Pill Placebo Research Articles

Parental anxiety as a predictor of medication and CBT response for anxious youth.

The aim of this investigation was to evaluate how parental anxiety predicted change in pediatric anxiety symptoms across four different interventions: cognitive-behavioral therapy, medication (sertraline; SRT), their combination (COMB), and pill placebo. Participants were 488 youths (ages 7-17) with separation anxiety disorder, generalized anxiety disorder, and/or social phobia and their primary caregivers. Latent growth curve modeling assessed how pre-treatment parental trait anxiety symptoms predicted trajectories of youth anxiety symptom change across 12 weeks of treatment at four time points. Interactions between parental anxiety and treatment condition were tested. Parental anxiety was not associated with youth's pre-treatment anxiety symptom severity. Controlling for parental trait anxiety, youth depressive symptoms, and youth age, youths who received COMB benefitted most. Counter to expectations, parental anxiety influenced youth anxiety symptom trajectory only within the SRT condition, whereas parental anxiety was not significantly associated with youth anxiety trajectories in the other treatment conditions. Specifically, within the SRT condition, higher levels of parental anxiety predicted a faster and greater reduction in youth anxiety over the acute treatment period compared to youths in the SRT condition whose parents had lower anxiety levels. While all active treatments produced favorable outcomes, results provide insight regarding the treatment-specific influence of parental anxiety on the time course of symptom change.

Long-Term Outcomes in Children with Anxiety Disorders

Children with anxiety disorders (social phobia, separation anxiety, generalized anxiety) showed good acute response to treatment in a randomized, placebo-controlled study (sertraline + cognitive-behavioral therapy [CBT], 81%; CBT, 60%; sertraline, 55%; pill placebo, 24%; NEJM JW Psychiatry Oct 30 2008). To learn about long-term outcomes, researchers conducted a follow-up study with in-person or telephone …

Predictors and moderators of treatment response in childhood anxiety disorders: Results from the CAMS trial.

We sought to examine predictors and moderators of treatment outcomes among 488 youths ages 7-17 years (50% female; 74% ≤ 12 years) meeting Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000) criteria for diagnoses of separation anxiety disorder, social phobia, or generalized anxiety disorder who were randomly assigned to receive either cognitive behavioral therapy (CBT), sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) in the Child/Adolescent Anxiety Multimodal Study (CAMS). Six classes of predictor and moderator variables (22 variables) were identified from the literature and examined using continuous (Pediatric Anxiety Ratings Scale; PARS) and categorical (Clinical Global Impression Scale-Improvement; CGI-I) outcome measures. Three baseline variables predicted better outcomes (independent of treatment condition) on the PARS, including low anxiety severity (as measured by parents and independent evaluators) and caregiver strain. No baseline variables were found to predict Week 12 responder status (CGI-I). Participants' principal diagnosis moderated treatment outcomes but only on the PARS. No baseline variables were found to moderate treatment outcomes on Week 12 responder status (CGI-I). Overall, anxious children responded favorably to CAMS treatments. However, having more severe and impairing anxiety, greater caregiver strain, and a principal diagnosis of social phobia were associated with less favorable outcomes. Clinical implications of these findings are discussed.

Stable remission and recovery after acute-phase cognitive therapy for recurrent major depressive disorder.

Continuation-phase cognitive therapy (C-CT) or fluoxetine (FLX) reduces relapse in adults with major depressive disorder (MDD; Jarrett, Minhajuddin, Gershenfeld, Friedman, & Thase, 2013). Among patients at higher risk for relapse, we hypothesized that continuation-phase treatment reduces residual symptoms and facilitates stable remission and recovery. Outpatients (N = 241) with recurrent MDD who responded to acute-phase CT with higher risk for relapse (i.e., had unstable remission defined by any of the last 7 acute-phase scores ≥ 7 using the Hamilton Rating Scale for Depression; Hamilton, 1960) were randomized to 8 months of C-CT, FLX, or pill placebo and followed for 24 additional months. Psychiatric status ratings (Keller et al., 1987) of 1 or 2 (absent or minimal depressive symptoms) for 6 and 35 continuous weeks post-randomization defined stable remission and recovery, respectively. Actuarial estimates of stable remission (97%) and recovery (94%) by the end of follow-up were high and did not differ among groups. Observed (unadjusted) proportions of patients remitting (70%) and recovering (47%) before relapse or attrition were lower. During the continuation phase, C-CT (d = 0.21) and FLX (d = 0.25) patients had significantly lower mean depressive symptoms than did controls, but C-CT and FLX patients did not differ from each other, nor did the 3 experimental groups differ during follow-up. Many patients who responded to CT with higher relapse risk subsequently remitted and recovered after discontinuation of acute-phase treatment. After discontinuation, C-CT and FLX decreased levels of residual depressive symptoms, but neither significantly increased the likelihood of stable remission or recovery, beyond the moderate to high levels observed among patients who did not relapse.

Preventing Depressive Relapse and Recurrence in Higher-Risk Cognitive Therapy Responders

Strategies to improve the course of recurrent major depressive disorder have great public health relevance. To reduce the risk of relapse/recurrence after acute phase cognitive therapy (CT), a continuation phase model of therapy may improve outcomes. To test the efficacy of continuation phase CT (C-CT) and fluoxetine for relapse prevention in a pill placebo (PBO)-controlled randomized trial and compare the durability of prophylaxis after discontinuation of treatments. A sequential, 3-stage design with an acute phase (all patients received 12 weeks of CT); 8-month experimental phase (responders at higher risk were randomized to C-CT, fluoxetine, or PBO); and 24 months of longitudinal, posttreatment follow-up. Two university-based specialty clinics. A total of 523 adults with recurrent major depressive disorder began acute phase CT, of which 241 higher-risk responders were randomized and 181 subsequently entered the follow-up. Cognitive therapy responders at higher risk for relapse were randomized to receive 8 months of C-CT (n = 86), fluoxetine (n = 86), or PBO (n = 69). Survival analyses of relapse/recurrence rates, as determined by blinded evaluators using DSM-IV criteria and the Longitudinal Interval Follow-up Evaluation. RESULTS As predicted, the C-CT or fluoxetine groups were significantly less likely to relapse than the PBO group across 8 months. Relapse/recurrence rates for C-CT and fluoxetine were nearly identical during the 8 months of treatment, although C-CT patients were more likely to accept randomization, stayed in treatment longer, and attended more sessions than those in the fluoxetine and PBO groups. Contrary to prediction, relapse/recurrence rates following the discontinuation of C-CT and fluoxetine did not differ. Relapse risk was reduced by both C-CT and fluoxetine in an enriched randomization sampling only CT responders. The preventive effects of C-CT were not significantly more durable than those of fluoxetine after treatment was stopped, suggesting that some higher-risk patients may require alternate longer-term interventions. clinicaltrials.gov Identifiers: NCT00118404, NCT00183664, and NCT00218764.

Cognitive-Behavioral Therapy vs Risperidone for Augmenting Serotonin Reuptake Inhibitors in Obsessive-Compulsive Disorder

Obsessive-compulsive disorder (OCD) is one of the world's most disabling illnesses according to the World Health Organization. Serotonin reuptake inhibitors (SRIs) are the only medications approved by the Food and Drug Administration to treat OCD, but few patients achieve minimal symptoms from an SRI alone. In such cases, practice guidelines recommend adding antipsychotics or cognitive-behavioral therapy consisting of exposure and ritual prevention (EX/RP). To compare the effects of these 2 SRI augmentation strategies vs pill placebo for the first time, to our knowledge, in adults with OCD. A randomized clinical trial (conducted January 2007-August 2012) at 2 academic outpatient research clinics that specialize in OCD and anxiety disorders. Patients (aged 18-70 years) were eligible if they had OCD of at least moderate severity despite a therapeutic SRI dose for at least 12 weeks prior to entry. Of 163 who were eligible, 100 were randomized (risperidone, n = 40; EX/RP, n = 40; and placebo, n = 20), and 86 completed the trial. While continuing their SRI at the same dose, patients were randomized to the addition of 8 weeks of risperidone (up to 4 mg/d), EX/RP (17 sessions delivered twice weekly), or pill placebo. Independent assessments were conducted every 4 weeks. The Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to measure OCD severity. Patients randomized to EX/RP had significantly greater reduction in week 8 Y-BOCS scores based on mixed-effects models (vs risperidone: mean [SE], -9.72 [1.38]; P < .001 vs placebo: mean [SE], -10.10 [1.68]; P < .001). Patients receiving risperidone did not significantly differ from those receiving placebo (mean [SE], -0.38 [1.72]; P = .83). More patients receiving EX/RP responded (Y-BOCS score decrease ≥25%: 80% for EX/RP, 23% for risperidone, and 15% for placebo; P < .001). More patients receiving EX/RP achieved minimal symptoms (Y-BOCS score ≤12: 43% for EX/RP, 13% for risperidone, and 5% for placebo; P = .001). Adding EX/RP was also superior to risperidone and placebo in improving insight, functioning, and quality of life. Adding EX/RP to SRIs was superior to both risperidone and pill placebo. Patients with OCD receiving SRIs who continue to have clinically significant symptoms should be offered EX/RP before antipsychotics given its superior efficacy and less negative adverse effect profile. clinicaltrials.gov Identifier: NCT00389493.

Somatic Complaints in Anxious Youth

This study examined (a) demographic and clinical characteristics associated with physical symptoms in anxiety-disordered youth and (b) the impact of cognitive-behavioral therapy (Coping Cat), medication (sertraline), their combination, and pill placebo on physical symptoms. Youth (N = 488, ages 7-17 years) with a principal diagnosis of generalized anxiety disorder, separation anxiety disorder, or social phobia participated as part of a multi-site, randomized controlled trial and received treatment delivered over 12 weeks. Diagnostic status, symptom severity, and impairment were assessed at baseline and week 12. The total number and severity of physical symptoms was associated with age, principal diagnosis, anxiety severity, impairment, and the presence of comorbid internalizing disorders. Common somatic complaints were headaches, stomachaches, head cold or sniffles, sleeplessness, and feeling drowsy or too sleepy. Physical symptoms decreased over the course of treatment, and were unrelated to treatment condition. Clinical implications and directions for future research are discussed (ClinicalTrials.gov number, NCT00052078).

Randomized, placebo-controlled trial of cognitive-behavioral therapy alone or combined with sertraline in the treatment of pediatric obsessive–compulsive disorder

BackgroundTo examine the efficacy of sequential sertraline and cognitive-behavioral therapy (CBT) treatment relative to CBT with pill placebo over 18 weeks in children and adolescents with obsessive–compulsive disorder (OCD). MethodsForty-seven children and adolescents with OCD (Range = 7–17 years) were randomized to 18-weeks of treatment in one of three arms: 1) sertraline at standard dosing + CBT (RegSert + CBT); 2) sertraline titrated slowly but achieving at least 8 weeks on the maximally tolerated daily dose + CBT (SloSert + CBT); or 3) pill placebo + CBT (PBO + CBT). Assessments were conducted at screening, baseline, weeks 1–9, 13, and 17, and post-treatment. Raters and clinicians were blinded to sertraline (but not CBT) randomization status. Primary outcomes included the Children's Yale-Brown Obsessive–Compulsive Scale, and response and remission status. Secondary outcomes included the Child Obsessive Compulsive Impact Scale–Parent/Child, Children's Depression Rating Scale-Revised, Multidimensional Anxiety Scale for Children, and Clinical-Global Impressions-Severity. ResultsAll groups exhibited large within-group effects across outcomes. There was no group by time interaction across all outcomes suggesting that group changes over time were comparable. ConclusionsAmong youth with OCD, there was no evidence that sequentially provided sertraline with CBT differed from those receiving placebo with CBT. ClinicalTrials.gov IdentifierNCT00382291.

Effects of Qishe Pill, a compound traditional Chinese herbal medicine, on cervical radiculopathy: study protocol for a randomized controlled trial

BackgroundNeck pain is a common symptom in most patients suffering from cervical radiculopathy. However, some conservative treatments are limited by their modest effectiveness. On the other hand, surgical intervention for cervical disc disorders is indicated when symptoms are refractory to conservative treatments and neurological symptoms are progressive. Many patients use complementary and alternative medicine, including traditional Chinese medicine, to address their symptoms. The purpose of the present study is to examine the efficacy and safety of Qishe Pill, a compound traditional Chinese herbal medicine, for neck pain in patients with cervical radiculopathy.Methods/designA multicenter, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of the Qishe Pill is proposed. The study will include 240 patients from five sites across China and diagnosed with cervical radiculopathy, according to the following inclusion criteria: age 18 to 65 with pain or stiffness in the neck for at least 2 weeks (neck disability index score 25 or more) and accompanying arm pain that radiates distally from the elbow. Qualified participants will be randomly allocated into two groups: Qishe Pill group and placebo group. The prescription of the trial medications (Qishe Pill/placebo) are 3.75 g each twice a day for 28 consecutive days. The primary outcome is pain severity. Secondary outcomes are functional status, patient satisfaction, and adverse events as reported in the trial.DiscussionQishe Pill is composed of processed Radix Astragali, Muscone, Szechuan Lovage Rhizome, Radix Stephaniae Tetrandrae, Ovientvine, and Calculus Bovis Artifactus. According to modern research and preparation standards, Qishe Pill is developed to improve on the various symptoms of cervical radiculopathy, especially for neck pain. As it has a potential benefit in treating patients with neck pain, we designed a double-blind, prospective, randomized-controlled trial and would like to publish the results and conclusions later. If Qishe Pill can alleviate neck pain without adverse effects, it may be a unique strategy for the treatment of cervical radiculopathy.Trial registrationThis study is registered at ClinicalTrials.gov, NCT01274936

SLEEP QUALITY PREDICTS TREATMENT OUTCOME IN CBT FOR SOCIAL ANXIETY DISORDER

Sleep quality may be an important, yet relatively neglected, predictor of treatment outcome in cognitive-behavioral therapy (CBT) for anxiety disorders. Specifically, poor sleep quality may impair memory consolidation of in-session extinction learning. We therefore examined sleep quality as a predictor of treatment outcome in CBT for social anxiety disorder and the impact of d-cycloserine (DCS) on this relationship. One hundred sixty-nine participants with a primary diagnosis of DSM-IV generalized social anxiety disorder were recruited across three sites. Participants were enrolled in 12 weeks of group CBT. Participants randomly received 50 mg of DCS (n = 87) or pill placebo (n = 82) 1 hr prior to sessions 3-7. Participants completed a baseline measure of self-reported sleep quality and daily diaries recording subjective feelings of being rested upon wakening. Outcome measures including social anxiety symptoms and global severity scores were assessed at each session. Poorer baseline sleep quality was associated with slower improvement and higher posttreatment social anxiety symptom and severity scores. Moreover, patients who felt more "rested" after sleeping the night following a treatment session had lower levels of symptoms and global severity at the next session, controlling for their symptoms and severity scores the previous session. Neither of these effects were moderated by DCS condition. Our findings suggest that poor sleep quality diminishes the effects of CBT for social anxiety disorder and this relation is not attenuated by DCS administration. Therapeutic attention to sleep quality prior to initiation of CBT and during the acute treatment phase may be clinically indicated.

Concurrent Naltrexone and Prolonged Exposure Therapy for Patients With Comorbid Alcohol Dependence and PTSD

Alcohol dependence comorbid with posttraumatic stress disorder (PTSD) has been found to be resistant to treatment. In addition, there is a concern that prolonged exposure therapy for PTSD may exacerbate alcohol use. To compare the efficacy of an evidence-based treatment for alcohol dependence (naltrexone) plus an evidence-based treatment for PTSD (prolonged exposure therapy), their combination, and supportive counseling. A single-blind, randomized clinical trial of 165 participants with PTSD and alcohol dependence conducted at the University of Pennsylvania and the Philadelphia Veterans Administration. Participant enrollment began on February 8, 2001, and ended on June 25, 2009. Data collection was completed on August 12, 2010. Participants were randomly assigned to (1) prolonged exposure therapy plus naltrexone (100 mg/d), (2) prolonged exposure therapy plus pill placebo, (3) supportive counseling plus naltrexone (100 mg/d), or (4) supportive counseling plus pill placebo. Prolonged exposure therapy was composed of 12 weekly 90-minute sessions followed by 6 biweekly sessions. All participants received supportive counseling. The Timeline Follow-Back Interview and the PTSD Symptom Severity Interview were used to assess the percentage of days drinking alcohol and PTSD severity, respectively, and the Penn Alcohol Craving Scale was used to assess alcohol craving. Independent evaluations occurred prior to treatment (week 0), at posttreatment (week 24), and at 6 months after treatment discontinuation (week 52). Participants in all 4 treatment groups had large reductions in the percentage of days drinking (mean change, -63.9% [95% CI, -73.6% to -54.2%] for prolonged exposure therapy plus naltrexone; -63.9% [95% CI, -73.9% to -53.8%] for prolonged exposure therapy plus placebo; -69.9% [95% CI, -78.7% to -61.2%] for supportive counseling plus naltrexone; and -61.0% [95% CI, -68.9% to -53.0%] for supportive counseling plus placebo). However, those who received naltrexone had lower percentages of days drinking than those who received placebo (mean difference, 7.93%; P = .008). There was also a reduction in PTSD symptoms in all 4 groups, but the main effect of prolonged exposure therapy was not statistically significant. Six months after the end of treatment, participants in all 4 groups had increases in percentage of days drinking. However, those in the prolonged exposure therapy plus naltrexone group had the smallest increases. In this study of patients with alcohol dependence and PTSD, naltrexone treatment resulted in a decrease in the percentage of days drinking. Prolonged exposure therapy was not associated with an exacerbation of alcohol use disorder. clinicaltrials.gov Identifier: NCT00006489.

Antidepressant Medication Augmented With Cognitive-Behavioral Therapy for Generalized Anxiety Disorder in Older Adults

OBJECTIVE Generalized anxiety disorder is common among older adults and leads to diminished health and cognitive functioning. Although antidepressant medications are efficacious, many elderly individuals require augmentation treatment. Furthermore, little is known about maintenance strategies for older people. The authors examined whether sequenced treatment combining pharmacotherapy and cognitive-behavioral therapy (CBT) boosts response and prevents relapse in older adults with generalized anxiety disorder. METHOD Participants were individuals at least 60 years of age with generalized anxiety disorder (N=73) who were recruited from outpatient clinics at three sites. Participants received 12 weeks of open-label escitalopram and were then randomly assigned to one of four conditions: 16 weeks of escitalopram (10-20 mg/day) plus modular CBT, followed by 28 weeks of maintenance escitalopram; escitalopram alone, followed by maintenance escitalopram; escitalopram plus CBT, followed by pill placebo; and escitalopram alone, followed by placebo. RESULTS Escitalopram augmented with CBT increased response rates on the Penn State Worry Questionnaire but not on the Hamilton Anxiety Rating Scale compared with escitalopram alone. Both escitalopram and CBT prevented relapse compared with placebo. CONCLUSIONS This study demonstrates effective strategies for treatment of generalized anxiety disorder in older adults. The sequence of antidepressant medication augmented with CBT leads to worry reduction in the short-term. Continued medication prevents relapse, but for many individuals, CBT would allow sustained remission without requiring long-term pharmacotherapy.

Differential change in specific depressive symptoms during antidepressant medication or cognitive therapy

Cognitive therapy and antidepressant medications are effective treatments for depression, but little is known about their relative efficacy in reducing individual depressive symptoms. Using data from a recent clinical trial comparing cognitive therapy, antidepressant medication, and placebo in the treatment of moderate-to-severe depression, we examined whether there was a relative advantage of any treatment in reducing the severity of specific depressive symptom clusters. The sample consisted of 231 depressed outpatients randomly assigned to: cognitive therapy for 16 weeks (n = 58); paroxetine treatment for 16 weeks (n = 116); or pill placebo for 8 weeks (n = 57). Differential change in five subsets of depressive symptoms was examined: mood, cognitive/suicide, anxiety, typical-vegetative, and atypical-vegetative symptoms. Medication led to a greater reduction in cognitive/suicide symptoms relative to placebo by 4 weeks, and both active treatments reduced these symptoms more than did placebo by 8 weeks. Cognitive therapy reduced the atypical-vegetative symptoms more than placebo by 8 weeks and more than medications throughout the trial. These findings suggest that medications and cognitive therapy led to different patterns of response to specific symptoms of depression and that the general efficacy of these two well-validated treatments may be driven in large part by changes in cognitive or atypical-vegetative symptoms.

Comparison of psychotherapies for adult depression to pill placebo control groups: a meta-analysis

The effects of antidepressants for treating depressive disorders have been overestimated because of selective publication of positive trials. Reanalyses that include unpublished trials have yielded reduced effect sizes. This in turn has led to claims that antidepressants have clinically insignificant advantages over placebo and that psychotherapy is therefore a better alternative. To test this, we conducted a meta-analysis of studies comparing psychotherapy with pill placebo. Ten 10 studies comparing psychotherapies with pill placebo were identified. In total, 1240 patients were included in these studies. For each study, Hedges' g was calculated. Characteristics of the studies were extracted for subgroup and meta-regression analyses. The effect of psychotherapy compared to pill placebo at post-test was g = 0.25 [95% confidence interval (CI) 0.14-0.36, I² = 0%, 95% CI 0-58]. This effect size corresponds to a number needed to treat (NNT) of 7.14 (95% CI 5.00-12.82). The psychotherapy conditions scored 2.66 points lower on the Hamilton Depression Rating Scale (HAMD) than the placebo conditions, and 3.20 points lower on the Beck Depression Inventory (BDI). Some indications for publication bias were found (two missing studies). We found no significant differences between subgroups of the studies and in meta-regression analyses we found no significant association between baseline severity and effect size. Although there are differences between the role of placebo in psychotherapy and pharmacotherapy research, psychotherapy has an effect size that is comparable to that of antidepressant medications. Whether these effects should be deemed clinically relevant remains open to debate.

Treatment for tobacco dependence: effect on brain nicotinic acetylcholine receptor density.

Cigarette smoking leads to upregulation of brain nicotinic acetylcholine receptors (nAChRs), including the common α4β2* nAChR subtype. Although a substantial percentage of smokers receive treatment for tobacco dependence with counseling and/or medication, the effect of a standard course of these treatments on nAChR upregulation has not yet been reported. In the present study, 48 otherwise healthy smokers underwent positron emission tomography (PET) scanning with the radiotracer 2-FA (for labeling α4β2* nAChRs) before and after treatment with either cognitive-behavioral therapy, bupropion HCl, or pill placebo. Specific binding volume of distribution (VS/fP), a measure proportional to α4β2* nAChR density, was determined for regions known to have nAChR upregulation with smoking (prefrontal cortex, brainstem, and cerebellum). In the overall study sample, significant decreases in VS/fP were found for the prefrontal cortex, brainstem, and cerebellum of -20 (±35), -25 (±36), and -25 (±31)%, respectively, which represented movement of VS/fP values toward values found in non-smokers (mean 58.2% normalization of receptor levels). Participants who quit smoking had significantly greater reductions in VS/fP across regions than non-quitters, and correlations were found between reductions in cigarettes per day and decreases in VS/fP for brainstem and cerebellum, but there was no between-group effect of treatment type. Thus, smoking reduction and cessation with commonly used treatments (and pill placebo) lead to decreased α4β2* nAChR densities across brain regions. Study findings could prove useful in the treatment of smokers by providing encouragement with the knowledge that decreased smoking leads to normalization of specific brain receptors.

BENEFITS OF CHILD-FOCUSED ANXIETY TREATMENTS FOR PARENTS AND FAMILY FUNCTIONING

To examine (1) changes in parent (global psychological distress, trait anxiety) and family (dysfunction, burden) functioning following 12 weeks of child-focused anxiety treatment, and (2) whether changes in these parent and family factors were associated with child's treatment condition and response. Participants were 488 youth ages 7-17 years (50% female; mean age 10.7 years) who met DSM-IV-TR criteria for social phobia, separation anxiety, and/or generalized anxiety disorder, and their parents. Youth were randomly assigned to 12 weeks of "Coping Cat" individual cognitive-behavioral therapy (CBT), medication management with sertraline (SRT), their combination (COMB), or medication management with pill placebo (PBO) within the multisite Child/Adolescent Anxiety Multimodal Study (CAMS). At pre- and posttreatment, parents completed measures of trait anxiety, psychological distress, family functioning, and burden of child illness; children completed a measure of family functioning. Blinded independent evaluators rated child's response to treatment using the Clinical Global Impression-Improvement Scale at posttreatment. Analyses of covariance revealed that parental psychological distress and trait anxiety, and parent-reported family dysfunction improved only for parents of children who were rated as treatment responders, and these changes were unrelated to treatment condition. Family burden and child-reported family dysfunction improved significantly from pre- to posttreatment regardless of treatment condition or response. Findings suggest that child-focused anxiety treatments, regardless of intervention condition, can result in improvements in nontargeted parent symptoms and family functioning particularly when children respond successfully to the treatment.

D-Cycloserine Enhancement of Fear Extinction is Specific to Successful Exposure Sessions: Evidence from the Treatment of Height Phobia

Whereas some studies have shown clear evidence for an augmentation effect of D-cycloserine (DCS) on exposure therapy for anxiety disorders, other studies have shown weak effects or no effect at all. Some preclinical data suggest that the DCS augmentation effect is moderated by the success of extinction learning. Therefore, we conducted a reanalysis of existing data to examine whether the effects of DCS on clinical outcome would vary as a function of response to the exposure session (i.e., exposure success). In a clinical trial, patients with height phobia received two sessions involving 30 minutes of virtual reality exposure therapy and were randomly assigned to a pill placebo (n = 14) or 50 mg of DCS (n = 15) immediately after each session. Mixed-effects regression analysis showed that the effects of DCS administration on clinical improvement was moderated by the level of fear experienced just before concluding exposure sessions. Patients receiving DCS exhibited significantly greater improvement in symptoms relative to patients who received placebo when fear was low at the end of the exposure. In contrast, when end fear was still elevated, patients receiving DCS improved less compared with those receiving placebo. D-cycloserine appears to enhance the benefits of exposure treatment when applied after a successful session, but it seems to have detrimental effects when administered after inadequate/unsuccessful exposure sessions.

Defining Treatment Response and Remission in Child Anxiety: Signal Detection Analysis Using the Pediatric Anxiety Rating Scale

ObjectiveTo determine optimal Pediatric Anxiety Rating Scale (PARS) percent reduction and raw score cut-offs for predicting treatment response and remission among children and adolescents with anxiety disorders. MethodData were from a subset of youth (N = 438; 7–17 years of age) who participated in the Child/Adolescent Anxiety Multimodal Study (CAMS), a multi-site, randomized controlled trial that examined the relative efficacy of cognitive-behavioral therapy (CBT; Coping Cat), medication (sertraline [SRT]), their combination, and pill placebo for the treatment of separation anxiety disorder, generalized anxiety disorder, and social phobia. The clinician-rated PARS was administered pre- and posttreatment (delivered over 12 weeks). Quality receiver operating characteristic methods assessed the performance of various PARS percent reductions and absolute cut-off scores in predicting treatment response and remission, as determined by posttreatment ratings on the Clinical Global Impression scales and the Anxiety Disorders Interview Schedule for DSM-IV. Corresponding change in impairment was evaluated using the Child Anxiety Impact Scale. ResultsReductions of 35% and 50% on the six-item PARS optimally predicted treatment response and remission, respectively. Post-treatment PARS raw scores of 8 to 10 optimally predicted remission. Anxiety improved as a function of PARS-defined treatment response and remission. ConclusionsResults serve as guidelines for operationalizing treatment response and remission in future research and in making cross-study comparisons. These guidelines can facilitate translation of research findings into clinical practice.

Placebo mechanisms for drug dose reduction: what is the evidence?

The mechanisms that generate and steer the placebo response in clinical trials and clinical practice are increasingly better understood. Pavlovian conditioning of physiological responses to medication that are associated with the intake of a drug, and expectation-driven evaluation of symptoms and symptom changes by the patient after the intake of a presumed medication, contribute to symptomatic improvement as well after intake of an inert pill (placebo), as long as he/she is unaware of its nature [1]. It has also been shown that the likelihood of receiving active treatment in clinical trials modulates the placebo response [2]. Recent research has, however, shown that even the knowledge to receive a placebo will generate clinical improvements as long as the patients have had a positive experience (history) with medication and positive expectations are maintained [3]. Separating expectancy-mediated and conditioned placebo responses may be feasible in experimental research, but in clinical trials as well as in daily routine, “much like the laws of gravity, the laws of learning are always in effect” [4] and do not allow such isolation. If expectation and conditioning are ingredients of the placebo response, the quest of how to make use of them in medical practice and research arises. One precondition is to rigorously follow principles of ‘associative learning’ that were set by Ivan P Pavlov. This was realized by – among others – Robert Ader (1932–2011), a psychologist at the Rockefeller University (NY, USA) who pioneered psychoimmunology, the investigation of CNS influence and control of immunological functions using Pavlovian conditioning principles since 1975 [5]. In the 1980s, Ader had hypothesized that the placebo effects as seen in clinical studies, specifically with randomized, placebo-controlled crossover trials (a frequently used design until today), may be due to conditioning [6]. He was among the first to propose using a conditioning procedure to partially replace drugs with placebos in tandomized-controlled trials [7], and he even patented a “Method and device for administering medication and/or placebo” to test his hypotheses [101]. In an initial study, the effects of atenolol, a beta-blocker, were investigated in 24 patients with mild or moderate hypertension [6]. Patients received either placebo, followed by the drug, followed by no treatment (Group 1); or the drug, followed by placebo (Group 2); or the drug, followed by no treatment (Group 3); with each period lasting for 1 week. Prior to drug intake, Group 1 did not differ from Group 2 and 3 in the average blood pressure taken daily at home. After 1 week of drug treatment for all, blood pressure and heart rate were significantly lower in the placebo treated group (Group 2) than in the nontreatment controls (Groups 1 and 3), indicating that the placebo response was more than a residual drug effect. This is consistent with a conditioning model of the placebo effect. Such a conditioned response to placebo pills can be achieved if it is preceded by an acquisition period that is sufficiently long and effective.

The Effect of Continuous Positive Airway Pressure Treatment on Blood Pressure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

We sought to provide an updated systematic review and meta-analysis of studies investigating the effect of positive airway pressure (PAP) treatment for obstructive sleep apnea (OSA) on systolic and diastolic blood pressure (SBP, DBP). Two independent investigators undertook a systematic search of the PubMed database (1980-2012) to identify randomized controlled trials comparing therapeutic PAP to sham-PAP, pill placebo, or standard care over at least one week in adult OSA patients without major comorbidities. The mean, variance, and sample size for diurnal and nocturnal SBP and DBP data were also extracted independently from each study. Random effects meta-analyses were conducted, followed by pre-specified subgroup and meta-regression analyses. 32 studies were identified, with data available from 28 studies representing n = 1,948 patients. The weighted mean difference in diurnal SBP (-2.58 mm Hg, 95% CI -3.57 to -1.59 mm Hg) and DBP (-2.01 mm Hg, 95% CI -2.84 to -1.18 mm Hg) both significantly favored PAP treatment over control arms, with similar results seen in nocturnal readings. Statistically significant reductions in BP were seen in studies whose patients were younger, sleepier, had more severe OSA, and exhibited greater PAP adherence. Meta-regression indicated that the reductions in DBP with PAP were predicted by mean baseline BP (β = -0.22, p = 0.02) and Epworth Sleepiness Scale scores (β = -0.27, p = 0.04). PAP treatment for OSA is associated with modest but significant reductions in diurnal and nocturnal SBP and DBP. Future research should be directed towards identifying subgroups likely to reap greater treatment benefits as well as other therapeutic benefits provided by PAP therapy.