Separation anxiety disorder from the perspective of DSM-5: clinical investigation among subjects with panic disorder and associations with mood disorders spectrum.

OBJECTIVE/INTRODUCTION: High levels of comorbidity between separation anxiety disorder (SEPAD) and panic disorder (PD) have been found in clinical settings. In addition, there is some evidence for a relationship involving bipolar disorder (BD) and combined PD and SEPAD. We aim to investigate the prevalence and correlates of SEPAD among patients with PD and whether the presence of SEPAD is associated with frank diagnoses of mood disorders or with mood spectrum symptoms. METHODS: Adult outpatients (235) with PD were assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID-I), the Panic Disorder Severity Scale (PDSS), the Structured Clinical Interview for Separation Anxiety Symptoms (SCI-SAS), and the Mood Spectrum Self-Report Instrument (MOODS-SR, lifetime version). RESULTS: Of ther 235 subjects, 125 (53.2%) were categorized as having SEPAD and 110 (46.8%) as not. Groups did not differ regarding onset of PD, lifetime prevalence of obsessive compulsive disorder (OCD), social phobia, simple phobia, BD I and II, or major depressive disorder (MDD). SEPAD subjects were more likely to be female and younger; they showed higher rates of childhood SEPAD, higher PDSS scores, and higher MOODS-SR total and manic component scores than subjects without SEPAD. Discussion SEPAD is highly prevalent among PD subjects. Patients with both PD and SEPAD show higher lifetime mood spectrum symptoms than patients with PD alone. Specifically, SEPAD is correlated with the manic/hypomanic spectrum component. CONCLUSION: Our data confirm the high prevalence of SEPAD in clinical settings. Moreover, our findings corroborate a relationship between mood disorders and SEPAD, highlighting a relationship between lifetime mood spectrum symptoms and SEPAD.

Clinical correlates of complicated grief among individuals with acute coronary syndromes.

OBJECTIVE: The study aimed at exploring bereavement and complicated grief (CG) symptoms among subjects without a history of coronary heart disease (CHD) at the time of a first acute coronary syndrome (ACS) and to evaluate the relationship of CG symptoms and ACS. METHOD: Overall, 149 subjects with ACS (namely, acute myocardial infarct with or without ST-segment elevation or unstable angina), with no previous history of CHD, admitted to three cardiac intensive care units were included and evaluated by the Structured Clinical Interview for Complicated Grief (SCI-CG), Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale, and the 36-item Short-Form Health Survey (MOS-SF-36). RESULTS: Of the total sample of 149 subjects with ACS, 118 (79.2%) met criteria for DSM-5 persistent complex bereavement disorder. Among these, subjects who lost a partner, child, or sibling were older (P=0.008), less likely to be working (P=0.032), and more likely to be suffering from hypertension (P=0.021), returned higher scores on the SCI-CG (P=0.001) and developed the index ACS more frequently between 12 and 48 months after the death than those who lost a parent or another relative (P≤0.0001). The occurrence of ACS 12-48 months (P=0.019) after the loss was positively correlated with SCI-CG scores. An inverse relationship with SCI-CG scores was observed for patients who experienced ACS more than 48 months after the loss (P=0.005). The SCI-CG scores significantly predicted lower scores on the "general health" domain of MOS-SF-36 (P=0.030), as well as lower scores on "emotional well-being" domain (P=0.010). CONCLUSION: A great proportion of subjects with ACS report the loss of a loved one. Among these, the loss of a close relative and the severity of CG symptoms are associated with poorer health status. Our data corroborate previous data indicating a strong relationship between CG symptoms and severe cardiac problems.

Influence of depression and anxiety on circulating endothelial progenitor cells in patients with acute coronary syndromes.

OBJECTIVES: Circulating endothelial progenitor cells (EPCs) are related to endothelial function and progression of coronary artery disease. There is evidence of decreased numbers of circulating EPCs in patients with a current episode of major depression. We investigated the relationships between the level of circulating EPCs and depression and anxiety in patients with acute coronary syndrome (ACS). METHODS: Patients with ACS admitted to three Cardiology Intensive Care Units were evaluated by the SCID-I to determine the presence of lifetime and/or current mood and anxiety disorders according to DSM-IV criteria. The EPCs were defined as CD133(+) CD34(+) KDR(+) and evaluated by flow cytometry. All patients underwent standardized cardiological and psychopathological evaluations. Parametric and nonparametric statistical tests were performed where appropriate. RESULTS: Out of 111 ACS patients, 57 were found to have a DSM-IV lifetime or current mood or anxiety disorder at the time of the inclusion in the study. The ACS group with mood or anxiety disorders showed a significant decrease in circulating EPC number compared with ACS patients without affective disorders. In addition, EPC levels correlated negatively with severity of depression and anxiety at index ACS episode. CONCLUSIONS: The current study indicates that EPCs circulate in decreased numbers in ACS patients with depression or anxiety and, therefore, contribute to explore new perspectives in the pathophysiology of the association between cardiovascular disorders and affective disorders.

Impact of depression on circulating endothelial progenitor cells in patients with acute coronary syndromes: a pilot study.

AIMS: Depression has been identified as a risk factor for an adverse prognosis and reduced survival in patients with acute coronary syndrome (ACS). The number of endothelial progenitor cells (EPCs) is an independent predictor of clinical outcomes in patients with ACS. The aim of this study was to evaluate the impact of depression on EPC levels in patients with ACS. METHODS: Out of 74 ACS patients [23 non-ST-segment elevation myocardial infarction (NSTEMI), 48 STEMI], 36 had a diagnosis of major depressive episode (MDE) according to the Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) criteria at the time of the inclusion in the study. Control groups were as follows: 15 healthy individuals and 18 patients with current MDE without a history of cardiovascular diseases. EPCs were defined as CD34CD133KDR and evaluated by flow cytometry. All patients underwent standardized cardiological and psychopathological evaluations. Parametric and nonparametric statistical tests were performed wherever appropriate. RESULTS: ACS patients with MDE showed a significant decrease in circulating EPC number compared with ACS patients without MDE (P < 0.001). The ACS study population was then subdivided into STEMI and NSTEMI groups, and within each group patients with MDE again showed a significant decrease in circulating CD34CD133KDR EPCs compared with others (P <0.001). CONCLUSION: We showed that ACS patients with MDE have a reduced number of circulating CD34CD133KDR cells compared with ACS patients without MDE, suggesting that the presence of MDE reduces the response of bone marrow to acute ischemic events. Considering the reparative role of EPCs in ACS patients, we propose that patients with MDE might be protected less than patients without MDE.

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.

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.

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.