Transporter-facilitated uptake of serotonin (5-hydroxytryptamine or 5-HT) has been implicated in anxiety in humans and animal models and is the site of action of widely used uptake-inhibiting antidepressant and antianxiety drugs. Human 5-HT transporter (5-HTT) gene transcription is modulated by a common polymorphism in its upstream regulatory region. The short variant of the polymorphism reduces the transcriptional efficiency of the 5-HTT gene promoter, resulting in decreased 5-HTT expression and 5-HT uptake in lymphoblasts. Association studies in two independent samples totaling 505 individuals revealed that the 5-HTT polymorphism accounts for 3 to 4 percent of total variation and 7 to 9 percent of inherited variance in anxiety-related personality traits in individuals as well as sibships.

https://science.sciencemag.org/content/sci/274/5292/1527.full.pdf

Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region

This meta-analysis reviews 208 laboratory studies of acute psychological stressors and tests a theoretical model delineating conditions capable of eliciting cortisol responses. Psychological stressors increased cortisol levels; however, effects varied widely across tasks. Consistent with the theoretical model, motivated performance tasks elicited cortisol responses if they were uncontrollable or characterized by social-evaluative threat (task performance could be negatively judged by others), when methodological factors and other stressor characteristics were controlled for. Tasks containing both uncontrollable and social-evaluative elements were associated with the largest cortisol and adrenocorticotropin hormone changes and the longest times to recovery. These findings are consistent with the animal literature on the physiological effects of uncontrollable social threat and contradict the belief that cortisol is responsive to all types of stressors.

http://anthro.vancouver.wsu.edu/media/Course_files/anth-260-edward-h-hagen/acute-stressors-and-cortisol-responses-a-theoretical-integration-and-synthesis-of-laboratory-research-1.pdf

Acute stressors and cortisol responses: a theoretical integration and synthesis of laboratory research.

• The history, rationale, and development of the Structured Clinical Interview for DSM-III-R (SCID) is described. The SCID is a semistuctured interview for making the major Axis I DSM-III-R diagnoses. It is administered by a clinician and includes an introductory overview followed by nine modules, seven of which represent the major axis I diagnostic classes. Because of its modular construction, it can be adapted for use in studies in which particular diagnoses are not of interest. Using a decision tree approach, the SCID guides the clinician in testing diagnostic hypotheses as the interview is conducted. The output of the SCID is a record of the presence or absence of each of the disorders being considered, for current episode (past month) and for lifetime occurrence.

https://jamanetwork.com/journals/jamapsychiatry/articlepdf/495830/archpsyc_49_8_005.pdf

The Structured Clinical Interview for DSM-III-R (SCID). I: History, rationale, and description.

We review psychometric and other evidence relevant to mixed anxiety-depression. Properties of anxiety and depression measures, including the convergent and discriminant validity of self- and clinical ratings, and interrater reliability, are examined in patient and normal samples. Results suggest that anxiety and depression can be reliably and validly assessed; moreover, although these disorders share a substantial component of general affective distress, they can be differentiated on the basis of factors specific to each syndrome. We also review evidence for these specific factors, examining the influence of context and scale content on ratings, factor analytic studies, and the role of low positive affect in depression. With these data, we argue for a tripartite structure consisting of general distress, physiological hyperarousal (specific anxiety), and anhedonia (specific depression), and we propose a diagnosis of mixed anxiety-depression.

Tripartite model of anxiety and depression: psychometric evidence and taxonomic implications.

This meta-analysis of 172 studies (N = 2,263 anxious, N = 1,768 nonanxious) examined the boundary conditions of threat-related attentional biases in anxiety. Overall, the results show that the bias is reliably demonstrated with different experimental paradigms and under a variety of experimental conditions, but that it is only an effect size of d = 0.45. Although processes requiring conscious perception of threat contribute to the bias, a significant bias is also observed with stimuli outside awareness. The bias is of comparable magnitude across different types of anxious populations (individuals with different clinical disorders, high-anxious nonclinical individuals, anxious children and adults) and is not observed in nonanxious individuals. Empirical and clinical implications as well as future directions for research are discussed.

/pdf/threat-related-attentional-bias-in-anxious-and-nonanxious-2pi60mj0pt.pdf

Threat-related attentional bias in anxious and nonanxious individuals: a meta-analytic study.

• Following promising preliminary evidence, the benzodiazepine-derivative alprazolam was studied in a large, placebocontrolled, eight-week, flexible-dose trial in patients with agoraphobia with panic attacks and panic disorder. Of 526 patients, 481 completed three weeks of treatment; however, significantly more placebo (102/234) than alprazolam (21/247) recipients subsequently dropped out of the trial, primarily citing ineffectiveness (of placebo) as the reason. Alprazolam was found to be effective and well tolerated. There were significant alprazolam-placebo differences in improvement for (1) spontaneous and situational panic attacks, (2) phobic fears, (3) avoidance behavior, (4) anxiety, and (5) secondary disability, all significant by the end of week 1. At the primary comparison point (week 4), 82% of the patients receiving alprazolam were rated moderately improved or better vs 43% of the placebo group. At that point, 50% of the alprazolam recipients vs 28% of placebo recipients were free of panic attacks.

Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial: I. Efficacy in Short-term Treatment

• Preliminary reports of discontinuation of alprazolam therapy in patients with panic disorder have revealed worsening of symptoms despite gradual withdrawal of medication. In this study, 126 patients with panic disorder and phobic avoidance received either alprazolam or placebo in doses of 2 to 10 mg daily for eight weeks. The medication was tapered over a period of four weeks, and patients were observed for another two weeks after all medication was discontinued. Sixty of the 63 alprazolam-treated patients and 49 of the 63 placebo-treated patients entered the taper and discontinuation study. After improvement in the active treatment period, the alprazolamtreated group had significant relapse between the first and last week of taper. However, during the second postdiscontinuation week, outcome scores were not significantly different from those of the placebo-treated group who did not deteriorate during taper. Twenty-seven percent of the alprazolamtreated group reported a rebound of panic attacks during taper and 13% reported a rebound of anxiety on the Hamilton Anxiety Scale. No serious or life-threatening withdrawal symptoms were reported, but distinct, transient, mild to moderate withdrawal syndrome occurred in 35% of the alprazolamtreated group and in none of the placebo-treated group. The coexistence of symptom rebound and a withdrawal syndrome occurred in 10% of the alprazolam-treated group, but both subsided by the end of the second week without alprazolam. We recommend that patients with panic disorder be treated for a longer period, at least six months, and that medication be tapered over a more prolonged period, at least eight weeks, especially where hiqh doses are emploved.

Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial: III. Discontinuation Effects

OBJECTIVE: The authors evaluated the efficacy, safety, and tolerability of sertraline, a selective serotonin reuptake inhibitor, in the treatment of generalized social phobia. METHOD: Adult outpatients with generalized social phobia (N=204) from 10 Canadian centers were randomly assigned to receive sertraline or placebo in a 2:1 ratio for a 20-week double-blind study following a 1-week, single-blind, placebo run-in. The initial dose of sertraline was 50 mg/day with increases of 50 mg/day every 3 weeks permitted after the fourth week of treatment (dosing was flexible up to a maximum of 200 mg/day). Primary efficacy assessments were the percentage of patients rated much or very much improved on the Clinical Global Impression (CGI) improvement item and the mean changes from baseline to study endpoint in total score on the social phobia subscale of the Marks Fear Questionnaire and total score on the Brief Social Phobia Scale. RESULTS: In intent-to-treat endpoint analyses of 203 of the patients, significantly ...

Sertraline Treatment of Generalized Social Phobia: A 20-Week, Double-Blind, Placebo-Controlled Study

Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study.

• Depressive symptomatology in 481 subjects with panic disorder and phobic avoidance was studied as part of an investigation of the efficacy of alprazolam in panic disorder. Subjects who had a major depressive episode (MDE) before the onset of their panic disorder were not included in the trial. With this exclusion criterion, 31% of subjects had a secondary MDE occurring after the onset of the panic disorder. The occurrence of secondary MDE was related to the length of time subjects were ill with panic disorder. Compared with the subjects without depression, those subjects with current MDE had higher scores on measures of anxiety and depression but not on the number of panic attacks per week. The presence of depression and the degree of phobic avoidance contributed independently to measures of the severity of the panic illness. Alprazolam was effective in reducing panic and depressive symptomatology in both depressed and nondepressed subjects with panic disorder. The presence of an MDE was not predictive of the outcome of treatment for the panic and phobic symptoms. Subjects with or without depression responded similarly to alprazolam.

John C. Pecknold

Papers

Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial: I. Efficacy in Short-term Treatment

Alprazolam in Panic Disorder and Agoraphobia: Results From a Multicenter Trial: III. Discontinuation Effects

Sertraline Treatment of Generalized Social Phobia: A 20-Week, Double-Blind, Placebo-Controlled Study

Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study.

Secondary depression in panic disorder and agoraphobia. I. Frequency, severity, and response to treatment.