Valproate Adjuvant Cognitive Behavioral Therapy in Panic Disorder Patients With Comorbid Bipolar Disorder: Case Series and Review of the Literature

Anxiety disorders are the most common comorbid psychiatric disorders in patients with bipolar disorder. Managing anxiety symptoms in comorbid conditions is challenging and has received little research interest. The findings from preclinical research on fear conditioning, an animal model of anxiety disorder, have suggested that memory reconsolidation updating (exposure-based therapy) combined with valproate might facilitate the amelioration of fear memories. Here, three cases of successful amelioration of agoraphobia and panic symptoms through valproate adjuvant therapy for cognitive behavioral therapy in patients who failed to respond to two to three consecutive standard pharmacotherapy trials over several years are described. To the best of the author’s knowledge, this is the first attempt to combine CBT with valproate in patients with panic disorder, agoraphobia, and comorbid bipolar disorder. Additionally, the background preclinical research on this combination therapy based on the reconsolidation-updating mechanism, the inhibition of histone deacetylase 2, and critical period reopening, off-label use of valproate in panic disorder, plasticity-augmented psychotherapy, and how to combine valproate with CBT is discussed.     

Functional Impairment in Patients with Panic Disorder

Objective Anxiety and depression and sociodemographic factors such as age, gender, education level, income, and marital status among people with panic disorder (PD) are associated with functional impairment in the areas of work, social, and family. Although both PD-specific scales such as the Panic Disorder Severity Scale (PDSS) and Anxiety Sensitivity Inventory-Revised (ASI-R) and early trauma have been investigated, their relationship with functional impairment in PD patients has not been clarified. Methods This study included 267 PD patients. The PDSS, Beck Depression Inventory (BDI), ASI-R, and Early Trauma Inventory were used. Pearson’s correlation and multiple linear regression analyses were performed. The Sheehan Disability Scale (SDS) was administered to assess the functional impairment level in PD patients. Results Our findings showed that high levels of PDSS, BDI, and ASI-R were significantly correlated with the functional impairment among PD patients. Multiple regression analyses showed that PDSS, BDI, and ASI-R can predict the functional impairment levels, and PDSS and ASI-R were significantly associated with lost and underproductive days in PD patients. Conclusion Panic-specific symptoms, depression, and AS are associated with functional impairment level in PD patients. Elevated symptom severity can play a role by affecting productivity and daily responsibilities in PD patients.     

Intolerance of uncertainty in youth: Psychometrics of the Intolerance of Uncertainty Index-A for Children

Intolerance of uncertainty (IU) is a cognitive vulnerability for pathological anxiety. The current study adapted the Intolerance of Uncertainty Index-A for Children (IUI-A-C), and created a single-item Intolerance of Uncertainty Clinician-Rated Index (IUCR), both of which assess a youth’s general inability to endure uncertainty. Psychometric properties of these two measures were evaluated. Participants were 146 youth aged 7–17 years seeking treatment for anxiety. The IUI-A-C evidenced individual item performance (i.e., correlations between each item and the total remainder score > .40, ps <.001), internal consistency, convergent validity with the IUCR and self-report measures of anxiety and functional impairment, divergent validity with ADHD severity, and retest reliability with a mean interval of over four weeks. The IUCR also evidenced convergent validity with the IUI-A-C and self-report measures of anxiety and functional impairment and divergent validity with ADHD severity. The IUI-A-C predicted composite principal diagnosis severity but did not predict composite GAD diagnosis severity. The IUI-A-C and IUCR have utility as measures of IU in youth. The role of IU in specific anxiety disorders and future research are discussed.     

Relationship between Personality and Insomnia in Panic Disorder Patients

Objective

Panic disorder (PD) is frequently comorbid with insomnia, which could exacerbate panic symptoms and contribute to PD relapse. Research has suggested that characteristics are implicated in both PD and insomnia. However, there are no reports examining whether temperament and character affect insomnia in PD. Thus, we examined the relationship between insomnia and personality characteristics in PD patients.

Methods

Participants were 101 patients, recruited from 6 university hospitals in Korea, who met the DSM-IV-TR criteria for PD. We assessed sleep outcomes using the sleep items of 17-item Hamilton Depression Rating Scale (HAMD-17)(item 4=onset latency, item 5=middle awakening, and item 6=early awakening) and used the Cloninger''s Temperament and Character Inventory-Revised-Short to assess personality characteristics. To examine the relationship between personality and insomnia, we used analysis of variance with age, sex, and severity of depression (total HAMD scores minus sum of the three sleep items) as the covariates.

Results

There were no statistical differences (p>0.1) in demographic and clinical data between patients with and without insomnia. Initial insomnia (delayed sleep onset) correlated to a high score on the temperamental dimension of novelty seeking 3 (NS3)(F_1,96=6.93, p=0.03). There were no statistical differences (p>0.1) in NS3 between patients with and without middle or terminal insomnia.

Conclusion

The present study suggests that higher NS3 is related to the development of initial insomnia in PD and that temperament and character should be considered when assessing sleep problems in PD patients.     

Clinical Experience with Mirtazapine in the Treatment of Panic Disorder

Data from treatment trials and biological challenge studies implicate involvement of both the serotonergic and the noradrenergic neurotransmitter systems in the pathophysiology of panic disorder. Mirtazapine, a newer antidepressant with a novel mechanism of action enhancing both norepinephrine and serotonin levels without reuptake inhibition, is a good candidate for the treatment of panic disorder. Ten adult outpatients with a primary diagnosis of panic disorder were treated openly with mirtazapine. Starting dose and titration were determined by individual clinical characteristics. Data on emergent side effects and clinical response were obtained at all follow-up visits, which typically occurred biweekly for 16 weeks. At the first follow-up visit (week 2–3), 4 of 10 patients met the criteria for response. Based on all available data, seven of the original sample demonstrated an acute response (defined as CGI = 2 or 3) by weeks 5–7, and six continued to have a positive long-term response at the 16-week end point. Side effects were reported by seven patients, with increased appetite and weight gain the most common. Prominent antihistaminic side effects such as sedation, enhanced appetite, and anxiolysis were often desired in the initial phase of treatment.     

不同性别惊恐障碍患者的临床症状比较

目的 了解惊恐障碍患者临床症状的性别差异。方法 对连续门诊的54例男性惊恐障碍患者和46例女性惊恐障碍患者的临床症状进行对照比较。结果 在头晕/步态不稳或晕厥,震颤或发抖,恶心或腹部不适等3项症状上,在性别存在显著的差异(P<0 .05)。结论 惊恐障碍可能存在男、女不同的亚型。     

Intolerance of uncertainty and obsessive-compulsive disorder dimensions

Intolerance of uncertainty (IU), which can include prospective (i.e., desire for predictability) and inhibitory (i.e., uncertainty paralysis) IU, is widely understood to be a central underlying component of obsessive-compulsive disorder (OCD). IU has several treatment implications, yet research on the differences in IU underlying OCD dimensions is limited and does not account for covarying effects of overlapping symptoms, shared variance in IU, demographic variables, and comorbid psychiatric conditions like generalized anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). A sample of 974 patients with diagnosed OCD enrolled in residential, partial hospitalization, and intensive outpatient treatment programs for OCD and anxiety completed self-report measures of OCD symptoms and IU at admission. Structural equation modeling included prospective. inhibitory IU, and common IU and covariates (i.e., race, ethnicity, level of care, and comorbid GAD and PTSD) as predictors of four common OCD dimensions found that contamination and unacceptable thoughts symptoms evidenced a unique relationship with IU. Specifically, whereas a common IU factor predicted all four OCD symptom dimensions, inhibitory IU uniquely predicted contamination and unacceptable thoughts symptoms over and above covarying effects. Individuals with contamination and unacceptable thoughts symptoms may be more likely to feel “paralyzed” by uncertainty due to overreliance on overt immediate rituals, outright avoidance, rumination, or difficulties with emotion regulation, and may benefit from additional psychoeducation, problem-solving, and accountability. Broadly, individuals with OCD may benefit from explicit discussions about IU-related expectancies and disconfirmation of fears.     

Orbito-Frontal Cortex Volumes in Panic Disorder

Objective

Given the association between the pathophysiology of panic disorder and prefrontal cortex function, we aimed to perform a volumetric MRI study in patients with panic disorder and healthy controls focusing on the in vivo neuroanatomy of the OFC.

Methods

Twenty right-handed patients with panic disorder and 20 right-handed healthy control subjects were studied. The volumes of whole brain, total white and gray matters, and OFC were measured by using T1-weighted coronal MRI images, with 1.5-mm-thick slices, at 1.5T. In addition, for psychological valuation, Hamilton Depression Rating (HDRS) and Panic Agoraphobia Scales (PAS) were administered.

Results

Unadjusted mean volumes of the whole brain volume, total white and gray matter were not different between the patients and healthy controls while the patient group had significantly smaller left (t=-6.70, p<0.0001) and right (t=-5.86, p<0.0001) OFC volumes compared with healthy controls.

Conclusion

Our findings indicate an alteration of OFC morphology in the panic disorder and suggest that OFC abnormalities may be involved in the pathophysiology of panic disorder.     

“But it might be a heart attack”: Intolerance of uncertainty and panic disorder symptoms

Panic disorder models describe interactions between feared anxiety-related physical sensations (i.e., anxiety sensitivity; AS) and catastrophic interpretations therein. Intolerance of uncertainty (IU) has been implicated as necessary for catastrophic interpretations in community samples. The current study examined relationships between IU, AS, and panic disorder symptoms in a clinical sample. Participants had a principal diagnosis of panic disorder, with or without agoraphobia (n = 132; 66% women). IU was expected to account for significant variance in panic symptoms controlling for AS. AS was expected to mediate the relationship between IU and panic symptoms, whereas IU was expected to moderate the relationship between AS and panic symptoms. Hierarchical linear regressions indicated that IU accounted for significant unique variance in panic symptoms relative to AS, with comparable part correlations. Mediation and moderation models were also tested and suggested direct and indirect effects of IU on panic symptoms through AS; however, an interaction effect was not supported. The current cross-sectional evidence supports a role for IU in panic symptoms, independent of AS.     

Clinical Characteristics of the Respiratory Subtype in Panic Disorder Patients

Objective

Panic disorder has been suggested to be divided into the respiratory and non-respiratory subtypes in terms of its clinical presentations. The present study aimed to investigate whether there are any differences in treatment response and clinical characteristics between the respiratory and non-respiratory subtypes of panic disorder patients.

Methods

Among the 48 patients those who completed the study, 25 panic disorder patients were classified as the respiratory subtype, whereas 23 panic disorder patients were classified as the non-respiratory subtype. All patients were treated with escitalopram or paroxetine for 12 weeks. We measured clinical and psychological characteristics before and after pharmacotherapy using the Panic Disorder Severity Scale (PDSS), Albany Panic and Phobic Questionnaire (APPQ), Anxiety Sensitivity Index-Revised (ASI-R), State-Trait Anxiety Inventory (STAI-T, STAI-S), Hamilton Anxiety Rating Scale (HAM-A), and Hamilton Depression Rating Scale (HAM-D).

Results

The prevalence of the agoraphobia was significantly higher in the respiratory group than the non-respiratory group although there were no differences in gender and medication between the two groups. The respiratory group showed higher scores on the fear of respiratory symptoms of the ASI-R. In addition, after pharmacotherapy, the respiratory group showed more improvement in panic symptoms than the non-respiratory group.

Conclusion

Panic disorder patients with the respiratory subtype showed more severe clinical presentations, but a greater treatment response to SSRIs than those with non-respiratory subtype. Thus, classification of panic disorder patients as respiratory and non-respiratory subtypes may be useful to predict clinical course and treatment response to SSRIs.     

Early Trauma Is Associated with Poor Pharmacological Treatment Response in Patients with Panic Disorder

Objective Pharmacotherapy is established as an effective method for reducing symptoms of panic disorder (PD). However, about 20–40% of PD patients are treatment-resistant. Predictors of pharmacotherapy outcomes for PD patients are needed. Methods This study included 152 PD patients to measure the clinical severities of PD symptoms and used the Early Trauma Inventory (ETI) to measure early trauma. Treatment response was defined as a 40% reduction in the total Panic Disorder Severity Scale score from baseline. We measured the treatment responses at 8 weeks and 6 months. Binary logistic regression was used to predict treatment response after controlling for confounding variables. Results Early sexual trauma alone was associated with poor treatment response at 8 weeks. However, at 6 months, the total ETI score was associated with an unfavorable treatment response. Conclusion Therefore, our study suggests that clinicians need to be aware of a history of early trauma to optimize treatment outcomes for PD patients.     

Panic Disorder, Panic Attacks and Panic Attack Symptoms across Race-Ethnic Groups: Results of the Collaborative Psychiatric Epidemiology Studies

The current study investigates race-ethnic differences in rates of panic disorder, panic attacks and certain panic attack symptoms by jointly combining three major national epidemiological databases. The compared groups were White, African American, Latino and Asian. The White group had significantly higher rates of panic disorder, and of many panic symptoms, including palpitations, as compared to the African American, Asian and Latino groups. Several expected race-ethnic differences were not found. An explanation for these findings are adduced, and suggestions are given for future studies so that possible ethnic-racial differences in panic disorder, panic attacks and panic attack symptoms can be investigated in a more rigorous manner.     

The Effects of 5-HTR1A Polymorphism on Cingulum Connectivity in Patients with Panic Disorder

Objective

Serotonin-1A receptors (5-HTR1A) is suggested to be involved in the etiology of several psychiatric disorders including panic disorder (PD). A few imaging studies have suggested the alterations of the cingulum bundle in PD. The objective of this study is to examine the structural changes of cingulum related to the 5-HTR1A polymorphism rs6295 in the patients with PD.

Methods

Thirty-two right-handed patients with PD [11 men, 21 women; 40.34±13.17 (mean±SD) age] who met the diagnostic criteria in Structured Clinical Interview for DSM-IV were examined by means of MRI at 3 Tesla. We divided the patients with PD into CC genotype group and non CC genotype group (GG/CG genotype group) of the 5-HTR1A rs6295 polymorphism to compare the cingulum white matter connectivity.

Results

Tract-based spatial statistics showed significantly increased fractional anisotropy (FA) values in cingulate gyrus process of left cingulum in 5-HTR1A CC genotype compared to GG/CG genotype in PD. Significant positive correlations were shown between the Albany Panic and Phobia Questionnaire (APPQ) interoceptive fear subscale scores, the Anxiety Sensitivity Inventory-Revised fear of publicly observable anxiety reaction subscale scores and FA values of cingulate gyrus process of left cingulum in 5-HTR1A rs6295 GG/CG genotype group. In CC genotype group, APPQ total, APPQ agoraphobia subscale and APPQ social phobia subscale scores also showed significant positive correlations with FA values of hippocampal process of right cingulum.

Conclusion

This preliminary study suggests that 5-HTR1A polymorphism may be associated with the cingulum white matter connectivity in PD.     

Psychometric properties of the Intolerance of Uncertainty Scale-12 in generalized anxiety disorder: Assessment of factor structure,measurement properties and clinical utility

Intolerance of uncertainty is a psychological vulnerability implicated in the development and maintenance of generalized anxiety disorder (GAD). The Intolerance of Uncertainty Scale-12 (IUS-12) is a widely used measure, however no studies have thoroughly tested the psychometric properties in a clinically diagnosed GAD sample. This study aimed to evaluate the factor structure, measurement properties and clinical utility of the IUS-12 in clinical and non-clinical samples. Participants were screened using the Anxiety Disorders Interview Schedule for DSM-IV to ascertain clinical (n = 136: principal diagnosis of GAD) or non-clinical status (n = 76). Confirmatory factor analysis determined that the bifactor type (two-factor testlet) model demonstrated significantly better fit in comparison to the unidimensional model for the clinical sample. The IUS-12 exhibited limited multidimensionality indicating that only the total score provides meaningful interpretation. The IUS-12 demonstrated good construct validity (with DASS-21, MCQ-30, and PSWQ), good internal consistency, as well as good test-retest reliability over 12-weeks. The IUS-12 demonstrated responsivity to treatment following cognitive behavioral therapy and mindfulness based psychological interventions. Receiver operating characteristic curve analysis indicated an optimal cut-off score of 28 for distinguishing individuals with GAD from non-clinical cases. Overall, the IUS-12 is a valid, reliable and clinically useful instrument for individuals with GAD.     

Panic Disorder in Clinically Referred Children and Adolescents

The present study examined the frequency and characteristics of panic disorder in children and adolescents who had been referred to a pediatric psychopharmacology clinic. Of the 280 children and adolescents evaluated in this clinic, 35 were diagnosed with panic disorder using a semi-structured clinical interview (K-SADS) and other objective measures. Approximately half of the youngsters with panic disorder also met criteria for the diagnosis of agoraphobia. There was extensive comorbidity between panic disorder and other internalizing and externalizing disorders. Parents reported clinically significant levels of child symptomatology on the CBCL. Teacher-and child-reported symptomatology on the CBCL was within the normal range. At the same time, it was notable that no child had been referred specifically for evaluation or treatment of panic disorder or agoraphobia. Implications for clinical assessment/identification and treatment are discussed. This paper was presented at the 39th Annual Convention of the Association for Behavioral and Cognitive Therapies, November 18, 2005, Washington, DC.     

Intolerance of uncertainty mediates the relationship between responsibility beliefs and compulsive checking

Both responsibility beliefs and intolerance of uncertainty have been implicated in compulsive checking behavior. Despite this, the exact relationship of these two variables with compulsive checking behavior is yet to be determined. Using a mixed sample of individuals consisting of compulsive checkers as well as non-clinical participants, we assessed the validity of a mediation model in which the relationship between responsibility beliefs and compulsive checking was mediated by intolerance of uncertainty. Although both responsibility beliefs and intolerance of uncertainty were correlated with the frequency of compulsive checking, the relationship between responsibility and checking was fully mediated by intolerance of uncertainty. Implications for the understanding of the relationship between these constructs, as well for conceptualisation of clinical checking problems are discussed.     

Serum S100B Protein Levels in Patients with Panic Disorder: Effect of Treatment with Selective Serotonine Reuptake Inhibitors

ObjectiveAltered serum S100B protein levels have been shown in several psychiatric disorders. Our aim was to investigate whether plasma S100B is different in patients with panic disorder (PD) when compared with controls. Our second aim was to investigate whether treatment with SSRIs have an effect on S100B levels in patients with PD.MethodsThe sample included 32 patients diagnosed with PD (21 women, 11 men) per DSM-IV criteria and 21 healthy controls (11 women, 10 men). S100B levels were measured with BioVendor Human S100B ELISA (Enzyme Linked Immunosorbent Assay) kit.Results14 patients were not on drug treatment (43.8%) while 18 patients were taking various SSRIs. Median S100B value was 151.7 pg/mL (minimum-maximum: 120.4-164.7 pg/mL) in the control group, 147.4 pg/mL (minimum-maximum: 138.8-154.1 pg/mL) in the drug free group and 153.0 pg/mL (minimum-maximum: 137.9-164.7 pg/mL) in the treatment group. Kruskal-Wallis analysis showed a significant diffrerence among the three groups (z=9.9, df=2, p=0.007). Follow up Mann-Whitney-U tests indicated that while the control and the patients with treatment were not significantly different (z=-0.05, p=0.96), there were significant differences between the control group and untreated patients (z=-2.6, p=0.009) and treated and untreated patients (z=-3.0, p=0.003).ConclusionOur results suggested that, serum S100B protein level might be decreased in untreated PD patients and that patients who were treated with SSRIs had similar S100B level to healthy controls.     

Intolerance of uncertainty and obsessive-compulsive symptom expression

Background and objectivesResearch suggests a relationship between intolerance of uncertainty (IU) and obsessive-compulsive disorder (OCD), though this has been limited to self-report measures of OCD symptoms. The current investigation examined the relationship between IU and multiple symptom domains of OCD using self-report and in vivo assessments of OC symptoms.MethodsFive separate studies are presented in which undergraduate students (N = 603) were administered a self-report measure of IU and tasks related to either ordering and arranging, checking, washing, contamination avoidance, or neutralization.ResultsIntolerance of uncertainty was found to be significantly related to each self-report measure of the OCD symptom domains (ps < .01). Further, IU was predictive of performance on all in vivo tasks (ps < .05) except one concerning neutralizing/harm-related obsessions.LimitationsThis study relied on an unselected sample and was correlational in design.ConclusionsThe current study demonstrates that IU is related to multiple OC symptom dimensions. Future experimental research is warranted to evaluate the causal role of IU in OCD.     

The Effect of Agoraphobia on Oxidative Stress in Panic Disorder

We aimed to investigate whether agoraphobia (A) in panic disorder (PD) has any effects on oxidative and anti-oxidative parameters. We measured total antioxidant capacity (TAC), paraoxonase (PON), arylesterase (ARE) antioxidant and malondialdehyde (MDA) oxidant levels using blood samples from a total of 31 PD patients with A, 22 PD patients without A and 53 control group subjects. There was a significant difference between the TAC, PON, ARE and MDA levels of the three groups consisting of PD with A, PD without A and the control group. The two-way comparison to clarify the group creating the difference showed that the TAC, PON, and ARE antioxidants were significantly lower in the PD with A group compared to the control group while the MDA oxidant was significantly higher. There was no significant difference between the PD without A and control groups for TAC, PON, ARE and MDA levels. We clearly demonstrated that the oxidative stress and damage to the anti-oxidative mechanism are significantly higher in the PD group with A. These findings suggest that oxidative/anti-oxidative mechanisms may play a more important role on the pathogenesis of PB with A.