John J. Worthington

A comparison of the efficacy of clonazepam and cognitive-behavioral group therapy for the treatment of social phobia

There is a growing body of evidence that social phobia may be treated effectively by either pharmacologic or cognitive-behavioral interventions. but few studies have examined the relative benefits of these treatments. In this study, we examined the relative efficacy of pharmacotherapy with clonazepam and cognitive-behavioral group therapy (CBGT) for treating social phobia. In addition, we examined potential predictors of differential treatment response. Outpatients meeting Diagnostic and Statistical Manual of Mental Disorders (3rd ed., revised) criteria for social phobia were randomly assigned to treatment. Clinician-rated and patient-rated symptom severity was examined at baseline and after 4, 8, and 12 weeks of treatment. All clinician-rated assessments were completed by individuals blind to treatment condition. Patients in both conditions improved significantly, and differences between treatment conditions were absent, except for greater improvement on clonazepam on several measures at the 12-week assessment. Symptom severity was negatively associated with treatment success for both methods of treatment, and additional predictors-sex, comorbidity with other anxiety or mood disorders, fear of anxiety symptoms, and dysfunctional attitudes-failed to predict treatment outcome above and beyond severity measures. In summary, we found that patients randomized to clinical care with clonazepam or CBGT were equally likely to respond to acute treatment, and pretreatment measures of symptom severity provided no guidance for the selection of one treatment over another.

TGFβ: a sleeping giant awoken by integrins

Transforming growth factor beta (TGFβ) controls numerous cellular responses, including proliferation, differentiation, apoptosis and migration. This cytokine is produced by many different cell types and has been implicated in the pathogenesis of many diseases, ranging from autoimmune disorders and infectious diseases to fibrosis and cancer. However, TGFβ is always produced as an inactive complex that must be activated to enable binding to its receptor and subsequent function. Recent evidence highlights a crucial role for members of the integrin receptor family in controlling the activation of TGFβ. These pathways are important in human health and disease, and new insights into the biochemical mechanisms that allow integrins to control TGFβ activation could prove useful in the design of therapeutics.

An Open Trial of Oral Sildenafilin Antidepressant-Induced Sexual Dysfunction

Background: Sildenafil is a selective inhibitor of cyclic GMP-specific phosphodiesterase type 5 that has been associated with greater improvement of erectile function compared to placebo among men with erectile dysfunction. The goal of our study was to evaluate its efficacy in a small sample of outpatients with antidepressant-induced sexual dysfunction. Methods: We studied the first 14 depressed outpatients (9 men and 5 women; mean age: 46.4 ± 8.4) who were consecutively treated with oral sildenafil. Twelve of the 14 patients were treated with an SSRI and 2 with mirtazapine. All patients were prescribed oral sildenafil tablets at the initial dose of 50 mg q.d. p.r.n., with the possibility of increasing the dose to 100 mg q.d. p.r.n., if clinically indicated. We administered a sexual functioning questionnaire derived from the Guided Interview Questionnaire for females and males and from the Arizona Sexual Experience Scale to all patients before and after at least 4 weeks of treatment with oral sildenafil. The mean sildenafil dose in our 14 patients was 57 ± 18 mg/day. Results: All 14 subjects completed the follow-up assessments and no subjects discontinued the drug prematurely. We observed statistically significant improvements in all domains of sexual functioning, including libido, arousal, orgasm, sexual satisfaction, and (in males only) erectile function, with a 69% rate of patients reporting themselves as much or very much improved. Oral sildenafil treatment appeared to be very well tolerated, with only 1 out of 14 (7%) patients reporting an adverse event (hot flashes). Conclusions: Our findings of statistically significant improvements in all domains of sexual functioning in a sample of 14 men and women with antidepressant-induced sexual dysfunction suggest that this agent may represent an efficacious approach to this population.

Randomized Controlled Trial of Mindfulness Meditation for Generalized Anxiety Disorder: Effects on Anxiety and Stress Reactivity

OBJECTIVE Mindfulness meditation has met increasing interest as a therapeutic strategy for anxiety disorders, but prior studies have been limited by methodological concerns, including a lack of an active comparison group. This is the first randomized, controlled trial comparing the manualized Mindfulness-Based Stress Reduction (MBSR) program with an active control for generalized anxiety disorder (GAD), a disorder characterized by chronic worry and physiologic hyperarousal symptoms. METHOD Ninety-three individuals with DSM-IV-diagnosed GAD were randomly assigned to an 8-week group intervention with MBSR or to an attention control, Stress Management Education (SME), between 2009 and 2011. Anxiety symptoms were measured with the Hamilton Anxiety Rating Scale (HAMA; primary outcome measure), the Clinical Global Impressions-Severity of Illness and -Improvement scales (CGI-S and CGI-I), and the Beck Anxiety Inventory (BAI). Stress reactivity was assessed by comparing anxiety and distress during pretreatment and posttreatment administration of the Trier Social Stress Test (TSST). RESULTS A modified intent-to-treat analysis including participants who completed at least 1 session of MBSR (n = 48) or SME (n = 41) showed that both interventions led to significant (P < .0001) reductions in HAMA scores at endpoint, but did not significantly differ. MBSR, however, was associated with a significantly greater reduction in anxiety as measured by the CGI-S, the CGI-I, and the BAI (all P values < .05). MBSR was also associated with greater reductions than SME in anxiety and distress ratings in response to the TSST stress challenge (P < .05) and a greater increase in positive self-statements (P = .004). CONCLUSIONS These results suggest that MBSR may have a beneficial effect on anxiety symptoms in GAD and may also improve stress reactivity and coping as measured in a laboratory stress challenge. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT01033851.

Effect of Acute Posttrauma Propranolol on PTSD Outcome and Physiological Responses During Script‐Driven Imagery

Introduction: Animal and human research suggests that the development of posttraumatic stress disorder (PTSD) may involve the overconsolidation of memories of a traumatic experience. Previous studies have attempted to use pharmaceutical agents, especially the β‐adrenergic blocker propranolol, to reduce this overconsolidation. Aims: In this randomized, placebo‐controlled study of the efficacy of propranolol in reducing the development of PTSD, we optimized dosages and conducted both psychophysiological and clinical assessments 1 and 3 months after the traumatic event. Forty‐one emergency department patients who had experienced a qualifying acute psychological trauma were randomized to receive up to 240 mg/day of propranolol or placebo for 19 days. At 4 and 12 weeks post‐trauma, PTSD symptoms were assessed. One week later, participants engaged in script‐driven imagery of their traumatic event while psychophysiological responses were measured. Results: Physiological reactivity during script‐driven traumatic imagery, severity of PTSD symptoms, and the rate of the PTSD diagnostic outcome were not significantly different between the two groups. However, post hoc subgroup analyses showed that in participants with high drug adherence, at the 5‐week posttrauma assessment, physiological reactivity was significantly lower during script‐driven imagery in the propranolol than in the placebo subjects. Conclusions: The physiological results provide some limited support for a model of PTSD in which a traumatic conditioned response is reduced by posttrauma propranolol. However, the clinical results from this study do not support the preventive use of propranolol in the acute aftermath of a traumatic event.

Double-blind study of high-dose fluoxetine versus lithium or desipramine augmentation of fluoxetine in partial responders and nonresponders to fluoxetine.

In a previous study, of 41 depressed patients who had not responded to fluoxetine 20 mg/day, 53% were treated with high-dose fluoxetine (40–60 mg/ day) and responded (i.e., their 17-item Hamilton Rating Scale for Depression [HAM-D-17] score was <7) versus 29% and 25% of patients treated with fluoxetine plus lithium (300–600 mg/day) or fluoxetine plus desipramine (25–50 mg/day), respectively. We wanted to assess whether these findings could be replicated in a larger sample of depressed outpatients. We identified 101 outpatients with major depressive disorder (52 men and 49 women; mean age, 41.6 + 10.6 years) who were either partial responders (n = 49) or nonresponders (n = 52) to 8 weeks of treatment with fluoxetine 20 mg/ day. These patients were randomized to 4 weeks of double-blind treatment with high-dose fluoxetine (40–60 mg/day), fluoxetine plus lithium (300–600 mg/day), or fluoxetine plus desipramine (25–50 mg/day). In the overall group of patients (N = 101), there was no significant difference in response rates across the three treatment groups (high-dose fluoxetine, 42.4%; fluoxetine plus desipramine, 29.4%; fluoxetine plus lithium, 23.5%). Dropout rates were also comparable, ranging from 9.1% (high-dose fluoxetine) to 14.7% (fluoxetine plus desipramine and fluoxetine plus lithium). There were also no significant differences in response rates across the three treatment groups among partial responders (high-dose fluoxetine, 50.0%; fluoxetine plus desipramine, 33.3%; fluoxetine plus lithium, 33.3%) and nonresponders (high-dose fluoxetine, 35.3%; fluoxetine plus desipramine, 26.3%; fluoxetine plus lithium, 12.5%). At the end of the study, the mean lithium level was 0.37 + 0.15 mEq/L (n = 27; range, 0.1–0.8 mEq/L) among lithium-treated patients, and the mean desipramine level was 104.7 + 58.8 ng/mL (n = 22; range, 25–257 ng/mL). There were no significant relationships between lithium or desipramine blood levels and degree of improvement (as measured by the change in HAM-D-17 score). We found no significant differences in efficacy among these three treatment strategies among patients who had failed to respond adequately to 8 weeks of treatment with fluoxetine 20 mg/day, although the high-fluoxetine group was associated with nonsignificantly higher response rates in both partial responders and nonresponders.

Quality of life in patients with panic disorder

In this study we assessed the quality of life of patients with panic disorder, with particular attention to the influence of anxiety and depression comorbidity on quality of life. Findings were compared with established general population norms as well as norms for patients with chronic medical conditions and major depression. The Medical Outcomes Study Short-Form Health Survey (SF-36) was administered to panic disorder patients entering clinical trials or treatment in an outpatient anxiety disorders program. Subjects were 73 consecutive patients with a primary diagnosis of panic disorder without current substance abuse or contributory medical illness. Their quality of life scores were compared with population mean estimates using single-sample t-tests, and the influence of comorbidity was examined with between-group comparisons. All SF-36 mental and physical health subscale scores were worse in patients with panic disorder than in the general population. This was true regardless of the presence of comorbid anxiety or mood disorders, although the presence of the comorbid conditions worsened select areas of functioning according to subscale analyses. SF-36 scores in panic patients were at approximately the same level as patients with major depression and tended to be worse in specific areas than patients with select medical conditions. This study provides evidence of the pervasive negative effects of panic disorder on both mental and physical health.

Aripiprazole as an augmentor of selective serotonin reuptake inhibitors in depression and anxiety disorder patients.

More than half of anxiety and depression patients treated with an adequate course of antidepressants fail to fully improve. We retrospectively examined whether treatment-resistant depression and anxiety disorder patients responded to and tolerated augmentation with the atypical antipsychotic, aripiprazole. We report on patients with depression and anxiety disorders, including panic disorder, generalized anxiety disorder, social anxiety and post-traumatic stress disorder, who had an incomplete response to a variety of selective serotonin reuptake inhibitors (SSRIs) and who received augmentation with aripiprazole. The primary outcome measure was the Clinical Global Impression of Improvement (CGI-I). In the intent-to-treat analysis, the mean±SD CGI-S was 3.8±1.3 at endpoint. Fifty-nine percent of subjects received CGI-I ratings of 1 or 2, ‘much improved’ or ‘very much improved,’ in terms of their depression and anxiety symptoms at the end of 12 weeks. Several patients showed an early (weeks 1–5), as well as sustained, response to augmentation with doses of aripiprazole between 15 and 30 mg/day. The results suggest that aripiprazole may be effective as an augmentation for patients with persistent depressive and anxiety disorders despite initial SSRI treatment. Because this is a retrospective case review, further prospective studies are required to confirm these findings.

Attention deficit hyperactivity disorder in childhood among adults with major depression

The prevalence of attention deficit hyperactivity disorder (ADHD) with childhood onset and its relationship to course and treatment outcome of major depressive disorder (MDD) in adults was studied in 116 patients (ages 18-65) consecutively enrolled for treatment of MDD. Sixteen percent of the patient were found to meet full or subthreshold criteria for the DSM-III-R diagnosis of childhood ADHD. Twelve percent endorsed persistence of ADHD symptoms into adulthood. Depressed adults meeting criteria for childhood ADHD did not differ significantly from other depressed adults on any measures related to the chronicity or severity of the mood disorder, Axis I comorbidity, or response to acute antidepressant treatment. Our results are clinically important as they suggest that clinicians need to be aware of the possibility that a substantial proportion of patients with MDD may suffer from comorbid ADHD and that treatments need to include the targeting of possible residual ADHD symptoms in addition to those of depression.

Personality disorders and depression.

BACKGROUND Personality disorders (PDs) were assessed among depressed out-patients by clinical interview before and after antidepressant treatment with fluoxetine to assess the degree of stability of PD diagnoses and determine whether changes in PD diagnoses across treatment are related to the degree of improvement in depressive symptoms. METHOD Three hundred and eighty-four out-patients (55% women; mean age = 39.9 +/- 10.5) with major depressive disorder (MDD) diagnosed with the SCID-P were enrolled into an 8 week trial of open treatment with fluoxetine 20 mg/day. The SCID-II was administered to diagnose PDs at baseline and endpoint. RESULTS A significant proportion (64%) of our depressed out-patients met criteria for at least one co-morbid personality disorder. Following 8 weeks of fluoxetine treatment, there was a significant reduction in the proportion of patients meeting criteria for avoidant, dependent, passive-aggressive, paranoid and narcissistic PDs. From baseline to endpoint, there was also a significant reduction in the mean number of criteria met for paranoid, schizotypal, narcissistic, borderline, avoidant, dependent, obsessive-compulsive, passive aggressive and self-defeating personality disorders. While changes in cluster diagnoses were not significantly related to improvement in depressive symptoms, there were significant relationships between degree of reduction in depressive symptoms (percentage change in HAM-D-17 scores) and degree of change in the number of criteria met for paranoid, narcissistic, borderline and dependent personality disorders. CONCLUSIONS Personality disorder diagnoses were found to be common among untreated out-patients with major depressive disorder. A significant proportion of these patients no longer met criteria for personality disorders following antidepressant treatment, and changes in personality disorder traits were significantly related to degree of improvement in depressive symptoms in some but not all personality disorders. These findings suggest that the lack of stability of PD diagnoses among patients with current MDD may be attributable in part to a direct effect of antidepressant treatment on behaviours and attitudes that comprise PDs.