Hyperventilation in panic disorder patients and healthy first-degree relatives

Our aim was to observe the induction of panic attacks by a hyperventilation challenge test in panic disorder patients (DSM-IV) and their healthy first-degree relatives. We randomly selected 25 panic disorder patients, 31 healthy first-degree relatives of probands with panic disorder and 26 normal volunteers with no family history of panic disorder. All patients had no psychotropic drugs for at least one week. They were induced to hyperventilate (30 breaths/min) for 4 min and anxiety scales were applied before and after the test. A total of 44.0% (N = 11) panic disorder patients, 16.1% (N = 5) of first-degree relatives and 11.5% (N = 3) of control subjects had a panic attack after hyperventilating (chi² = 8.93, d.f. = 2, P = 0.011). In this challenge test the panic disorder patients were more sensitive to hyperventilation than first-degree relatives and normal volunteers. Although the hyperventilation test has a low sensitivity, our data suggest that there is no association between a family history of panic disorder and hyperreactivity to an acute hyperventilation challenge test. Perhaps cognitive variables should be considered to play a specific role in this association since symptoms of a panic attack and acute hyperventilation overlap.

Mirtazapine versus fluoxetine in the treatment of panic disorder

Mirtazapine is an antidepressant whose side effect profile differs from that of first-line agents (selective serotonin reuptake inhibitors) used in the treatment of panic disorder. The present study compared the effect of mirtazapine and fluoxetine in the treatment of panic disorder in a double-blind, randomized, flexible-dose trial conducted with outpatients. After a 1-week single-blind placebo run-in, 27 patients entered an 8-week double-blind phase in which they were randomly assigned to treatment with either mirtazapine or fluoxetine. Both groups improved significantly in all but one efficacy measure (P<=0.01). ANOVA showed no significant differences between the two treatment groups in number of panic attacks, Hamilton Anxiety Scale or Sheehan Phobic Scale, whereas measures of patient global evaluation of phobic anxiety were significantly different between groups (F1,20 = 6.91, P = 0.016) favoring mirtazapine. For the 22 patients who completed the study, the mean daily dose of mirtazapine was 18.3 ± 1.3 vs 14.0 ± 1.0 mg for fluoxetine at the endpoint. Weight gain occurred more frequently in the mirtazapine group (50 vs 7.7%, P = 0.04) and nausea and paresthesia occurred more often in the fluoxetine group (P = 0.01). Results suggest that mirtazapine has properties that make it attractive for the treatment of panic disorder.

Respiratory panic disorder subtype and sensitivity to the carbon dioxide challenge test

The aim of the present study was to verify the sensitivity to the carbon dioxide (CO2) challenge test of panic disorder (PD) patients with respiratory and nonrespiratory subtypes of the disorder. Our hypothesis is that the respiratory subtype is more sensitive to 35% CO2. Twenty-seven PD subjects with or without agoraphobia were classified into respiratory and nonrespiratory subtypes on the basis of the presence of respiratory symptoms during their panic attacks. The tests were carried out in a double-blind manner using two mixtures: 1) 35% CO2 and 65% O2, and 2) 100% atmospheric compressed air, 20 min apart. The tests were repeated after 2 weeks during which the participants in the study did not receive any psychotropic drugs. At least 15 of 16 (93.7%) respiratory PD subtype patients and 5 of 11 (43.4%) nonrespiratory PD patients had a panic attack during one of two CO2 challenges (P = 0.009, Fisher exact test). Respiratory PD subtype patients were more sensitive to the CO2 challenge test. There was agreement between the severity of PD measured by the Clinical Global Impression (CGI) Scale and the subtype of PD. Higher CGI scores in the respiratory PD subtype could reflect a greater sensitivity to the CO2 challenge due to a greater severity of PD. Carbon dioxide challenges in PD may define PD subtypes and their underlying mechanisms.

The size and prevalence of the cavum septum pellucidum are normal in subjects with panic disorder

Panic disorder is thought to involve dysfunction in the septohippocampal system, and the presence of a cavum septum pellucidum might indicate the aberrant development of this system. We compared the prevalence and size of cavum septum pellucidum in 21 patients with panic disorder and in 21 healthy controls by magnetic resonance imaging. The length of the cavum septum pellucidum was measured by counting the number of consecutive 1-mm coronal slices in which it appeared. A cavum septum pellucidum of >6 mm in length was rated as large. There was no significant difference in the proportion of patients (16 of 21 or 76.2%) and controls (18 of 21 or 85.7%) with a cavum septum pellucidum (P = 0.35, Fisher's exact test, one-tailed), and no members of either group had a large cavum septum pellucidum. The mean cavum septum pellucidum rating in the patient and control groups was 1.81 (SD = 1.50) and 2.09 (SD = 1.51), respectively. There were also no significant differences between groups when we analyzed cavum septum pellucidum ratings as a continuous variable (U = 196.5; P = 0.54). Across all subjects there was a trend towards a higher prevalence of cavum septum pellucidum in males (100%, 10 of 10) than females (75%, 24 of 32; P = 0.09, Fisher's exact test, one-tailed). Thus, we conclude that, while panic disorder may involve septo-hippocampal dysfunction, it is not associated with an increased prevalence or size of the cavum septum pellucidum.

Is avoidant disorder part of the social phobia spectrum in a referred sample of Brazilian children and adolescents?

The diagnosis of avoidant disorder was deleted from the Diagnostic and Statistical Manual of Mental disorders - fourth edition (DSM-IV) based on a `committee decision' suggesting that avoidant disorder is part of the social phobia spectrum. The objective of the present study was to examine the nature of this clinical association in a referred sample of Brazilian children and adolescents. We assessed a referred sample of 375 youths using semi-structured diagnostic interview methodology. Demographic (age at admission to the study and sex) and clinical (level of impairment, age at onset of symptoms and pattern of comorbidity) data were assessed in subsamples of children with avoidant disorder (N = 7), social phobia (N = 26), and comorbidity between both disorders (N = 24). Although a significant difference in the male/female ratio was detected among groups (P = 0.03), none of the other clinical variables differed significantly among subjects that presented each condition separately or in combination. Most of the children with avoidant disorder fulfilled criteria for social phobia. Thus, our findings support the validity of the conceptualization of avoidant disorder as part of the social phobia spectrum in a clinical sample.

Social disability of Brazilian mood disorder patients

Mood disorders cause many social problems, often involving family relationships. Few studies are available in the literature comparing patients with bipolar, unipolar, dysthymic, and double depressive disorders concerning these aspects. In the present study, demographic and disease data were collected using a specifically prepared questionnaire. Social adjustment was assessed using the Disability Adjustment Scale and family relationships were evaluated using the Global Assessment of Relational Functioning Scale. One hundred patients under treatment for at least 6 months were evaluated at the Psychiatric Outpatient Clinic of the Botucatu School of Medicine, UNESP. Most patients were women (82%) more than 50 (49%) years old with at least two years of follow-up, with little schooling (62% had less than 4 years), and of low socioeconomic level. Logistic regression analysis showed that a diagnosis of unipolar disorder (P = 0.003, OR = 0.075, CI = 0.014-0.403) and dysthymia (P = 0.001, OR = 0.040, CI = 0.006-0.275) as well as family relationships (P = 0.002, OR = 0.953, CI = 0914-0.992) played a significant role in social adjustment. Unipolar and dysthymic patients presented better social adjustment than bipolar and double depressive patients (P < 0.001), results that were not due to social class. These patients, treated at a teaching hospital, may represent the severest mood disorder cases. Evaluations were made knowing the diagnosis of the patients, which might also have influenced some of the results. Social disabilities among mood disorder patients are very frequent and intensive.

The reliability of the Brazilian version of the Composite International Diagnostic Interview (CIDI 2.1)

The objective of the present study was to determine the reliability of the Brazilian version of the Composite International Diagnostic Interview 2.1 (CIDI 2.1) in clinical psychiatry. The CIDI 2.1 was translated into Portuguese using WHO guidelines and reliability was studied using the inter-rater reliability method. The study sample consisted of 186 subjects from psychiatric hospitals and clinics, primary care centers and community services. The interviewers consisted of a group of 13 lay and three non-lay interviewers submitted to the CIDI training. The average interview time was 2 h and 30 min. General reliability ranged from kappa 0.50 to 1. For lifetime diagnoses the reliability ranged from kappa 0.77 (Bipolar Affective Disorder) to 1 (Substance-Related Disorder, Alcohol-Related Disorder, Eating Disorders). Previous year reliability ranged from kappa 0.66 (Obsessive-Compulsive Disorder) to 1 (Dissociative Disorders, Maniac Disorders, Eating Disorders). The poorest reliability rate was found for Mild Depressive Episode (kappa = 0.50) during the previous year. Training proved to be a fundamental factor for maintaining good reliability. Technical knowledge of the questionnaire compensated for the lack of psychiatric knowledge of the lay personnel. Inter-rater reliability was good to excellent for persons in psychiatric practice.

The validity and 4-year test-retest reliability of the Brazilian version of the Eating Attitudes Test-26

In a cross-sectional study conducted four years ago to assess the validity of the Brazilian version of the Eating Attitudes Test-26 (EAT-26) for the identification of abnormal eating behaviors in a population of young females in Southern Brazil, 56 women presented abnormal eating behavior as indicated by the EAT-26 and the Edinburgh Bulimic Investigation Test. They were each matched for age and neighborhood to two normal controls (N = 112) and were re-assessed four years later with the two screening questionnaires plus the Composite International Diagnostic Interview (CIDI). The EAT results were then compared to diagnoses originating from the CIDI. To evaluate the temporal stability of the two screening questionnaires, a test-retest design was applied to estimate kappa coefficients for individual items. Given the prevalence of eating disorders of 6.2%, the CIDI psychiatry interview was applied to 161 women. Of these, 0.6% exhibited anorexia nervosa and 5.6%, bulimia nervosa (10 positive cases). The validity coefficients of the EAT were: 40% sensitivity, 84% specificity, and 14% positive predictive value. Cronbach's coefficient was 0.75. For each EAT item, the kappa index was not higher than 0.344 and the correlation coefficient was lower than 0.488. We conclude that the EAT-26 exhibited low validity coefficients for sensitivity and positive predictive value, and showed a poor temporal stability. It is reasonable to assume that these results were not influenced by the low prevalence of eating disorders in the community. Thus, the results cast doubts on the ability of the EAT-26 test to identify cases of abnormal eating behaviors in this population.

Prenatal and perinatal risk factors for bipolar disorder

Bipolar disorder (BPD) is a severe mental disorder associated with considerable morbidity and mortality. Prenatal insults have been shown to be associated with later development of mental disorders and there is a growing interest in the potential role of prenatal and perinatal risk factors in the development of BPD. The aims of this thesis were to describe the overall study design of the Finnish Prenatal Study of Bipolar Disorders (FIPS-B) and demographic characteristics of the sample. Furthermore, it was aimed to examine the association of parental age, parental age difference, perinatal complications and maternal smoking during pregnancy with BPD. This thesis is based on FIPS-B, a nested case-control study using several nationwide registers. The cases included all people born in Finland between January 1st 1983 and December 31st 1998 and diagnosed with BPD according to the Finnish Hospital Discharge Register (FHDR) before December 31st 2008. Controls for this study were people who were without BPD, schizophrenia or diagnoses related to these disorders, identified from the Population Register Centre (PRC), and matched two-fold to the cases on sex, date of birth (+/- 30 days), and residence in Finland on the first day of diagnosis of the matched case. Conditional logistic regression models were used to examine the association between risk factors and BPD. This study included 1887 BPD cases and 3774 matched controls. The mean age at diagnosis was 19.3 years and females accounted for 68% of the cases. Mothers with the lowest educational level had the highest odds of having BPD in offspring. Being born in Eastern and Southern region of Finland increased the odds of having BPD later in life. A U-shaped distribution of odds ratio was observed between paternal age and BPD in the unadjusted analysis. Maternal age and parental age difference was not associated with BPD. Birth by planned caesarean section was associated with increased odd of BPD. Smoking during pregnancy was not associated with BPD in the adjusted analyses. Region of birth and maternal educational level were associated with BPD. Both young and old father’s age was associated with BPD. Most perinatal complications and maternal smoking during pregnancy were not associated with BPD. The findings of this thesis, considered together with previous literature, suggest that the pre- and perinatal risk factor profile varies among different psychiatric disorders.

A randomized crossover clinical study showing that methylphenidate-SODAS improves attention-deficit/hyperactivity disorder symptoms in adolescents with substance use disorder

Our objective was to evaluate the effectiveness of a long-acting formulation of methylphenidate (MPH-SODAS) on attention-deficit/hyperactivity disorder (ADHD) symptoms in an outpatient sample of adolescents with ADHD and substance use disorders (SUD). Secondary goals were to evaluate the tolerability and impact on drug use of MPH-SODAS. This was a 6-week, single-blind, placebo-controlled crossover study assessing efficacy of escalated doses of MPH-SODAS on ADHD symptoms in 16 adolescents with ADHD/SUD. Participants were randomly allocated to either group A (weeks 1-3 on MPH-SODAS, weeks 4-6 on placebo) or group B (reverse order). The primary outcome measures were the Swanson, Nolan and Pelham Scale, version IV (SNAP-IV) and the Clinical Global Impression Scale (CGI). We also evaluated the adverse effects of MPH-SODAS using the Barkley Side Effect Rating Scale and subject reports of drug use during the study. The sample consisted of marijuana (N = 16; 100%) and cocaine users (N = 7; 43.8%). Subjects had a significantly greater reduction in SNAP-IV and CGI scores (P < 0.001 for all analyses) during MPH-SODAS treatment compared to placebo. No significant effects for period or sequence were found in analyses with the SNAP-IV and CGI scales. There was no significant effect on drug use. MPH-SODAS was well tolerated but was associated with more severe appetite reduction than placebo (P < 0.001). MPH-SODAS was more effective than placebo in reducing ADHD symptoms in a non-abstinent outpatient sample of adolescents with comorbid SUD. Randomized clinical trials, with larger samples and SUD intervention, are recommended.

Anxiety and depression in parents of a Brazilian non-clinical sample of attention-deficit/ hyperactivity disorder (ADHD) students

Higher prevalence rates of anxiety and depression have been reported in parents of children with attention-deficit/hyperactivity disorder (ADHD). The interaction between the burden of ADHD in offspring, a higher prevalence rate of this highly inherited disorder in parents, and comorbidities may explain this finding. Our objective was to investigate levels of ADHD, anxious and depressive symptomatology, and their relationship in parents of ADHD children from a non-clinical sample using a dimensional approach. The sample included 396 students enrolled in all eight grades of a public school who were screened for ADHD using the SNAP IV rating scale. Positive cases were confirmed through a semi-structured interview. Parents of all 26 ADHD students and 31 paired controls were enrolled. A sample of 36 parents of ADHD children (21 mothers, 15 fathers) and 30 parents of control children (18 mothers, 12 fathers) completed the Adult Self Report Scale, State-Trait Anxiety Inventory, and Beck Depression Inventory in order to investigate anxious and depressive symptomatology. Probands' mothers presented a higher level of ADHD symptomatology (with only inattention being a significant cluster). Again, mothers of ADHD children presented higher depressive and anxiety levels; however, these did not correlate with their own ADHD symptomatology. Only trait-anxiety levels were higher in ADHD mothers. Our findings suggest that: 1) anxious and depressive symptoms might be more prevalent in mothers of ADHD students; 2) anxious and depressive symptomatology might be independent of impairment associated with ADHD symptoms; 3) anxious and depressive symptoms are independent of the presence of ADHD.

Effect of auditory training on the middle latency response in children with (central) auditory processing disorder

The purpose of this study was to determine the middle latency response (MLR) characteristics (latency and amplitude) in children with (central) auditory processing disorder [(C)APD], categorized as such by their performance on the central auditory test battery, and the effects of these characteristics after auditory training. Thirty children with (C)APD, 8 to 14 years of age, were tested using the MLR-evoked potential. This group was then enrolled in an 8-week auditory training program and then retested at the completion of the program. A control group of 22 children without (C)APD, composed of relatives and acquaintances of those involved in the research, underwent the same testing at equal time intervals, but were not enrolled in the auditory training program. Before auditory training, MLR results for the (C)APD group exhibited lower C3-A1 and C3-A2 wave amplitudes in comparison to the control group [C3-A1, 0.84 µV (mean), 0.39 (SD - standard deviation) for the (C)APD group and 1.18 µV (mean), 0.65 (SD) for the control group; C3-A2, 0.69 µV (mean), 0.31 (SD) for the (C)APD group and 1.00 µV (mean), 0.46 (SD) for the control group]. After training, the MLR C3-A1 [1.59 µV (mean), 0.82 (SD)] and C3-A2 [1.24 µV (mean), 0.73 (SD)] wave amplitudes of the (C)APD group significantly increased, so that there was no longer a significant difference in MLR amplitude between (C)APD and control groups. These findings suggest progress in the use of electrophysiological measurements for the diagnosis and treatment of (C)APD.

The novel p.E89K mutation in the SRY gene inhibits DNA binding and causes the 46,XY disorder of sex development

Male sex determination in humans is controlled by the SRY gene, which encodes a transcriptional regulator containing a conserved high mobility group box domain (HMG-box) required for DNA binding. Mutations in the SRY HMG-box affect protein function, causing sex reversal phenotypes. In the present study, we describe a 19-year-old female presenting 46,XY karyotype with hypogonadism and primary amenorrhea that led to the diagnosis of 46,XY complete gonadal dysgenesis. The novel p.E89K missense mutation in the SRY HMG-box was identified as a de novo mutation. Electrophoretic mobility shift assays showed that p.E89K almost completely abolished SRY DNA-binding activity, suggesting that it is the cause of SRY function impairment. In addition, we report the occurrence of the p.G95R mutation in a 46,XY female with complete gonadal dysgenesis. According to the three-dimensional structure of the human SRY HMG-box, the substitution of the conserved glutamic acid residue by the basic lysine at position 89 introduces an extra positive charge adjacent to and between the positively charged residues R86 and K92, important for stabilizing the HMG-box helix 2 with DNA. Thus, we propose that an electrostatic repulsion caused by the proximity of these positive charges could destabilize the tip of helix 2, abrogating DNA interaction.

Psychopharmacotherapy of panic disorder: 8-week randomized trial with clonazepam and paroxetine

The objective of the present randomized, open-label, naturalistic 8-week study was to compare the efficacy and safety of treatment with clonazepam (N = 63) and paroxetine (N = 57) in patients with panic disorder with or without agoraphobia. Efficacy assessment included number of panic attacks and clinician ratings of the global severity of panic disorders with the clinical global impression (CGI) improvement (CGI-I) and CGI severity (CGI-S) scales. Most patients were females (69.8 and 68.4% in the clonazepam and paroxetine groups, respectively) and age (mean ± SD) was 35.9 ± 9.6 years for the clonazepam group and 33.7 ± 8.8 years for the paroxetine group. Treatment with clonazepam versus paroxetine resulted in fewer weekly panic attacks at week 4 (0.1 vs 0.5, respectively; P < 0.01), and greater clinical improvements at week 8 (CGI-I: 1.6 vs 2.9; P = 0.04). Anxiety severity was significantly reduced with clonazepam versus paroxetine at weeks 1 and 2, with no difference in panic disorder severity. Patients treated with clonazepam had fewer adverse events than patients treated with paroxetine (73 vs 95%; P = 0.001). The most common adverse events were drowsiness/fatigue (57%), memory/concentration difficulties (24%), and sexual dysfunction (11%) in the clonazepam group and drowsiness/fatigue (81%), sexual dysfunction (70%), and nausea/vomiting (61%) in the paroxetine group. This naturalistic study confirms the efficacy and tolerability of clonazepam and paroxetine in the acute treatment of patients with panic disorder.

The response of social anxiety disorder patients to threat scenarios differs from that of healthy controls

The objective of the present study was to evaluate the response of social anxiety disorder (SAD) patients to threat scenarios. First-choice responses to 12 scenarios describing conspecific threatening situations and mean scores of defensive direction and defensive intensity dimensions were compared between 87 SAD patients free of medication and 87 matched healthy controls (HC). A significant gender difference in the first-choice responses was identified for seven scenarios among HCs but only for two scenarios among SAD patients. A significantly higher proportion of SAD patients chose "freezing" in response to "Bush" and "Noise" scenarios, whereas the most frequent response by HCs to these scenarios was "check out". SAD males chose "run away" and "yell" more often than healthy men in response to the scenarios "Park" and "Elevator", respectively. There was a positive correlation between the severity of symptoms and both defensive direction and defensive intensity dimensions. Factorial analysis confirmed the gradient of defensive reactions derived from animal studies. SAD patients chose more urgent defensive responses to threat scenarios, seeming to perceive them as more dangerous than HCs and tending to move away from the source of threat. This is consistent with the hypothesis that the physiopathology of anxiety disorders involves brain structures responsible for defensive behaviors.