Pediatric Social Anxiety Disorder: Predictors of Response to Pharmacological Treatment

Abstract

Objective:

Pediatric social anxiety disorder (SAD) is associated with an increased risk of comorbid mental disorders, with implications for prognosis and treatment strategy. The aim of this study is to explore predictors of treatment response, and the role of comorbidity in affecting refractoriness.

Methods:

One hundred and forty consecutive youths (81 males, 57.9%), ages 7–18 years (mean age 13.7±2.5 years, mean age at onset of SAD 10.6±2.7 years) met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for SAD as primary diagnosis, according to a structured clinical interview (Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children—Present and Lifetime Version [K-SADS-PL]). All received a pharmacological treatment with serotonin reuptake inhibitors (SSRIs) targeted to SAD, associated with additional medications for comorbidities (mood stabilizers in 27.1%, antipsychotics in 12.8%) and 57.9% received an additional psychotherapy.

Results:

Eighty-nine patients (63.6%) responded to treatments after 3 months, namely 72.8% with psychotherapy plus medication and 50.8% with medication only. Nonresponders had more severe symptoms at baseline in terms of both clinical severity and functional impairment, and had more comorbid disruptive behavior disorders. The backward logistic regression indicated that clinical severity and functional impairment at baseline, comorbid disruptive behavior disorders, and bipolar disorders were predictors of nonresponse.

Conclusion:

Our data suggest that SSRIs can be effective in pediatric SAD, but that the more severe forms of the disorder and those with heavier comorbidity are associated with poorer prognosis.

Introduction

C ross-sectional studies have shown that anxiety disorders are the most prevalent psychiatric diagnoses, with an estimated prevalence ranging from 9.9% to 16.7% worldwide (Kessler et al. 2007). Approximately 50% of all anxiety disorders have their onset before age 11, and about 75% before age 21 (Beesdo et al. 2009). Among the anxiety disorders, social anxiety disorder (SAD) is characterized by extreme and persistent fear about social situations in which a person may be exposed to negative evaluations, embarrassment, or humiliation, particularly with unfamiliar people, with intense distress and avoidance (American Psychiatric Association 2000). Although the most vulnerable period is in the adolescent years, SAD can start as early as in childhood (Stein et al. 2001), with strong stability over time, and increased developmental risk for further psychopathology (Hayward et al. 2008; Hirshfeld-Becker 2010). A longitudinal study indicated that only 13% of patients with baseline diagnosis of SAD were free of any psychiatric diagnosis after a 10 year follow-up, 35% reported the same disorder, and 64% reported another anxiety disorder or depression (Wittchen et al. 1999b). The risk of lifetime depression is particularly high for those with earlier onsets of SAD (Lecrubier and Weiller 1997; Beesdo et al. 2007), with prevalence rates ranging from 25% to 31% in epidemiological settings and from 17% to 52% in clinical settings (Essau et al. 1999; Chavira et al. 2004). In an epidemiological Finnish study including a general adolescent population, depressive disorders co-occurred with SAD in 41% of cases, the same rate of co-occurrence as anxiety disorders (Ranta et al. 2009). Obsessive-compulsive disorder (OCD), bipolar disorders, substance-related disorders, and disruptive behaviour disorders may co-occur as well (Beidel et al. 1999). Usually SAD precedes comorbid conditions, and can be considered a potential risk factor for superimposed mental diseases and/or their more malignant course (Stein et al. 2001; Beesdo et al. 2007).

According to epidemiological studies, few individuals with SAD receive adequate treatment, despite overall increased healthcare utilization (Wittchen et al. 1999a; Emslie 2008). Controlled trials demonstrated efficacy of cognitive-behavioral therapy (CBT) (Beidel et al. 2007; Kendall et al. 2008; Silverman et al. 2008) and serotonin reuptake inhibitors (SSRIs) such as fluvoxamine (Research Unit on Pediatric Psychopharmacology Study Group, 2001), fluoxetine (Birmaher et al., 2003; Beidel et al., 2007), paroxetine (Wagner et al., 2004), and the norepinephrine-selective reuptake inhibitor (NSRI) venlafaxine (March et al., 2007). Efficacy of CBT and/or SSRIs is confirmed in the more recent Child-Adolescent Anxiety Multimodal Study (CAMS), including 488 youth (7–17 years) with SAD and/or generalized anxiety disorder or separation anxiety disorder (Walkup et al. 2008).

The aims of our study are to explore patterns of comorbidity in a large consecutive sample of youth referred for SAD as primary diagnosis and currently receiving an SSRI targeted to SAD symptomatology, and to assess possible predictors of response to treatment.

Methods

Patients

This naturalistic, retrospective study is based on a clinical database of 257 youth, ages 7–18 years (mean age 13.7±2.5 years, mean age at onset 10.6±2.7 years), who met American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for SAD, according to historical information and a diagnostic interview, the Kiddie Schedule for Affective Disorders and Schizophrenia for School-Aged Children-Present and Lifetime Version (K-SADS-PL) (Kaufman et al. 1997). All patients with mental retardation, pervasive developmental disorders, and schizophrenia were excluded. Among these patients, 140 youth presented SAD as primary diagnosis, received an SSRI targeted to the actual SAD symptomatology, and were included in this study. We considered SAD as the primary diagnosis when it was the most impairing disorder at the referral, and other comorbid conditions (including mood disorders and disruptive behavior disorders) were stable and well treated with medications. The SSRIs were fluoxetine (n=68, 48.6%), sertraline (n=44, 31.4%) and fluvoxamine (n=28, 20.0%).

Some of the subjects received an additional medication for co-occurring comorbidities, 35 (25.0%) a mood stabilizer, 18 (12.8%) an antipsychotic, and 5 (3.6%) a psychostimulant. These medications were allowed to be continued as long as there had been no dose changes in the last 4 weeks before starting SSRIs. Finally 81 (57.9%) patients received concurrent psychotherapy (individual sessions), without specific involvement of parents, except for a generic counseling during the psychiatric consultations. Among these patients, only 21 (15%) were on SSRI alone, without additional medications and/or CBT. Furthermore, no subjects received more than two drugs. The decisions regarding the medication choice (combination vs. medication treatment alone) was based solely on the clinician rating, according to the severity of the clinical picture, clinical response, and the management of the comorbidities.

The severity of the illness was recorded at baseline with the Clinical Global Impressions Severity (CGI-S) score (Guy 1976). Functional impairment was assessed during the same visits using the Child Global Assessment Scale (C-GAS) (Shaffer et al. 1983). Patients were considered responders to treatment (in terms of overall improvement of SAD) when they presented, after a 3 month follow-up, a CGI-Improvement score of 1 or 2, a CGI-Severity score ≤3, and a C-GAS score >60 for at least three further consecutive monthly visits.

All the patients and their families participated voluntarily in the study. Informed consent was obtained for assessment and treatment procedures.

Chi-square analysis was used on categorical variables and t-tests were used on continuous variables. Because of the multiple comparisons and the number of patients, results are prone both to type I and type II errors. Therefore, Bonferroni correction for multiple comparisons was used setting significance at 0.002 level, two tailed. To examine which variables were associated with treatment response, a backward stepwise logistic regression was performed. An α of 0.05 was selected as the threshold for inclusion in the regression analysis. All statistical analyses were performed with version 15 for Windows SPSS.

Results

As reported in Table 1, patients were characterized by a male prevalence (57.1%) and a marked severity (mean CGI-S score=5.0, SD=0.7) and functional impairment (C-GAS mean score=44.7, SD=6.6) corresponding to moderate degree of interference in functioning in most social areas, or severe impairment in one area, and frequent comorbidities, particularly with depression, generalized anxiety disorder (GAD), separation anxiety disorder and OCD. Less frequent comorbidities were with bipolar disorder and disruptive behaviour disorders (attention-deficit/hyperactivity disorder [ADHD], oppositional defiant disorder, conduct disorder).

Table 1.

Demographic Characteristics of Children and Adolescents with Social Anxiety Disorder (n=140)

Gender (males), n (%)	81 (57.9)
Age, mean (SD)	13.7 (2.6)
Age at onset, mean (SD)	10.5 (2.7)
CGI-S (baseline), mean (SD)	5.0 (.7)
CGI-I, mean (SD)	2.3 (.7)
C-GAS (baseline), mean (SD)	44.7 (6.6)
Responders, n (%)	89 (63.6)
Lifetime comorbidity, n (%)
Tic disorder	12 (8.6)
Depression	70 (50.0)
Bipolar disorder	16 (11.4)
Separation anxiety disorder	48 (34.3)
Generalized anxiety disorder	101 (72.1)
Panic disorder	20 (14.3)
Simple phobias	37 (26.4)
Obsessive-compulsive disorder	45 (32.1)
Attention-deficit/hyperactivity disorder	11 (7.9)
Oppositional defiant/Conduct disorder	17 (12.1)
Total number (SD)	3.4 (1.1)
Externalizing disorders	0.2 (.5)
Internalizing disorders	3.6 (1.2)
Pharmacotherapy, n (%)
Serotonin reuptake inhibitors	140 (100)
Mood stabilizers	35 (25.0)
Antipsychotics	18 (12.8)
Psychostimulants	5 (3.6)
Psychotherapy	81 (57.9)

CGI-S=Clinical Global Impressions – Severity; CGI-I=Clinical Global Impressions – Improvement; C-GAS=Children Global Assessment Scale.

According to our criteria, 89 patients (63.6%) responded to pharmacological treatment, without significant differences among the SSRIs (fluoxetine 46/68, 67.6%; sertraline 27/44, 61.4%; fluvoxamine 16/28, 57.1%, χ²=1.1, df=2, p=0.583). When responders were considered according to the treatment (medication only or medication plus psychotherapy), responders were 59 (72.8%) of those receiving both the treatments and 30 (50.8%) of those receiving only medication, but the difference did not survive Bonferroni correction (χ² =6.2, df=1, p=0.013). Age, age at onset of SAD, gender, baseline severity, comorbidities, and pharmacological treatments did not differ between patients receiving or not receiving psychotherapy.

When responders and nonresponders were compared according to selected variables (Table 2), gender, age, and age at onset did not differ between responders and nonresponders. Nonresponders had had more severe symptoms than had responders at baseline, in terms of clinical severity (assessed with the CGI-S) (p<0.001) and functional impairment (assessed with the C-GAS) (p=0.001). Regarding psychiatric comorbidity, only co-occurring externalizing disorders were associated with nonresponse (p<0.001), whereas the prevalence of bipolar comorbidity in nonresponders did not survive Bonferroni correction.

Table 2.

Comparisons Between Children and Adolescents with Social Anxiety Disorder Who Were Responders or Nonresponders to Treatments

	Responders n=89	Nonresponders n=51	t/χ ² (df)	p
Gender (males), n (%)	50 (56.2)	31 (60.8)	0.1 (1)	0.724
Age, mean (SD)	13.7 (2.6)	13.6 (2.6)	0.2 (138)	0.827
Age at onset, mean (SD)	10.7 (2.6)	10.3 (2.8)	0.9 (138)	0.396
CGI-S (baseline), mean (SD)	4.8 (.6)	5.3 (.7)	−4.5 (138)	0.000^*
CGI-I, mean (SD)	1.9 (.5)	3.1 (.3)	−15.6 (138)	0.000^*
C-GAS (baseline), mean (SD)	46.0 (6.3)	42.3 (6.4)	3.3 (138)	0.001^*
Lifetime comorbidity, n (%)
Tic	9 (10.1)	3 (5.9)	0.1 (1)	0.149
Generalized anxiety disorder	59 (66.3)	42 (82.4)	3.6 (1)	0.065
Depression	49 (55.1)	21 (41.2)	2.0 (1)	0.160
Bipolar disorder	6 (6.7)	10 (19.6)	3.2 (1)	0.043°
Separation anxiety disorder	34 (38.2)	14 (27.5)	1.2 (1)	0.269
Panic disorder	17 (19.1)	3 (5.9)	3.6 (1)	0.057
Simple phobia	24 (25.0)	13 (25.5)	0.0 (1)	0.993
Obsessive-compulsive disorder	30 (27.0)	15 (29.4)	0.1 (1)	0.737
ADHD	6 (6.7)	5 (9.8)	0.1 (1)	0.748
Oppositional-Defiant/Conduct disorder	4 (4.5)	13 (25.5)	11.5 (1)	0.000^*
Disrupt. Behavior Disorders, mean (SD)	0.1 (.3)	0.4 (.6)	−3.9 (138)	0.000^*
Anxiety Disorders, mean (SD)	3.5 (1.1)	3.2 (1.1)	1.4 (255)	0.123
Total number, mean (SD)	3.6 (1.2)	3.6 (1.4)	0.6 (255)	0.554
Treatments, n (%)
Serotonin reuptake inhibitors	89 (100)	51 (100)
Mood stabilizers	14 (15.7)	21 (41.2)	9.9 (1)	0.002^*
Antipsychotics	8 (9.0)	10 (19.6)	2.4 (1)	123
Methylphenidate	3 (3.4)	2 (3.9)	0.1 (1)	0.761
Psychotherapy	59 (66.4)	22 (43.1)	3.4 (1)	0.081

statistically significant, p<0.002 (Bonferroni correction).

°significant, p<0.05.

CGI-S=Clinical Global Impressions–Severity; CGI-I=Clinical Global Impressions–Improvement; C-GAS=Children Global Assessment Scale; ADHD=attention-deficit/hyperactivity disorder.

The backward logistic regression indicated that clinical severity at baseline (OR=7.34, 95% CI=0.243–0.784, p=0.006), comorbid conduct disorder (OR=6.39, 95% CI=1.402–14.36, p=0.011), and bipolar disorder (OR=3.85, 95% CI=1.00–9.90, p=0.050) were all predictors of nonresponse.

The SSRI treatment was well tolerated, with no patients discontinuing medication because of side effects during the follow-up. Twenty-two patients (15.7%) experienced mild-to-moderate agitation, prevalently in the first 2 weeks of treatment, 14 (10.0%) complained of mild and transient nausea, and 7 (5%) of increased appetite. Five adolescents reported mild sexual side effects. No significant effects were revealed in blood parameters during the follow-up period.

Discussion

A better description of the incidence patterns of comorbidity of pediatric SAD in its early stages is important, as it may allow us to decrease this developmental risk and to implement more effective and timely interventions.

The present study included a consecutive series of patients with SAD as primary diagnosis who were referred to a third-level hospital for pharmacological treatment and treated with an SSRI. These patients were characterized by severe clinical symptomatology and functional impairment and a high rate of psychiatric comorbidity, namely with GAD and depression, with rates consistent with previous reports in older patients (Grant et al. 2005). The uneven gender ratio (male prevalence 57.9%) is consistent with findings according to which gender ratio tends to shift to female preponderance as age increases (Ranta et al. 2009). In our sample, a strong minority of children were in prepubertal age. Furthermore, in an epidemiological study in Turkey, males reported higher scores than females in a specific questionnaire on social anxiety (Cakin Memik et al. 2010).

The high rate of comorbidity with depression in our sample (50%) is consistent with previous studies, indicating a strong association in general population between lifetime SAD and major depressive disorder (OR=2.9) (Kessler et al. 1999). Beesdo et al. (2007) reported that in the first three decades of life, SAD is associated with subsequent depression, independent of age at onset for SAD (relative risk range, 1.49–1.85, controlling for age and sex). Approximately half of our patients presented this comorbidity during childhood or adolescence, suggesting that this association might start early in life, even though the incidence of depression in cases with SAD extends up to 25 years, with a later gradual plateau (Beesdo et al. 2007). Kessler and coworkers hypothesized that early diagnosis and treatment of SAD in youth might decrease the risk for subsequent development of depression in adolescence and early adulthood, as ∼10% of mood disorders can be prevented by a successful early intervention on SAD (Kessler et al. 1999).

All patients received an SSRI to treat SAD symptomatology. The response rate in terms of SAD improvement after 12 weeks of naturalistic treatment was consistent with data from the CAMS study. Patients receiving psychotherapy plus medication were more frequently responders than those receiving medication only (72.8% vs. 50.8%). Even though the difference was not significant after Bonferroni correction, this finding is consistent with the CAMS study, which supports a greater efficacy of the combined treatment.

When responders and nonresponders were compared, baseline clinical severity and functional impairment at the baseline were both associated with a poorer response. It is noteworthy that both co-occurring disruptive behaviour and bipolar comorbidities were independently negative predictors of treatment response. Although these comorbidities were not the main concern, as SAD was the principal diagnosis and the target of the treatment, our data suggest that the association with these disorders significantly affects the outcome.

This study presents several methodological limitations, the first being that the therapist evaluated treatment outcomes, introducing the possibility of bias. Another limitation is that the CGI, used as an outcome measure, is not a specific index of anxiety severity and improvement. However, the CGI-I criterion corresponds to what clinicians use to assess efficacy and effectiveness of a treatment in daily practice. A possible limitation may be a referral bias, because our third-level university hospital may have selected the more severely disturbed and help-seeking patients, and those with the highest rates of comorbidities. The severity of the symptomatology and the rate of comorbidity is greater in referred samples than in general, non-referred populations (Goodman et al. 1997).

Most important, our sample is not homogeneous in terms of clinical presentation (comorbid conditions) as well as in terms of treatments (different medications, only 60% received psychotherapy). Such confounding factors may be particularly relevant because different medications, including SSRIs, mood stabilizers, and antipsychotics, may have anti-anxiety properties, even though they were unchanged in the last 4 weeks before starting the SSRI. However, our findings describe an unselected sample of consecutive children and adolescents with SAD as primary diagnosis treated as needed (mono- or polypharmacy), and followed up in an “ordinary” clinical setting, which may actually be one of the strengths of our study. No exclusion criteria were applied (except for mental retardation, pervasive developmental disorders, and schizophrenia); all other comorbid conditions, which are often excluded in controlled trials but represent the rule in clinical settings, were included in the study. Given that only a minority of patients present a “pure” SAD, and/or are treated with a SSRI monotherapy, the role of comorbidity in clinical presentation and response to treatment allows broader inferences regarding the effectiveness of treatment over extended periods of time under ordinary clinical conditions.

Conclusion

SAD can be a heavily impairing disorder, and it is frequently comorbid with other mental disorders in children and adolescents, particularly other anxiety disorders and depression. In our sample, 63% of these patients responded to pharmacological treatments. Patients with more severe baseline impairment and/or co-occurring disruptive behavior disorders and bipolar disorders had a poorer response to treatments.

Clinical Significance

SAD should be carefully explored in young patients, as it is often complicated with comorbid conditions. These comorbidities can affect outcome and treatment response. Further studies should address whether an early detection and treatment of SAD may decrease the risk and/or the severity of superimposed mental disorders.

Footnotes

Disclosures

Dr. Masi is in the advisory boards for Eli Lilly, Shire, and Novartis; has received research grants from Eli Lilly and Shire; and has been a speaker for Eli Lilly, Shire, Sanofi-Aventis, and Novartis. Dr. Pfanner has received research grants from Eli Lilly and has been a speaker for Eli Lilly. Dr. Perugi is in the advisory boards for Sanofi-Aventis, Astra Zeneca, Janssen Cilag, Lundbeck, BMS Otsuka, and Eli Lilly; has received grants from Astra Zeneca, Eli Lilly, and Lundbeck; and has received honoraria for talks from Astra Zeneca, Janssen Cilag, Eli Lilly, Sanofi Aventis, Lundbeck, and BMS Otsuka, and Servier. Dr Mucci, Dr. Berloffa, Dr. Magazù, and Dr. Parolin have no conflicts of interest to declare.

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