduction of risperidone, the symptoms decreased in a few hours and disappeared after 3 days. CONCLUSION: Eleven cases of rabbit syndrome have been documented since the implementation of newer antipsychotics. Future research is needed to better understand the etiopathogenesis of rabbit syndrome in psychiatric populations treated with the atypical antipsychotics. Understanding the differences and similarities of rabbit syndrome and tardive dyskinesia is crucial to the creation of a successful treatment paradigm.

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.

Augmentation strategy with olanzapine in resistant obsessive compulsive disorder: an Italian long-term open-label study.

The present study reports the results of an open-label trial on the use of the combination of olanzapine (an atypical antipsychotic) serotonin reuptake inhibitors (SRIs) in 26 resistant outpatients affected by resistant obsessive-compulsive disorder (OCD). All patients had been suffering from OCD, according to DSM IV criteria, for at least 2 years and had different comorbid disorders; they had been treated with an SRI at adequate dosages for at least 6 months, or had tried different augmentation strategies with no or poor response. As a result, olanzapine was added and continued for 1 year. After 12 weeks of this regimen, most of the patients (17) had shown a reduction in OC symptoms, as assessed by a decrease in the Yale-Brown Obsessive Compulsive Scale total score, which continued throughout subsequent months. Only mild side-effects were recorded and no patient halted the treatment. The addition of olanzapine would appear to be a useful short- and long-term strategy for augmenting SRI effectiveness in resistant OCD patients, especially in those presenting comorbidity with bipolar disorders.

Mood disorders in subjects with bruxing behavior.

OBJECTIVE: An investigation was conducted on 105 subjects to assess the existence of an association between mood psychopathology and bruxism. METHODS: Validated clinical criteria were used to diagnose bruxism and a self-report validated questionnaire (MOODS-SR) was filled out by each patient for an evaluation of depression and mania symptoms of mood spectrum. RESULTS: Prevalence of mood psychopathology, as identified by MOODS-SR score> or =60, was significantly higher in bruxers (11/38, 28.9% vs. 6/67, 8.9%; P=0.007). Significant differences between bruxers and non-bruxers also emerged in total MOODS-SR (P=0.001) scores and in total scores of domains evaluating manic (P=0.001) and depressive symptoms (P=0.007). CONCLUSIONS: Support to the existence of an association between bruxism and mood disorders has been provided. Further studies are strongly needed to clarify mechanisms underlying the described association.

Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study.

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. METHOD: 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test. RESULTS: The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups. CONCLUSION: The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.

Serotonin-mediated phosphorylation of extracellular regulated kinases in platelets of patients with panic disorder versus controls.

Phosphorylation of extracellular signal-regulated kinases (ERK 1/2) represents a converging intracellular signalling pathway which is involved in the modulation of gene transcription and may contribute to the feed-back regulation of neurotransmitter receptor functioning. The purpose of the current study was to investigate the serotonin-mediated phosphorylation of ERK 1/2 in platelets from patients (n = 17) with panic disorder, with respect to healthy volunteers (n = 17). Patients presented a severe symptomatology as assessed by the self-report rating scales for panic-agoraphobic (PAS-SR) and mood (MOOD-SR) spectrum, and by Clinical Global Impression Severity Scale (CGI-S). In platelets from healthy volunteers, serotonin induced a rapid increase of ERK 1/2 phosphorylation with a transient monophasic kinetic. The dose-response curves showed this effect was concentration dependent with an average of the EC(50) value of 22.8 +/- 2.4 microM. Platelet pre-incubation with 5HT(1A) and 5HT(2A) antagonists, pindobind and ritanserin, significantly inhibited serotonin-mediated kinase activation with an EC(50) of 3.2 +/- 0.2 and 1.99 +/- 0.08 nM, respectively, suggesting an involvement of these specific receptor subtypes in serotonin-mediated response. Furthermore, the 5HT(1A) and 5HT(2A) agonists, 8-hydroxy-N,N-dipropyl-aminotetralin (8OH-DPAT) and 1-(2,5-dimethoxy)-4-iodophenyl-2-aminopropane (DOI), were able to modulate ERK 1/2 phosphorylation in a concentration-dependent manner with an EC(50) value of 3.1 +/- 0.2 and 76 +/- 4.5 nM, respectively. ERK 1/2 phosphorylation was not observed after serotonin treatment of platelets from drug-free panic disorder patients, suggesting an alteration in intracellular phosphorylative pathways. Since ERK 1/2 responsiveness to other stimulus, such as collagen and thrombin, was comparable in platelets from healthy volunteers and patients, our results suggested that a specific alteration of serotonergic system occurred in panic disorder. Further studies to investigate 5HT(1A) and 5HT(2A) receptor expression and threonine phosphorylation levels showed that, nevertheless no significant differences in the receptor expression levels were detected, an increase of both 5HT receptor phosphorylation, on threonine residues, occurred in platelet from panic patients with respect to controls, suggesting that a reduction of serotonin receptor functioning was involved in the loss of serotonin responsiveness in panic.

Clozapine, norclozapine plasma levels, their sum and ratio in 50 psychotic patients: influence of patient-related variables.

Steady-state plasma concentrations of clozapine and norclozapine, its major metabolite, as well as their sum and ratio (norclozapine/clozapine), were evaluated in 50 in- and outpatients taking clozapine and naturalistically recruited. Drug plasma concentrations were measured by means of a reversed-phase high-performance liquid chromatography (RPLC) method with an ultraviolet detection. Daily doses (milligrams per kilogram of body weight) of clozapine correlated positively with clozapine plasma parameters, except with the norclozapine/clozapine ratio, in all patients. When the patients were divided in subgroups with respect to gender, the corresponding plasma concentrations were no longer dose-related in men. A lack of significant correlation was observed also in patients (n=23) co-treated with typical neuroleptics. Conversely, dose-concentration correlations were significant in either smoker or nonsmoker patients. No significant relationship between body weight and clozapine plasma parameters was reported. Further, we observed (1) a trend towards higher medians of clozapine or total analytes in women than those reported in men (P=.09 and .07); (2) no significant difference in plasma levels obtained in subjects younger than 34 years and subjects 34 years old or older; (3) a trend towards higher norclozapine and clozapine plus norclozapine levels (P=.05 and .08) in nonsmoker than smoker patients; (4) no significant difference between clozapine plasma parameters measured in patients co-medicated with typical neuroleptics and in patients receiving clozapine alone.

REM sleep dysregulation in depression: state of the art.

Disturbances of sleep are typical for most depressed patients and belong to the core symptoms of the disorder. Since the 1960s polysomnographic sleep research has demonstrated that besides disturbances of sleep continuity, depression is associated with altered sleep architecture, i.e., a decrease in slow wave sleep (SWS) production and disturbed rapid eye movement (REM) sleep regulation. Shortened REM latency (i.e., the interval between sleep onset and the occurrence of the first REM period), increased REM sleep duration and increased REM density (i.e., the frequency of rapid eye movements per REM period) have been considered as biological markers of depression which might predict relapse and recurrence. High risk studies including healthy relatives of patients with depression demonstrate that REM sleep alterations may precede the clinical expression of depression and may thus be useful in identifying subjects at high risk for the illness. Several models have been developed to explain REM sleep abnormalities in depression, like the cholinergic-aminergic imbalance model or chronobiologically inspired theories, which are reviewed in this overview. Moreover, REM sleep alterations have been recently considered not only as biological "scars" but as true endophenotypes of depression. This review discusses the genetic, neurochemical and neurobiological factors that have been implicated to play a role in the complex relationships between REM sleep and depression. We hypothesize on the one hand that REM sleep dysregulation in depression may be linked to a genetic predisposition/vulnerability to develop the illness; on the other hand it is conceivable that REM sleep disinhibition in itself is a part of a maladaptive stress reaction with increased allostatic load. We also discuss whether the REM sleep changes in depression may contribute themselves to the development of central symptoms of depression such as cognitive distortions including negative self-esteem and the overnight consolidation of negatively toned emotional memories.

Impulsivity, gender, and the platelet serotonin transporter in healthy subjects.

The present study explored the possible relationships between impulsivity, gender, and a peripheral serotonergic marker, the platelet serotonin (5-HT) transporter (SERT), in a group of 32 healthy subjects. The impulsivity was measured by means of the Barratt Impulsivity Scale, version 11 (BIS-11), a widely used self-report questionnaire, and the platelet SERT was evaluated by means of the specific binding of (3)H-paroxetine ((3)H-Par) to platelet membranes, according to standardized protocols. The results showed that women had a higher BIS-11 total score than men, and also higher scores of two factors of the same scale: the motor impulsivity and the cognitive complexity. The analysis of the correlations revealed that the density of the SERT proteins, as measured by the maximum binding capacity (B(max)) of (3)H-Par, was significantly and positively related to the cognitive complexity factor, but only in men. Men showed also a significant and negative correlation with the dissociation constant, Kd, of ((3)H-Par) binding, and the motor impulsivity factor. These findings suggest that women are generally more impulsive than men, but that the 5-HT system is more involved in the impulsivity of men than in that of women.