Serum uric acid levels and different phases of illness in bipolar I patients treated with lithium.

Recent findings support the role of purinergic system dysfunction in the pathophysiology of bipolar disorder (BD). The present study aimed to evaluate the pattern of serum uric acid levels in a sample of 98 BD I patients followed-up prospectively in a naturalistic study and treated with lithium monotherapy or in association with other mood stabilizers (valproate or carbamazepine), in relation to different phases of illness and to pharmacological treatment. The results showed that uric acid levels were significantly higher in patients suffering from a manic/mixed episode, than in those euthymic or during a depressive phase. Further, these levels were related to the Clinical Global Impression-Bipolar Version (CGI-BP) scale score for the severity of manic symptoms. A positive correlation was found also with male sex and with serum lithium levels. These findings suggest that a dysregulation of the purinergic system may occur during manic/mixed episodes, and they support a possible role of serum uric acid levels as a state-dependent marker of BD manic phases.

Prescribing patterns of lithium or lithium+valproate in manic or mixed episodes: a naturalistic study.

The present study aimed to identify the prescribing patterns of lithium or of lithium+valproate in 75 bipolar I outpatients in a manic or a mixed phase within a naturalistic setting. The differences between the two treatments and the correlation between serum lithium levels and response were also examined. The results showed that patients with lithium levels of 0.60 mEq/l or more had higher remission rates and greater symptom reduction than the other patients. Patients on lithium and valproate showed greater improvement in mixed, anxiety, and psychotic symptoms than those on lithium only, as assessed by the Clinical Global Impression-Bipolar version scale scores. Finally, our findings suggest that a range of lithium levels between 0.40 and 0.60 mEq/l, albeit below the therapeutic range, seems sufficient to maintain a good effect when lithium is coadministered with valproate.

[Long-term treatment of bipolar disorder: how should we use lithium salts?]. / Trattamento a lungo termine del disturbo bipolare: quale impiego dei sali di litio nella pratica clinica?

UNLABELLED: Despite the great quantity of evidence supporting the efficacy of lithium in the maintenance treatment of bipolar disorder (BD), its use has often been limited because of issues about the management of this compound. W aimed to evaluate the use of lithium in common clinical practice and to identify possible relationships between the trend over time of serum lithium levels and clinical course of the illness. METHODS: 98 patients with bipolar I and bipolar II disorder (DSM-IV-TR) on maintenance treatment with lithium salts were recruited and followed up in a naturalistic trial at the Day Hospital of Psychiatric Clinic of Pisa. Diagnosis was confirmed using a structured interview, the SCID-I. During symptom assessment, the Clinical Global Impression-Bipolar Version Scale (CGI-BP) was used. RESULTS: The sample is made up mainly of BI patients (87.8%) and lithium is used in association with anticonvulsants in 63%. Less than half of the sample (48%) presents average serum lithium levels in the therapeutic range (0.5-0.8 mEq/L); serum values of lithium within the range were seen more frequently in patients with manic/mixed episode, with manic/mixed polarity of onset, with a greater number of previous episodes, with a higher percentage of rapid cycling and in subjects treated with lithium associated with anticonvulsants. During the follow-up patients with average serum lithium levels within the therapeutic range obtained a clinical improvement in a significantly greater proportion compared to patients with average serum lithium levels lower than 0.50 mEq/L. DISCUSSION: In clinical practice, lithium is often used at doses determining serum levels at the lower limits of the therapeutic range. Preliminary data on the prospective course of the illness support the importance of maintaining serum values of lithium within the therapeutic range.

The relationship between adult separation anxiety disorder and complicated grief in a cohort of 454 outpatients with mood and anxiety disorders.

BACKGROUND: Recent epidemiological studies indicate that separation anxiety disorder occurs more frequently in adults than children. Data from literature suggest that Adult Separation Anxiety Disorder (ASAD) may develop after a bereavement or threat of loss. Research has demonstrated that bereaved persons may present a clinically significant grief reaction, defined as Complicated Grief (CG) that causes a severe impairment in the quality of life. The aim of this study was to evaluate the relationship between ASAD and CG in a large cohort of outpatients with mood and anxiety disorders. METHODS: Study participants comprised 454 adult psychiatric outpatients with DSM-IV mood or anxiety disorders diagnoses. Diagnostic assessments were performed using the SCID-I; ASAD was assessed using an adapted version of the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-adult). Complicated grief symptoms were assessed by the Inventory of Complicated Grief (ICG). Social and work impairments were evaluated using the Sheehan Disability Scale (SDS). Adult attachment styles were assessed by the Relationship Questionnaire (RQ). RESULTS: The overall frequency of ASAD in our sample was 43% and that of CG was 23%. Individuals with CG had a greater frequency of ASAD (56%) with respect to those without CG (40%). Subjects with CG plus ASAD reported higher scores on ICG and greater impairment on quality of life, as measured with SDS, than CG patients without ASAD. CONCLUSIONS: Adult separation anxiety disorder occurs in a high proportion of adult psychiatric outpatients with complicated grief. The association between these two conditions should be further investigated in light of their clinical implications.

Reductions in platelet 18-kDa translocator protein density are associated with adult separation anxiety in patients with bipolar disorder.

BACKGROUND: Recent studies indicate that adult separation anxiety disorder is a discrete diagnostic entity and worthy of attention. Previously, we found a significant association between platelet expression of the 18-kDa translocator protein (TSPO) and adult separation anxiety in patients with panic disorder or major depression. The aim of this study was to explore whether adult separation anxiety might be a factor differentiating TSPO expression in a sample of patients with bipolar disorder. METHODS: The equilibrium binding parameters of the specific TSPO ligand [(3)H]PK 11195 were estimated on the platelet membranes of 24 adult outpatients with a DSM-IV diagnosis of bipolar disorder (with or without separation anxiety disorder) and 14 healthy controls. Patients were assessed by SCID-I, HAM-D, YMRS, the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-A) and the Adult Separation Anxiety Self-Report Checklist (ASA-27). RESULTS: A significant reduction in mean platelet TSPO density was found in bipolar patients with respect to controls. However, the lower density was only evident in the subgroup of bipolar patients who also fulfilled DSM-IV criteria for adult separation anxiety disorder. Individual TSPO density values correlated significantly and negatively with both SCI-SAS-A and ASA-27 total scores. CONCLUSIONS: TSPO expression may be a useful biological marker of adult separation anxiety co-occurring with other anxiety and mood disorders, including bipolar disorder.

Oxytocin receptor polymorphisms and adult attachment style in patients with depression.

Much evidence of an association between specific attachment styles and depression prompted us to investigate, in depressive disorders, the potential role of polymorphisms within the gene encoding the receptor of the main neurohormone involved in attachment processes, oxytocin. For this purpose, two single nucleotide polymorphisms (SNPs), 6930G>A (rs53576) and 9073G>A (rs2254298), within the oxytocin receptor gene (OXTR), were studied in a cohort of 185 patients with major depression (50.3%) or bipolar I or II disorders (49.7%) and 192 matched healthy controls. A positive association between the GG genotype of OXTR SNPs (6930G>A or 9073G>A) and unipolar depression was demonstrated. In this group, GG individuals showed high scores on Attachment Style Questionnaire factors that have been previously associated with depression. Moreover, the GG genotype was also associated with high levels of adult separation anxiety. These findings support the involvement of the oxytocinergic system in the mechanisms that underlie depression and specific adult attachment styles.

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.

Platelet 18 kDa Translocator Protein density is reduced in depressed patients with adult separation anxiety.

RATIONALE: Recent studies indicate that Adult Separation Anxiety Disorder (ASAD) may represent a discrete diagnostic entity worthy of attention. Adults with separation anxiety report extreme anxiety and fear about separations from major attachment figures (partner, children or parents). These symptoms affect individual's behavior, lead to severe impairment in social relationships and are not better accounted for by the presence of agoraphobia. In a previous study we found platelet expression reduction of the 18 kDa Translocator Protein (TSPO) (the new nomenclature for the peripheral-type benzodiazepine receptor) in patients with panic disorder who also fulfilled the diagnostic criteria for ASAD. OBJECTIVES: To explore whether separation anxiety might be a factor differentiating TSPO expression in a sample of patients with major depression. METHODS: The equilibrium binding parameters of the specific TSPO ligand [3H]PK 11195 were estimated on platelet membranes from 40 adult outpatients with DSM-IV diagnosis of MDD, with or without separation anxiety symptoms, and 20 healthy controls. Patients were assessed by SCID-I, HAM-D, the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS-A) and the Adult Separation Anxiety Self-report Checklist (ASA-27). RESULTS: A significant reduction of platelet TSPO density mean value was found in depressed patients with associated ASAD symptoms, while no significant differences were found between depressed patients without ASAD and the control group. Individual TSPO density values were significantly and negatively correlated with both SCI-SAS-A and ASA-27 total scores, but not with HAM-D total score or HAM-D anxiety/somatization factor score. CONCLUSIONS: The reduction of platelet TSPO density in our sample of patients with depression was specifically related to the presence of ASAD. These data suggest that TSPO expression evaluation is a useful biological marker of ASAD.

Social anxiety disorder comorbidity in patients with bipolar disorder: a clinical replication.

BACKGROUND: The authors investigated frequency, clinical correlates and onset temporal relationship of social anxiety disorder (SAD) in adult patients with a diagnosis of bipolar I disorder. METHODS: Subjects were 189 patients whose diagnoses were assessed by the Structured Clinical Interview for DSM-III-R-Patient Version. RESULTS: Twenty-four patients (12.7%) met DSM-III-R criteria for lifetime SAD; of these, 19 (10.1% of entire sample) had SAD within the last month. Significantly more bipolar patients with comorbid SAD also had substance use disorders compared to those without. On the HSCL-90, levels of interpersonal sensitivity, obsessiveness, phobic anxiety and paranoid ideation were significantly higher in bipolar patients with SAD than in those without. Bipolar patients with comorbid SAD recalled separation anxiety problems (school refusal) more frequently during childhood than those without. Lifetime SAD comorbidity was associated with an earlier age at onset of syndromal bipolar disorder. Pre-existing OCD tended to delay the onset of bipolarity. CONCLUSIONS: Social anxiety disorder comorbidity is not rare among patients with bipolar disorder and is likely to affect age of onset and phenomenology of bipolar disorder. These findings may influence treatment planning and the possibility of discovering a pathophysiological relationship between SAD and bipolarity.

Clinical correlates and significance of separation anxiety in patients with bipolar disorder.

OBJECTIVES: To evaluate frequency and severity of separation anxiety (SA) symptoms, as well as frequency of DSM-IV diagnosis of childhood separation anxiety disorder (CSAD) and adult separation anxiety disorder (ASAD), in a group of patients with bipolar disorder (BD) when compared with patients with panic disorder (PD) or major depression (MDD) and to a control group of healthy individuals (HC). METHODS: Outpatients with, respectively, bipolar I disorder (BD), PD, MDD and a group of individuals with no psychiatric diagnoses (HC) were assessed for diagnosis by the SCID-I and for SA by the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS), the Separation Anxiety Symptoms Inventory (SASI) and the Adult Separation Anxiety Checklist (ASA-CL). RESULTS: Thirty-one patients with BD without comorbid PD (BD-PD), 22 with BD with comorbid PD (BD + PD), 24 with PD, 20 with MDD and 15 HC were included in the analyses. As to childhood SA, the BD-PD group had higher scores than PD group and HC. The BD + PD group had higher scores than the PD group, MDD group and HC. As to adulthood SA, the BD-PD group had higher scores than HC on both SCI-SAS and Adult Separation Anxiety Questionnaire (ASA-27). The BD + PD had higher scores on both scales than BD-PD, PD group, MDD group and HC. The PD group and MDD group had higher scores than HC on the ASA-27. Adult SA symptoms were significantly associated with an earlier age at onset of BD. CONCLUSIONS: This is the first study, to our knowledge, exploring the frequency and severity of SA symptoms during childhood and adulthood in a sample of bipolar patients in comparison to subjects with other anxiety and mood disorders. Our data appear to be preliminary grounds for investigating further the possibility that SA may deserve greater recognition in adults with BD.

Peripheral-type benzodiazepine receptor binding sites in platelets of patients with panic disorder associated to separation anxiety symptoms.

RATIONALE: Although it is still a matter of debate whether panic disorder (PD) and separation anxiety (SA) are associated or causally linked disorders, some investigators have suggested that SA may be a specific subtype of panic-agoraphobic spectrum. Several psychiatric disorders, including PD, are associated with lower levels of peripheral-type benzodiazepine receptor (PBR). OBJECTIVES: The aim of the present study was to evaluate the kinetic binding parameters of the specific PBR ligand, PK 11195, in platelets from patients with PD in relation to the presence and severity of adulthood SA. METHODS: Using the specific radioligand, [(3)H] PK 11195, the kinetic binding parameters of PBR were determined on platelet membranes of 27 adult outpatients with a DSM-IV diagnosis of PD and 18 healthy controls. Patients were assessed with the SCID-I, the Panic Disorder Severity Scale, the Structured Clinical Interview for Separation Anxiety Symptoms and the Adult Separation Anxiety Checklist. RESULTS: PD patients had significantly lower PBR density than controls. However, the lower density was only evident in the subgroup of PD patients who also fulfilled the DSM-IV criteria for adult separation anxiety disorder. PBR density was negatively correlated with each of the two SA scales total scores. CONCLUSIONS: Patients with SA symptoms had significantly lower densities of PBRs. PBR expression might become a useful biological marker of these two associated conditions.