A preliminary investigation of the effects of cognitive behavioral therapy for panic disorder on gastrointestinal distress in patients with comorbid panic disorder and irritable bowel syndrome.

BACKGROUND: High comorbidity between panic disorder with/without agoraphobia (PD/A) and irritable bowel syndrome (IBS) has been identified in the literature. These findings have resulted in the recent development of neurobiological models to explain their overlapping symptoms and related origins. This study was a preliminary investigation of the influence of cognitive behavioral therapy (CBT) for PD/A on PD/A patients with and without comorbid IBS. METHODS: All patients completed a thorough intake assessment, brief waitlist period, and a 12-week CBT group for PD/A. RESULTS: The results demonstrated significant reductions in the symptoms of anxiety, depression, and overall impairment in both patient groups (ts>2.3; Ps<.05). In addition, PD/A patients with comorbid IBS also experienced reductions in the disability and distress associated with their gastrointestinal symptoms of IBS (ts>1.9; Ps<.07). CONCLUSIONS: Although additional research still is needed, these preliminary findings suggest that CBT for PD/A can be used to simultaneously treat comorbid symptoms of PD/A and IBS. Implications for the neurobiological models for these comorbid conditions were discussed.

Comparative efficacy of pregabalin and benzodiazepines in treating the psychic and somatic symptoms of generalized anxiety disorder.

Prior research suggests that SSRIs may have greater efficacy for psychic compared to somatic anxiety, while benzodiazepines show greater somatic efficacy. The goal of this analysis was to evaluate the efficacy of pregabalin (PGB) in treating psychic and somatic symptoms of anxiety. Data were combined from six short-term, double-blind, placebo-controlled, fixed-dose trials of PGB in patients with generalized anxiety disorder (GAD). The following PGB daily dose groups were studied: 150 mg (n=210), 300-450 mg (n=455), and 600 mg (n=406), benzodiazepines (6 mg/d lorazepam and 1.5 mg/d alprazolam, n=299), vs. placebo (n=484). Changes in Hamilton Anxiety Rating Scale (HAMA) psychic and somatic anxiety factors and individual items were analysed. Treatment with 300-600 mg PGB significantly improved both the HAMA psychic and somatic anxiety factors. In contrast, treatment with 150 mg PGB appeared to be less effective, achieving significance only on the psychic anxiety factor. PGB (300-450 mg) was associated with significant improvement on 13 out of 14 HAMA items, while treatment with 600 mg PGB was associated with significant improvement in 10 out of 14 HAMA items. Treatment with benzodiazepines was also associated with significant improvement in both psychic and somatic anxiety factors, with significant improvement occurring in 5 out of 14 HAMA items. The results of this pooled analysis indicate that both PGB and benzodiazepines had significant efficacy in treating both HAMA psychic and somatic anxiety. A dose-response effect was evident for PGB that reached a plateau at a dose of 300 mg/d.

Anxiety disorders and comorbid medical illness.

OBJECTIVE: To provide an overview of the role of anxiety disorders in medical illness. METHOD: The Anxiety Disorders Association of America held a multidisciplinary conference from which conference leaders and speakers reviewed presentations and discussions, considered literature on prevalence, comorbidity, etiology and treatment, and made recommendations for research. Irritable bowel syndrome (IBS), asthma, cardiovascular disease (CVD), cancer and chronic pain were reviewed. RESULTS: A substantial literature supports clinically important associations between psychiatric illness and chronic medical conditions. Most research focuses on depression, finding that depression can adversely affect self-care and increase the risk of incident medical illness, complications and mortality. Anxiety disorders are less well studied, but robust epidemiological and clinical evidence shows that anxiety disorders play an equally important role. Biological theories of the interactions between anxiety and IBS, CVD and chronic pain are presented. Available data suggest that anxiety disorders in medically ill patients should not be ignored and could be considered conjointly with depression when developing strategies for screening and intervention, particularly in primary care. CONCLUSIONS: Emerging data offer a strong argument for the role of anxiety in medical illness and suggest that anxiety disorders rival depression in terms of risk, comorbidity and outcome. Research programs designed to advance our understanding of the impact of anxiety disorders on medical illness are needed to develop evidence-based approaches to improving patient care.

Pregabalin for treatment of generalized anxiety disorder: a 4-week, multicenter, double-blind, placebo-controlled trial of pregabalin and alprazolam.

BACKGROUND: Pregabalin inhibits release of excess excitatory neurotransmitters, presumably by binding to the alpha2-delta subunit protein of widely distributed voltage-dependent calcium channels in the brain and spinal cord. OBJECTIVE: To assess the anxiolytic efficacy of pregabalin in patients with generalized anxiety disorder. DESIGN: Double-blind, placebo-controlled, active-comparator trial. Patients were randomized to 4 weeks of treatment with pregabalin, 300 mg/d (n = 91), 450 mg/d (n = 90), or 600 mg/d (n = 89); alprazolam, 1.5 mg/d (n = 93); or placebo (n = 91). SETTING: Psychiatry research and clinic settings. PATIENTS: Outpatients meeting the DSM-IV criteria for generalized anxiety disorder, with a baseline Hamilton Anxiety Rating Scale (HAM-A) total score of 20 or greater. MAIN OUTCOME MEASURES: Change from baseline to end point in total HAM-A score in the pregabalin and alprazolam groups compared with the placebo group. The end point response criterion was 50% or greater reduction in the HAM-A total score. RESULTS: Pregabalin and alprazolam produced a significantly greater reduction in mean +/- SE HAM-A total score at last-observation-carried-forward end point compared with placebo (-8.4 +/- 0.8): pregabalin, 300 mg (-12.2 +/- 0.8, P<.001), 450 mg (-11.0 +/- 0.8, P = .02), and 600 mg (-11.8 +/- 0.8, P = .002), and alprazolam (-10.9 +/- 0.8, P = .02). By week 1 and at last-observation-carried-forward end point, the 3 pregabalin groups and the alprazolam group had significantly (P<.01) improved HAM-A psychic anxiety symptoms compared with the placebo group. Compared with the placebo group, HAM-A somatic anxiety symptoms were also significantly (P<.02) improved by the 300- and 600-mg pregabalin groups, but not by the 450-mg pregabalin (week 1, P = .06; week 4, P = .32) and the alprazolam groups (week 1, P = .21; week 4, P = .15). Of the 5 treatment groups, the 300-mg pregabalin group was the only medication group that differed statistically in global improvement at treatment end point not only from the placebo group but also from the alprazolam group. CONCLUSION: Pregabalin was significantly more efficacious than placebo for the treatment of psychic and somatic symptoms of generalized anxiety disorder and was well tolerated by most study patients.

Increased prevalence of functional gastrointestinal disorders in panic disorder: clinical and theoretical implications.

BACKGROUND: Functional gastrointestinal disorders (FGID) are a group of disorders characterized by recurrent gastrointestinal distress for which no structural or biochemical cause can be discerned. Irritable bowel syndrome (IBS) is an FGID estimated to affect 10% to 25% of the United States population. IBS occurs in over 40% of individuals with panic disorder, and in patients with IBS, 25% to 30% have panic disorder, which has led to speculation about possible shared pathophysiology between the two. Less is known about the prevalence of other FGID in individuals with panic disorder. OBJECTIVE: The purpose of this study was to examine the prevalence of IBS and all the other FGID in patients with current Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) panic disorder. INTRODUCTION: We assessed FGIDs in 73 treatment-seeking DSM-IV panic disorder patients via the Diagnostic Interview Questions for Functional Gastrointestinal Disorders and made descriptive comparisons with a large convenience sample from an already-completed United States Household Survey (USHS), which employed the same diagnostic criteria. RESULTS: The prevalence of IBS and other FGIDs in both men and women with panic disorder were substantially higher than in the USHS respondents. Women with panic disorder had significantly more functional chest pain than men, but there was no gender difference in IBS. With the exception of functional anorectal and biliary disorders, the FGID prevalences were comparatively higher in panic disorder versus the USHS respondents. DISCUSSION: This survey supports earlier reports of a high prevalence of IBS in individuals with panic disorder and also suggests that the prevalence of several other FGIDs were comparatively high as well. Methodological limitations precluded direct statistical analysis. It may be that commonly overlapping psychiatric and often-painful FGIDs, and extra-intestinal disorders increase the risk for comorbidity in already-affected individuals via shared pathophysiology. One potential model for which there is some evidence for a role in stress, panic disorder, FGIDs and several extra-intestinal functional conditions is dysregulation of corticotropin-releasing factor function. CONCLUSION: The prevalence of FGIDs in DSM-IV panic disorder was comparatively higher than in USHS respondent community sample, which used similar FGID diagnostic criteria. The cause for the apparent close association of panic disorder with FGID may represent shared pathophysiology. Increased understanding of the mechanism of the overlap may allow for improved treatment of the significant proportion of the population suffering from comorbid psychiatric and functional medical conditions.

A potential role for thalamocingulate circuitry in human maternal behavior.

BACKGROUND: Little is known about the regional brain basis of human maternal behavior. To understand this better, we have been examining brain activity in mothers listening to infant cries. METHODS: We measured functional Magnetic Resonance Imaging brain activity in healthy, breastfeeding first-time mothers with young infants while they listened to infant cries, white noise control sounds, and a rest condition. Based on the thalamocingulate theory of maternal behavior and pilot work, we hypothesized that the cingulate, medial thalamus, medial prefrontal cortex, and right orbitofrontal cortex would display more activity with infant cries than with white noise (comparison 1) and would uniquely activate with the cries, meaning that these regions would display activity with cry minus rest but not with white noise minus rest (comparison 2). RESULTS: In hypothesized regions, the group displayed more activity in the medial thalamus, medial prefrontal and right orbitofrontal cortices with both comparisons. The anterior and posterior cingulate cortex displayed more activity only with comparison 1. In non-hypothesized brain regions, several other structures thought important in rodent maternal behavior displayed activity with both comparisons including the midbrain, hypothalamus, dorsal and ventral striatum, and vicinity of the lateral septal region. CONCLUSIONS: Our results partially support our hypotheses and are generally consistent with neuroanatomical studies of rodent maternal behavior.

The role of GABA in anxiety disorders.

Anxiety stems from and perpetuates dysregulation of neurobiological systems, but the exact mechanisms of anxiety disorders are still only partially understood. Gamma-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter known to counterbalance the action of the excitatory neurotransmitter glutamate. Several pharmacologic agents target the GABA system and modulate the overall effect of GABA. This article highlights multiple neurobiological interactions that play a role in anxiety and reviews selected studies of plasma neurosteroid levels, plasma GABA levels, and benzodiazepine binding site sensitivity and density in patients with anxiety disorders. The article concludes with further support for the role of the GABA system in anxiety by summarizing the current evidence supporting the use of novel GABAergic agents including tiagabine in the treatment of anxiety disorders.

Impact of gastrointestinal symptom severity on response to venlafaxine extended-release in patients with generalized anxiety disorder.

BACKGROUND: This retrospective analysis evaluated the prevalence and severity of pre-treatment gastrointestinal (GI) symptoms in patients with generalized anxiety disorder (GAD), the impact of these GI symptoms on the efficacy and tolerability of venlafaxine extended-release (XR), and the effect of treatment on prestudy GI symptoms. METHOD: Data from 1932 nondepressed GAD patients were pooled from 5 randomized, double-blind, placebo-controlled studies of venlafaxine XR clinically conducted between May 1995 and December 1997. The GI symptom severity at baseline was estimated from item 11 on the Hamilton Rating Scale for Anxiety (HAM-A). Patients with a GI symptom severity score < or = 2 (moderate or less) and those with a GI symptom severity score > 2 (severe/very severe) were compared for baseline characteristics and short-term (8-week) and long-term (24-week) outcomes. RESULTS: At baseline, for all randomized patients with a HAM-A item 11 score, GI symptoms were rated moderate or lower in 82.8% of patients (GI-low) and severe/very severe in 17.2% (GI-high). The GI-high subgroup was statistically significantly (p < .05) younger, had a longer duration of GAD, and had higher mean HAM-A total scores than the GI-low subgroup. Compared with placebo, venlafaxine XR significantly reduced HAM-A total and psychic anxiety factor scores, regardless of baseline GI symptom severity. The incidence of adverse events, particularly nausea, was higher for the GI-high versus GI-low subgroup. CONCLUSION: Baseline severity of GI symptoms correlated with overall severity of GAD but had no impact on treatment outcome with venlafaxine XR. These data do not support the hypothesis that high baseline GI symptom severity has a negative effect on treatment with venlafaxine XR in GAD patients.

The effectiveness of St. John's Wort in major depressive disorder: a naturalistic phase 2 follow-up in which nonresponders were provided alternate medication.

BACKGROUND: A continuation study of an extract of St. John's wort (Hypericum perforatum) for depression was performed in follow-up to an acute study that found no significant difference between St. John's wort extract and placebo. METHOD: Seventeen subjects with DSM-IV-defined major depressive disorder who responded to St. John's wort extract in the acute-phase study (phase 1) were continued on double-blind treatment with the same preparation for 24 weeks. Ninety-five subjects who did not respond to either St. John's wort or placebo were treated with an antidepressant for 24 weeks. RESULTS: During antidepressant treatment, mean scores on the Hamilton Rating Scale for Depression for phase 1 nonresponders decreased significantly (p <.0001), with no significant difference between St. John's wort nonresponders and placebo nonresponders. Of the 17 subjects continued on treatment with St. John's wort extract, 5 (29.4%) relapsed. CONCLUSIONS: The subjects who did not respond to St. John's wort extract or placebo in phase 1 were, by and large, not resistant to antidepressant treatment. This suggests that the lack of efficacy found by Shelton et al. in the acute-phase study was unlikely to be the result of a high proportion of treatment-resistant subjects.

Neural correlates of speech anticipatory anxiety in generalized social phobia.

Patients with generalized social phobia fear embarrassment in most social situations. Little is known about its functional neuroanatomy. We studied BOLD-fMRI brain activity while generalized social phobics and healthy controls anticipated making public speeches. With anticipation minus rest, 8 phobics compared to 6 controls showed greater subcortical, limbic, and lateral paralimbic activity (pons, striatum, amygdala/uncus/anterior parahippocampus, insula, temporal pole)--regions important in automatic emotional processing--and less cortical activity (dorsal anterior cingulate/prefrontal cortex)--regions important in cognitive processing. Phobics may become so anxious, they cannot think clearly or vice versa.

Assessing abuse liability in clinical trials.

In this article, the use of data collected in registration-focused clinical trials to provide information concerning abuse liability of compounds under development is discussed. Registration-focused trials are limited by the small and select sample chosen for study participation and design constraints. However, most compounds under development are first administered to humans during the conduct of registration-focused trials, so this presents an opportunity to collect potentially important information about the effects of drugs in humans. At present, information concerning subjective effects and symptoms associated with drug discontinuation are not collected systematically. Reports are generally considered as adverse events (AEs) and are recorded on the case report forms (CRFs) in the investigators own language. There is generally no rating of drug "liking". The authors suggest strategies that could be implemented in registration-focused clinical trials to improve the information gathered with regard to subjective effects, abuse liability and discontinuation-emergent symptoms. Importantly, there remains much groundwork to be done in developing and validating appropriate assessment instruments and determining "threshold" levels for concern. Under the best of circumstances, registration-focused clinical trials have limited potential to detect abuse liability because of the small number of patients seen and the exclusion of many subjects who might be particularly vulnerable to the abuse of marketed compounds (i.e. individuals with substance use disorders). In cases where there are reasons to suspect that a drug under development has abuse potential, systematic exploration with a series of studies specifically designed to assess abuse potential must be conducted.

From the Bench to the Trench: A Comparison of Sertraline Treatment of Major Depression in Clinical and Research Patient Samples.

BACKGROUND: New medications that enter the marketplace have been tested almost exclusively in controlled clinical trials conducted in specialty research settings. There is some concern that these carefully selected patient samples may not provide information generalizable to the "real world" clinical population. The purpose of this investigation was to compare results from a large, open-label study of sertraline in the treatment of major depression in the clinical practice setting with pooled results from 2 multicenter, double-blind, placebo-controlled studies conducted in specialty research settings. METHOD: Clinical practice patients (N = 1482), aged 21 to 65 years, from 228 psychiatric clinical practice sites across the United States participated in the open-label treatment study (Clinical Practice sample). Patients who met DSM-III-R criteria for moderate-to-severe unipolar major depression (i.e., had pretreatment Hamilton Rating Scale for Depression [HAM-D] scores >/= 18) were treated for 8 weeks with sertraline in a flexible dosing fashion (50-200 mg daily). Outcomes on the HAM-D and Clinical Global Impressions-Improvement scale (CGI-I) were compared with the pooled results from 2 previously published placebo-controlled, multicenter treatment studies of sertraline in outpatients with major depression (N = 280). The overall response to sertraline in the Clinical Practice sample was compared with the outcome from the research study patient sample (Clinical Research sample). Additionally, comparison of outcomes of patients with common depressive subtypes (double depression, anxious depression, and melancholic ["endogenous"] depression) were examined. RESULTS: The percentage of sertraline-treated patients rated as responders on the CGI-I was significantly higher in the Clinical Practice sample compared with the Clinical Research sample (87% vs. 73%; p <.001). Sertraline was also much better tolerated in the Clinical Practice sample than in the Clinical Research sample as evidenced by significantly lower overall reports of adverse events (9.4% vs. 13.2%; p <.05) and lower patient dropout rates (17.5% vs. 34.3%; p <.01). Among clinical practice patients, sertraline was found to be equally effective in treating endogenous/melancholic and anxious subtypes and only mildly less effective in achieving a response in patients with double depression (chronic low-grade depression with a superimposed major depression). A regression analysis identified older age and double depression as being predictors of a slower time to response. More than 70% of patients who reported nonresponse to previous treatment with fluoxetine or a tricyclic antidepressant responded to sertraline. CONCLUSION: The effectiveness and tolerability of sertraline treatment was found to be significantly better in the Clinical Practice sample, suggesting that the results from controlled studies in research settings may represent an underestimate of the benefits of a drug. More effectiveness research is needed to confirm and extend these findings.

The Social Thoughts and Beliefs Scale: a new inventory for assessing cognitions in social phobia.

Development and initial psychometric features of a new inventory to assess cognitions associated with social phobia are described. The Social Thoughts and Beliefs Scale (STABS) is designed to assess cognitions in individuals with social phobia. In the 1st study, an initial pool of 45 items was reduced to 21. In the 2nd study, psychometric features of the scale were examined in a sample of individuals with social phobia, other anxiety disorders, and no psychiatric disorder. Total scores and two factor scores significantly differentiated individuals with social phobia from those in the other groups and were found to have adequate test-retest reliability and internal consistency. Potential usefulness of the STABS for assessing cognitions associated with social phobia is discussed.

Levetiracetam in generalized social anxiety disorder: a double-blind, randomized controlled trial.

OBJECTIVE: This multicenter, double-blind, placebo-controlled, 2-arm, parallel-group study was carried out to determine the effectiveness and safety of the novel anticonvulsant levetiracetam for the treatment of generalized social anxiety disorder (GSAD). METHOD: After a 1-week, single-blind, placebo run-in period, 217 adult outpatients meeting DSM-IV criteria for social anxiety disorder, generalized type, were randomly assigned (1:1) to 12 weeks of double-blind treatment with either levetiracetam (n = 111) or placebo (n = 106). Participants were required to have scores of >or= 60 on the Liebowitz Social Anxiety Scale (LSAS) and a total score of or= 30% reduction in LSAS score) were similar with 41.3% (levetiracetam) and 46.6% (placebo). No significant between-group differences were found on secondary outcome measures, which included changes in Sheehan Disability Scale, Clinical Global Impression of Change, and HDRS scores. CONCLUSIONS: Although well-tolerated, levetiracetam failed to separate from placebo in this trial for the treatment of moderate to severe GSAD.

Quetiapine monotherapy as treatment for anxiety symptoms in patients with bipolar depression: a pooled analysis of results from 2 double-blind, randomized, placebo-controlled studies.

OBJECTIVE: To evaluate the efficacy and tolerability of quetiapine monotherapy for anxiety symptoms in patients with bipolar disorder experiencing depression in the BipOLar DEpRession (BOLDER I and II) studies. METHOD: A post hoc analysis of anxiety symptoms in 1,051 acutely depressed patients with bipolar I or II disorder (DSM-IV) from 2 double-blind, randomized, placebo-controlled 8-week studies of quetiapine (300 or 600 mg once daily) was conducted. Anxiety symptoms were assessed using Hamilton Anxiety Rating Scale (HARS) total and psychic (items 1-6, 14) and somatic (items 7-13) anxiety subscale scores (mixed-model repeated measure and last-observation-carried-forward analysis of change from baseline at each assessment). The BOLDER I study was conducted between September 2002 and October 2003, and the BOLDER II study was conducted between June 2004 and August 2005. RESULTS: Mean baseline HARS total scores were similar across the treatment groups (300 mg/d: 18.9, 600 mg/d and placebo: both 18.6). There was a significantly greater improvement from baseline in mean HARS total scores at the first evaluation (week 1) in both quetiapine groups compared with placebo (300 mg/d: -4.6, P < .001 and 600 mg/d: -4.1, P = .003 vs placebo: -2.8). These improvements were sustained through week 8 with both quetiapine doses (300 mg/d: -10.1, P < .001 and 600 mg/d: -10.5, P < .001 vs placebo: -6.9). At week 8, there was also significant improvement from baseline in HARS psychic and somatic anxiety subscale scores compared with placebo (P < .001). The baseline severity of anxiety did not impact the improvement in depressive symptoms. Common adverse events included dry mouth, sedation, somnolence, and dizziness. CONCLUSIONS: In this pooled analysis, quetiapine monotherapy was more effective than placebo and generally well tolerated for the treatment of both depressive and anxiety symptoms in patients with bipolar disorder. TRIAL REGISTRATION: clinicaltrials.gov Identifiers: NCT00060489 (BOLDER I) and NCT00083954 (BOLDER II).

Low doses of controlled-release paroxetine in the treatment of late-life depression: a randomized, placebo-controlled trial.

OBJECTIVE: To evaluate the efficacy and tolerability of low daily doses of controlled-release (CR) paroxetine in patients with late-life depression. METHOD: This was a 10-week, multicenter, placebo-controlled, double-blind, fixed-dose trial randomly assigning patients >or= 60 years old to daily doses of paroxetine CR 12.5 mg (N = 168), paroxetine CR 25 mg (N = 177), or placebo (N = 180). Patients had major depressive disorder (DSM-IV criteria) and 17-item Hamilton Rating Scale for Depression (HAM-D) total scores of >or= 18. The primary efficacy variable was the change from baseline to study endpoint in total HAM-D scores. The study was conducted from June 2003 to October 2004. RESULTS: The drug/placebo difference in HAM-D change from baseline at study endpoint was -1.8 (95% CI = -3.41 to -0.19, p = .029) for paroxetine CR 12.5 mg, and -3.3 (95% CI = -4.84 to -1.68, p < .001) for paroxetine CR 25 mg. A significantly larger percentage of patients achieved remission (HAM-D total score or= 60 years of age, although effect sizes are relatively smaller with the 12.5 mg/day dose.

Posttraumatic stress disorder: characteristics and treatment.

This Distance Rounds reviews the DSM-IV definition of posttraumatic stress disorder (PTSD) and associated features. PTSD is a prevalent mental health problem that occurs in some people after combat or civilian trauma and is influenced by certain risk factors. Psychotherapy and pharmacotherapy have both been found efficacious, and treatment selection should be tailored to the individual patient. Pharmacotherapy options include selective serotonin reuptake inhibitors, tricyclic antidepressants, monoamine oxidase inhibitors, atypical antipsychotics, mood stabilizers, and medications for trauma-related nightmares. Treatment often involves multiple modalities.

Recognition and treatment of panic disorder.

Panic disorder is a common, disabling condition that affects 3% to 5% of the world's population. Although it is treatable, panic disorder goes unrecognized and untreated in many patients. Patients with panic disorder have an increased risk for other psychiatric disorders, especially other anxiety disorders, and panic disorder is associated with other medical conditions such as migraines, fibromyalgia, and irritable bowel syndrome. Clinicians treating panic disorder must be able to recognize the disorder, differentiate it from other disorders in which panic attacks are part of the symptomatology, and map out an individualized treatment plan for each patient. This presentation discusses the importance of collaboration between doctor and patient and details available treatment options, including antidepressants, benzodiazepines, and cognitive-behavioral therapy.

Recognition and treatment of obsessive-compulsive disorder.

Obsessive-compulsive disorder (OCD) is prevalent, chronic, and potentially disabling. It is characterized by recurrent, unwanted, and distressing thoughts (obsessions) and repetitive, irresistible, behaviors (compulsions). Individuals with OCD recognize that the obsessions and compulsions are senseless or excessive yet they are unable to stop these behaviors. Some etiologic theories of OCD suggest a biological origin, including hypotheses involving the serotonergic system, the glutamatergic system, the orbital cortex and the basal ganglia, and streptococcal throat infections in children. Standard treatments for OCD include selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavior therapy. Combining SSRIs with other medications has relatively little empirical support; however, the adjunctive use of antipsychotics has been shown to be effective. Neurosurgery, such as deep brain stimulation, has also been shown to be effective in select patients with debilitating and refractory OCD.

Management of treatment-resistant panic disorder.

Panic disorder (PD) is a severe, chronic disorder characterized by one or more unexpected panic attacks followed by worry about additional attacks and/or the implications of the attacks. If attacks are sufficiently severe or frequent, they can promote marked, sometimes debilitating behavioral changes. Many panic disorder sufferers appear to be incompletely responsive to treatment and are subject to relapse after remission. In this article, we highlight the current understanding of the pathophysiology of PD using a "fear circuit" model. Using this model as a reference point, we review the evidence base supporting existing and emerging treatments and suggest strategies for optimizing initial treatment response. Finally, a differential diagnostic approach for clinical evaluation of unsatisfactory response to treatment in PD is presented.