Effectiveness of the Unified Protocol for transdiagnostic treatment of emotional disorders in group format in Spain: Results from a randomized controlled trial with 6-months follow-up.

BACKGROUND: The present study aims to investigate the effectiveness of the Unified Protocol (UP), a transdiagnostic treatment of emotional disorders (EDs), when applied in a group format in the public mental health system in Spain. METHODS: 488 participants with a primary diagnosis of ED were randomized to the UP group or to the treatment as usual (TAU; individual, disorder-specific cognitive behavioral therapy). Personality, depression and anxiety symptoms, affect, and quality of life were assessed at pre-treatment, 3 months after treatment onset (coinciding with the end of the UP treatment), and 6 and 9 months after treatment onset (follow-ups). The moderating effect of the treatment condition and the number of sessions received in the evolution of study outcomes was investigated with a linear mixed model analysis. RESULTS: A significant improvement in outcomes occurred in both conditions, except for extraversion in the TAU. Improvements in depression, anxiety and quality of life were larger in the UP condition. After the treatment, improvements were maintained at follow-ups in all study outcomes. An interaction between Time*Condition*Sessions was found for depression. CONCLUSION: The results add to the existing evidence on the effectiveness of the UP and may be important for implementation purposes in the Spanish or other similar public mental health systems. Trial registration number NCT03064477 (March 10, 2017).

Individualized vaginal bleeding experience of women with uterine fibroids in the PEARL I randomized controlled trial comparing the effects of ulipristal acetate or placebo.

RESEARCH QUESTION: What is the individualized bleeding experience of women with fibroids and anaemia in a 3 month randomized placebo controlled trial (PEARL I) of the selective progesterone receptor modulator (SPRM), ulipristal acetate (UPA)? SUMMARY ANSWER: In contrast to continuing excessive regular menstruation in the placebo group, a majority of women treated with UPA (63.1% of those on 5 mg/day and 71.3% of those on 10 mg/day) experienced the rapid onset of amenorrhoea or minimal blood loss [pictorial blood loss assessment chart (PBAC) < 12]. The remainder experienced various patterns of bleeding and intensity of blood loss that are described for the first time, including an association of irregular bleeding on UPA with sub-mucous fibroids. WHAT IS KNOWN ALREADY: The majority experience on UPA is amenorrhoea but the bleeding experience of the others has not been characterized. STUDY DESIGN, SIZE, DURATION: A 13 week randomized controlled trial in women, eligible for surgery for uterine fibroids and anaemia, comparing placebo (n = 48), UPA 5 mg (n = 95) or UPA 10 mg (n = 94). The treatment aim was fibroid shrinkage and the primary definitions and outcomes are published elsewhere; here the secondary outcome measure of vaginal bleeding pattern is described. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women, 18-50 years old, with fibroids and haemoglobin ≤10.2 g/dl, justifying surgery. At least one fibroid was 3-10 cm diameter and uterus ≤16 weeks pregnancy size. All used the daily PBAC methodology in a screening cycle (Ps) and throughout treatment, and for the 4 weeks preceding Week 26 and Week 38 in those who did not have surgery. An excessive menstruation is PBAC > 100. The bleeding patterns were characterized using the classification of Belsey, developed under auspices of WHO. MAIN RESULTS AND THE ROLE OF CHANCE: In the placebo group, all women had an excessive screening PBAC [median 376; interquartile range (IQR) 241-574]; 81.3% of them had regular menstrual bleeding and the intensity of bleeding remained similar, so that the median PBAC in the next three periods was 90, 92 and 93% of the screening value. Four of the 48 women had spontaneous improvement in bleeding and one developed amenorrhoea and elevation of gonadotrophins. In the placebo group, 22 women provided Week 26 and 21 women provided Week 38 PBAC data. The median Week 26 PBAC (312: IQR 102-524) and Week 38 PBAC (236; IQR 103-465) indicated ongoing excessive bleeding. In the UPA group, screening PBAC confirmed excessive bleeding (UPA 5 mg, median 358; IQR 232-621; UPA 10 mg, median 330; IQR 235-542). UPA was initiated from the start of a menstruation (P1) and no women had regular periods on treatment. Following P1 through the whole of the remaining 13 weeks of UPA treatment amenorrhoea or minimal loss (PBAC < 12 for whole phase) occurred in 63.1% (UPA 5 mg) or 71.3% (UPA 10 mg). The characterization of the individualized bleeding experience of the remaining women on 5 mg and 10 mg UPA, respectively, were infrequent bleeding in 17.9 and 12.8%; frequent or prolonged bleeding or both in 12.7 and 11.7% and irregular bleeding in 5.3 and 3.2%. In those with prolonged, frequent or irregular bleeding there was a high chance that sub-mucous fibroids were present (UPA 5 mg 100% and UPA 10 mg 78.6%) but no correlation with progesterone receptor modulator-associated endometrial changes. LIMITATIONS, REASONS FOR CAUTION: The follow-up PBAC data at Week 26 and Week 38 are only valid for women who did not have surgical intervention. These groups may not be representative of the groups at screening. WIDER IMPLICATIONS OF THE FINDINGS: This first detailed description of these SPRM bleeding patterns provides clinicians with an indication of potential responses in women using the SPRM UPA and provides an extended definition of bleeding in untreated women with excessive bleeding and fibroids. STUDY FUNDING/COMPETING INTEREST(S): Funded by PregLem/Gedeon Richter. D.H.B. is a member of the Scientific Advisory Board of PregLem, and in this role participated in the study design and supervision. Stock originally held in PregLem was given up when PregLem was incorporated into Gedeon Richter; D.H.B. does not currently hold stock. M.A.L. has received payment from Gideon Richter to attend a meeting to present these data (Barcelona, April 2013) but no financial support in preparing the manuscript. B.C.J.M.F. is a member of the Scientific Advisory Board of PregLem and has received fees and grant support from the following companies: Andromed, Ardana, Auxogyn, Ferring, Genovum, Gedeon Richter, Merck Serono, MSD, Organon, Pantharei Bioscience, PregLem, Roche, Schering, Schering Plough, Serono, Watson Laboratories and Wyeth. P.T. is a paid statistical consultant for PregLem SA. E.B. is a full time employee of PregLem and received payment from stocks sold in October 2010 from the company's full acquisition by Gedeon Richter Group. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT00755755 (PEARL I).

The EMAS 2008 update on clinical recommendations on postmenopausal hormone replacement therapy.

Hormone therapy is still the most commonly used treatment to relieve menopausal symptoms and the consequences of oestrogen deficiency. The decision process is complex and benefits needs to be balanced vs. risks. Not all reported benefits and risks have been as well highlighted by the media throughout recent years, it is therefore important to update regularly the current scientific knowledge. This is an actualization of the last EMAS statement concerning hormone replacement therapy use.

Advances in the psychosocial treatment of anxiety disorders. Implications for national health care.

Recent developments in the psychosocial treatments for anxiety disorders suggest that we have reached an early plateau. Evidence now exists on the effectiveness of psychosocial treatment approaches for every anxiety disorder when compared with no treatment or credible psychosocial placebos. In many cases these procedures have limited clinical effectiveness and much remains to be learned about the disseminability and clinical utility of these approaches in the context of emerging national health care plans. We are just beginning the first generation of multisite studies examining the potentially synergistic effects of proven psychosocial treatments and proven drug treatments. These studies that have substantial significance for national health care are reviewed and some preliminary results are reported.

The influence of an illusion of control on panic attacks induced via inhalation of 5.5% carbon dioxide-enriched air.

The current study tested the notion that a sense of control can mitigate anxiety and panic attacks caused by the inhalation of 5.5% carbon dioxide (CO2)-enriched air. Twenty patients with panic disorder inhaled a mixture of 5.5% CO2-enriched air for 15 minutes. All patients were instructed that illumination of a light directly in front of them would signal that they could decrease the amount of CO2 that they were receiving, if desired, by turning a dial attached to their chair. For ten patients, the light was illuminated during the entire administration of CO2. For the remaining ten patients, the light was never illuminated. In fact, all patients experienced the full CO2 mixture, and the dial was ineffective. When compared with patients who believed they had control, patients who believed they could not control the CO2 administration (1) reported a greater number of DSM-III-revised panic attack symptoms, (2) rated the symptoms as more intense, (3) reported greater subjective anxiety, (4) reported a greater number of catastrophic cognitions, (5) reported a greater resemblance of the overall inhalation experience to a naturally occurring panic attack, and (6) were significantly more likely to report panic attacks. These data illustrate the contribution of psychologic factors to laboratory induction of panic attacks through inhalation of 5.5% CO2-enriched air.

The components of rapists' sexual arousal.

The erections of rapists and nonrapists were measured during audio descriptions of rape and nonrape sexual scenes. On the basis of their erection measures, rapists were separated from nonrapists in that the former developed erections to rape descriptions while the latter did not. The method also discriminated those rapists with the highest frequency of rape, those who had injured their victim, and those who chose children as victims.

Gender identity change in transsexuals. Follow-up and replications.

An apparently successful change in gender identity of an adolescent transsexual was reported several years ago. Gender-specific motor behavior, appropriate sex role social behavior, cognitive sexual activity, and finally sexual arousal patterns were defined, measured, and sequentially modified. In this report, a 6 1/2-year follow-up is presented and the application of a similar therapeutic package to two additional cases is described. In the first case, sweeping changes in gender identity, sex-role behavior, and sexual arousal patterns were observed. In the second of these cases, rigid feminine gender was given up, but the patient chose to retain homosexual arousal. Social adaptation was satisfactory. These findings and other recent developments point to the possibility of psychosocial intervention as an alternative to surgery in the treatment of transsexualism.

Reliability of DSM-III anxiety disorder categories using a new structured interview.

The reliability of DSM-III anxiety disorder diagnoses was determined using a new structured interview, the Anxiety Disorders Interview Schedule (ADIS). Two interviewers examined 60 consecutive outpatients at an anxiety disorders clinic and assigned primary and secondary diagnoses based on the ADIS. The kappa statistic, calculated on the basis of perfect matches on primary diagnoses, indicated good agreement for anxiety, affective, and adjustment disorders, as well as for the specific anxiety disorder categories of agoraphobia, panic, social phobia, and obsessive-compulsive disorder, but not for generalized anxiety disorder. We evaluated the causes for diagnostic disagreement, particularly in relation to the difficult differentiation between generalized anxiety disorder and other anxiety disorders.

Reliability of DSM-III-R anxiety disorder categories. Using the Anxiety Disorders Interview Schedule-Revised (ADIS-R).

A large reliability study of DSM-III-R anxiety disorders is reported in which outpatients (n = 267) received two independent structured interviews (Anxiety Disorders Interview Schedule-Revised). It is the only reliability study to date in which the final DSM-III-R criteria are used throughout the study. Reliability was assessed for each diagnosis when it was assigned as a principal diagnosis and when it was assigned as either a principal or an additional diagnosis. Excellent reliability was obtained for current principal diagnoses of simple phobia, social phobia, and obsessive-compulsive disorder. Agreement was good for panic disorder when all severity levels of agoraphobic avoidance were combined. Reliability was fair for generalized anxiety disorder. Remaining diagnostic difficulties, particularly in identifying levels of agoraphobic avoidance and in reliably diagnosing generalized anxiety disorder, are discussed in the context of changes in diagnostic criteria that are under consideration for DSM-IV.

Impact of life events on subjects with panic disorder and on comparison subjects.

A questionnaire measure of major life events was given to 64 subjects with diagnoses of panic disorder with agoraphobia, 33 subjects with other anxiety disorders, and 34 nonanxious subjects. Anxious subjects indicated the life events that had occurred in the 6-month period immediately before their current disorder began and rated the impact of each event on a 7-point scale. Nonanxious subjects made the same ratings for a 6-month period 1 1/2-2 years before the study. There was no significant difference between groups in the number of life events reported. However, anxious subjects rated these events as having a significantly greater negative impact than did nonanxious subjects.

Response to hyperventilation and 5.5% CO2 inhalation of subjects with types of specific phobia, panic disorder, or no mental disorder.

OBJECTIVE: This study tested the hypothesis that compared to other DSM-IV specific phobia types, situational specific phobias have more in common with panic disorder and agoraphobia. METHOD: Responses to hyperventilation and CO2 inhalation were compared across groups of patients with the four main DSM-IV specific phobia types, a group with panic disorder, and a group of comparison subjects with no anxiety disorder (N = 15 per group). RESULTS: Although these challenges have been shown previously to distinguish patients with panic disorder from other groups, no groups differed significantly in their responses to hyperventilation. In addition, whereas the patients with panic disorder responded more to the CO2 challenge than did the normal subjects, the specific phobia groups did not differ from one another or from the other groups on most measures. For the few CO2 measures on which specific phobia groups differed, patients with situational and natural environment phobias showed the greatest response. CONCLUSIONS: Overall, these findings provided only limited support for the hypothesis that situational specific phobias are related to panic disorder.

The empirical basis of generalized anxiety disorder.

OBJECTIVE: The authors review the empirical data on generalized anxiety disorder, a diagnostic category that has been among the more conceptually challenging in psychiatric nosology. METHOD: Published studies and recent findings that were considered by the Generalized Anxiety Disorder Subcommittee of the DSM-IV Anxiety Disorders Work Group are reviewed. Among the issues examined are diagnostic reliability, comorbidity, boundaries with other disorders, and clinical features. RESULTS: A variety of data on the reliability and validity of generalized anxiety disorder have been produced. Some authors have suggested that generalized anxiety disorder is better conceptualized as a vulnerability that should be located on axis II, and others have recommended that the category be eliminated. Although the diagnostic reliability of generalized anxiety disorder is lower than that of other anxiety disorders, the features constituting the diagnostic criteria for generalized anxiety disorder have been found to be reliable. An important development has been the determination of a set of somatic symptoms associated with generalized anxiety disorder that differs substantially from those for other anxiety disorders. These findings led to reduction in the number of items in the symptom criterion, from 18 in DSM-III-R to six in DSM-IV. Another substantial revision is greater emphasis on the uncontrollability of worry. CONCLUSIONS: Whereas the data on construct and discriminant validity, age at onset, course, familial transmission, and response to treatment generally support the DSM-IV definition of generalized anxiety disorder, the construct continues to have weaknesses and further research is needed.

Suicidal ideation and suicide attempts among patients with panic disorder: a survey of two outpatient clinics.

OBJECTIVE: Recent epidemiologic studies found that 20% of subjects with the diagnosis of panic disorder had attempted suicide. This study sought to determine the prevalence of suicidal ideation and suicide attempts among patients with panic disorder and whether the presence of comorbid borderline personality disorder influenced the prevalence of suicidal thoughts and behavior. METHOD: At two outpatient clinics, experienced clinicians conducted retrospective reviews of data from the intake interviews and charts of 59 patients with panic disorder and comorbid borderline personality disorder and 234 patients with panic disorder with or without axis II disorders other than borderline personality disorder. RESULTS: Suicide attempts were reported by 2% of the patients with panic disorder, compared to 25% of the patients with both panic disorder and borderline personality disorder. In addition, 2% of the patients with panic disorder, compared to 27% of the patients with panic disorder and borderline personality disorder, reported suicidal ideation that was judged to be of clinical significance. CONCLUSIONS: The rate of suicidal ideation and suicide attempts for psychiatric outpatients with panic disorder was discrepant with the findings of the earlier studies. The increased suicide risk in this group of patients was associated with borderline personality disorder, increased substance abuse, and affective instability. While 61% of the panic disorder patients and 78% of the patients with both panic disorder and borderline personality disorder reported thinking about death, this must be distinguished from actual suicidal ideation and clinical risk of suicide.

Generalized anxiety and generalized anxiety disorder: description and reconceptualization.

One hundred eight patients complaining of anxiety were diagnosed using the Anxiety Disorders Interview Schedule and classified into the various anxiety disorder categories as well as major depression. Although patients with a primary diagnosis of generalized anxiety disorder were more chronic than were panic disorder patients, most patients in each category met the DSM-III criteria for generalized anxiety disorder with the exception of simple phobic patients. On the basis of these data, it would seem that generalized anxiety disorder is a residual category within the anxiety disorders, since generalized anxiety disorder symptoms are almost always present. But if one distinguishes anticipatory anxiety, which is often part of panic or phobic disorders, from generalized anxiety, an independent anxiety disorder category emerges. This category is characterized by apprehensive expectation or chronic worry focused on multiple life situations.

The DSM-IV field trial for mixed anxiety-depression.

OBJECTIVE: This field trial was designed to answer four questions. First, are patients presenting with anxious or depressed symptoms that are associated with significant impairment but do not meet DSM-III-R definitional thresholds for axis I anxiety or mood disorders? Second, is the impairment experienced by these patients simply the consequence of the severity of their medical conditions? Third, what percent of these patients present with depressive symptoms only, anxious symptoms only, and a mixture of both? Fourth, how should the operational criteria for the syndrome(s) presented by these patients be defined? METHOD: A total of 666 patients from five primary care medical sites and two outpatient mental health sites were administered a semistructured psychiatric interview. RESULTS: Patients presenting with affective symptoms that did not meet definitional thresholds for DSM-III-R axis I disorders were at least as common as patients with several of the already established anxiety and mood disorders in each of the seven sites, and their disorders were associated with significant distress or impairment. A nonspecific pattern of anxious and depressed symptoms was the modal presentation among these patients with currently subdefinitional threshold disorders, and they could be significantly differentiated in terms of current symptoms from patients presenting with a principal diagnosis of generalized anxiety disorder, major depressive episode, or panic disorder with agoraphobia. CONCLUSIONS: The authors recommend that a mixed anxiety-depression category be included in the DSM-IV appendix for proposed diagnostic categories that need further study. A criteria set is proposed.

Multicenter collaborative panic disorder severity scale.

OBJECTIVE: To address the lack of a simple and standardized instrument to assess overall panic disorder severity, the authors developed a scale for the measurement of panic disorder severity. METHOD: Ten independent evaluators used the seven-item Panic Disorder Severity Scale to assess 186 patients with principal DSM-III-R diagnoses of panic disorder (with no or mild agoraphobia) who were participating in the Multicenter Collaborative Treatment Study of Panic Disorder. In addition, 89 of these patients were reevaluated with the same scale after short-term treatment. A subset of 24 patients underwent two independent assessments to establish interrater reliability. Internal consistency, convergent and discriminant validity, and sensitivity to change were also determined. RESULTS: The Panic Disorder Severity Scale was associated with excellent interrater reliability, moderate internal consistency, and favorable levels of validity and sensitivity to change. Individual items showed good convergent and discriminant validity. Analysis suggested a two-factor model fit the data best. CONCLUSIONS: The Panic Disorder Severity Scale is a simple, efficient way for clinicians to rate severity in patients with established diagnoses of panic disorder. However, further research with more diverse groups of panic disorder patients and with a broader range of convergent and discriminant validity measures is needed.

Pretreatment attrition in a comparative treatment outcome study on panic disorder.

OBJECTIVE: Whereas the fact of attrition during the course of treatment is well documented, little is known about the factors that affect sample selection before the beginning of a study ("pretreatment attrition"). The present study reports on the degree and sources of pretreatment attrition at two sites of a multicenter study on panic disorder that compared treatment outcomes for imipramine and cognitive behavior therapy. METHOD: Data were collected at two clinical research sites, one with a pharmacological treatment orientation (N = 420) and one with a psychosocial treatment orientation (N = 208). RESULTS: The main source of pretreatment attrition was participant refusal. At both research sites, eligible patients most often refused participation because they were either unwilling to start treatment with imipramine (30.6% and 47.4%, respectively) or discontinue their current medication (22.6% and 35.1%, respectively). CONCLUSIONS: Results from comparative treatment outcome studies are limited not only to people who meet the study criteria but also to those who are willing to begin a medication treatment and discontinue their current medication.

Efficient allocation of patients to treatment cells in clinical trials with more than two treatment conditions.

OBJECTIVE: Clinical trials generally allocate patients to equal-sized treatment groups. The authors propose that it may be more efficient to allocate unequal proportions of the total sample size to treatments when more than two treatments are being compared. METHOD: This proposal is illustrated with two examples. One involved a comparison of three treatments and used a dichotomous categorical outcome. The other involved comparison of three treatments and used a continuous measure. RESULTS: In both examples, a considerable increase in efficiency was realized by reducing the number of patients assigned to the placebo cell. CONCLUSIONS: Unequal allocation of patients to treatments should be considered when more than two groups are compared.

Identification of G alpha s messenger ribonucleic acid splice variants in human granulosa cells.

Granulosa cells are essential for follicular development and corpus luteum formation and their functions are regulated by gonadotrophins through G protein-coupled receptors. The dominant second messenger pathway involves the stimulation of cyclic AMP formation by G alpha s-linked receptors. In this paper we have investigated the expression of G alpha s mRNA splice variants in relation to expression of G alpha s protein isoforms in granulosa cells obtained from patients undergoing in vitro fertilization. We have carried out ribonuclease protection assays using cRNA riboprobes which are capable of detecting all G alpha s mRNA isoforms as well as quantifying total amounts of G alpha s mRNA. Granulosa cells express the message for G alpha s-Large and G alpha s-Small and the presence of two distinct protein products was confirmed by immunoblotting using the antibody RM/1. Moreover, the data show that a significant fraction of G alpha s-Large and G alpha s-Small mRNAs contain an extra CAG codon. This should generate proteins with an extra serine residue, resulting in G alpha s variants with the consensus sequence of a protein kinase C phosphorylation site. These results highlight the possible interaction between different signalling pathways in the control of cAMP production and the need to investigate the relationship between G alpha s variants and different adenylyl cyclase isozymes in patients with normal and abnormal ovarian function.

The development of anxiety: the role of control in the early environment.

Current developments in cognitive and emotion theory suggest that anxiety plays a rather central role in negative emotions. This article reviews findings in the area of anxiety and depression, helplessness, locus of control, explanatory style, animal learning, biology, parenting, attachment theory, and childhood stress and resilience to articulate a model of the environmental influences on the development of anxiety. Evidence from a variety of sources suggests that early experience with diminished control may foster a cognitive style characterized by an increased probability of interpreting or processing subsequent events as out of one's control, which may represent a psychological vulnerability for anxiety. Implications for research are discussed.