Promiscuous mutations activate the noncanonical NF-kappaB pathway in multiple myeloma.

Activation of NF-kappaB has been noted in many tumor types, however only rarely has this been linked to an underlying genetic mutation. An integrated analysis of high-density oligonucleotide array CGH and gene expression profiling data from 155 multiple myeloma samples identified a promiscuous array of abnormalities contributing to the dysregulation of NF-kappaB in approximately 20% of patients. We report mutations in ten genes causing the inactivation of TRAF2, TRAF3, CYLD, cIAP1/cIAP2 and activation of NFKB1, NFKB2, CD40, LTBR, TACI, and NIK that result primarily in constitutive activation of the noncanonical NF-kappaB pathway, with the single most common abnormality being inactivation of TRAF3. These results highlight the critical importance of the NF-kappaB pathway in the pathogenesis of multiple myeloma.

Panic attacks in generalized anxiety disorder.

Panic attacks have been reported by patients with generalized anxiety disorder (GAD) in response to catastrophic worry. This has not been characterized in the literature. We examined the prevalence of GAD panic attacks in an anxiety disorders clinic sample. Charts of 254 patients with DSM-IV GAD were retrospectively evaluated. The presence and type of panic attacks were examined as well as correlates including comorbidity, baseline symptom severity, demographic variables, and family history. Twenty-one percent had GAD panic attacks, 21.7% had situationally predisposed attacks, 15.6% had situationally bound attacks, and 39.4% had unexpected panic attacks. The individuals who had GAD panic attacks had higher scores on the Anxiety Sensitivity Index compared with those who also had other types of panic attacks. One in five patients with GAD reported GAD panic attacks; however, these individuals did not differ significantly on the correlates that were evaluated. These findings require replication and further evaluation.

Frontal brain oscillatory coupling in children of parents with social phobia: a pilot study.

Spectral coupling between delta and beta oscillations has been related to anxiety. The authors provide preliminary evidence that frontal brain oscillatory coupling discriminates children born to socially phobic versus healthy parents, despite there being no difference in parental perceptions of their children's shyness.

Potential use of Internet-based screening for anxiety disorders: a pilot study.

BACKGROUND: The Internet is a widely used resource for obtaining health information. Internet users are able to obtain anonymous information on diagnoses and treatment, seek confirmatory information, and are able to self-diagnose. We posted a self-report diagnostic screening questionnaire for DSM-IV anxiety and mood disorders (MACSCREEN) on our clinic website. METHOD: Three hundred and two individuals completed the MACSREEN. For those who qualified for a DSM-IV disorder, self-report symptom severity measures were completed for the specified disorder: Quick Inventory of Depressive Symptomatology, self-report, Social Phobia Inventory, GAD-7, Davidson Trauma Scale, Panic and Agoraphobia Scale, and Yale/Brown Obsessive Compulsive Scale, self-report. Cutoff scores for each self-report measure were used to evaluate clinically significant symptom severity. Respondents were also asked to complete a series of questions regarding their use of the Internet for health information. RESULTS: The mean age of the MACSCREEN sample was 35.2 years (±13.9), where the majority (67.2%) were female. The most frequently diagnosed conditions were social phobia (51.0%), major depressive disorder (32.4%), and generalized anxiety disorder (25.5%). Sixty-five percent of the sample met criteria for at least one disorder. Most respondents reported completing the MACSCREEN, as they were concerned they had an anxiety problem (62.3%). The majority of respondents reported seeking health information concerning specific symptoms they were experiencing (54.6%) and were planning to use the information to seek further assessment (60.3%). CONCLUSION: Individuals with clinically significant disorder appear to be using the Internet to self-diagnose and seek additional information.

The burden of anxiety disorders on the family.

It is well established that individuals with anxiety disorders experience significant impairments in social and occupational functioning. However, the impact of anxiety disorders on family members has not been adequately studied. The objective of the present study was to examine the burden experienced by relatives of anxiety disorder patients. In all, 74 outpatients and 74 family members participated in the study. Family members completed measures that assessed the impact of having an anxiety disordered relative. Results indicate that family members experience significant burden. The burden encompasses several domains including negative effects on physical health, psychological well-being, and family functioning. Burden was positively correlated with the severity of the patient's condition. The presence of a comorbid mood disorder in patients was associated with increased burden. Health-care professionals should assess the impact of anxiety disorders on the patient's family and provide interventions to reduce burden and improve the quality of life of family members.

Trichotillomania in youth: a retrospective case series.

BACKGROUND: The purpose of this study was to investigate the outcome of the naturalistic treatment of youth with Trichotillomania (TTM) in an anxiety disorders clinic sample. METHODS: A retrospective chart review was conducted on 11 treated patients between the ages of 6 and 17, with DSM-IV TTM. RESULTS: Ten patients were initially treated with a serotonin reuptake inhibitor (SRI), whereas one patient was initially treated with an antipsychotic. Three of the 10 patients who started with an SRI had a response (Clinical Global Impression-Improvement Scale (CGI-I)>or=2) in TTM symptoms. Nine patients of the 11 patients were treated with an antipsychotic medication (in 8 patients the antipsychotic was added after an initial trial with an SRI, in 1 patient the antipsychotic was the first line agent), 2 patients remained on an SRI; 8/9 were responders to antipsychotic treatment and 2 patients remitted (complete cessation of hair pulling). Adverse events to the SRI or antipsychotic were experienced by 7/11 patients but did not lead to treatment discontinuation. CONCLUSIONS: This retrospective case series suggests that youth with TTM maybe responsive to pharmacological interventions with SRIs and/or antipsychotic agents, although the response seemed to be more robust with antipsychotics. These preliminary findings will need to be replicated in a larger scale controlled design.

Childhood maltreatment linked to greater symptom severity and poorer quality of life and function in social anxiety disorder.

BACKGROUND: There is a paucity of data examining the prevalence and impact of childhood maltreatment in patients presenting with a primary diagnosis of social anxiety disorder (SAD). We thus examined the presence of a broad spectrum of childhood maltreatment, including physical, sexual, and emotional abuse and neglect, in treatment-seeking individuals with the generalized subtype of SAD (GSAD). We hypothesized that a history of childhood maltreatment would be associated with greater SAD symptom severity and poorer associated function. METHODS: One hundred and three participants with a primary diagnosis of GSAD (mean age 37+/-14; 70% male) completed the well-validated, self-rated Childhood Trauma Questionnaire (CTQ), as well as measures of SAD symptom severity and quality of life. RESULTS: Fully 70% (n=72) of the GSAD sample met severity criteria for at least one type of childhood abuse or neglect as measured by the CTQ subscales using previously established thresholds. CTQ total score adjusted for age and gender was associated with greater SAD severity, and poorer quality of life, function, and resilience. Further, the number of types of maltreatment present had an additive effect, with specific associations for emotional abuse and neglect with SAD severity. CONCLUSIONS: Despite the use of validated assessments, our findings are limited by the retrospective and subjective nature of self-report measures used to assess childhood maltreatment. Nonetheless, these data suggest a high rate of childhood maltreatment in individuals seeking treatment for GSAD, and the association of maltreatment with greater disorder severity suggests that screening is clinically prudent.

Pharmacotherapy for social anxiety disorder: an update.

Since the emergence of social phobia into the diagnostic nomenclature, we have seen an exponential expansion in our knowledge regarding effective treatment of this disorder. The literature clearly supports the use of SSRIs and the SNRI venlafaxine ER as first line pharmacological agents in the treatment of GSAD. In this article, treatment studies of pharmacotherapy of social phobia are summarized. Additional issues such as comparative efficacy, treatment resistance and relapse-prevention are reviewed.

Symptom relapse following switch from Celexa to generic citalopram: an anxiety disorders case series.

Generic agents do not require large clinical trials of safety and efficacy to enter the market, although they must demonstrate both pharmacological and bioequivalence to the brand name drug. Bioequivalence is attained when the extent of absorption of the generic falls within an FDA predefined range relative to the brand name drug. This potential variation in bioequivalence is not thought to be clinically meaningful, however, there are reports of a lack of therapeutic equivalence between some generic medications and the brand name. This study examines the potential risks posed by a switch from Celexa to generic citalopram. Twenty patients at an Anxiety Disorders Clinic who were unknowingly switched to generic citalopram, from Celexa (Lundbeck, Montreal, Quebec, Canada) and experienced a re-emergence of their anxiety symptoms or development of new adverse events are described in this case series report. The mean time for re-emergence of symptoms or development of adverse events was 3.4 +/- 1.6 weeks (range 0.5-8 weeks). All patients reestablished previous treatment response with a change back to Celexa in a mean time of 3.8 +/- 2.6 weeks (range 0.7-12 weeks). Given these results, it is important for clinicians to be aware of the potential for loss of treatment effect or symptom re-emergence posed by a switch to a generic agent. Randomized, double blind, controlled investigations would likely provide useful information as current bioequivalence and pharmacological equivalence do not necessarily translate into clinical equivalence.

Emerging treatments for child and adolescent social phobia: a review.

Social anxiety disorder, or social phobia (SP), is an anxiety disorder characterized by excessive fear of exposure to situations that involve potential scrutiny by others. SP is a common psychiatric problem in children and adolescents, often presenting with comorbid anxiety and mood disorders. Although the onset of SP is typically in late childhood or early adolescence, most afflicted individuals go undiagnosed for years, not seeking treatment until adulthood. First-line treatments for SP in adults support the use of pharmacotherapy and cognitive behavioral therapy. There is new and emerging data in youths with SP to support the use of similar treatments. This paper will review the clinical characteristics, epidemiology, and treatment of SP in youths. Current investigations using selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors, benzodiazepines, and monoamine oxidase inhibitors in youths will be reviewed. Several studies on the use of cognitive behavioral therapy in youths will also be examined. Practical guidelines for clinicians who treat children and adolescents are also presented.

Antiepileptic drugs in the treatment of anxiety disorders: role in therapy.

Pharmacotherapy for anxiety disorders is an active area of research. A variety of drug groups have been shown to be effective in treating many of the anxiety disorders, with selective serotonin reuptake inhibitors (SSRIs) being considered first-line agents for virtually all anxiety disorders. There is a clinical need for alternative drug treatments, as many patients do not achieve a complete response and experience significant adverse effects. The successful use of antiepileptic drugs in mood disorders has led clinicians and researchers to investigate their potential efficacy in other psychiatric disorders, particularly in anxiety disorders. There have been a number of investigations conducted in the form of case reports, case series and open-label trials, suggesting the potential usefulness of antiepileptic drug treatment in a variety of anxiety disorders. More reliable evidence for the use of antiepileptic drugs in anxiety disorders can be gleaned from recent placebo-controlled trials. Thus far, the strongest placebo-controlled evidence has demonstrated the efficacy of pregabalin in treating social phobia and generalised anxiety disorder, while smaller or less robust controlled trials have suggested the potential efficacy of gabapentin in social phobia, lamotrigine in post-traumatic stress disorder, and valproic acid in panic disorder. Antiepileptic drugs may have a place in the treatment of anxiety disorders; however, further investigation is warranted to determine in what circumstances they should be used as monotherapy or as augmenting agents in individuals who are partially or non-responsive to conventional therapy.

An open trial of topiramate in the treatment of generalized social phobia.

BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) are the current gold standard in the pharmacologic treatment of generalized social phobia. SSRIs are only effective in approximately 50% of individuals with generalized social phobia and can be associated with significant side effects. Based on the successful use of the anticonvulsants gabapentin and pregabalin in treating generalized social phobia, we conducted an open trial examining the efficacy of the glutamatergic and GABAergic anticonvulsant topiramate in the treatment of generalized social phobia. METHOD: Twenty-three adult outpatients with DSM-IV social phobia, generalized type, were entered into a 16-week open trial of topiramate, starting at 25 mg/day, and gradually titrated up to a maximum dose of 400 mg/day. RESULTS: Twelve of 23 patients completed the trial. In the intent-to-treat (ITT) analysis, 11 (47.8%) of 23 were responders by a Clinical Global Impressions Improvement (CGI-I) scale rating of "much" or "very much" improved. The mean drop in the Liebowitz Social Anxiety Scale (LSAS) score for the ITT group was 29.4%. The change in LSAS score from baseline to endpoint was significant for the ITT group (F = 3.44, df = 4,110; p = .01). In the completers group, 9 (75.0%) of 12 were responders by CGI-I at 16 weeks, with a mean drop in LSAS score of 45.1%. The rate of remission in the ITT sample, using a definition of an LSAS score of

Topiramate treatment for SSRI-induced weight gain in anxiety disorders.

BACKGROUND: Antidepressants, including selective serotonin reuptake inhibitors (SSRIs), have been associated with significant weight gain, a problem that frequently leads to noncompliance and premature discontinuation of treatment. Topiramate is a novel anticonvulsant that has also been used as a mood stabilizer and augmentation agent in mood disorders. Topiramate has been observed to have an interesting side effect of weight loss in some individuals. In this study, topiramate was added to the treatment regimen of patients with a primary DSM-IV anxiety disorder who had experienced substantial SSRI-induced weight gain, in an attempt to induce weight loss. METHOD: Topiramate was added to SSRI treatment in 15 anxiety disorder patients, starting at a dose of 50 mg/day and titrating up to a target daily dose of 100 mg/day, with a maximum dose of 250 mg/day. Subjects' weight was measured at baseline and after 5 and 10 weeks of treatment. RESULTS: Before topiramate treatment, SSRI-treated subjects in this sample had gained a mean of 13.0 +/- 8.4 kg (28.6 +/- 18.5 lb). After the addition of a mean dose of 135.0 +/- 44.1 mg/day of topiramate for approximately 10 weeks, subjects lost a mean of 4.2 +/- 6.0 kg (9.3 +/- 13.3 lb). CONCLUSION: Topiramate may have a role in managing SSRI-induced weight gain in anxiety disorder patients.

Does SSRI augmentation with antidepressants that influence noradrenergic function resolve depression in obsessive-compulsive disorder?

BACKGROUND: Obsessive compulsive disorder (OCD) often coexists with major depressive disorder (MDD). Serotonergic antidepressant medications have emerged as the treatment of choice for both OCD and MDD. In the usual course of events, both the patient's OCD and depressive symptoms improve in parallel following initiation of serotonin reuptake inhibitor (SRI) treatment for OCD. However, such is not always the case. We report here on a series of ten patients whose OCD but not depression improved following a trial of SRI therapy. METHOD: Ten patients with OCD and comorbid MDD who experienced a worsening or exacerbation of depressive symptoms while being maintained on an adequate dose of SRI therapy were treated using a combination of SRIs and agents with effects on noradrenergic reuptake. Response to treatment was based on clinician-ratings of severity and improvement of OCD and MDD (CGI-S and CGI-I). RESULTS: Following augmentation, nine of the ten patients had a significant improvement/resolution of their MDD, with little further change in the severity of their OCD. LIMITATIONS: Inferences from the results of this study are limited by the lack of a control group, the small sample size, and the use of nonstandardized ratings as measures of symptom severity. CONCLUSIONS: These results are of practical significance to clinicians insofar as they suggest a possible guideline to clinicians treating depression in OCD with SSRIs without success.

A PET provocation study of generalized social phobia.

In an investigation of the neural circuits that may mediate the subjective experience of social phobia (SP), six male patients with a primary DSM-IV diagnosis of generalized social phobia watched, in the presence of a group of "communication experts," a videotape of themselves giving an impromptu talk (Exposure condition). In the control Baseline condition, they viewed a videotape of a socially competent stranger giving a talk. Regional cerebral blood flow was measured thrice under each condition. The study revealed significant deactivations from Baseline during Exposure in the right lingual gyrus (BA 18) and in the right medial frontal gyrus (BA 11); significant activations during Exposure were not observed. Deactivation of these regions may reflect a strategy of visual avoidance employed by the patients to dampen their phobic experience.

Optimizing treatment in social phobia: a review of treatment resistance.

Over the last 25 years, there has been a rapid expansion of our knowledge base of social phobia (SP). Although there are a number of well-validated treatment modalities, including pharmacotherapy and cognitive-behavioral therapy, significant gaps remain in our ability to achieve full remission in most patients. Despite advances in the neurobiology of SP, the etiology has yet to be determined. Investigations examining potential predictors of response have provided little guidance in selecting an appropriate treatment modality. These gaps in our knowledge have pushed us to examine issues related to treatment resistance. This paper presents a review of the current literature and issues related to treatment-resistant SP, including a discussion of the functional impairment associated with SP, definitions of treatment response and remission, as well as outcome measures that have been used in clinical investigations of SP. In addition, criteria for a standard treatment trial, predictors of treatment response, a review of treatment resistance studies, and potential directions for future research are examined. The most promising strategies to attain remission, will likely involve augmenting selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors with agents such as anticonvulsants, benzodiazepines, and antipsychotics as well as combining pharmacotherapy with cognitive-behavioral therapy. Our current treatment target of simply attaining a response needs to be refocused, so that an asymptomatic state and high end state functioning become the final goal of treatment.

The impact of anxiety disorders on educational achievement.

Anxiety disorders typically have an age of onset in childhood and adolescence, resulting in significant disability in social and occupational functioning. Epidemiological evidence suggests that persons with psychiatric disorders and perhaps especially social phobia are at increased risk for premature withdrawal from school [Am. J. Psychiatry 157 (2000) 1606]. In order to further determine the impact of anxiety disorders on school functioning and/or premature withdrawal from school, 201 patients meeting DSM-IV criteria for a primary anxiety disorder completed a school leaving questionnaire as well as self-report measures of anxiety, depression, and social adjustment. About 49% (n = 98) reported leaving school prematurely and 24% of those indicated that anxiety was the primary reason for this decision. Patients who had left school prematurely were significantly more likely to have a lifetime diagnosis of generalized social phobia, a past history of alcohol abuse/dependence and a greater number of lifetime diagnoses than those who completed their desired level of education. This study suggests that anxiety disorders, and perhaps especially generalized social phobia, are associated with premature withdrawal from school. Further studies are required to determine methods for early identification and treatment of anxiety disorders in school aged children to enable these students to reach their full potential.

Quality of life and the anxiety disorders.

Quality of life (QoL) is a concept that has become increasingly used in mental health care. Recent studies have compared the impact of different anxiety disorders on different domains of QoL; however, instruments generally used to assess QoL in this population have varying specificity, considerable redundancy, and occasionally inappropriate content. Three hundred and sixty consecutive admissions to an anxiety disorders clinic were assessed. Participants and clinicians completed a number of QoL measures. Results indicated that impairment measures designed for use with anxiety-disordered samples in fact assess only occupational functioning and relationships and activities outside of occupation, and that individuals with Social Phobia (SP) were more impaired on the latter than those with Panic Disorder (PD). Furthermore, only Social Phobia accounted for unique variance in the three Medical Outcome Study Health Survey (MOS) subscales relevant to quality of life. Of the MOS subscales relevant to symptoms, mood regulation, physical functioning, and pain were associated with compromised overall QoL.

Adult attention deficit hyperactivity disorder in an anxiety disorders population.

Adult Attention Deficit Hyperactivity Disorder (ADHD) is a life-long, chronic disorder, which has its onset in childhood and is associated with significant functional impairment. ADHD appears to be highly comorbid with other psychiatric disorders, however, literature is lacking concerning ADHD/anxiety comorbidity. To that end, we examined the prevalence of ADHD in an anxiety disorder sample. Consecutive patients referred to an anxiety disorders clinic completed a variety of anxiety disorder self-report measures as well as the Adult ADHD self-report scale and were clinically assessed using the Structured Clinical Interview for DSM-IV, and the ADHD module of the Mini International Neuropsychiatric Interview. Of the 129 patients assessed, the rate of adult ADHD was 27.9%. The mean age of the sample was 33.1 ± 12.5 years, and the mean baseline CGI-S was 4.6 ± 1.1 (moderate to marked severity). The majority of the sample was female (63.6%) and single (49.5%). The most common comorbid disorders associated with ADHD were major depressive disorder (53.8%), social phobia (38.5%), generalized anxiety disorder (23.1%), and impulse control disorders (30.8%). Individuals with ADHD had higher symptom severity scores for obsessive-compulsive disorder, (P≤ 0.05) and for GAD (P≤ 0.05) and reported a significantly earlier age of onset for depression as compared to those without (P≤ 0.05). The prevalence of adult ADHD was higher in our anxiety disorders clinic sample than found in the general population. Clinical implications of these findings are discussed.

The impact of changing diagnostic criteria in posttraumatic stress disorder in a Canadian epidemiologic sample.

BACKGROUND: Since its inclusion in DSM-III, posttraumatic stress disorder (PTSD) has undergone a number of changes in its diagnostic criteria, including the expansion of Criterion A (traumatic stressor), the addition of symptom duration (none specified in DSM-III), and the requirement for impairment or distress (Criterion F, DSM-IV only). METHOD: This study examined the impact of changes in PTSD diagnostic criteria using a Canadian PTSD epidemiologic sample. The rates of PTSD and its correlates were evaluated in a nationally representative random sample of 3,006 adults. DSM-III, DSM-III-R, DSM-IV, and ICD-10 criteria were employed. DSM-III, DSM-III-R, and ICD-10 rates were re-evaluated, substituting specific DSM-IV criteria (A-F). RESULTS: The prevalence rates of lifetime PTSD ranged from 13.4% (DSM-III) to 13.0% (ICD-10) to 12.2% (DSM-III-R) to 9.2% (DSM-IV); all rates differed significantly from each other (P < .001). Regardless of diagnostic criteria, most people reported more than 1-year duration of symptoms, although rates were significantly higher in those with DSM-IV PTSD (68.2%, P < .0001). Rates of comorbid major depressive disorder and alcohol and substance abuse and dependence were also significantly higher (P < .05) using the DSM-IV PTSD criteria, and those with DSM-IV PTSD reported significantly higher rates of help-seeking (P < .001). When Criterion F was added to earlier versions, lifetime PTSD rates became much closer to those obtained using DSM-IV criteria: 10.6% (DSM-III), 10.2% (DSM-III-R), and 9.9% (ICD-10); however, rates fluctuated when operational definitions of Criterion F were modified. DSM-III PTSD was also substantially affected by DSM-IV Criteria A and C. CONCLUSIONS: DSM-IV PTSD may identify a more severe disorder. The addition of the clinical significance criterion (F) appeared to affect the greatest change in prevalence rates. Defining Criterion F as having both clinically significant psychological distress and functional impairment lowered the diagnostic threshold to a greater degree than did either distress or impairment alone. This information may be useful for future revisions of PTSD diagnostic criteria.