Genome-wide significant risk loci for mood disorders in the Old Order Amish founder population.

Genome-wide association studies (GWAS) of mood disorders in large case-control cohorts have identified numerous risk loci, yet pathophysiological mechanisms remain elusive, primarily due to the very small effects of common variants. We sought to discover risk variants with larger effects by conducting a genome-wide association study of mood disorders in a founder population, the Old Order Amish (OOA, n = 1,672). Our analysis revealed four genome-wide significant risk loci, all of which were associated with >2-fold relative risk. Quantitative behavioral and neurocognitive assessments (n = 314) revealed effects of risk variants on sub-clinical depressive symptoms and information processing speed. Network analysis suggested that OOA-specific risk loci harbor novel risk-associated genes that interact with known neuropsychiatry-associated genes via gene interaction networks. Annotation of the variants at these risk loci revealed population-enriched, non-synonymous variants in two genes encoding neurodevelopmental transcription factors, CUX1 and CNOT1. Our findings provide insight into the genetic architecture of mood disorders and a substrate for mechanistic and clinical studies.

Finding Rare, Disease-Associated Variants in Isolated Groups: Potential Advantages of Mennonite Populations.

Large-scale genotyping and next-generation sequencing techniques have allowed great advances in the field of molecular genetics. Numerous common variants of low impact have been associated with many complex human traits and diseases, such as bipolar disorder and schizophrenia. Although they may exert a greater impact on risk, few rare disease variants have been found, owing to the greatly increased sample sizes that are typically necessary to demonstrate association with rarer variants. One alternative strategy is to study isolated populations, where historical bottlenecks reduce genetic diversity and some otherwise rare variants may drift to higher frequencies. Here we describe the Mennonite population settlements, considering their history of multiple bottlenecks followed by demographic expansion and a currently widespread geographical distribution. We argue that Mennonite populations are valuable partners for studies seeking genetic variants that exert a high impact on risk for a variety of common disorders, including mental illnesses.

Compliance, persistence, costs and quality of life in young patients treated with antipsychotic drugs: results from the COMETA study.

BACKGROUND: Little data is available on the real-world socio-economic burden and outcomes in schizophrenia. This study aimed to assess persistence, compliance, costs and Health-Related Quality-of-Life (HRQoL) in young patients undergoing antipsychotic treatment according to clinical practice. METHODS: A naturalistic, longitudinal, multicentre cohort study was conducted: we involved 637 patients aged 18-40 years, with schizophrenia or schizophreniform disorder diagnosed ≤10 years before, enrolled in 86 Italian Mental Health Centres and followed-up for 1 year. Comparisons were conducted between naïve (i.e., patients visiting the centre for the first time and starting a new treatment regimen) and non naïve patients. RESULTS: At enrolment, 84% of patients were taking atypical drugs, 3.7% typical, 10% a combination of the two classes, and 2% were untreated. During follow-up, 23% of patients switched at least once to a different class of treatment, a combination or no treatment. The mean Drug-Attitude-Inventory score was 43.4, with 94.3% of the patients considered compliant by the clinicians. On average, medical costs at baseline were 390.93€/patient-month, mostly for drug treatment (29.5%), psychotherapy (29.2%), and hospitalizations (27.1%). Patients and caregivers lost 3.5 days/patient-month of productivity. During follow-up, attitude toward treatment remained fairly similar, medical costs were generally stable, while productivity, clinical statusand HRQoL significantly improved. While no significantly different overall direct costs trends were found between naïve and non naïve patients, naïve patients showed generally a significant mean higher improvement of clinical outcomes, HRQoL and indirect costs, compared to the others. CONCLUSIONS: Our results suggest how tailoring the treatment strategy according to the complex and specific patient needs make it possible to achieve benefits and to allocate more efficiently resources. This study can also provide information on the most relevant items to be considered when conducting cost-effectiveness studies comparing specific alternatives for the treatment of target patients.

Neural correlates of negative and disease-specific emotional stimuli in panic disorder: a functional magnetic resonance imaging study.

OBJECTIVE: Decades of research have highlighted the involvement of the prefrontal cortex, anterior cingulated cortex, and limbic areas (amygdala) in panic disorder (PD). However, little attention has been given specifically to the inferior frontal gyrus. The current study aimed to investigate the neural substrates, including the inferior frontal gyrus, of both panic-related and negative conditions among individuals with PD and healthy controls. METHODS: We examined 13 medication-free PD patients and 14 healthy controls with functional magnetic resonance imaging (fMRI) during exposure to negative and neutral pictures and a set of specific panic-related pictures. RESULTS: Subtraction between the conditions indicated activation of the left amygdala region and the right inferior frontal gyrus in PD patients during the specific panic-related condition, whereas the left amygdalar region and left inferior frontal gyrus were activated during the negative condition in controls. CONCLUSION: These results suggest that in patients with PD, a prominent bottom-up process is involved in specific panic-related conditions, which might be associated with weak modulation of the left frontal area. These data add to our current understanding of the neural correlates of PD and can contribute to future clinical interventions targeting the functional reestablishment of these regions.

Tapering clonazepam in patients with panic disorder after at least 3 years of treatment.

High-potency benzodiazepines, such as clonazepam, are frequently used in the treatment of panic disorder (PD) because of their rapid onset of action and good tolerability. However, there is concern about their potential to cause withdrawal symptoms. We aimed to develop a protocol for safely tapering off clonazepam in patients with PD who had been receiving treatment for at least 3 years. A specific scale for judging withdrawal was also developed, the Composite Benzodiazepine Discontinuation Symptom Scale. We selected 73 patients with PD who had been asymptomatic for at least 1 year and who wished to discontinue the medication. The trial consisted of a 4-month period of tapering and an 8-month follow-up period. The dosage of clonazepam was decreased by 0.5 mg per 2-week period until 1 mg per day was reached, followed by a decrease of 0.25 mg per week. The mean dosage at the start of tapering was 2.7 +/- 1.2 mg/d. In total, 51 (68.9%) of the patients were free of the medication after the 4 months of tapering according to the protocol, and 19 (26.0%) of the patients needed another 3 months to be free of medication. Clonazepam discontinuation symptoms were mostly mild and included mainly: anxiety, shaking/trembling/tremor, nausea/vomiting, insomnia/nightmares, excessive sweating, tachycardia/palpitations, headache, weakness, and muscle aches. The improvement in PD and general well-being was maintained during both the taper and follow-up phases. Clonazepam can be successfully discontinued without any major withdrawal symptoms if the dose is reduced gradually. We recommend reducing the dosage of clonazepam after intermediate-term use by 0.25 mg/wk.

Double-blind comparison of 30 and 60 mg tranylcypromine daily in patients with panic disorder comorbid with social anxiety disorder.

Our objective was to explore the dose-response relationship in patients with panic disorder and social anxiety disorder comorbidity (DSM-IV). After 1 week of no-drug washout, 36 such patients were assigned to a double-blind controlled comparison of the effects of 30 mg and 60 mg of tranylcypromine, and were followed up for 12 weeks. The main instrument used to measure the number of panic attacks was the Sheehan Panic and Anticipatory Anxiety Scale. The primary outcome measure for social anxiety disorder symptoms was the mean change from baseline in the Liebowitz Social Anxiety Scale (LSAS). After 12 weeks of treatment, panic attacks were reduced 69.6% from baseline in the 30-mg group (n=19) compared with a 74.8% reduction in the 60-mg group (n=17). Twelve patients (70.6%) of the higher dose group and 14 patients (68.4%) of the lower dose were completely free of panic attacks. There was no difference in efficacy between the tranylcypromine groups in the panic disorder symptoms. The 60-mg dose was more efficacious as measured by the LSAS scores, showing a significant difference in relation to the lower group. Mean change from baseline in LSAS total score (mean+/-SD) for 30-mg group was 17.9+/-14.7 and for the 60-mg group was 35.0+/-14.8. The social anxiety symptom scale showed a two-fold greater change with the 60-mg dose, and the 30-mg dose group could be considered the equivalent of a placebo control group. Tranylcypromine--60 mg daily--was found effective in the treatment of panic disorder and social anxiety disorder comorbidity.

Polygenic risk for anxiety influences anxiety comorbidity and suicidal behavior in bipolar disorder.

Bipolar disorder is often comorbid with anxiety, which is itself associated with poorer clinical outcomes, including suicide. A better etiologic understanding of this comorbidity could inform diagnosis and treatment. The present study aims to test whether comorbid anxiety in bipolar disorder reflects shared genetic risk factors. We also sought to assess the contribution of genetic risk for anxiety to suicide attempts in bipolar disorder. Polygenic risk scores (PRS) were calculated from published genome-wide association studies of samples of controls and cases with anxiety (n = 83,566) or bipolar disorder (n = 51,710), then scored in independent target samples (total n = 3369) of individuals with bipolar disorder who reported or denied lifetime anxiety disorders or suicidal attempts in research interviews. Participants were recruited from clinical and nonclinical settings and genotyped for common genetic variants. The results show that polygenic risk for anxiety was associated with comorbid anxiety disorders and suicide attempts in bipolar disorder, while polygenic risk for bipolar disorder was not associated with any of these variables. Our findings point out that comorbid anxiety disorders in bipolar disorder reflect a dual burden of bipolar and anxiety-related genes; the latter may also contribute to suicide attempts. Clinical care that recognizes and addresses this dual burden may help improve outcomes in people living with comorbid bipolar and anxiety disorders.

Freezing reaction in panic disorder patients associated with anticipatory anxiety.

BACKGROUND: Anticipatory anxiety can be described as a conditioned response with a defensive posture of freezing and autonomic activation. The purpose of this study was to assess the postural control analysis and autonomic activation in panic disorder (PD) patients presented with visual stimuli. METHODS: PD patients (n=29) and healthy controls (n=27) stood on a force platform while viewing a series of anxiogenic, mutilation, and neutral pictures. Skin conductance responses and the displacements of the center of pressure were measured. RESULTS: Overall, the PD patients demonstrated significantly reduced body sway, increased mean power frequency, and increased skin conductance compared to control group throughout the experiment (P<.05). PD patients also showed a negative correlation between anticipatory anxiety and mean sway area throughout the experiment. However, there was no significant difference in body sway velocity compared to healthy controls while viewing the anxiogenic block of pictures or the neutral block. CONCLUSIONS: Our data shows that PD patients experiencing anticipatory anxiety may present with lower mobility, consistent with the freezing behavior of the defense cascade. The data also shows that PD patients do not have a postural instability when confronted with specific anxiogenic context. The importance of this study is that it objectively demonstrates freezing-like behavior in PD patients.

Panic disorder and social anxiety disorder subtypes in a caffeine challenge test.

Studies have demonstrated the vulnerability of anxiety disorder patients to challenge tests. Our aim was to observe if panic disorder (PD) patients and generalized social anxiety disorder (GSAD) and performance social anxiety disorder (PSAD) patients respond in a similar way to the induction of anxiety symptoms and panic attacks by an oral caffeine challenge test. We compared 28 PD patients, 25 GSAD patients, 19 PSAD, and 26 control subjects after a 480-mg caffeine test. The patients had not received psychotropic drugs for at least a 4-week period. In a randomized double-blind experiment performed in two occasions 7 days apart, 480 mg of caffeine and a caffeine-free solution were administered and anxiety scales were administered before and after each test. A panic attack was induced in 17 (60.7%) PD patients, 4 (16.0%) GSAD patients, and 10 (52.6%) PSAD patients, during the caffeine test. None of the control subjects had a panic attack after the caffeine intake. Neither patients nor any control subject had a panic attack after drinking the caffeine-free solution. Our data suggest that there is an association between PD and PSAD hyperreactivity to an oral caffeine challenge test. The PD and PSAD patients had a higher number of induced panic attacks, some specific anxiety symptoms, and a more severe anxiety response than GSAD patients and normal volunteers.

Traumatic experiences and cognitive profiles of schizophrenia cases influenced by the BDNF Val66met polymorphism.

The association of early trauma exposure with current cognition was examined in a research series of 56 schizophrenia cases with respect to the BDNF Val66Met polymorphism (rs6265, Val66Val, Val66Met, Met66Met), as met allele carriers have reduced neurotrophic activity. The Perceptual Organization Index had a significant negative correlation with trauma exposures only in met carriers, including early physical abuse, general trauma after age 18 years, and physical abuse. Within the Val66Val subgroup, there were no significant correlations between WAIS indices and traumatic experiences.

A caffeine challenge test in panic disorder patients, their healthy first-degree relatives, and healthy controls.

Our aim was to observe the induction of anxiety symptoms and panic attacks by a caffeine challenge test in panic disorder (PD) patients (DSM-IV) and their healthy first-degree relatives. We randomly selected 25 PD patients, 27 healthy first-degree relatives of probands with PD, and 22 healthy volunteers with no family history of PD. In a randomized double-blind experiment performed over two occasions 7 days apart, 480 mg caffeine and a caffeine-free solution were administered in a coffee form. Using specific panic attack criteria, 52.0% (n=13) PD patients, 40.7% (n=11) first-degree relatives (chi2=1.81, df=1, P=0.179), and none of the control subjects had a panic attack after the test (chi2=51.7, df=2, P<0.001). In this caffeine challenge test, PD patients and their first-degree relatives were more sensitive than healthy volunteers to the panic attack symptoms but less sensitive to headache, increase in blood pressure, and insomnia. Our data suggest that there is an association between panic attacks after the intake of 480 mg of caffeine in PD patients and their first-degree relatives. There is a clear differentiation of PD patients and their first-degree relatives by a caffeine test from the healthy group.

Demographic and clinical features of panic disorder comorbid with bipolar I disorder: a 3-year retrospective study.

BACKGROUND: Mood disorders are considered related to anxiety disorders and their association may determine clinical course and prognosis. We aimed to describe with retrospective methodology the demographic, clinical, and treatment features in a group of panic disorder comorbid with bipolar I disorder (PD-BI) patients who were been treated for at least 3 year-period and compare them with bipolar I (BI) patients who were treated during the same period. METHOD: We compared the demographic and clinical data of 26 PD-BI, 28 BI, and 25 panic disorder (PD) outpatients without history of comorbidity with mood disorder were diagnosed and treated for at least 3 years in the Federal University of Rio de Janeiro. RESULTS: PD group have a higher educational level, are more married, and are more economically active. In the PD-BI and BI patients the disorders started earlier. They also turn out to have an equivalent pattern in the presence of drug abuse episodes, moderate or severe depressive episodes, psychotic episodes, suicide attempts, maniac episodes, mixed episodes, use of fewer days of antidepressants and benzodiazepines, and use of more days of antipsychotics and mood stabilizers. The PD-BI and the BI groups had a higher frequency of depressive episodes and psychotic episodes. LIMITATIONS: It is a retrospective data description based on a naturalistic treatment. The sample has a small size and the some data could be different in a large sample. CONCLUSION: PD-BI patients have demographic, clinical and therapeutic features similar to BI and the data support its validation as a special severe bipolar I disorder subgroup.

Panic disorder respiratory subtype: a comparison between responses to hyperventilation and CO2 challenge tests.

In this study 117 panic disorder patients were divided into a respiratory subtype group and a non-respiratory subtype group. The respiratory subtype patients were observed to be more sensitive to the 35% CO(2) inhalation challenge test and the hyperventilation test than the non-respiratory subtype patients.

Clinical features of respiratory and nocturnal panic disorder subtypes.

Our aim is to compare the panic disorder (PD) respiratory subtype and the nocturnal panic subtype. A group of 193 PD patients (DSM-IV) was examined in the Laboratory of Panic and Respiration in the Institute of Psychiatry of the Federal University of Rio de Janeiro. The diagnoses were made using the SCID-I for DSM-IV. The subtypes were the respiratory (with 4 out of 5 prominent respiratory symptoms during the panic attacks [PA]) vs. non-respiratory, likewise PD with nocturnal (during sleep) PAs vs. PD with only diurnal PAs. The respiratory subtype accounted for 56.5% (n=109) of our sample; the non-respiratory subtype, 43.5% (n=84); the nocturnal subtype, 49.2% (n=95); and the non-nocturnal subtype, 50.8% (n=98). Despite a rich literature concerning correlations between the respiratory system and nocturnal panic attacks, our data do not support these findings, as the comparison of proportions in the respiratory and nocturnal groups did not differ. The non-nocturnal subtype was significantly associated with agoraphobia, and the respiratory subtype was not associated with these variables.

Personality traits spectrum in panic disorder and major depression.

OBJECTIVE: Our aim was to identify the personality traits in patients with panics disorder, major depression and with both disorders (comorbidity). METHOD: Diagnoses were made with the Structured Clinical Interview for DSM-IV before the treatment, and the personality evaluation with the Maudsley Personality Inventory was made during the follow-up. Four groups were analyzed: a control group (n = 30), a major depression without panic disorder group (n = 45); a panic disorder without major depression group (n = 56) and a comorbidity group (n = 21), with major depression and panic disorder, simultaneously. RESULTS: All disorder groups had significantly higher neuroticism means when compared to the control group. The highest mean was in the comorbidity group, followed by the major depression group and the panic disorder group. The difference of neuroticism means between the comorbidity group and the panic disorder group also reached statistical significance. The lowest extraversion mean was in the comorbidity group, followed by the major depression group, the panic disorder group, and the control group. Compared to normal controls, extraversion was significantly low in the comorbidity and major depression groups. CONCLUSION: In our sample, there was a continuum of personality traits between panic disorder and major depression and, the co-occurrence of these disorders was associated with accentuated personality traits.

Comparison between hyperventilation and breath-holding in panic disorder: patients responsive and non-responsive to both tests.

Our aim was to compare the demographic and psychopathological features of panic disorder (PD) patients who underwent hyperventilation and breath-holding challenge tests, and to describe the features of patients who had a panic attack after both tests versus those patients who did not experience panic after either test. Eighty-five PD patients were induced to hyperventilate (30 breaths/min) for 4 min, and a week later to hold their breath for as long as possible four times with a 2-min interval in between. Anxiety scales were applied before and after the tests. Patients who responded with a panic attack to both tests (BPA, n = 25) were compared with patients who experienced spontaneous panic attacks but did not panic in response to the two tests (NPA, n = 16). The BPA group had a significantly higher presence of respiratory symptoms during a panic attack. The criteria for the respiratory PD subtype were fulfilled in 18 (72.0%) BPA patients and in 6 (37.5%) NPA patients. The BPA patients had a later onset of panic disorder and a higher familial prevalence of PD. Our data suggest that there is a distinction between PD patients who were sensitive to both hyperventilation and breath-holding tests and PD patients who were not affected by the challenge tests. The panic attack may be a final common pathway for different types of stimuli, and respiratory tests may characterize different PD subgroups.

Do social anxiety disorder patients belong to a bipolar spectrum subgroup?

BACKGROUND: It has been proposed that all forms of bipolar disorder-perhaps all primary affective disorders-are best conceptualized as a spectrum of related illness, clinically overlapping but not necessarily genetically uniform illnesses. We aim to describe with retrospective methodology the demographic, clinical, and therapeutic response in a group of social anxiety disorder (SA) patients who improves while taking antidepressants and compare them with bipolar II (B-II) patients. METHODS: 57 SA outpatients (DSM-IV) were diagnosed and naturalistic efficacious treated with selective serotonin reuptake inhibitors (SSRI). Their demographic, clinical features and therapeutic response were compared with 41 DSM-IV bipolar II patients in their starting evaluations in our outpatient clinic in the Federal University of Rio de Janeiro, Brazil. RESULTS: There is a sub-group of SA patients who improves while taking antidepressants and presents a clear hypomanic phase. Their improvement is identical to a mild/moderate hypomanic state. Without the antidepressant, the symptoms of SA return. The SA and B-II patients have a similar number of previous depressive episodes, alcohol abuse, suicide attempts, and family history for mood disorder. LIMITATIONS: It is a retrospective data description based on a naturalist follow-up. CONCLUSION: Some SA patients have demographic, clinical and therapeutic features similar to B-II patients and they might just be a Bipolar-III sub-group with a higher level of complains to social situations and without spontaneous hypomania during lifetime.

Demographic and clinical features of schizoaffective (schizobipolar) disorder--a 5-year retrospective study. Support for a bipolar spectrum disorder.

BACKGROUND: Schizobipolar disorder is considered related to both schizophrenia and bipolar disorder. We aimed to describe with retrospective methodology the demographic, clinical, and treatment features in a group of schizobipolar disorder patients who have been treated for at least a 5-year period and compare them with bipolar I and schizophrenic patients who were treated during the same period. METHOD: We compared the demographic and clinical data of 61 schizobipolar, 57 bipolar I, and 55 schizophrenic outpatients who were diagnosed and treated for at least 5 years in the outpatient clinic in the Federal University of Rio de Janeiro. RESULTS: The schizobipolar disorder patients had a profile similar to the bipolar I patients but are significantly different from schizophrenic patients in educational level, marital status, occupation, drug and alcohol abuse episodes, presence of depressive, mixed and maniac episodes, family history of bipolar I and mood disorders, and use of medications. Only the age of onset, suicide attempts, and family history of suicide are not significantly different among the groups. The schizophrenic patients used antipsychotics for more days and the schizobipolar and bipolar I used more antidepressants and mood stabilizers. 37 (60.6%) schizobipolar patients had their diagnosis changed to bipolar disorder by their physician in different periods during the period studied. LIMITATIONS: It is a retrospective data description based on a naturalistic treatment. The family history was collected from the patient and whenever possible from one first-degree relative. CONCLUSION: Schizobipolar disorder patients have demographic, clinical and therapeutic features similar to bipolar I patients and data support its definite inclusion in the bipolar spectrum group.

A three-year follow-up study of patients with the respiratory subtype of panic disorder after treatment with clonazepam.

The demographic, clinical and therapeutic features of the respiratory subtype of panic disorder (PD) versus the non-respiratory subtype were studied in a prospective design. Sixty-seven PD outpatients (DSM-IV), who had previously been categorized into respiratory (n=35) and non-respiratory (n=32) subgroups, were openly treated with clonazepam for a 3-year period. The principal measure of efficacy was the number of panic attacks, obtained from the Sheehan Panic and Anticipatory Anxiety Scale. In the first 8 weeks of treatment (acute phase), the respiratory subtype group had a significantly faster response to clonazepam. During the follow-up (weeks 12-156), the two subgroups did not differ significantly in the number of panic attacks experienced from baseline to end point. Patients in the respiratory subtype were characterized by a later onset of disorder and a family history of PD. Patients in the non-respiratory subgroup had a significantly higher number of past depressive episodes than those in the respiratory subgroup. The respiratory subgroup had a faster response after 8 weeks of treatment and an equivalent response in the 3-year follow-up period. Clonazepam had a sustained therapeutic effect over the entire treatment period.

Diurnal panic attacks with and without nocturnal panic attacks: are there some phenomenological differences?

OBJECTIVE: To compare nocturnal and diurnal panic attacks in a cross-sectional study and in a longitudinal prospective short-term follow-up. METHODS: We selected 57 panic disorder (PD) subjects (DSM-IV) and rated them with the Panic Disorder Severity Scale (PDSS) at baseline and after 30 days of treatment with nortriptyline, and with the Eysenck Personality Inventory and the Brown Attention Deficit Disorder (ADD) Scale at baseline. RESULTS: The sample was divided into a nocturnal and diurnal panic attack (NDPA) group--57.9% (n = 33)--and a diurnal panic attack (DPA) group--42.1% (n = 24). The groups showed a similar mean age at onset of PD and a pattern of prominent respiratory symptoms. The PDSS did not differ between the groups following short-term treatment (p = 0.451). There were also neither significant differences in Neuroticism (p = 0.094) and Extroversion (p = 0.269) nor in the Brown ADD Scale (p = 0.527). CONCLUSION: In our study, patients with both nocturnal and diurnal panic attacks showed similar features in their phenomenology and short-term outcome when compared to pure diurnal panic attacks patients.