Meta-Analysis of Anxiety Disorders and Temperament

Anxiety disorders are characterized by fear or anxious distress, or both, and often by avoidant behavior secondary to emotional symptoms [1]. On the other hand, long-lasting fearful or avoidant behavioral patterns may predispose to anxiety disorders [2,3]. In the current international classification of diseases, separate anxiety disorders have marked overlapping criteria resulting in low specificity and high comorbidity rates [4]. On the other hand, genetic endophenotypes [5] with high vulnerability to different anxiety disorders cannot be detected in clinical practice or health screenings, although this early detection could have a preventive function and influence the outcome of these disorders. The dimensional models of personality have added knowledge about the stability and genetic and other neurobiological factors of anxiety-related behavior. In the psychobiological model by Cloninger et al. [6], the personality is divided into temperament and character dimensions. The most commonly used questionnaires within this model are the Tridimensional Personality Questionnaire (TPQ) and its later version, the Temperament and Character Inventory (TCI or revised TCI) [6]. The TCI includes 4 facets of temperament, namely novelty seeking (NS), harm avoidance (HA), reward dependence (RD) and persistence, and 3 facets of character, namely self-directedness, cooperativeness and self-transcendence [6]. HA is the temperament dimension that corresponds to behavioral inhibition in the TCI. In the TPQ, there are 3 temperament dimensions, NS, HA and RD, and the later developed persistence is included in the RD.

There are also some other validated dimensional models of personality. Costa and McCrae [7] developed a 5-factor model (FFM) of personality using the Neuroticism-Extraversion-Openness Inventory (NEO-PI, NEO-PI-R or NEO-FFI) in the assessment of the dimensions. This model includes the dimensions extraversion, agreeableness, conscientiousness, neuroticism and openness to experience, of which the dimensions neuroticism and extraversion are the most extensively studied in relation to genetic variability. A meta-analysis by Kotov et al. [8] showed several types of relationships between symptoms of anxiety disorders and personality traits according to the FFM. Neuroticism was associated with anxiety disorders in general, and more specifically low extraversion was associated with social phobia. In specific phobias, weaker associations were detected with all traits. In Eysenck's model of personality [9], the corresponding dimensions are neuroticism, psychoticism and extraversion. The questionnaire based on this model is the Eysenck Personality Questionnaire (or its revised version). The Temperament Evaluation of the Memphis, Pisa, Paris and San Diego questionnaire model divides temperament into depressive, hyperthymic, cyclothymic and irritable dimensions [10], of which depressive and cyclothymic dimensions are related to high HA, and hyperthymic and cyclothymic dimensions to high NS [11].

The construct within each of these models that corresponds most closely to an anxiety-related trait differs, with Costa and McCrae's FFM and Eysenck's model reflecting a neuroticism construct, and Cloninger's tridimensional theory reflecting an HA construct. The neuroticism construct reflects a tendency to experience negative emotions and interpret situations as threatening [7], whereas the HA construct is defined as avoidance of aversive stimuli, anxiety proneness and an aversion to risk-taking [12]. In his paper on the theoretical background of chronic anxiety, Cloninger postulated that long-term anxiety can be divided into cognitive anxiety with ‘obsessional' information-processing type (responding high HA), somatic anxiety with ‘histrionic' information-processing type (responding high NS) and social detachment or stability of behavior (responding RD and persistence) dimensions. This classification of anxiety was different from the clinical features identified and the criteria determined for separate anxiety disorders in the DSM-III [12].

Panic disorder (PD) or specific phobias can be more clearly separated from an anxious temperament trait according to the specific symptoms, as well as the typical onset age and stability in the course, whereas social anxiety disorder (SAD) or generalized anxiety disorders (GAD) are much more difficult to distinguish from this trait [13]. Also, a tendency to misinterpret physical sensations as danger signals, which has been determined as anxiety sensitivity trait, has been associated most specifically with PD in a meta-analytic study [14].

According to twin studies, TCI temperament dimensions have shown moderate (RD and persistence) to strong heritability (HA and NS) [15], with RD also sharing some environmental effects [16]. In neurobiological studies trait anxiety, which is characterized by hypervigilance and hyperarousal, can be differentiated from fear, but these two are also overlapping phenomena [17]. High HA has been found to be associated with decreased white matter tract density measures in the areas responsible for emotional processing and reappraisal (corticolimbic pathways) [18]. Studied with functional magnetic resonance imaging (fMRI), the inhibited temperament feature in adulthood has been connected with higher amygdala reactivity to expected fearful faces, which clinically corresponds to anticipatory anxiety and hypervigilance [19]. Also, inhibited behavior in early childhood predicts later bilateral amygdalar hyperreactivity to novel stimuli studied by fMRI [20]. The circuit between amygdala and ventrolateral prefrontal cortex is engaged when threats capture attention [21]. The nucleus accumbens, which is involved in modulating behavioral responses to both rewarding and aversive events, is activated in an active avoidance pattern rather than with passive avoidance [22]. The connectivity between dorsal and rostral anterior cingulate cortex and anterior insula studied by fMRI without external stimuli also correlates with HA in healthy individuals [23]. Anxiety-related traits in adulthood have also been associated with serotonin transporter gene polymorphism [24] and abnormal cortisol response during stress [25].

To systematically examine and expand the current knowledge on underlying temperament-based endophenotypes representing the vulnerability for different anxiety disorders, the study focused on the following question: are symptoms of different anxiety disorders or symptoms occurring at a later stage (during follow-up) associated with the different levels and patterns of temperament dimension (HA, NS, RD or persistence) scores according to the psychobiological model by Cloninger et al. [6]?

A literature search was conducted in the databases below on November 5, 2013, using the terms (‘temperament' or ‘harm avoidance' or ‘TCI' or ‘TPQ') and (‘anxiety disorders' or ‘obsessive-compulsive disorder' or ‘generalized anxiety disorder' or ‘social anxiety disorder' or ‘panic disorder' or ‘post-traumatic stress disorder' or ‘phobic disorders') and limiting the search to peer-reviewed journal articles published in English. The databases were the Cochrane Library, PubMed (Medline), Web of Science, Psycinfo and PsycArticles. The initial search resulted in a total of 1,668 articles.

The inclusion criteria for the papers selected were: using a TPQ/TCI as a temperament measure and focusing on (1) the severity, symptom quality or diagnostic criteria of anxiety disorders classified in the DSM-IV and temperament profiles in adult or late adolescent samples (ages 15 and over). The exclusion criteria were: (1) duplicates and (2) papers reporting other clinical features than those related to classified anxiety disorders despite the assessment of temperament profiles, or studies assessing solely personality profiles in relation to anxiety disorders. Reports on studies using identical samples were considered as single studies in the analyses. However, as all the results reported in different papers using the same samples were explored, the final number of papers included was greater than the number of studies. Publications with a similar focus according to reference lists of selected papers were also searched. During the selection phase, in cases of initial disagreement a final consensus was reached after discussion between at least 2 researchers. The quality of the evidence in individual studies was graded according to the GRADE workgroup recommendation by 2 or more researchers [26].

The selected 40 papers were analyzed according to the results reported in each paper. The levels of temperament dimension scores (NS, HA, RD and persistence) were compared in each anxiety disorder - PD, GAD, SAD, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD) - with the corresponding scores in control groups in each study. We conducted meta-analyses for each temperament dimension (NS, HA, RD and persistence) in PD, SAD and OCD studies, which comprised at least 5 studies with a control group and including the available TCI or TPQ data (tables 1, 2, 3, 4, 5). The TPQ dimensional scores were converted into TCI scores according to the results from Finnish normative data [27,28] and the reported persistence subscale scores were used in analyses with TPQ studies. The meta-analyses were calculated with MIX Pro software (version 2.0 [29]) using the fixed effects model and inverse variance as a weighting method, and using age as a covariate. The analyses using age as a covariate yielded results similar to those without this covariate. Due to heterogeneity in gender distributions between patient and control groups in studies on SAD, gender was also used as a covariate, but the results were similar to those without this covariate. Therefore, only the latter analyses (without age or gender correction) are reported. The gender distributions had only minor differences in PD and OCD studies, and therefore no analyses with gender correction were conducted on these disorders. The random effects model was also tested in samples with heterogeneity levels >80% (HA in PD and OCD, NS in SAD, RD in OCD and persistence in SAD and OCD), but this model produced results similar to those yielded by the fixed effects model. The results of the meta-analyses are presented as mean differences between patient and control sample scores for each temperament dimension (positive values indicate higher patient scores than scores of controls) with 95% confidence intervals. Heterogeneity testing between individual studies in each analysis was calculated by I² statistics with confidence intervals (table 6). The magnitude of clinical significance (effect size) in individual findings was estimated as Cohen's d (mean difference between patient and control groups divided by the standard deviation of the data), and the level of clinical significance was set at d >0.4.

A hundred and forty-one papers were further selected for thorough reading on the basis of the information in the article title and/or abstract. The final selection agreed on by 2 or more investigators comprised 40 papers reporting 38 different studies (in 2 cases different results from the same sample were reported in 2 different papers). Of these papers, the temperament dimension scores for patient and control groups had been reported as mean and standard deviation values in 24 papers, and these were included in the meta-analyses (fig. 1). All papers included concerned prospective studies. Twelve of the 40 papers selected focused on PD (table 1), with 2 of the studies including 2 different reports, 4 on GAD (table 2), with 1 of the studies including both PD and GAD groups, 8 on SAD (table 3), 11 on OCD (table 4), with 1 of the studies including 2 different reports, and 6 on PTSD (table 5). No papers on simple phobia with a selected focus were found.

The findings of the meta-analyses were (1) a definite and clear positive association between HA temperament dimension and the occurrence of PD, SAD and OCD, with a most marked effect in SAD, and a moderate effect in OCD and PD, (2) less remarkable and clinically marginal negative associations between NS score, SAD and OCD, (3) a positive, but clinically insignificant association between RD score in PD, and (4) no associations between RD score and other anxiety disorders studied or between persistence scores in any of the disorders studied.

The results of the meta-analyses of the PD, SAD and OCD studies with each temperament dimension are presented in table 6 and forest plots for each temperament dimension in these disorders in figure 1. Three out of 4 GAD studies reported a positive association between HA and current or subsequent GAD symptoms (table 2). All 6 PTSD studies reported a positive association between symptoms and HA, 3 studies reported a positive association with NS, and the same 3 studies also reported a negative association with RD (table 5).

The purpose of this meta-analysis was to test for differences in self-rating scores on the temperament dimensions of the Cloninger test in different anxiety disorders. The method of analyzing the differences in temperament dimensions between patients and control subjects aimed at investigating the possible genetic influence of each disorder studied. This may both help to differentiate the vulnerability factors between and within the disorders studied and also to generate further hypotheses and to determine more suitable phenotype markers for future genetic studies. Also, the high comorbidity rates between anxiety disorders [4] imply that the present classification of these disorders is still far from specific, but rather represents a historical paradigm of recognizing and clustering the different symptoms of anxiety. The temperament dimensions determined in the psychobiological model of Cloninger et al. [6] reflect the various immediate and long-term forms of individuals' automatic reactions forming the basis for human behavior, including sensitivity to anxious reactions regarded as the vulnerability factor for the subsequent development of clinical anxiety disorders.

When analyzing the quality of individual studies, we focused on the criteria of sample selection, follow-up time and rates of missing data [26]. The level of evidence remained moderate to low in many of the studies selected. This was most commonly due to small sample size, cross-sectional designs and in 6 studies to an absence of control groups. Four of the studies with no control group addressed the three disorders (PD, SAD or OCD) and on these there were indeed sufficient eligible studies to permit meta-analysis. In the cases of GAD and PTSD, the number of eligible studies was too low for meta-analysis, and only descriptive analyses were feasible for these disorders. No studies on simple phobias were found for this review.

There was heterogeneity in the results on all temperament dimensions, and this was especially common in the analyses of SAD and OCD. This may be due to variation in sample selection, the small number of subjects in many of the studies, and other issues related to study design. Many of the studies included also used TPQ as the assessment instrument, and although the conversion into TCI scores was based on Finnish normative data [27,28], the different structures of the two scales as regards RD may explain some of the heterogeneity found, especially between SAD and OCD, but not between PD studies. The finding is even more likely due to the wide individual variation in the assessment of temperament regarding separate dimensions and their subscales, as well as the wide individual variation in anxiety disorder symptomatology. The fixed effects method was preferred in the meta-analysis assuming that the same outcome measure (TCI) in all studies included and similar inclusion criteria for the patient samples within each diagnosis would yield a reliable analysis with this particular method. To ensure this, the alternative random effects method was tested with the groups of studies showing the most marked heterogeneity, and the results were comparable with the fixed effects method analyses. There was also some heterogeneity between studies in the age and sex distributions. Age was not found to be a markedly confounding factor in an earlier meta-analysis of temperament and gender differences [70]. The present meta-analyses yielded similar results regardless of the covariation of sample age or without this variable, which supports the earlier result. Likewise, the covariance of gender was not significant even in the studies of SAD, where the variation in gender distributions between patient and control groups was more marked in contrast to PD and OCD studies, which had only little variation in gender ratios between patient and control groups. Also, most of the selected studies in the meta-analyses had age- and gender-matched control groups or, if not, the control groups represented epidemiological samples. It is, however, possible that some of the heterogeneity in the results is attributed to the differences in age or sex distributions in patient and control samples in individual studies.

When considering the overall level of evidence and the clinical effects of findings on each temperament dimension and in distinct disorders (PD, SAD and OCD), the differences between the patient samples and controls were found to be most marked in HA scores in all these disorders. The clinical effect in HA was large in SAD and moderate in PD and OCD. In all three disorders the association between HA score and the disorder was positive. With NS scores there was no association in PD, and a negative association in SAD and OCD. However, the mean differences in NS between patients and controls even in SAD and OCD were not clinically significant. With RD scores, only PD was positively associated, but this difference likewise yielded no clinical effect. In SAD and OCD no associations were found. The persistence scores revealed no differences in any of the disorders between patients and controls. Although most of the studies selected were of limited samples, and there was some heterogeneity in the results, almost all studies included (except 2/8 PD studies) showed significant differences in HA between patients and controls, and the level of evidence with increase in the HA scores can be considered high in all three disorders. When evaluating the temperament profiles including HA, NS and RD temperament dimensions in each disorder analyzed, PD showed a pattern of high HA/moderate NS/high RD, SAD a very high HA/low NS/moderate RD, and OCD a high HA/low NS/moderate RD.

The finding of increased HA in anxiety disorders corresponds to a finding observed earlier in major depression and with depressive symptoms in general samples [71]. There are several possible explanations for the relationship in these two categories, namely the common genetic background related to the neurobiological regulation of emotions and stress, overlapping in the clinical picture, which may explain the high comorbidity rates, and similar stress-induced changes in automatic behavioral reaction patterns associated with the clinical state in both disorder groups. With NS the distinct anxiety disorders resulted in varying profiles, with an unchanged score in PD compared to controls, but a lower score in SAD and OCD. Although the effect size of these changes was below clinical significance, it may be interpreted to corroborate the earlier conclusion on classifying different profiles of anxiety disorders as regards the axis fear versus distress [72]. The unchanged NS in relation to the high HA score, as represented solely in PD, could reflect the positive association found earlier between both NS and HA, and extraversion of NEO-PI on sympaticotonic bodily symptoms [73], which are the core feature in PD. Conversely, as Wu et al. [74] confirmed among some earlier studies, the extraversion dimension of the NEO-PI scale was found to be lower in OCD patients than in controls, which may reflect the affective nature being of the distress type more than of the fear type in this disorder. In clinical practice this disorder is characterized by ruminating thoughts that in many cases have a very limited thematic content, but it often leads to poor functioning and social isolation. The descriptive analysis of the results of GAD revealed an inconclusive association with the HA trait only. As GAD is a chronic disorder with a potentially stronger association with trait aspects, the relationship of this disorder with temperament is undoubtedly an important topic for future studies. In comparison to the present findings regarding HA and NS, Jylhä et al. [75] recently reported high NS to be associated with cluster B and high HA levels with cluster C personality disorders, which concurs with the earlier reported specificity of personality clusters and temperament, that also includes the association with low RD and cluster A personality disorders [76]. In patients with bipolar disorder, high HA and low persistence dimensional scores have been found in several studies, whereas the findings for NS and RD have been contradictory [77]. All in all, when considering the findings both in affective disorders and in the present study, these disorders can also be seen as dimensions on which scores in the normal populations represent, perhaps, milder forms of psychopathological symptoms.

The possible genetic, neurobiological and associative learning-related mechanisms predisposing to different forms of anxiety disorders involve (1) the genetic risk factors related to functions of the hippocampus and prefrontal cortex, (2) hyperreactivity in the amygdala and learned avoidant behavioral pattern in childhood leading to negative emotionally biased episodic memory functioning, (3) alertness towards threat-associated stimuli, and (4) continued learned avoidant behavior in adulthood. The present findings on temperament dimensions reflect the anxiety-state-dependent signs, symptoms, attitudes and beliefs as only a small minority of the studies involving a longitudinal perspective. This prevents reliable causal interpretations. Thus, according to these results, no assumptions on trait-dependent changes in temperament can be made. The low consistence and relationship of the disorders with RD are probably also due to the lack of true comparability between the RD scale in the TPQ and TCI. Moreover, the meta-analytic procedure has several limitations [78]. Due to the low to moderate level of evidence in the majority of individual studies, the results of this analysis should be interpreted with caution.

This review was focused solely on TPQ and TCI assessments. A comparison with the FFM has shown moderate correlations between the corresponding dimensions in the two models, but mainly a marked inconsistency [79]. Kotov et al. [8] conducted a meta-analysis of the FFM and anxiety disorders. Their results corroborated the present HA findings, suggesting heightened neuroticism scores with very high effect sizes in PD, SAD and OCD. With extraversion scores, the finding was somewhat different from the present study, showing lowered extraversion scores in all 3 disorders with high effect sizes. The inconsistent results are likely to reflect the diverging concepts between FFM and Cloninger's models [79].

In conclusion, PD, SAD and OCD share a marked and state-dependent avoidant behavioral pattern. However, PD showed a slightly different pattern of arousal to novel stimuli from SAD and OCD, which may partly explain the different course and clinical picture of these disorders.