Genetic risk profiles for depression and anxiety in adult and elderly cohorts.

The first generation of genome-wide association studies (GWA studies) for psychiatric disorders has led to new insights regarding the genetic architecture of these disorders. We now start to realize that a larger number of genes, each with a small contribution, are likely to explain the heritability of psychiatric diseases. The contribution of a large number of genes to complex traits can be analyzed with genome-wide profiling. In a discovery sample, a genetic risk profile for depression was defined based on a GWA study of 1738 adult cases and 1802 controls. The genetic risk scores were tested in two population-based samples of elderly participants. The genetic risk profiles were evaluated for depression and anxiety in the Rotterdam Study cohort and the Erasmus Rucphen Family (ERF) study. The genetic risk scores were significantly associated with different measures of depression and explained up to ∼0.7% of the variance in depression in Rotterdam Study and up to ∼1% in ERF study. The genetic score for depression was also significantly associated with anxiety explaining up to 2.1% in Rotterdam study. These findings suggest the presence of many genetic loci of small effect that influence both depression and anxiety. Remarkably, the predictive value of these profiles was as large in the sample of elderly participants as in the middle-aged samples.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

Is a combined therapy more effective than either CBT or SSRI alone? Results of a multicenter trial on panic disorder with or without agoraphobia.

OBJECTIVE: To establish whether the combination of cognitive-behavioral therapy (CBT) and pharmacotherapy (SSRI) was more effective in treating panic disorder (PD) than either CBT or SSRI alone, and to evaluate any differential effects between the mono-treatments. METHOD: Patients with PD (n = 150) with or without agoraphobia received CBT, SSRI or CBT + SSRI. Outcome was assessed after 9 months, before medication taper. RESULTS: CBT + SSRI was clearly superior to CBT in both completer and intent-to-treat analysis (ITT). Completer analysis revealed superiority of CBT + SSRI over SSRI on three measures and no differences between CBT and SSRI. ITT analysis revealed superiority of SSRI over CBT on four measures and no differences between CBT + SSRI and SSRI. CONCLUSION: Both the mono-treatments (CBT and SSRI) and the combined treatment (CBT + SSRI) proved to be effective treatments for PD. At post-test, CBT + SSRI was clearly superior to CBT, but differences between CBT + SSRI and SSRI, and between SSRI and CBT, were small.

The effect of social roles on mental health: a matter of quantity or quality?

The effect of social roles (partner, parent, worker) on mental health may depend on the total number or the quality of the individual occupied social roles. With longitudinal data from the Netherlands Mental Health Survey and Incidence Study (NEMESIS), the effect of the number and quality of occupied social roles on mental health over three years was examined among 2471 men and women aged 25-55 years without mental disorders at baseline. Mental health was assessed using 3-year change in the SF-36 mental health scale as well as using the 3-year incidence of anxiety and depressive disorders defined by DSM-III criteria. The quality of social roles was assessed by the GQSB (Groningen Questionnaire Social Behavior). The number of social roles had no significant effect on the risk of developing depressive and anxiety disorders, but particularly the partner-role had a significant positive effect on mental health (beta of mental health=1.19, p=0.01; HR of incident disorders=0.75, 95% CI:0.51-1.00, p=0.05). A good quality of each of the three social roles was associated with higher levels of mental health and lower risks of incident disorders over 3 years. More than the number of social roles, knowledge about social role quality might provide opportunities for prevention of depressive and anxiety disorders.

Work and family roles and the association with depressive and anxiety disorders: differences between men and women.

BACKGROUND: This study examined the associations of (combinations of) social roles (employee, partner and parent) with the prevalence of anxiety and depressive disorders and whether social roles contribute to the explanation of the female preponderance in these disorders. METHOD: This was a cross-sectional study using data from 3857 respondents aged 25-55 of NEMESIS (Netherlands Mental Health Survey and Incidence Study). Depression and anxiety disorders were measured using the CIDI 1.1. RESULTS: The OR of depressive disorders and anxiety disorders among women compared to men was 1.71 (95% CI: 1.40-2.10). Among both genders, the partner role was associated with decreased risks of depression and anxiety and the parent role was not. The work role was a significant protective factor of depression and anxiety for men (OR=0.40; 95% CI: 0.24-0.69) but not for women (OR=0.86; 95% CI: 0.66-1.12). The effect of the work role was positive among women without children (OR=0.28; 95% CI: 0.14-0.54), but not among those with children (OR=1.01; 95% CI: 0.75-1.35). The gender risk for depression and anxiety decreased significantly by adding the work role variables into the model. LIMITATIONS: This was a cross-sectional study. This study did not give insight into the quality of social roles. CONCLUSION: The work role contributed to the explanation of the female preponderance in depression and anxiety disorders. Considering depression and anxiety among women, a focus upon quality and meaning of the work role, and barriers in combining the work role and parent role may be essential.

Psychosis in epilepsy patients and other chronic medically ill patients and the role of cerebral pathology in the onset of psychosis: a clinical epidemiological study.

BACKGROUND: In a 3-year epidemiological survey (N=2623) prevalence of psychosis in epilepsy patients as compared with other chronic medically ill patients is assessed. AIM: To explore the role of cerebral pathology as compared to the role of chronic burden of disease in the onset of psychosis. METHOD: One thousand seven hundred fifty two patients with chronic medical disorders admitted to an Academic Hospital and 901 patients with epilepsy admitted to a tertiary care epilepsy clinic were assessed by CIDI, MINI and clinical psychiatric interview in a two stage screening survey. Medical files were searched for MRI scans about cerebral pathology. Poisson regression analysis was performed to estimate the relative risk for psychosis in both groups. RESULTS: In total, 52 patients with prevalent psychosis were found: 49 (5.4%) in the epilepsy clinic and 3 (0.17%) in the Academic Hospital. Age range (18-88), mean age (42) and gender distribution (equal) were similar in both samples. RR is 8.37 (2.74, 25.52). In 16 of the 49 epilepsy patients, cerebral pathology existed with mainly temporal and frontal localisation and of childhood-onset vascular or infectious origin. CONCLUSIONS: This finding suggests that in the onset of psychosis in epilepsy patients, the role of cerebral pathology, especially localized left temporal and frontal, is of strong etiological importance. The following epilepsy endophenotypes should be explored as factors in vulnerability for psychosis as well: frequent and severe epileptic activity; and psychotic reactions to certain AEDs, such as Topiramate and Lamotrigine. Burden of disease does not seem to play an important role.

[The effectiveness of anxiety treatment on alcohol-dependent patients with a comorbid phobic disorder: a randomised controlled trial]. / Effectiviteit van een toegevoegde behandeling voor angstklachten bij alcoholafhankelijke patiënten met een fobische stoornis.

BACKGROUND: There is evidence that the post-treatment relapse rate for alcohol-dependent patients with a comorbid anxiety disorder is higher than for alcohol-dependent patients without this disorder. aim To discover whether the post-treatment relapse rate in alcohol-dependent patients who suffer from both alcohol-dependence and a comorbid anxiety disorder can be lowered by giving them additional treatment specifically for the comorbid anxiety disorder. METHOD: A 32-week randomised controlled trial among 96 abstinent patients with a primary diagnosis of alcohol dependence and a comorbid anxiety disorder involving agoraphobia or social phobia. The patients were randomly assigned either to an intensive psychosocial relapse-prevention programme only (n = 49) or to a combined programme in which the aforementioned programme was supplemented by an anxiety treatment programme comprising cognitive behavioural therapy and optional pharmacotherapy in the form of an SSRI (n = 47). The primary outcome measure was the percentage of patients who suffered an alcohol relapse during a 32-week period. The secondary outcome measures were: total abstinence, a reduction in the number of days of heavy drinking and a reduction in anxiety symptoms. results Although the anxiety symptoms in the group receiving cognitive behavioural therapy diminished more than in the group not receiving this therapy, the alcohol relapse rates in the former group were not significantly lower than in the latter group. CONCLUSION: Anxiety treatment for alcohol-dependent patients with a comorbid anxiety disorder can alleviate anxiety symptoms but has no significant effect on the outcome of alcohol treatment programmes.

Memory of childhood trauma before and after long-term psychological treatment of borderline personality disorder.

The present study investigated the consistency of self-reports of childhood traumatic events in a sample of 50 patients with a borderline personality disorder (BPD) before and after 27 months of intensive treatment with schema focused therapy or transference focused psychotherapy. The mean number of reported sexual, physical and emotional traumatic events did not change following treatment. Test-retest correlations of the trauma-interview also indicated high stability of the total number of sexual, physical and emotional events reported. The majority of the patients, however, did no longer report at least one of the 33 listed events after psychotherapy, and the majority reported at least one event that they had not mentioned before the start of treatment. These findings were not related to type of treatment or changes in suppression, intrusions, avoidance of intrusions, dissociative symptoms, depressive symptoms, and borderline symptoms.

Predictability, controllability, and fear of symptoms of anxiety in epinephrine-induced panic.

BACKGROUND: Psychological manipulations (supplied information, safety cues) may influence panic rates during pharmacologic challenge tests in subjects with panic disorder (PD). Psychological panic models assume that fear of stress-related bodily sensations is central to the etiology of PD. METHODS: Prior to infusion of epinephrine, 50 subjects with PD were randomly assigned to one out of four experimental conditions: with or without extensive information and with or without external control, according to a 2 x 2 design. The panic rate was hypothesized to be lower in subgroups possessing extensive information and/or control. Fear of bodily sensations was used as a predictor. RESULTS: Thirty-four out of 50 patients (68%) panicked during the infusion. Subjects who received extensive information were marginally less likely to panic, but manipulation of control did not influence panic rates. Panickers did not differ from nonpanickers in measures of fear of fear. Anxiety sensitivity best predicted baseline anxiety and cognitive symptom scores, but was not associated with other outcome measures in panickers. Only baseline partial pressure of CO2 discriminated between panickers and nonpanickers. CONCLUSIONS: Manipulating external safety cues appears to be of limited value in modulating responses to epinephrine challenge. Together with our finding that fear of anxiety symptoms does not predict panic rates, these data argue against "fear of fear" as a key mechanism in epinephrine-induced panic.

Hyperventilation and panic attacks.

OBJECTIVE: Hyperventilation has been posed as an important symptom-producing mechanism in panic attacks. Some arguments and experimental findings, such as the possibility of inducing panic symptoms by voluntary hyperventilation in panic disorder patients, seem to favor this suggestion. This study was undertaken to clarify the role of hyperventilation in panic disorder. Long-term ambulatory measurement of transcutaneous arterial CO2 pressure (PCO2) offers an opportunity to test directly the co-occurrence of panic and hyperventilation under natural conditions. METHOD: Transcutaneous PCO2 was measured during three to four sessions of approximately 7 hours each in 28 panic disorder patients. Patients were instructed to expose themselves to fear-provoking situations and to press a button as soon as they experienced panic. One-half of the patients experienced one or more panic attacks during these sessions. RESULTS: A decrease in PCO2 was observed during only one of the 24 registered panic attacks that lasted at least 3 minutes. Even during this particular attack, the degree of hyperventilation was not impressive. CONCLUSIONS: These findings indicate that the hypothesis that hyperventilation is an important symptom-producing mechanism in panic may be dismissed.

Treatment of panic disorder with agoraphobia: comparison of fluvoxamine, placebo, and psychological panic management combined with exposure and of exposure in vivo alone.

OBJECTIVE: The purpose of this comparative outcome study was to investigate whether the effects of exposure in vivo treatment for panic disorder with agoraphobia could be enhanced by adding interventions specifically for panic attacks before the start of exposure treatment. The additional effect of two types of treatment for panic attacks--pharmacological (fluvoxamine) and psychological (repeated hyperventilation provocations and respiratory training)--was examined. Thus, the combined treatment of panic interventions with exposure in vivo could be compared to exposure in vivo alone. METHOD: Ninety-six patients were randomly assigned to four treatment conditions: double-blind, placebo-controlled fluvoxamine followed by exposure in vivo, psychological panic management followed by exposure, and exposure in vivo alone. Outcome was assessed by self-report measures, a standardized multitask behavioral avoidance test, and continuous monitoring of panic attacks. Seventy-six patients completed the study. RESULTS: All four treatments were effective and resulted in a significant decrease of agoraphobic avoidance. Moreover, the combination of fluvoxamine and exposure in vivo demonstrated efficacy superior to that of the other treatments and had twice as large an effect size (difference between pre- and posttreatment scores) on self-reported agoraphobic avoidance. The other treatments did not differ among each other in effectiveness. CONCLUSIONS: Results of the study indicate that the short-term outcome of exposure in vivo treatment can be enhanced by adding fluvoxamine treatment. Psychological panic management combined with exposure was not superior to exposure alone of equal duration.

Anxiety and depression in later life: Co-occurrence and communality of risk factors.

OBJECTIVE: The purpose of this study was to examine the comorbidity of and communality of risk factors associated with major depressive disorder and anxiety disorders in later life. METHOD: A random age- and sex-stratified community-based sample (N=3,056) of the elderly (age 55-85 years) in the Netherlands was studied. A two-stage screening design was used, with the Center for Epidemiologic Studies Depression Scale as a screening instrument and the National Institute of Mental Health Diagnostic Interview Schedule as a criterion instrument. Risk factors were measured with well-validated instruments and represented a broad range of vulnerability and stress-related factors associated with anxiety and depression. Multivariate analyses examined risk factors associated with pure major depressive disorder, pure anxiety disorders, and comorbid conditions. RESULTS: Comorbidity was highly prevalent: 47.5% of those with major depressive disorder also met criteria for anxiety disorders, whereas 26.1% of those with anxiety disorders also met criteria for major depressive disorder. While the only variables associated with pure major depressive disorder were younger age and external locus of control, risk factors representing a wide range of both vulnerability and stress were associated with pure anxiety disorders. External locus of control was the only common factor. The group with anxiety disorders plus major depressive disorder had a distinct risk factor profile and may represent those with a more severe disorder. CONCLUSIONS: Although high levels of comorbidity between major depressive disorder and anxiety disorders were found, comparing risk factors associated with pure major depressive disorder and pure anxiety disorders revealed more differences than similarities. Anxiety disorders in later life merit separate study.

Paroxetine, clomipramine, and cognitive therapy in the treatment of panic disorder.

BACKGROUND: This 12-week, placebo-controlled study was carried out to compare the relative efficacy of paroxetine, clomipramine, and cognitive therapy in the treatment of DSM-III-R-defined panic disorder with or without agoraphobia. METHOD: After a 3-week single-blind, placebo run-in period, 131 patients were randomly assigned to receive double-blind medication or 12 sessions of cognitive therapy based on the model of Clark. Efficacy assessments included the daily panic attack diary, the Clinical Global Impression scale, the Patient Global Evaluation, the Hamilton Rating Scale for Anxiety, the Marks-Sheehan Phobia Scale, the Montgomery-Asberg Depression Rating Scale, and the Sheehan Disability Scale. RESULTS: Comparisons with placebo revealed significant superiority of paroxetine (20-60 mg/day) and clomipramine (50-150 mg/day) on nearly all outcome measures. On most measures, paroxetine also showed higher efficacy than cognitive therapy. With few exceptions, cognitive therapy did not differ significantly from placebo. The number of subjects becoming panic-free (66%) was higher and the onset of action was faster in the paroxetine-treated group. Treatment with cognitive therapy yielded the highest drop-out rate (26%). CONCLUSION: In this short-term study assessing treatment of panic disorder and agoraphobia, paroxetine and clomipramine were consistently superior to pill placebo, whereas cognitive therapy was superior on only a few measures.

Epinephrine-induced panic attacks and hyperventilation.

To assess the effects of epinephrine on ventilation in patients with panic disorder and in social phobics, analyses were performed on pooled data from two previous infusion studies. Throughout the infusion, changes in transcutaneous PCO2 (tcPCO2), subjective anxiety, heart rate and blood pressure were recorded continuously. Twenty-nine patients received epinephrine, ten patients received placebo. Thirteen patients (45%) had a panic attack during epinephrine. The fall in tcPCO2 and the cardiovascular response was greater in panicking patients than patients who did not panic. Although the fall in tcPCO2 associated with panic was not substantial and did not indicate clinically significant acute hyperventilation, it appears to be a sensitive index for epinephrine-induced panic. The fall in tcPCO2 was predicted rather by the frequency of occurrence of anxiety-related somatic symptoms than by the fear of these symptoms. These findings further reduce a role for fear of bodily sensations in epinephrine-induced panic attacks and favor a biological sensitivity to sympathetic stimulation.

An open study of paroxetine in hypochondriasis.

1. Despite the high prevalence of hypochondriasis, this disorder is found to be the focus of research only minimally. 2. This open study evaluates the efficacy and tolerance of paroxetine in 11 patients with DSM-III-R hypochondriasis. 3. Using paired samples t-test, a significant reduction on measures of hypochondriasis was found after 12 weeks of treatment compared to baseline. Two patients dropped out prematurely. At post-test, eight out of nine patients who completed the study had improved to a clinically relevant degree. Of these, five attained scores in the reach of the normal population. 4. In one patient who completed the study and one patient who dropped out, tolerance of paroxetine was poor, whereas in remaining patients tolerance was moderate to good. 5. The results of this study suggest that patients with hypochondriasis may be responsive to paroxetine. A controlled study is recommended.

Somatoform dissociative symptoms as related to animal defensive reactions to predatory imminence and injury.

The authors hypothesized that there would be a similarity between animal defensive responses to variable predatory imminence and injury and certain somatoform dissociative symptoms of trauma-reporting patients who have dissociative disorder. As a first test of this hypothesis, 12 somatoform symptom clusters consisting of clinically observed somatoform dissociative phenomena were constructed. All clusters discriminated between patients with dissociative disorders (n = 50) and patients with other psychiatric diagnoses (n = 50). Those expressive of the hypothesized similarity--freezing, anesthesia-analgesia, and disturbed eating--belonged to the 5 most characteristic symptoms of dissociative disorder patients. Anesthesia-analgesia, urogenital pain, and freezing symptom clusters independently contributed to predicted presence of dissociative disorder. Using an independent sample, it appeared that anesthesia-analgesia best predicted presence of dissociative disorder after controlling for symptom severity. The results were largely consistent with the hypothesized similarity.

Accurate heartbeat perception in panic disorder: fact and artefact.

The hypothesis was investigated that more accurate perception of heartbeats by patients with panic disorder is an artefact of arousal. Twenty-three patients with panic disorder, 16 patients with a mood disorder and 21 normal controls were tested. There were more panic patients who accurately perceived their heart rates (N = 7) than depressed patients (N = 0) or normals (N = 2). The nine accurate perceivers had higher scores on questionnaires measuring the cognitions associated with panic. For non-accurate perceivers, perceived heart rates were unrelated to actual heart rates, unrelated to cognitive factors, but significantly related to arousal. It is concluded that the accurate perception of heartbeats by patients with panic disorder is both fact and artefact: some patients are accurate perceivers, but the majority are not.

Epinephrine infusions in panic disorder: a double-blind placebo-controlled study.

Twenty-four subjects with Panic Disorder were infused with epinephrine in physiological doses or placebo according to a double-blind design. The panic rate in the epinephrine group (67%) was higher than in the placebo group (25%). Placebo panic occurred early during the procedure and was apparently associated with anticipation anxiety and stress-provoking situational factors. Panickers were characterized by a greater increase in heart rate as well as a drop in pCO2. Fear of bodily sensations was only weakly associated with state anxiety levels at point of panic. It is concluded that cognitive factors may not be important in epinephrine-induced panic.

Double-blindness procedure did not mask giving of medication in panic disorder.

BACKGROUND: The purpose of this study was to measure the degree to which patients and their treating physicians correctly guessed whether patients were on an active treatment (paroxetine or clomipramine) or pill-placebo, and whether correctness of these guesses was related to treatment outcome. METHODS: Ninety-five panic disorder patients, randomized to receive double-blind treatment with paroxetine, clomipramine or placebo for twelve weeks, were asked half-way through this period to classify treatment as active or placebo. Medical doctors were asked the same. RESULTS: Both patients and physicians guessed correctly to a degree much greater than would be expected by chance whether the patient was on an active treatment. Neither patients nor physicians were good at estimating correctly whether a patient was on a placebo. There was a trend approaching significance for patients on a placebo, whose physicians believed that they were on active treatment, to have a higher rating of symptom improvement than those patients who were correctly guessed to be on placebo. CONCLUSION: The 'double-blindness' procedure did not mask the giving of antidepressive medication in panic disorder. There is some evidence that physicians who incorrectly classify patients on a placebo as receiving active treatment relate this to better treatment outcome.