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. Author manuscript; available in PMC: 2021 Sep 1.
Published in final edited form as: J Affect Disord. 2020 May 23;274:995–1003. doi: 10.1016/j.jad.2020.05.119

Evidence for inhibited temperament as a transdiagnostic factor across mood and psychotic disorders.

Brandee Feola a, Kristan Armstrong a, Elizabeth A Flook a, Neil D Woodward a, Stephan Heckers a, Jennifer Urbano Blackford a,b
PMCID: PMC7540608  NIHMSID: NIHMS1603107  PMID: 32664044

Abstract

Background:

The conceptualization of risk for psychiatric illness is moving from risk factors for specific psychiatric disorders to factors that confer risk for multiple disorders. One potential transdiagnostic risk factor is inhibited temperament, a trait characterized by a fearful or avoidant response to novelty. Inhibited temperament is an established risk factor for anxiety disorders, and evidence suggests inhibited temperament is elevated in schizophrenia, bipolar disorder, and major depressive disorder.

Methods:

In the current study, we tested the hypothesis that inhibited temperament is a transdiagnostic factor in 490 participants including individuals with schizophrenia (n=184), psychotic bipolar disorder (n=61), major depression disorder (n=53), or no disorders (n=192). Participants completed assessments of temperament, personality, clinical symptoms, cognition, and functioning. An ANOVA was used to test for group differences in inhibited temperament scores. Regressions were used to test whether inhibited temperament scores were associated with the current measures and whether the associations were similar across disorders.

Results:

Inhibited temperament was similarly elevated in all patient groups compared to controls. Inhibited temperament was similarly associated with anxiety, depression, negative affect, and quality of life across patient groups. Inhibited temperament was not associated with cognition or functional impairment.

Limitation:

Although the inhibited temperament measure is commonly used, it is a retrospective self-report which may be susceptible to biases.

Conclusions:

The current study provides evidence that inhibited temperament is a transdiagnostic factor impacting affective systems across mood and psychotic disorders. Inhibited patients may especially benefit from treatments that specifically target anxiety and depression.

Keywords: Anxiety, Depression, Bipolar Disorder, Psychosis, Quality of Life, Negative Affect

Background

The identification of risk factors for psychiatric disorders is critical for screening, early detection, and interventions, which hold promise for preventing the development of chronic, disabiling disorders in high-risk individuals. One common strategy for identifying risk factors is to identify variables associated with heightened risk for specific psychiatric disorders. More recently, researchers have turned to identifying transdiagnostic risk factors that are shared across disorders. Transdiagnostic research has increased substantially since the introduction of the Research Domain Criteria (RDoC; Insel et al., 2010). Transdiagnostic factors help explain the co-occurrence of symptoms or comorbidities across disorders (Harvey et al., 2011; Mansell et al., 2009; Sauer-zavala et al., 2017). Given the heterogeneity and high comordities of disorders within psychiatry, transdiagnostic approaches may be especially beneficial.

One possible transdiagnostic risk factor is childhood inhibited temperament, a trait characterized by a fearful or avoidant response to novel places, people, or objects (Kagan, Reznick, & Snidman, 1988). Inhibited temperament is expressed along a continuum; on one end of the continuum are extremely inhibited individuals who are fearful, cautious, and wary when encountering new places, people, and experiences, and on the other end are uninhibited individuals who are bold, outgoing, and risk-seeking when encountering novel situations. Recent work demonstrates inhibited temperament in childhood may lead to later psychopathology outcomes through multiple mechanisms including hyper responsivity to novel stimuli, emotion regulation, and cognitive processing issues (Blackford et al., 2018; Buzzell et al., 2017; Henderson et al., 2015; Pérez-Edgar et al., 2011). Inhibited temperament confers substantial risk for the development of anxiety disorders (Biederman et al., 2001; Chronis-Tuscano et al., 2009; Clauss and Blackford, 2012; Essex et al., 2010; Schwartz et al., 1999). For example, a meta-analysis of prospective longitudinal studies found that almost 50% of inhibited children develop social anxiety disorder by mid-adolescence compared to 12% of non-inhibited children, an increase in odds of 7.59 (Clauss and Blackford, 2012). Preliminary evidence suggests that inhibited temperament may also be related to mood and psychotic disorders. In the Dunedin study, children exhibiting reticent and inhibited behaviors at age 3 were more likely to be diagnosed with depression at age 21 (Caspi et al., 1996), and adults with a history of depression had higher childhood inhibited temperament scores compared to adults without depression (Gladstone and Parker, 2006). Patients with bipolar disorder also show higher levels of anxious temperament (Karam et al., 2010) and harm avoidance (Engström et al., 2004; Kesebir et al., 2005; Porcelli et al., 2018), two traits that are conceptually similar to inhibited temperament. Patients with schizophrenia have also been shown to have higher levels of childhood inhibited temperament (Feola et al., 2019; Goldberg and Schmidt, 2001; Jetha et al., 2011). Together, these studies raise the possibility that inhibited temperament is transdiagnostic; however, inhibited temperament has yet to be examined across patients with mood and psychotic disorders within a single study.

Inhibited temperament may also be a transdiagnostic risk factor that is responsible for shared symptoms, characteristics, or comorbidities across disorders. Transdiagnostic factors can help explain heterogeneity within disorders by demonstrating similar associations with symptoms or comorbidities across disorders. Several studies have shown associations between inhibited temperament and affective symptoms across community samples and in various patient groups. Within non-psychiatric community samples, inhibited temperament is associated with increased anxiety and depressive symptoms (Muris et al., 2001, 1999; Reznick et al., 1986). In patients with schizophrenia, higher levels of inhibited temperament have been associated with increased anxiety and depression symptoms, increased distress, and lower quality of life (Feola et al., 2019). In addition, the neurobiological alterations found in inhibited temperament share similarities with alterations found in mood and psychotic disorders. For example, heightened arousal and stress responses are observed in inhibited temperament (Garcia Coll et al., 1984; Kagan et al., 1987; Schmidt et al., 1999; Stevenson-Hinde and Marshall, 1999), depression (Brochier and Olié, 2005), and psychotic disorders (Mondelli et al., 2018; Pruessner et al., 2017; Shah and Malla, 2015; Vaessen et al., 2018). Greater EEG frontal lobe asymmetry is found in both inhibited temperament (Schmidt et al., 1999), depression (Henriques and Davidson, 1991; Schaffer et al., 1983), and schizophrenia (Jetha et al., 2009). Right frontal asymmetry represents the brain based tendency to approach or avoid novelty, impacting the reaction to and processing of novel situations, people, and places (Davidson, 1993) and is associated with shyness and sociability in schizophrenia (Jetha et al., 2009). In addition, reduced hippocampal habituation to novel faces is observed in inhibited temperament (Blackford et al., 2013; Blackford et al., 2011) and schizophrenia (Avery et al., 2019; Williams et al., 2013). Failure to habituate suggests an inability to learn that people and situations are safe and predictable (Avery and Blackford, 2016), and has been linked to social dysfunction (Avery and Blackford, 2016; Bas-Hoogendam et al., 2016; Kleinhans et al., 2009). Thus, overlapping symptoms and neurobiological alterations provide intriguing initial evidence that inhibited temperament may be a transdiagnostic factor associated with symptoms and characteristics across disorders.

Although inhibited temperament has the potential to be a transdiagnostic factor, to our knowledge, no study has examined this question within a single study. Thus, the aim of the current study is to determine if inhibited temperament is transdiagnostic across more severe mental illnesses including mood and psychotic disorders and could potentially explain symptoms and characteristics across disorders. First, we tested if inhibited temperament was elevated in patients with schizophrenia spectrum disorders, psychotic bipolar disorder, and major depressive disorder compared to controls. Second, we examined if inhibited temperament demonstrates similar associations with clinical characteristics, personality traits, cognition, quality of life, and functional impairment across psychiatric disorders. Continuous measures of symptoms rather than comorbidities were used to better capture the association between inhibited temperament and symptoms. We predicted that inhibited temperament would be elevated across disorders and associated with multiple symptoms including heighted anxiety, depression, and distress across disorders. Evidence that inhibited temperament is transdiagnostic could inform early identification of risk across psychiatric disorders, personalized treatments targeting inhibited temperament or specific symptoms across disorders, and the conceptualization of affective symptoms across psychotic and mood disorders.

Methods

Sample

Participants were drawn from a registered repository of patients from 2008 through 2019 (clinicaltrials.gov; NCT00762866). For the respository, patients were recruited from the inpatient and outpatient programs at Vanderbilt Psychiatric Hospital and controls were recruited through advertisements in the community. Participants were considered for the repository if they were between 14–65 years old, had premorbid IQ >70, no history of traumatic brain injury, and did not suffer from a chronic medical illness (eg. HIV, cancer) or a central nervous system disorder. The Structured Clinical Interview of the DSM-IV-TR (SCID) (First et al., 2002) was conducted for all participants by trained research staff. In healthy control participants, the SCID was used to rule out past or current psychiatric illness, including substance abuse or dependence. Healthy control participants were not enrolled in the repository if they had a history of psychiatric disorders. For patients, the SCID was used to confirm diagnosis of schizophrenia spectrum disorders, bipolar disorder with psychotic features, major depressive disorder, and anxiety disorders. The registered repository was approved by the Vanderbilt University Institutional Review Board and informed consent was obtained from all participants.

For this study, participants were selected from the repository based on completion of the assessment of temperament, age between 18–35 years, and either had mood or psychosis diagnosis (schizophrenia spectrum disorders, bipolar disorders with psychotic features, major depressive disorder) or was a healthy control. The final sample consisted of 490 adults including: 184 patients with schizophrenia; 61 patients with bipolar disorder type I with psychotic features (hereafter referred to as “psychotic bipolar disorder”); 53 patients with major depressive disorder; and 192 healthy controls.

Assessment Procedures

Inhibited Temperament.

The Retrospective Self Report of Inhibition (RSRI) was used to assess childhood inhibited temperament (Reznick et al., 1992). The RSRI is a retrospective self-report questionnaire to assess inhibited behaviors in childhood (grades 1–6). The RSRI includes 30 questions using a 1–5 likert scale with higher values indicating higher levels of inhibited temperament. The RSRI includes questions such as “Were you afraid of the dark?”, “Did it upset you to be called up to the blackboard?”, and “Did you sleep over at friends’ houses?”. The mean value of the 30 questions was calculated for the measures of inhibited temperament. In this sample, the RSRI had excellent reliability (all Cronbach‟s alphas > 0.82:, schizophrenia = 0.89, psychotic bipolar = 0.86, major depression = 0.86, healthy controls = 0.82) and construct validity, indicated by strong agreement between self-reports by individuals and reports from their parents, and by correlations with concurrent measures (Reznick et al., 1992).

Clinical Symptoms.

Mood and anxiety symptoms were assessed using the Mood and Anxiety Symptom Questionnaire (MASQ; Watson et al., 1995), Hamilton Depression Rating Scale (HAM-D; Hamilton, 1960), and Montgomery–Åsberg Depression Rating Scale (MADRS; Montgomery and Asberg, 1979). The MASQ is a self-report measure of mood and anxiety symptoms experienced in the past week. The MASQ is a 90-item self-report measure of anxiety and depression symptoms that uses a 1–5 Likert scale (1 = not at all, 5 = extremely). The tripartite model of depression and anxiety suggests three distinct components of symptoms, including anxious arousal (specific to anxiety), anhedonic depression (specific to depression), and negative affect (shared by anxiety and depression). To address the distinct and shared components of mood and anxiety, five MASQ subscales were used, including three general distress (mixed, anxious, depression), anxious arousal, and anhedonic depression. The HAM-D and MADRS are two clinician-rated assessments of the presence and severity of depressive symptoms. The HAM-D is a measure of depression symptoms within the past week (Hamilton, 1960), and the MADRS is used to assess the severity of depressive episodes in patients with mood disorders. The HAM-D includes 28 questions assessing symptoms on a scale of 0–4 and the MADRS includes assessments of 10 symptoms on a scale of 0–6. For both scales, higher values represent more severe symptoms. Clinicians also administered the Positive and Negative Syndrome Scale (PANSS; Kay, Fiszbein and Oplet, 1987) to assess the severity of symptoms in patients with schizophrenia or psychotic bipolar disorder. The PANSS assesses 30 symptoms within the past two weeks on a scale of 1–7 with higher values representing higher severity. A five-factor model was used to create PANSS factors for Negative, Positive, Disorganized, Excitement, and Distress symptoms (van der Gaag et al., 2006; Wallwork et al., 2012).

Personality.

Personality was assessed using the NEO Five Factor Inventory (NEO-FFI; Costa Jr and McCrae, 1992) and the Schizotypal Personality Questionnaire (SPQ; Raine, 1991). The NEO-FFI is a self-report questionnaire that provides an assessment of five domains of personality (Neuroticism, Extraversion, Conscientiousness, Agreeableness, Openness). The NEO-FFI is composed of 60 questions with 12 assessing each domain.The SPQ is a self-report questionnaire with 74 questions that assess levels of nine schizotypal personality traits and provides an overall average value of schizotypal personality trait. The SPQ was added after the start of the study and is therefore only available for a subset of participants (131 schizophrenia, 48 bipolar disorder, 27 major depression).

Cognition.

Premorbid and current cognitive function was assessed with two cognitive tests: the Wechsler Test of Adult Reading (WTAR; Holdnack, 2001) and Screen for Cognitive Impairment in Psychiatry (SCIP; Purdon, 2005). The WTAR provides an assessment of premorbid cognitive function that required individuals to pronounce irregular words with a maximum score of 50. The SCIP provides an overall assessment of current cognition function including five domains of current cognition: immediate memory, working memory, verbal fluency, delayed memory, processing speed. The WTAR total score and the SCIP total standardized score were used as the measures of cognition.

Functioning.

The impact of the psychiatric disorder on the individual’s life was assessed using the clinician-rated Global Assessment of Functioning (GAF; American Psychiatric Association, 2000). The GAF is a clinician rated assessment of functioning in their daily life across multiple domains. Scores range from 0–100 with higher values representing better functioning. Quality of life was assessed using the Quality of Life Enjoyment and Satisfaction Questionnaire – Short Form (Q-LES-Q-SF), a self-report measure of the degree of enjoyment and satisfaction across multiple domains of functioning in the past week (Becchi et al., 2004). The Q-LES-Q-SF has 16 Likert scale items (1=very poor, 5=very good) and the quality of life score is the total across all items (range 16 – 80).

Data Analyses

To determine if childhood inhibited temperament is elevated across disorders, two analyses were performed. An analysis of variance (ANOVA) with planned contrasts was performed to test for group differences (patient/control) on inhibited temperament scores for each of the three disorders. A second ANOVA was performed to test for diagnosis differences (schizophrenia/bipolar disorder/depression) on inhibited temperament scores. We considered evidence for inhibited temperament being transdiagnostic as: 1) higher inhibited temperament scores in the patient group relative to the control group; 2) inhibited temperament scores are not significantly different between diagnostic groups.

Regressions were performed to determine whether inhibited temperament was associated with clinical symptoms, personality, cognition, and functioning across disorders and whether associations differed across disorders. The predictor variables were diagnostic group, inhibited temperament, and the diagnosis x temperament interaction. Analyses were performed separately for each outcome variable. We considered a significant main effect of inhibited temperament and the lack of a diagnosis x temperament as evidence for a similar association between inhibited temperament and the outcome variables across diagnostic groups. In addition to statistical power, we also used principles from equivalence clinical trials to provide a conservative estimate of ‘lack of a diagnosis x temperament’ effect as evidence for a transdiagnostic association. When the null is predicted, an equivalence limit can be used to evaluate whether the observed effect is within a sufficiently small range around 0. To our knowledge there are no clear standards on equivalence limits for transdiagnostic factors; we consider effect sizes less than “small” (i.e., Cohen‟s d = .20 or η2 = .01) to provide evidence for equivalence across diagnoses. Both a p-value and semi partial effect size (η2) with 95% confidence intervals are included in the tables reporting statistical values for the main effect of inhibited temperament, main effect of diagnosis, and interaction between inhibited temperament and diagnosis.

Multiple imputation methods were used to handle missing data (SAS PROC MI, 10 imputations FCS algorithm, and PROC MIANALYZE). Sample sizes, descriptive data, and results from the original sample (casewise deletion) are provided in the Supplement. Age, sex, and race (white versus non-white) were included as covariates for each analyses within the patient group. Statistical analyses were conducted using SAS software (Version 9.4, SAS Institute Inc., Cary, NC), α< 0.05. Some participants were missing data for specific questionnaires. Besides the Schizotypal Personality Questionnaire (see above), 26 participants were missing data for at least one questionnaire (4 bipolar disorder, 9 major depression, 13 schizophrenia; Supplemental Table 1).

Results

Sample Characteristics

Descriptive statistics for all of the variables are provided in Table 1. Patients and controls were similar on all demographic characteristics, except for levels of education; patients had less education than controls (p < 0.001). When comparing the three patient groups, the groups differed on age, race, sex, and education (all p < 0.01): patients with schizophrenia had a higher percentage of non-whites and less education than the bipolar disorder or depression groups; the depression group was older and had more females than the bipolar disorder and schizophrenia groups.

Table 1.

Participant Demographics by Diagnosis Group

Bipolar Disorder Major Depression Schizophrenia Controls
N 61 53 184 192
% Male 55.7% 30.2% 66.8% 59.4%
% White 78.7% 81.1% 62.5% 71.9%
Age (SD) 30.59 (13.36) 37.55 (11.45) 29.47 (11.55) 29.30 (10.70)
Education (SD) 14.13 (2.24) 14.90 (2.31) 13.23 (2.34) 15.18 (2.30)
Parental Education (SD) 14.61 (2.56) 14.64 (2.98) 14.32 (2.94) 14.57 (1.38)
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Comparison of Inhibited Temperament in Patients and Controls

Inhibited temperament was elevated in psychotic bipolar (F (3, 489) = 25.14, p < .0001; η2 = 0.05, 95% CI [0.02, 0.09]); depression (F (3, 489) = 37.20, p < .0001; η2 = 0.09, 95% CI [0.05, 0.14]); and schizophrenia (F (3, 489) = 84.49, p < .0001; η2 = 0.14, 95% CI [0.09, 0.20]) groups compared to healthy controls. The diagnostic groups did not differ significantly on inhibited temperament (F (2, 297) = 1.42, p = 0.24; η2 = 0.19, 95% CI [0.12, 0.25]); Table 2). The distributions of inhibited temperament for the healthy controls and three diagnostic groups are displayed in Figure 1.

Table 2.

Participant Characteristics by Diagnosis Group

Bipolar Disorder Major Depression Schizophrenia Controls
Mean (SD) Mean (SD) Mean (SD) Mean (SD)
Inhibited Temperament
 RSRI 2.26 (0.54) 2.44 (0.53) 2.37 (0.61) 1.90 (0.38)
Anxiety
 MASQ Anxious Arousal 1.64 (0.59) 1.52 (0.53) 1.73 (0.65) 1.14 (0.21)
Depression
 MASQ Anhedonic 2.74 (0.79) 3.42 (0.78) 2.90 (0.64) 2.18 (0.47)
 Depression
 HAM-D 7.07 (6.38) 14.94 (8.99) 8.90 (6.47) 0.52 (1.02)
 MADRS 6.59 (7.81) 18.42 (12.55) 9.60 (8.23) 0.38 (1.04)
Negative Affect
 MASQ General Distress-Anxiety 1.92 (0.69) 2.05 (0.64) 1.98 (0.74) 1.36 (0.36)
 MASQ General Distress-Depression 2.18 (0.85) 2.95 (1.11) 2.33 (0.96) 1.46 (0.48)
 MASQ General Distress-Mixed 2.33 (0.77) 2.64 (0.77) 2.39 (0.85) 1.54 (0.46)
PANSS
 Negative 1.29 (0.59) --- 2.25 (1.24) ---
 Positive 2.28 (1.38) --- 2.98 (1.28) ---
 Excitement 1.62 (0.79) --- 1.51 (0.67) ---
 Disorganization 2.12 (1.00) --- 2.52 (1.15) ---
 Distress 1.85 (0.79) --- 2.28 (1.03) ---
Personality
 Neuroticism 23.31 (10.57) 29.31 (8.76) 25.17 (8.57) 13.52 (6.98)
 Extraversion 29.39 (7.74) 20.45 (8.12) 25.25 (7.56) 30.97 (6.10)
 Openness 31.39 (7.70) 29.17 (8.33) 28.81 (6.77) 29.82 (6.52)
 Conscientiousness 30.95 (8.26) 28.11 (8.78) 28.68 (7.99) 35.16 (5.76)
 Agreeableness 30.13 (7.44) 31.64 (6.09) 30.10 (6.03) 34.54 (5.92)
 Schizotypal 29.90 (21.10) 22.52 (18.98) 35.08 (19.07) 8.91 (10.22)
Cognition
 WTAR 106.48 (12.97) 113.02 (11.99) 99.71 (16.01) 110.37 (11.39)
 SCIP Z Score −0.61 (0.91) 0.24 (0.84) −1.18 (0.88) .11 (0.62)
Functioning
 Quality of Life 49.84 (11.65) 43.21 (11.02) 48.25 (9.47) 58.58 (5.86)
 GAF 58.63 (16.37) 63.49 (16.04) 46.11 (15.06) 92.29 (0.56)
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Figure 1:

Figure 1:

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Distribution of inhibited temperament scores in schizophrenia, bipolar disorder, and major depression compared to healthy controls

Transdiagnotic Associations of Inhibited Temperament and Clinical Symptoms

Anxiety.

Within the patients, inhibited temperament was associated with increased anxiety as measured by the MASQ anxious arousal (Table 3; Figure 2). There was no significant effects of diagnostic group or the diagnosis x temperament interaction. The interaction effect size was smaller than the equivalence criteria.

Table 3.

Effects of Inhibited Temperament and Diagnosis on Outcome Variables

Main Effect Main Effect Interaction
Outcome Variable Diagnosis Inhibited Temperament Diagnosis x Temperament
P value η2 [CI] P value η2 [CI] P value η2 [CI]
Anxiety
 MASQ Anxious Arousal 0.66 0.04 [0.00, 0.08] <.0001 0.21 [0.12, 0.29] 0.92 0.00 [0.00, 0.01]
Depression
 MASQ Anhedonic Depression 0.58 0.07 [0.02, 0.13] <.0001 0.13 [0.06, 0.20] 0.51 0.005 [0.00, 0.03]
 HAM-D 0.04 0.10 [0.04, 0.17] 0.006 0.07 [0.03, 0.13] 0.17 0.02 [0.00, 0.04]
 MADRS 0.15 0.14 [0.07, 0.20] 0.001 0.09 [0.04, 0.15] 0.44 0.006 [0.00, 0.03]
Negative Affect
 MASQ General Distress-Anxiety 0.82 0.00 [0.00, 0.02] <.0001 0.19 [0.12, 0.27] 0.76 0.002 [0.00, 0.02]
 MASQ General Distress-Depression 0.46 0.05 [0.01, 0.10] <.0001 0.22 [0.14, 0.30] 0.38 0.007 [0.00, 0.03]
 MASQ General Distress-Mixed 0.77 0.00 [0.00, 0.02] <.0001 0.28 [0.19, 0.35] 0.82 0.001 [0.00, 0.01]
PANSS Factors
 Negative 0.16 0.11 [0.05, 0.19] 0.45 0.01 [0.00, 0.05] 0.89 0.00 [0.00, 0.01]
 Positive 0.02 0.04 [0.01, 0.01] 0.10 0.01 [0.00, 0.04] 0.12 0.01 [0.00, 0.05]
 Excitement 0.32 0.01 [0.00, 0.04] 0.45 0.02 [0.00, 0.07] 0.21 0.007 [0.00, 0.04]
 Disorganized 0.09 0.02 [0.00, 0.06] 0.69 0.01 [0.00, 0.04] 0.22 0.007 [0.00, 0.04]
 Distress 0.22 0.05 [0.01, 0.10] 0.02 0.09 [0.03, 0.16] 0.04 0.02 [0.00, 0.06]
Personality
 Neuroticism 0.29 0.04 [0.00,0.03] 0.0001 0.27 [0.02, 0.12] 0.42 0.006 [0.00, 0.03]
 Extraversion 0.96 0.10 [0.04, 0.17] <.0001 0.16 [0.09, 0.23] 0.353 0.007 [0.00, 0.03]
 Openness 0.07 0.02 [0.00, 0.06] 0.02 0.02 [0.00, 0.06] 0.08 0.02 [0.00, 0.05]
 Conscientiousness 0.69 0.01 [0.00, 0.04] <.0001 0.12 [0.05, 0.18] 0.80 0.002 [0.00, 0.02]
 Agreeableness 0.29 0.006 [0.00, 0.03] <.0001 0.06 [0.02, 0.12] 0.18 0.01 [0.00, 0.05]
 Schizotypal <.0001 0.12 [0.06, 0.19] <.0001 0.27 [0.19, 0.35] 0.11 0.02 [0.00, 0.06]
Cognition
 WTAR 0.61 0.10 [0.00, 0.02] 0.80 0.00 [0.00, 0.03] 0.78 0.002 [0.00, 0.02]
 SCIP Z Score 0.13 0.27 [0.18, 0.34] 0.25 0.02 [0.00, 0.06] 1.00 0.00 [0.00, 0.00]
Functioning
 Quality of Life 0.82 0.02 [0.00, 0.06] <.0001 0.15 [0.08, 0.22] 0.77 0.002 [0.00, 0.02]
 GAF 0.13 0.17 [0.09, 0.24] 0.24 0.01 [0.00, 0.05] 0.92 0.00 [0.00, 0.01]
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Note: Bolded inhibited temperament values denote statistical significance. Bolded interaction effect sizes denote equivalence (η2 < .01). Shaded rows indicate evidence for a transdiagnostic factor based on a significant main effect of inhibited temperament and group equivalence on the interaction.

Figure 2:

Figure 2:

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Scatterplots illustrating the relationship between inhibited temperament and outcome measures across patient groups

Negative Affect.

Within the patients, inhibited temperament was associated with higher negative affect across all three disorders (Table 3; Figure 2). Inhibited temperament was positively associated with the three MASQ general distress measures: mixed, anxious, and depressed. For all three negative affect variables, there were no significant effects of diagnostic group or diagnosis x temperament interaction and the interaction effect sizes were smaller than the equivalence criteria.

Depression.

Inhibited temperament was positively associated with all of the depression measures including HAM-D, MADRS, and MASQ anhedonic depression (Table 3; Figure 2). The main effect of diagnostic group was significant for the HAM-D; patients with depression had the highest HAM-D scores, followed by patients with schizophrenia, and patients with bipolar disorder had the lowest scores. The diagnosis x temperament interaction was not significant for any of the depression variables. The equivalence criteria was met for the MADRS and MASQ anhedonic depression scores, but not the HAM-D (η2 = 0.014).

Psychosis and General Psychopathology.

Data from the PANSS (Distress, Excitement, Disorganization, Negative, Positive factors) was available for the psychotic bipolar disorder and schizophrenia groups. There was a main effect of inhibited temperament for the PANSS Distress factor. However, the diagnosis x temperament interaction was also significant suggesting that the relationship between temperament and PANSS Distress differed by groups. The main effect of diagnosis was significant for the Postive factor, the schizophrenia group had more positive symptoms than the bipolar disorder. There were no significant main effects or interactions for the Negative, Disorganization, and Excitement factors. The means are provided in Table 2, and the test statistics are provided in Table 3.

Transdiagnostic Associations of Inhibited Temperament and Personality

As shown in Table 3, within the patients, the main effect of inhibited temperament was significant for the schizotypal personality measure and all five of the NEO-FFI factors (Neuroticism, Extraversion, Openness, Agreeableness, and Conscientiousness). Inhibited temperament was positively associated with schizotypal personality scores and Neuroticism, and negatively associated with Extraversion, Agreeableness, Conscientiousness, and Openness. The main effect of diagnosis was significant for the schizotypal personality measure but not any of the NEO-FFI factors. Patients with schizophrenia had the highest levels of schizotypal personality traits, followed by the patients with bipolar disorder, and the patients with major depression group had the lowest levels. The diagnosis x temperament interaction term was not significant for any of the personality scores, but the equivalence criteria was only met for Neuroticism, Extraversion, and Conscientiousness.

Transdiagnostic Associations of Inhibited Temperament and Cognition

Within the patients, there were no significant main effects or interactions for current cognitive function (SCIP) or premorbid cognitive function (WTAR; Table 3; Figure 2).

Transdiagnostic Associations of Inhibited Temperament and Functioning

The main effect of inhibited temperament was significant for the self-report measure of quality of life, with higher inhibited temperament associated with lower quality of life (Table 3; Figure 2). The main effect of diagnosis was not significant. The diagnosis x temperament interaction was not significant and the effect size did meet the equivalence criteria. For the global assessment of function (GAF) score, there were no main effects or interactions (Table 3; Figure 2). Since inhibited temperament was associated with both anxiety and depressive symptoms and quality of life, we conducted post-hoc exploratory analyses to investigate whether anxiety or depressive symptoms mediated the effect of inhibited temperament on quality of life. Specifically, a mediation analysis utilizing a non-parametric bootstrap approach (PROCESS, 5,000 bootstraps; Preacher and Hayes, 2008) was performed to determine whether the relationship between inhibited temperament and quality of life were mediated by either the anxiety symptoms (MASQ-anxious arousal) or the depression symptoms (HAM-D, MADRS, MASQ-anhedonic depression). A significant indirect mediation effect (ab) would be indicated by a confidence interval that does not contain zero. The mediation analyses revealed a significant indirect effect for MASQ Anxious Arousal (ab = −1.85, CI = [−2.93, −0.94]), MASQ Anhedonic Depression (ab = −4.29, CI = [−5.76, −2.94]), HAMD (ab = −1.92, CI [−3.01, −0.10]), and MADRS (ab = −1.98, CI [−3.02, −1.09]). Thus, a significant amount of the impact of inhibited temperament on quality of life was mediated by anxiety and depression.

Discussion

The study results provide evidence that inhibited temperament is similarly elevated in patients with schizophrenia, bipolar disorder, and depression; strongly correlated with multiple measures of affective components (clinical characteristics/personality traits), and that these associations are similar across disorders confirming that inhibited temperament is transdiagnostic. This finding is novel and important because it significantly expands our understanding of inhibited temperament from a specific risk factor for anxiety disorders to a broader transdiagnostic risk factor for mood and psychotic disorders. Inhibited temperament was significantly and similarly elevated across patients with schizophrenia, psychotic bipolar disorder, and major depressive disorder. Across patient groups, higher inhibited temperament showed strong associations across multiple domains including: higher levels of anxiety and depression; higher levels of affective personality traits; and lower quality of life. Inhibited temperament was not associated with cognition or global functioning, suggesting an important specificity to more affective components of the three disorders.

The study findings show that inhibited temperament is similarly elevated across all patients groups relative to controls. For each diagnostic group, inhibited temperament scores were significantly higher than scores in the control group and the temperament scores were similarly elevated in patients with schizophrenia, psychotic bipolar, and major depressive disorder compared to healthy controls. Our findings of higher temperament scores in all three diagnostic groups are consistent with the handful of previous studies that have found temperament differences in major depressive disorder (Caspi et al., 1996; Gladstone and Parker, 2006; Muris et al., 2001; Muris and Ollendick, 2005; Reznick et al., 1986), bipolar disorder (Engström et al., 2004; Kesebir et al., 2005; Porcelli et al., 2018), and schizophrenia (Feola et al., 2019; Goldberg and Schmidt, 2001; Jetha et al., 2011). Our findings make a novel contribution to the literature by demonstrating that inhibited temperament scores are similarly elevated across schizophrenia, bipolar disorder, and major depression; to our knowledge, inhibited temperament has yet to be examined across these three groups within a single sample using the same methods and measures. While the mean inhibited temperament scores were higher in patients, there was also substantial variability, pointing to potentially important heterogeneity in temperament. Future studies are needed to determine whether there are clinically meaningful temperament subgroups.

Inhibited temperament was characterized by a subset of clinical symptoms (anxiety, negative affect, depression), personality factors (Neuroticism, Extraversion and Conscientiousness) and quality of life across disorders. For the clinical symptoms, there was evidence for a transdiagnostic association between inhibited temperament and anxiety, negative affect, and depression. Previous studies have also reported correlations between inhibited temperament and anxiety or depression in community samples (Gladstone and Parker, 2006; Schofield et al., 2009) and in patients with schizophrenia (Feola et al., 2019). Here, we extend those findings to patients with major depressive disorder and psychotic bipolar disorder. For the personality measures, there was evidence for a transdiagnostic association beween inhibited temperament and the NEO factors of Neuroticism, Extraversion, and Conscientiousness. Across diagnoses, individuals with higher inhibited temperament had higher Neuroticism scores, lower Extraversion scores, lower Conscientiousness scores and higher schizotypal personality scores. In a community sample of children Muris et al (2009), found that inhibited temperament was correlated with higher Neuroticism, lower Extraversion, lower Conscientiousness and lower Openness, similar to our findings, suggesting that inhibited temperament and personality factors are associated across developmental stages and also in non-clinical samples. This transdiagnostic association may be capturing an overlapping trait of higher levels of negative affect, lower distress tolerance, and lack of enjoyability of social interactions across disorders. Finally, higher inhibited temperament was correlated with lower self-report of quality of life, despite similar clinician-rated functioning. Mediation analyses revealed that anxiety and depression mediated the association between higher inhibited temperament and lower quality of life, consistent with other studies that have shown that anxiety, depression, and personality factors predict lower quality of life in a variety of health conditions (Boylan et al., 2004; Lysaker and Salyers, 2007; Mendlowicz and Stein, 2000; Ridgewell et al., 2016). Thus, improving anxiety and depression in patients with mood or psychotic disorders may be an important target for also increasing quality of life.

Inhibited temperament was not associated with variability in cognitive measures or overall functioning; therefore, we propose that the impact of inhibited temperament is specific and is through affective or emotional systems. Inhibited temperament is thought to impact developmental trajectories through both bottom-up mechanisms, like heightened emotional reactivity, and top-down mechanisms, like deficits in emotion regulation and cognitive control (Blackford et al., 2018). Specific neurobiological alterations in affective systems is also consistent with the shared neurobiological alterations in stress and arousal (Garcia Coll et al., 1984; Kagan et al., 1987; Schmidt et al., 1999; Stevenson-Hinde and Marshall, 1999; Brochier and Olié, 2005; Mondelli et al., 2018; Pruessner et al., 2017; Shah and Malla, 2015; Vaessen et al., 2018), frontal lobe asymmetry (Schmidt et al., 1999; Henriques and Davidson, 1991; Schaffer et al., 1983; Jetha et al., 2009), and neural habituation (Blackford et al., 2013; Blackford et al., 2011; Avery et al., 2019; Williams et al., 2013). Although affect and cognition are highly interactive systems, dissociations between affect and cognition have been suggested for major depressive disorder (Zuckerman et al., 2018) and schizophrenia (Myin-Germeys and van Os, 2007). Furthermore, mood and psychotic disorders are heterogeneous and patients often have relative impairments in affective versus cognitive symptoms that are associated with different symptom patterns and outcomes (Dickinson et al., 2018; Green et al., 2004; Martino et al., 2014; McIntyre et al., 2013; Tabarés-Seisdedos et al., 2008). Thus, it is possible that clinically-relevant subgroups exist within mood and psychotic disorders, with an inhibited temperament subgroup characterized by heightened affect and preserved cognitive function. Future studies will be critical for replicating this initial finding, investigating potential subgroups, and determining whether the observed affective differences reflect underlying neurobiological alterations.

There were several study limitations. First, the measure of childhood temperament was a self-report retrospective questionnaire, meaning patients may be unreliable reporters. However, the RSRI was used previously in patients with psychosis (Feola et al., 2019; Goldberg and Schmidt, 2001; Jetha et al., 2011) and was correlated with other measures associated with temperament including shyness and sociability (Goldberg and Schmidt, 2001; Jetha et al., 2011). Although childhood assessments of temperament in prospective studies are the gold standard, long-term longitudinal studies are rarely sufficiently powered to identify associations with low prevalence disorders like schizophrenia and bipolar disorder. The second limitation was that the data were cross-sectional. Previous cross sectional studies show temperament predicts psychopathology (Gladstone et al., 2005) and are consistent with longitudinal studies (Chronis-Tuscano et al., 2009; Clauss and Blackford, 2012; Essex et al., 2010). However, it will be crucial to collect prospective longitudinal data in order to determine whether inhibited temperament increases risk for these disorders. Third, the characteristics and behaviors captured in the temperament questionnaire may be reflecting phenotypic-similar patterns associated with the disorders rather than early temperament. Future longitudinal studies should aim to study early temperament prior to the onset of psychopathology to disentangle early temperament from disorder related phenotypes. Fourth, the current study included patients with bipolar disorder with psychotic features, and major depressive disorders without psychotic features, which limits the generalizability of these findings to all mood and psychotic disorders. Future studies should examine these associations within a patient group with all mood and psychotic disorders. Finally, the scope of this study focused on childhood inhibited temperament. Future studies will be critical for examining the contributions of stability or change in temperament across development as well as the predictive probabilities of childhood versus current temperament.

In conclusion, the study findings provide evidence that inhibited temperament is transdiagnostic across mood and psychotic disorders. These findings represent an important expansion of our understanding of inhibited temperament as primarily a risk factor for developing anxiety disorders. First, inhibited temperament may confer a broader risk across many psychiatric disorders rather than a risk factor for anxiety disorders. Inhibited temperament can be identified early in development, allowing for earlier detection and interventions that may alter a child’s trajectory away from psychiatric risk. Second, inhibited temperament may explain heterogeneity in symptoms that may guide treatment development targeting core features of inhibited temperament to reduce anxiety and depression and increase quality of life in individuals suffering from mood or psychotic disorders.

Supplementary Material

Updated Supplemental Material

Highlights.

  • Mood and psychotic disorder patients had elevated childhood inhibited temperament.

  • Childhood inhibited temperament was associated with affect but not cognition.

  • Inhibited temperament is a possible risk factor for mood and psychotic disorders.

  • Treatments targeting affective symptoms may benefit inhibited patients.

Acknowledgments

Support for this project was provided by the Charlotte and Donald Test Fund, the Jack Martin MD Research Professorship in Psychopharmacology (JUB), NIMH grant R01-MH70560 (SH), NIMH grant R01-MH102266 (NDW), NIH grant T32MH018921 (BF, EAF), the Vanderbilt Psychiatric Genotype/Phenotype Project, and the Vanderbilt Institute for Clinical and Translational Research (through grant 1-UL-1-TR000445 from the National Center for Research Resources/NIH).

Role of the Funding Source

The funding sources had no involvement.

Footnotes

Conflict of Interest

No authors have competing interests to declare. Declaration of interests: none.

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NIHMS1603107-supplement-Updated_Supplemental_Material.docx (44.8KB, docx)

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