The relationships among separation anxiety disorder, adult attachment style and agoraphobia in patients with panic disorder.

Epidemiological studies indicate that separation anxiety disorder occurs more frequently in adults than children. It is unclear whether the presence of adult separation anxiety disorder (ASAD) is a manifestation of anxious attachment, or a form of agoraphobia, or a specific condition with clinically significant consequences. We conducted a study to examine these questions. A sample of 141 adult outpatients with panic disorder participated in the study. Participants completed standardized measures of separation anxiety, attachment style, agoraphobia, panic disorder severity and quality of life. Patients with ASAD (49.5% of our sample) had greater panic symptom severity and more impairment in quality of life than those without separation anxiety. We found a greater rate of symptoms suggestive of anxious attachment among panic patients with ASAD compared to those without ASAD. However, the relationship between ASAD and attachment style is not strong, and adult ASAD occurs in some patients who report secure attachment style. Similarly, there is little evidence for the idea that separation anxiety disorder is a form of agoraphobia. Factor analysis shows clear differentiation of agoraphobic and separation anxiety symptoms. Our data corroborate the notion that ASAD is a distinct condition associated with impairment in quality of life and needs to be better recognized and treated in patients with panic disorder.

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.

The multiple dimensions of the social anxiety spectrum in mood disorders.

Major depressive disorder and bipolar spectrum disorders are debilitating conditions associated with severe impairment. The presence of co-occurring social phobia can make the clinical course of these disorders even more challenging. To better understand the nature of social anxiety in the context of ongoing mood disorders, we report the results of exploratory factor analyses of the Social Phobia Spectrum Self-Report Instrument (SHY), a 162-item measure designed to capture the full spectrum of manifestations and features associated with social anxiety experienced across the lifespan. We examined data from 359 adult outpatients diagnosed with major depressive disorder and 403 outpatients diagnosed with a bipolar spectrum disorder. The measure was divided into its two components: the SHY-General (SHY-G), reflecting general social anxiety features, and the SHY-Specific (SHY-S), reflecting anxiety in specific situations. Exploratory factor analyses were conducted for each using tetrachoric correlation matrices and an unweighted least squares estimator. Item invariance was evaluated for important patient subgroups. Five factors were identified for the SHY-G, representing general features of social anxiety: Fear of Social Disapproval, Childhood Social Anxiety, Somatic Social Anxiety, Excessive Agreeableness, and Behavioral Submission. Seven specific-situation factors were identified from the SHY-S: Writing in Public, Dating, Public Speaking, Eating in Public, Shopping Fears, Using Public Restrooms, and Unstructured Social Interactions. The identified dimensions provide clinically valuable information about the nature of the social fears experienced by individuals diagnosed with mood disorders and could help guide the development of tailored treatment strategies for individuals with co-occurring mood disorders and social anxiety.

The role of psychomotor activation in discriminating unipolar from bipolar disorders: a classification-tree analysis.

OBJECTIVE: Multiple studies indicate that bipolar disorders are often underrecognized, misdiagnosed, and incorrectly treated. The aim of the present report is to determine which combination of clinical, demographic, and psychopathological factors and corresponding cutoff scores best discriminate patients with unipolar disorder from those with bipolar disorders. METHOD: The study sample includes outpatients and inpatients (N = 1,158) participating in 5 studies carried out in the United States and Italy between October 2001 and March 2008, one of which was a randomized clinical trial. Diagnostic assessment was carried out with the SCID, which allows diagnoses to be made according to DSM-IV-TR criteria. Using an exploratory statistical approach based on a classification tree, we employed 5 mania spectrum factors and 6 depression spectrum factors derived from the Mood Spectrum Self-Report Instrument (MOODS-SR) in combination with demographic and clinical characteristics to discriminate participants with unipolar versus bipolar disorders. RESULTS: The psychomotor activation factor, assessing the presence of thought acceleration, distractibility, hyperactivity, and restlessness for 1 or more periods of at least 3 to 5 days in the lifetime, identified subgroups with an increasing likelihood of bipolar disorder diagnosis. Mixed instability and suicidality contributed to further subtyping the sample into mutually exclusive groups, characterized by a different likelihood of receiving a diagnosis of bipolar disorder. Of the demographic and clinical characteristics included in the analysis, only sex proved to be useful to improve the discrimination. CONCLUSIONS: The psychomotor activation factor proved to be the most potent discriminator of those with unipolar versus bipolar diagnoses. The items that constitute this factor, together with those that constitute the mixed instability, suicidality, and euphoria factors, might be useful in making the differential diagnosis.

Incidence and predictors of relapse during continuation treatment of major depression with SSRI, interpersonal psychotherapy, or their combination.

BACKGROUND: Despite the availability of many effective treatments, patients with major depression remain at risk for relapse following remission of a depressive episode. The aims of this report are to estimate the relapse rates associated with the acute treatment strategies employed in this study and to investigate demographic and clinical predictors of relapse. METHODS: The study sample includes 225 patients who entered the 6-month continuation treatment phase after remitting from an acute depressive episode. Treatment during the acute phase was interpersonal psychotherapy, SSRI (escitalopram), or the combination of the two when monotherapy did not lead to response. Relapse was defined by a Hamilton Depression Rating Scale score ≥15, confirmed by the diagnosis of major depression. The probability of relapsing was modeled using logistic regression. Three separate models were fit with subgroups of covariates. RESULTS: Of the 225 patients, 29 (12.9%) relapsed and 28 (12.4%) discontinued the protocol prematurely. The proportion of patients who relapsed among the group requiring combination treatment to achieve remission was three times as high as among patients who had remitted with monotherapy. In the final logistic regression model, older age, higher baseline HDRS scores, last month (residual) depressive mood spectrum factor score, and requiring combination treatment to achieve remission were each associated with an increased likelihood of relapse. CONCLUSIONS: Our results suggest that greater initial depression severity, greater difficulty in stabilizing symptoms, and presence of residual mood spectrum symptoms once remission is achieved are predictive of relapse. Risk of relapse is more likely as age increases, partly because aging confers lower resilience.

From the third month of pregnancy to 1 year postpartum. Prevalence, incidence, recurrence, and new onset of depression. Results from the perinatal depression-research & screening unit study.

OBJECTIVE: Perinatal depression is a particular challenge to clinicians, and its prevalence estimates are difficult to compare across studies. Furthermore, to our knowledge, there are no studies that systematically assessed the incidence of perinatal depression. The aim of this study is to estimate the prevalence, incidence, recurrence, and new onset of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, minor and major depression (mMD) in an unselected population of women recruited at the third month of pregnancy and followed up until the 12th month postpartum. METHOD: One thousand sixty-six pregnant women were recruited. Minor and major depression was assessed in a naturalistic, longitudinal study. The Edinburgh Postnatal Depression Scale and the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Disorders were administered at different time points during pregnancy and in the postpartum period. RESULTS: The period prevalence of mMD was 12.4% in pregnancy and 9.6% in the postpartum period. The cumulative incidence of mMD in pregnancy and in the postpartum period was 2.2% and 6.8%, respectively. Thirty-two (7.3%) women had their first episode in the perinatal period: 1.6% had a new onset of depression during pregnancy, 5.7% in the postpartum period. CONCLUSIONS: Our postpartum prevalence figures, which are lower than those reported in the literature, may reflect treatment during the study, suggesting that casting a multiprofessional network around women in need of support may be potentially useful for reducing the effects of this disorder on the mother and the newborn child. Furthermore, our results indicate that women with a history of depression have a 2-fold risk of developing mMD in the perinatal period.

L-type calcium channels and psychiatric disorders: A brief review.

Emerging evidence from genome-wide association studies (GWAS) support the association of polymorphisms in the alpha 1C subunit of the L-type voltage-gated calcium channel gene (CACNA1C) with bipolar disorder. These studies extend a rich prior literature implicating dysfunction of L-type calcium channels (LTCCs) in the pathophysiology of neuropsychiatric disorders. Moreover, calcium channel blockers reduce Ca(2+) flux by binding to the α1 subunit of the LTCC and are used extensively for treating hypertension, preventing angina, cardiac arrhythmias and stroke. Calcium channel blockers have also been studied clinically in psychiatric conditions such as mood disorders and substance abuse/dependence, yielding conflicting results. In this review, we begin with a summary of LTCC pharmacology. For each category of disorder, this article then provides a review of animal and human data. In particular, we extensively focus on animal models of depression and clinical trials in mood disorders and substance abuse/dependence. Through examining rationale and study design of published clinical trials, we provide some of the possible reasons why we still do not have definitive evidence of efficacy of calcium-channel antagonists for mood disorders. Refinement of genetic results and target phenotypes, enrollment of adequate sample sizes in clinical trials and progress in physiologic and pharmacologic studies to synthesize tissue and isoform specific calcium channel antagonists, are all future challenges of research in this promising field. © 2010 Wiley-Liss, Inc.

Neuroleptic malignant syndrome: further lessons from a case report.

BACKGROUND: Neuroleptic malignant syndrome (NMS) represents an iatrogenic form of malignant catatonia, and simple catatonia has been shown to predispose to NMS. OBJECTIVE: The authors present the case of a bipolar patient with catatonic features who developed NMS after receiving haloperidol. METHOD: Supportive therapy, including rehydration, electrolyte restoration, and blood pressure aids were given, together with antipyretics, antibiotics, and anticoagulants. The patient was also started on bromocriptine and diazepam. RESULTS: Supportive care, diazepam, and dopamine agonists yielded only partial benefit. However, switching from diazepam to lorazepam, in combination with electroconvulsive therapy (ECT) and a long-acting dopamine agonist led to the resolution of NMS. CONCLUSION: This case sheds further light on the relationship between catatonia and NMS. As noted in the literature, ECT in combination with lorazepam proved to be safe and effective for NMS.

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.

Beyond "postpartum depressions": specific anxiety diagnoses during pregnancy predict different outcomes: results from PND-ReScU.

OBJECTIVE: Literature underlines that the Edinburgh Postnatal Depression Scale (EPDS) is the most common measure to assess postpartum depression (PPD) worldwide and suggests that the rate of false positives is high. Furthermore, the EPDS does not distinguish between depression and anxiety. This study describes different definitions of PPD and whether pregnancy anxiety disorders are risk factors for different PPDs at both 1month and 1year postpartum. METHOD: 1066 women were recruited during pregnancy and followed until the 12th month postpartum (N=500). Women were administered the SCID and completed the PDPI-R during pregnancy. During the postpartum women who had an EPDS score of 13 or more were administered the SCID to distinguish minor or major depressive episodes (mMD) from false positives. RESULTS: 41.5% and 44.9% of the PPD assessed with the EPDS were false positives at the 1st month and during the 1st year postpartum respectively. The difference observed in prevalence rates estimated with EPDS and SCID was statistically significant both at the 1st month and during the 1st year postpartum. Overall the effect of anxiety diagnoses in predicting PPD was stronger at the 1st month than during the 1st year postpartum. The role of panic disorder is associated both with probable depression (ES=0.82) and with mMD (ES=0.87) at the 1st month postpartum, and predicted mMD during the 1st year postpartum (ES=0.71). OCD predicted false positives at the 1st month postpartum (ES=0.89). CONCLUSION: An antenatal screening of specific anxiety diagnoses could be extremely useful for the prevention of possible postpartum distress outcomes.

Distinguishing affective depersonalization from anhedonia in major depression and bipolar disorder.

BACKGROUND: Affective depersonalization has received limited attention in the literature, although its conceptualization may have implications in terms of identification of clinical endophenotypes of mood disorders. Thus, this study aims to test the hypothesis that anhedonia and affective depersonalization represent 2 distinct psychopathological dimensions and to investigate their clinical correlates in patients with major depressive disorder (MDD) and bipolar disorder (BD). METHODS: Using a data pool of 258 patients with mood and anxiety disorders, an item response theory-based factor analysis approach was carried out on 16 items derived from 2 clinical instruments developed in the Spectrum Project (the Structured Clinical Interview for Mood Spectrum and the Structured Clinical Interview for Derealization-Depersonalization Spectrum). Clinical correlates of these psychometrically derived dimensions were subsequently investigated in patients with BD or MDD. RESULTS: Using an item response theory-based factor analysis, a 2-factor solution was identified, accounting overall for the 47.0% of the variance. Patients with BD showed statistically significant higher affective depersonalization factor scores than those with MDD (Z = 2.215, P = .027), whereas there was no between-groups difference in anhedonia scores (Z = 0.825 P = .411). In patients with BD, age of onset of the disease correlated with affective depersonalization factor scores (rho = -0.330, P = .001) but not with anhedonia factor scores (rho = -0.097, P = .361). CONCLUSIONS: Affective depersonalization and anhedonia seem to be 2 distinct psychopathological dimensions, although closely related, bearing the opportunity to identify patients with a specific profile for a better clinical and neurobiological definition.

Relationship of residual mood and panic-agoraphobic spectrum phenomenology to quality of life and functional impairment in patients with major depression.

The aim of this study was to analyze the relationship of residual mood and panic-agoraphobic spectrum phenomenology to functional impairment and quality of life in 226 adult outpatients who had remitted from a major depressive episode. Quality of life and functioning were assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire and the Work and Social Adjustment Scale. Residual symptoms were assessed using the Mood and Panic-Agoraphobic Spectrum Questionnaires. Linear and logistic regression models were used to analyze the relationship of mood and panic-agoraphobic spectrum factors with quality of life and functioning. Poor quality of life was associated with the Mood Spectrum Self-Report Questionnaire factors 'depressive mood' and 'psychotic features' and the Panic-Agoraphobic Spectrum Self-Report Questionnaire factors 'separation anxiety' and 'loss sensitivity'. Functional impairment was associated with the Mood Spectrum Self-Report Questionnaire factor 'psychomotor retardation' and the Panic-Agoraphobic Spectrum Self-Report Questionnaire factor 'fear of losing control'. These relationships were held after controlling for the severity of depression at the entry in the continuation treatment phase. In conclusion, the spectrum assessment is a useful tool for clinicians to identify areas of residual symptomatology that can be targeted with focused and effective long-term treatment strategies.

Effect of age, weight, and CYP2C19 genotype on escitalopram exposure.

The purpose of this study was to characterize escitalopram population pharmacokinetics (PK) in patients treated for major depression in a cross-national, US-Italian clinical trial. Data from the 2 sites participating in this trial, conducted at Pittsburgh (United States) and Pisa (Italy), were used. Patients received 5, 10, 15, or 20 mg of escitalopram daily for a minimum of 32 weeks. Nonlinear mixed effects modeling was used to model the PK characteristics of escitalopram. One- and 2-compartment models with various random effect implementations were evaluated during model development. Objective function values and goodness-of-fit plots were used as model selection criteria. CYP2C19 genotype, age, weight, body mass index, sex, race, and clinical site were evaluated as possible covariates. In total, 320 plasma concentrations from 105 Pittsburgh patients and 153 plasma concentrations from 67 Pisa patients were available for the PK model development. A 1-compartmental model with linear elimination and proportional error best described the data. Apparent clearance (CL/F) and volume of distribution (V/F) for escitalopram without including any covariates in the patient population were 23.5 L/h and 884 L, respectively. CYP2C19 genotype, weight, and age had a significant effect on CL/F, and patient body mass index affected estimated V/F. Patients from Pisa, Italy, had significantly lower clearances than patients from Pittsburgh that disappeared after controlling for patient CYP2C19 genotype, age, and weight. Postprocessed individual empirical Bayes estimates on clearance for the 172 patients show that patients without allele CYP2C19(*)2 or (*)3 (n = 82) cleared escitalopram 33.7% faster than patients with heterogeneous or homogeneous (*)2 or (*)3 ((*)17/(*)2, (*)17/(*)3, (*)1/(*)2, (*)1/(*)3, (*)2/(*)2, (*)2/(*)3, and (*)3/(*)3, n = 46). CL/F significantly decreased with increasing patient age. Patients younger than 30 years (n = 45) cleared escitalopram 20.7% and 42.7% faster than patients aged 30 to 50 years (n = 84) and older than 50 years of age (n = 43), respectively. CYP2C19 genotype, age, and weight strongly influenced the CL/F of escitalopram. These variables may affect patient tolerance of this antidepressant and may provide important information in the effort to tailor treatments to patients' individual needs.

Phenotypic effects of a bipolar liability gene among individuals with major depressive disorder.

Variations in voltage-dependent calcium channel L-type, alpha 1C subunit (CACNA1C) gene have been associated with bipolar disorder in a recent meta-analysis of genome-wide association studies [Ferreira et al., 2008]. The impact of these variations on other psychiatric disorders has not been yet investigated. Caucasian non-Hispanic participants in the STAR*D study of treatment for depression for whom DNA was available (N = 1213) were genotyped at two single-nucleotide polymorphisms (SNPs) (rs10848635 and rs1006737) in the CACNA1C gene. We examined putative phenotypic indicators of bipolarity among patients with major depression and elements of longitudinal course suggestive of latent bipolarity. We also considered remission and depression severity following citalopram treatment. The rs10848635 risk allele was significantly associated with lower levels of baseline agitation (P = 0.03; beta = -0.09). The rs1006737 risk allele was significantly associated with lesser baseline depression severity (P = 0.04; beta = -0.4) and decreased likelihood of insomnia (P = 0.047; beta = -0.22). Both markers were associated with an increased risk of citalopram-emergent suicidality (rs10848635: OR = 1.29, P = 0.04; rs1006737: OR = 1.34, P = 0.02). In this exploratory analysis, treatment-emergent suicidality was associated with two risk alleles in a putative bipolar liability gene.

The spontaneous Ala147Thr amino acid substitution within the translocator protein influences pregnenolone production in lymphomonocytes of healthy individuals.

The de novo production of steroids and neurosteroids begins in mitochondria by the conversion of cholesterol to pregnenolone through cytochrome P450 side-chain cleavage (CYP11A1) enzymatic activity. The C-terminal amino acid domain of the translocator protein (TSPO) has been demonstrated to bind cholesterol, thereby determining its mitochondrial translocation. The goal of the present study was to investigate the effect of the Ala147Thr single-nucleotide polymorphism localized in this TSPO region on pregnenolone production in healthy volunteers. Pregnenolone production was evaluated in a peripheral cell model, represented by circulating lymphomonocytes. First, CYP11A1 expression, both at mRNA and protein level, was demonstrated. Pregnenolone production varied among genotype groups. Comparison of pregnenolone mean values revealed that Thr147 homozygous or heterozygous individuals had significantly lower pregnenolone levels compared with Ala147 homozygous individuals. These findings suggested a dominant effect of the minor allelic variant Thr147 to produce this first metabolite of the steroidogenesis pathway. Interestingly, Ala147 homozygous individuals exhibited significant higher levels of circulating cholesterol-rich low-density lipoproteins with respect to heterozygous individuals. In conclusion, our results demonstrate that the Ala147Thr spontaneous amino acid substitution within TSPO is able to affect pregnenolone production; this should encourage further studies to investigate its potential role in polygenic dyslipidemias.

A multidimensional spectrum approach to post-traumatic stress disorder: comparison between the Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS) and the Self-Report instrument (TALS-SR).

Dimensional approaches to psychiatric disorders have shown an increased relevance in the ongoing debate for the forthcoming Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. In line with previously validated instruments for the assessment of different mood, anxiety, eating and psychotic spectra, we tested the validity and reliability of a newly developed Structured Clinical Interview for Trauma and Loss Spectrum (SCI-TALS). The instrument is based on a multidimensional approach to post-traumatic stress spectrum that includes a range of threatening or frightening experiences, as well as a variety of potentially significant losses, to which an individual can be exposed. Furthermore, it explores the spectrum of the peritraumatic reactions and post-traumatic symptoms that may ensue from either type of life events, targeting soft signs and subthreshold conditions, as well as temperamental and personality traits that may constitute risk factors for the development of the disorder. The aim of the present study is to describe the reliability of the self-report version of the SCI-TALS: the TALS-SR. Thirty patients with PTSD and thirty healthy control subjects were assessed with the Structured Clinical Interview for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. Half of the patients and controls received the TALS-SR first and the SCI-TALS after 15 days; for the other half of the sample, the order of administration was reversed. Agreement between the self-report and the interview formats was substantial. Intraclass correlation coefficients ranged from 0.934 to 0.994, always exceeding the threshold of 0.90. Our findings provide substantial support for the reliability of the TALS-SR questionnaire.

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.