Iman Alaie

Reporting of harms in randomized controlled trials of psychological interventions for mental and behavioral disorders: A review of current practice

BACKGROUND Data suggest that certain psychological interventions can induce harm in a significant number of patients. While the need for adequate reporting of harms in clinical trials has repeatedly been emphasized, it is uncertain whether such information is routinely collected and reported in trials within this research field. METHOD We used the two major databases in clinical psychology and medicine (PsycINFO and PubMed) to identify original publications from 2010 reporting randomized controlled trials of psychological interventions for patients with mental and behavioral disorders. Two reviewers searched the full-text reports for information about monitoring of adverse events, side effects, and deterioration. RESULTS A total of 132 eligible trials were identified. Only 28 trials (21%) included information that indicated any monitoring of harms on patient level. Four (3%) of these trials provided a description of adverse events as well as the methods used for collecting these data. Five of the trials (4%) reported adverse events but did not give complete information about the method. An additional four reports (3%) briefly stated that no adverse events occurred, whereas 15 trials (11%) only provided information on deterioration or indicated monitoring of deterioration. The probability of including harm-related information was related to the journal impact factor. CONCLUSION Important information about harms is not reported systematically within this research field, suggesting that the risk of reporting bias is nontrivial in conclusions about the risk-benefit ratio of psychological treatments. Guidelines on how to define, detect, and report harms related to psychological interventions could facilitate better reporting.

Serotonin Synthesis and Reuptake in Social Anxiety Disorder: A Positron Emission Tomography Study.

IMPORTANCE Serotonin is involved in negative affect, but whether anxiety syndromes, such as social anxiety disorder (SAD), are characterized by an overactive or underactive serotonin system has not been established. Serotonin 1A autoreceptors, which inhibit serotonin synthesis and release, are downregulated in SAD, and serotonin transporter availability might be increased; however, presynaptic serotonin activity has not been evaluated extensively. OBJECTIVE To examine the serotonin synthesis rate and serotonin transporter availability in patients with SAD and healthy control individuals using positron emission tomography (PET) with the radioligands 5-hydroxytryptophan labeled with carbon 11 ([11C]5-HTP) and 11C-labeled 3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile [11C]DASB. DESIGN, SETTING, AND PARTICIPANTS We performed a cross-sectional study at an academic clinical research center. Eighteen patients with SAD (9 men and 9 women; mean [SD] age, 32.6 [8.2] years) and 18 sex- and age-matched healthy controls (9 men and 9 women; mean [SD] age, 34.7 [9.2] years) underwent [11C]5-HTP PET imaging. We acquired [11C]DASB PET images for 26 additional patients with SAD (14 men and 12 women; mean [SD] age, 35.2 [10.7] years) and the same 18 sex- and age-matched healthy controls. Participants were recruited through newspaper advertisements. Data were acquired from March 12, 2002, through March 5, 2012, and analyzed from March 28, 2013, through August 29, 2014. MAIN OUTCOMES AND MEASURES The influx rate of [11C]5-HTP as a measure of serotonin synthesis rate capacity and [11C]DASB binding potential as an index of serotonin transporter availability were acquired during rest. We used the Liebowitz Social Anxiety Scale to measure severity of social anxiety symptoms. RESULTS The PET data were not available for analysis in 1 control for each scan. Increased [11C]5-HTP influx rate was observed in the amygdala, raphe nuclei region, caudate nucleus, putamen, hippocampus, and anterior cingulate cortex of patients with SAD compared with healthy controls (P < .05 corrected), supporting an enhanced serotonin synthesis rate. Increased serotonin transporter availability in the patients with SAD relative to healthy controls was reflected by elevated [11C]DASB binding potential in the raphe nuclei region, caudate nucleus, putamen, thalamus, and insula cortex (P < .05 corrected). CONCLUSIONS AND RELEVANCE Neurotransmission in SAD is characterized by an overactive presynaptic serotonin system, with increased serotonin synthesis and transporter availability. Our findings could provide important new insights into the etiology of anxiety disorders.

The Factor Structure of Traumatic Stress in Parents of Children With Cancer: A Longitudinal Analysis

Objectives To determine the factor structure of posttraumatic stress symptoms (PTSS) and assess its stability over time among parents of children diagnosed with cancer. Methods Parents of children with cancer included in a longitudinal study completed the posttraumatic stress disorder (PTSD) Checklist–Civilian Version 2 weeks (n = 249) and 2 (n = 234) and 4 (n = 203) months after their childs diagnosis. Confirmatory factor analysis (CFA) was used to assess 3 models of the underlying dimensions of PTSD and invariance tests were used to assess stability over time. Results A longitudinal CFA with the factors reexperiencing, avoidance, dysphoria, and hyperarousal provided best fit to the data. Invariance testing suggested that the pattern and size of loadings were equivalent across the three assessments. Discussions Findings tentatively suggest that PTSS among parents of children with cancer consist of four factors. Implications for research and clinical practice are discussed.

Enlargement of visual processing regions in social anxiety disorder is related to symptom severity

Social anxiety disorder (SAD) is associated with altered brain function and structure, but most structural studies include small samples and findings are mixed. This study compared regional gray matter volume between 48 SAD patients and 29 healthy controls (HC) as well as the relationship between volume and symptom severity. Structural magnetic resonance images from SAD patients and HC were evaluated using standard voxel-based morphometry (VBM) processing in the SPM8 software package. Social anxiety symptom severity was rated in SAD patients by a clinician using the Liebowitz Social Anxiety Scale (LSAS). SAD patients had greater regional gray matter volume in the lingual gyrus and lateral occipital cortex than the controls, and within the SAD group a positive correlation was found between symptom severity and regional gray matter volume in the lingual gyrus and the retrosplenial cortex. These findings replicate and extend earlier reports of enlarged visual processing areas in SAD. Increased gray matter volume in regions involved in visual processing and self-consciousness could underlie, or be the result of, abnormal emotional information processing and self-focused attention previously demonstrated in patients with SAD.

Combining escitalopram and cognitive-behavioural therapy for social anxiety disorder: randomised controlled fMRI trial.

BACKGROUND Selective serotonin reuptake inhibitors (SSRIs) and cognitive-behavioural therapy (CBT) are often used concomitantly to treat social anxiety disorder (SAD), but few studies have examined the effect of this combination. AIMS To evaluate whether adding escitalopram to internet-delivered CBT (ICBT) improves clinical outcome and alters brain reactivity and connectivity in SAD. METHOD Double-blind, randomised, placebo-controlled neuroimaging trial of ICBT combined either with escitalopram (n = 24) or placebo (n = 24), including a 15-month clinical follow-up (trial registration: ISRCTN24929928). RESULTS Escitalopram+ICBT, relative to placebo+ICBT, resulted in significantly more clinical responders, larger reductions in anticipatory speech state anxiety at post-treatment and larger reductions in social anxiety symptom severity at 15-month follow-up and at a trend-level (P = 0.09) at post-treatment. Right amygdala reactivity to emotional faces also decreased more in the escitalopram+ICBT combination relative to placebo+ICBT, and in treatment responders relative to non-responders. CONCLUSIONS Adding escitalopram improves the outcome of ICBT for SAD and decreased amygdala reactivity is important for anxiolytic treatment response.

Recent randomized controlled trials of psychological interventions in healthcare: A review of their quantity, scope, and characteristics

OBJECTIVE This study aimed to describe the quantity, scope, and fundamental characteristics of recently published randomized controlled trials (RCTs) of psychological interventions. METHODS We queried two major databases (PsycINFO and PubMeD) for primary reports published in 2010 of RCTs of psychological interventions for participants with a medical condition. We collected data on the characteristics of the trials, participants, interventions, outcomes, and reports. RESULTS Of 3696 retrieved reports 295 primary publications were included. About half (53%) of trials included participants with a mental disorder and more than half evaluated interventions based on a cognitive behavioral therapy (CBT) framework. A majority of trials recruited participants in North America and Europe (79%). A minority of the trials focused on children and adolescents (17%) or the elderly (8%). The median sample size of the intervention arm was n=41. Thirty-nine percent of trials reported solely patient-reported outcomes. Only 5% of reports indicated funding from for-profit organizations. The median 2010 impact factor of the journals in which reports were published was 2.96. CONCLUSION This snapshot of the research on psychological interventions suggests that the evidence base for psychological interventions is expanding mainly for CBT interventions for adults in high-income countries. Although the restrictive inclusion criteria limit the generalizability of these results, researchers and funding agencies might be advised to strive for greater diversity regarding interventions, geographical/cultural settings and age groups. Regularly updated reviews of this research field, with gradually refined methodology and increased scope, may further inform funders and researchers.

Do You Believe It? Verbal Suggestions Influence the Clinical and Neural Effects of Escitalopram in Social Anxiety Disorder: A Randomized Trial

Background Selective serotonin reuptake inhibitors (SSRIs) are commonly prescribed for depression and anxiety, but their efficacy relative to placebo has been questioned. We aimed to test how manipulation of verbally induced expectancies, central for placebo, influences SSRI treatment outcome and brain activity in patients with social anxiety disorder (SAD). Methods We did a randomized clinical trial, within an academic medical center (Uppsala, Sweden), of individuals fulfilling the DSM-IV criteria for SAD, recruited through media advertising. Participants were 18 years or older and randomized in blocks, through a computer-generated sequence by an independent party, to nine weeks of overt or covert treatment with escitalopram (20 mg daily). The overt group received correct treatment information whereas the covert group was treated deceptively with the SSRI described, by the psychiatrist, as active placebo. The treating psychiatrist was necessarily unmasked while the research staff was masked from intervention assignment. Treatment efficacy was assessed primarily with the self-rated Liebowitz Social Anxiety Scale (LSAS-SR), administered at week 0, 1, 3, 6 and 9, also yielding a dichotomous estimate of responder status (clinically significant improvement). Before and at the last week of treatment, brain activity during an emotional face-matching task was assessed with functional magnetic resonance imaging (fMRI) and during fMRI sessions, anticipatory speech anxiety was also assessed with the Spielberger State-Trait Anxiety Inventory - State version (STAI-S). Analyses included all randomized patients with outcome data at posttreatment. This study is registered at ISRCTN, number 98890605. Findings Between March 17th 2014 and May 22nd 2015, 47 patients were recruited. One patient in the covert group dropped out after a few days of treatment and did not provide fMRI data, leaving 46 patients with complete outcome data. After nine weeks of treatment, overt (n = 24) as compared to covert (n = 22) SSRI administration yielded significantly better outcome on the LSAS-SR (adjusted difference 21.17, 95% CI 10.69–31.65, p < 0.0001) with more than three times higher response rate (50% vs. 14%; χ2(1) = 6.91, p = 0.009) and twice the effect size (d = 2.24 vs. d = 1.13) from pre-to posttreatment. There was no significant between-group difference on anticipatory speech anxiety (STAI-S), both groups improving with treatment. No serious adverse reactions were recorded. On fMRI outcomes, there was suggestive evidence for a differential neural response to treatment between groups in the posterior cingulate, superior temporal and inferior frontal gyri (all z thresholds exceeding 3.68, p ≤ 0.001). Reduced social anxiety with treatment correlated significantly with enhanced posterior cingulate (z threshold 3.24, p = 0.0006) and attenuated amygdala (z threshold 2.70, p = 0.003) activity. Interpretation The clinical and neural effects of escitalopram were markedly influenced by verbal suggestions. This points to a pronounced placebo component in SSRI-treatment of SAD and favors a biopsychosocial over a biomedical explanatory model for SSRI efficacy. Funding resources The Swedish Research Council for Working Life and Social Research (grant 2011-1368), the Swedish Research Council (grant 421-2013-1366), Riksbankens Jubileumsfond – the Swedish Foundation for Humanities and Social Sciences (grant P13-1270:1).