The Trend in Morning Levels of Salivary Cortisol in Children With ADHD During 6 Months of Methylphenidate Treatment

Abstract

Objective: To determine the trend in cortisol levels in children with ADHD treated with methylphenidate (MPH) and nontreated healthy controls over a 6-month period. Method: The morning salivary cortisol levels of 50 patients with ADHD (40 boys and 10 girls, mean age = 7.6 years) and 50 age- and gender-matched healthy controls were measured at baseline and at 1, 3, and 6 months from baseline. The neuropsychological performance of the ADHD patients was measured via administration of the Continuous Performance Test. Results: The cortisol levels of ADHD patients increased significantly after 1 month of MPH treatment before decreasing to an intermediate level, but were significantly positively correlated with neuropsychological performance throughout the 6-month treatment period. The cortisol levels of the controls did not change significantly over the 6-month period. Conclusion: MPH administration appears to positively influence the functioning of the hypothalamic–pituitary–adrenal axis in ADHD patients.

Keywords

ADHD methylphenidate cognitive function psychostimulant neurobiology

Introduction

ADHD is a common neuropsychiatric disorder in children and adolescents (American Psychiatric Association [APA], 2000). Dysfunction of the hypothalamic–pituitary–adrenal (HPA) axis, which plays an important role in regulating neurotransmitters of the central nervous system as well as behaviors such as attention, emotion, memory, and learning (Talge, Neal, & Glover, 2007), has been implicated in the pathophysiology of ADHD (Ma, Chen, Chen, Liu, & Wang, 2011). The functioning of the HPA axis has typically been assessed by measurement of cortisol levels from various sources (saliva, urine, and blood plasma) at key points in time (morning, afternoon, or evening; Hellhammer, Wust, & Kudielka, 2009).

One major challenge in assessing the role of cortisol levels in children with ADHD has been the inconsistency of the findings regarding this role as reported in the growing body of literature. Such inconsistency might be explained by the heterogeneity of the study populations, study design, and/or means of symptom assessment used by different studies. For example, the results of several studies that investigated cortisol levels following either a stress challenge or an awakening response (Pesonen et al., 2011; Reynolds, Lane, & Gennings, 2010; Stadler et al., 2011; Yang, Shin, Noh, & Stein, 2007) generally indicated that children with a severe tendency toward disruptive or aggressive behaviors experienced hyporeactivity of their cortisol response. Other studies that measured the basal level of morning cortisol (between 08:00 and 10:00; Wang et al., 2011; Young, Sweeting, & West, 2011) found no significant differences in cortisol levels between patients with ADHD and healthy controls. Yet, other investigations aiming to identify the relationship between cortisol levels and social/behavioral ADHD symptoms (Alink et al., 2008; Strous et al., 2001) or neurocognitive performance (Hong, Shin, Lee, Oh, & Noh, 2003; S. H. Lee, Shin, & Stein, 2010) yielded discrepant findings.

Methylphenidate (MPH), classified as a psychostimulant, is the most widely used drug for the pharmacological management of children with ADHD (Wilens, 2008). With regard to its influence on the HPA axis, Weizman et al. (1987) reported that although the plasma cortisol levels of patients with ADHD increased within 2 hours of an acute challenge with MPH, these levels did not increase when the participants were rechallenged 4 weeks later. In related studies, Hibel, Granger, Cicchetti, and Rogosch (2007) found no association between MPH administration and salivary cortisol levels or diurnal variation, whereas M. S. Lee et al. (2008) found no significant change in cortisol levels among patients with ADHD treated with MPH during a 12-week period. Several researchers have proposed that dysfunction of the HPA axis in children with ADHD might be reflected in underarousal or an elevated threshold for the detection of stressors (Freitag et al., 2009).

Due to such discrepant findings, the debate regarding whether MPH modulates the functioning of the HPA axis, as reflected in cortisol levels, continues unabated. It is thus important to elucidate the neurobiological pathogenesis of ADHD by increasing understanding of the functioning of the HPA axis. To date, most studies investigating the relationship between cortisol levels and ADHD symptomatology have used a cross-sectional study design. Among these studies, only a few reported that the cortisol response at baseline is associated with the 1-year outcome (King, Barkley, & Barrett, 1998) and with treatment effects in patients with ADHD (van de Wiel, van Goozen, Matthys, Snoek, & van Engeland, 2004). Among the few longitudinal studies that have investigated cortisol levels in patients with ADHD, very few assessed neurocognitive functioning (King et al., 1998; M. S. Lee et al., 2008). Moreover, despite knowledge that HPA-axis functioning in children with ADHD might be influenced by MPH treatment in the clinical setting, no study has investigated the effect of long-term treatment with MPH on cortisol levels and their association with ADHD symptomatology.

To fill this research gap and thereby elucidate the long-term relationship between cortisol levels and both clinical symptomatology and neuropsychological performance in children with ADHD, the present study aimed to determine the trend in the morning salivary cortisol levels in patients with ADHD during 6 months of MPH treatment and compare it with the trend in healthy untreated controls.

Method

This observational, 24-week prospective study was conducted at the Child and Adolescent Psychiatry Outpatient Department of Chang Gung Memorial Hospital, Keelung, Taiwan. The Chang Gung Memorial Hospital Institutional Review Board approved this study. The purpose of the study was explained to all participants and their caregivers, and informed consent of the participants and their guardians was gathered at the start of this study.

Participants

Patients aged 6 and 12 years of age who met the criteria for ADHD presented in the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; APA, 2000) were recruited as experimental participants and 50 age- and gender-matched children in the same catchment area without ADHD or other psychiatric disorders were recruited as healthy controls. Assessment of ADHD was performed using the Chinese version of the Kiddie Epidemiologic Version of the Schedule for Affective Disorders and Schizophrenia (K-SADS-E; Kaufman et al., 1997), which had been developed from the original version by the Child Psychiatry Research Group in Taiwan (Gau & Soong, 1999). The inclusion criterion was recent diagnosis of ADHD or existing diagnosis for which no medication had been administered for at least the 6 months preceding study initiation. The exclusion criterion was history of major physical or additional psychiatric diseases, such as pervasive developmental disorder, oppositional defiant disorder, or conduct disorder.

Clinical Measures

The parent version of the ADHD–Rating Scale (ADHD-RS) is an 18-item checklist derived from the 18 criteria outlined in the DSM-IV (APA, 1994). The symptom/behavior presented in each item is assessed by selection of a score along a 4-point Likert-type scale ranging from 0 to 3, with higher scores indicating greater severity of ADHD. The ADHD-RS includes both Inattentive subscales (odd-numbered items) and Hyperactive/Impulsive subscales (even-numbered items), and has been reported to have good interrater reliability (Zhang, Faries, Vowles, & Michelson, 2005).

The Swanson, Nolan, and Pelham–Version IV Scale (SNAP-IV) is a 26-item questionnaire used to evaluate the symptoms and severity of ADHD. The SNAP-IV consists of 9 items assessing inattention, 9 items assessing hyperactivity/impulsivity, and 8 items assessing oppositional subscales (Bussing et al., 2008) through the use of a 4-point Likert-type scale. The Chinese version of the SNAP-IV test has been reported to have satisfactory levels of reliability and concurrent validity (Liu et al., 2006).

The Child Behavior Checklist (CBCL) is an instrument completed by parents or caregivers that evaluates the social and behavioral competence of children between 4 and 16 years of age over the preceding 6 months (Achenbach, 1991). Among the eight subscales of the CBCL, the Aggressive and Delinquency subscales reflect outward-directed problems in children with disruptive behavior disorders (Biederman, Monuteaux, Kendrick, Klein, & Faraone, 2005). The T-scores for each scale are typically used for research analysis. The Chinese version of the CBCL has been found to have high test–retest reliability and validity (Leung et al., 2006).

Conners’ Continuous Performance Test (CPT) is a 14-min computerized test that primarily assesses attention and impulse control (Conners, 1985). Briefly, participants are required to respond to the stimuli on a computer screen by pressing a space bar for every letter except the letter “X.” Among the multiple dependent measures that may be used, omissions, commissions, and detectability (D′) are the most commonly used indices. Omissions refer to situations in which the target stimulus appears but to which the participant does not respond by pressing the response button, commissions to those in which the target stimulus does not appear but to which the participant responds by pressing the response button, and D′ is an indication of the ability to distinguish targets from nontargets accurately and is interpreted as a measure of perceptual sensitivity. The T-score of the CPT, with a lower T-score indicating better performance, is commonly used in research analyses (Conners, 2004).

Study Procedures

The design of this study was that of a 24-week, nonrandomized, observational, prospective investigation. At Visit 1 (V1; pre-treatment), saliva samples from the patients with ADHD were collected at 08:00 in the outpatient department. After the collection of the samples, the patients’ parents or caregivers were interviewed by a clinician, with the ratings using the ADHD-RS assigned being determined by a child psychiatrist, and then requested to complete the SNAP-IV and CBCL. At approximately 09:00, the patients were administered the computerized CPT in a room dedicated to the testing to minimize the variability of the test conditions. After testing had been completed, the patients and their parents or caregivers were counseled regarding the treatment program before initiation of drug therapy. The patients were then prescribed a dosage of MPH based on the severity of their clinical symptoms and their age, height, and body weight. Concomitant medications were not permitted.

During Visit 2 (V2), which occurred 1 month after V1, the patients were administered MPH at approximately 07:30 and saliva samples were collected at 08:00. The ADHD-RS, SNAP-IV, and CBCL measures were then completed before the patients were administered the CPT at approximately 09:00. At Visit 3 (V3), which occurred 3 months after V1, and Visit 4 (V4), which occurred 6 months after V1, the procedures performed at V2 were repeated.

Patient care was left to the discretion of the psychiatrists, who were given no treatment instructions and simply encouraged to manage their patients according to usual practice. Modification of the MPH dosage may have occurred for some patients at V2, V3, or V4. Drug compliance was confirmed at each visit based on reports of the patients’ parents or caregivers and presentation of the remaining MPH. The psychiatrists assessed stress level by asking the patients and their parents whether the patients had recently experienced a stressful event.

Saliva samples were collected from healthy controls at 08:00 in the school infirmary during four visits (V1-V4) from the researchers that corresponded to the time intervals of the visits of the patients with ADHD.

Laboratory Testing of Cortisol Levels

To ensure reliable measurement of cortisol levels, both the patients with ADHD and the controls were instructed to avoid excessive levels of physical activity 24 h before testing, to fast the night before testing, to wake up at approximately 07:00 the morning of the testing, and not to drink or brush their teeth 30 min before testing. Saliva samples were placed in collecting tubes using the passive drool method, immediately placed on ice, and then stored at −30°C until further analysis. The cortisol levels were quantified using a Cortisol ELISA kit (RE52611; IBL Gesellschaft Für Immunchemie und Immunbiologie MBH, Hamburg, Germany). The range of detection using this method has been reported to be 0.015 to 4 µg/dl and the intra- and interassay coefficients of variation to be 3.2% to 6.4% and 6.2% to 9.1%, respectively (Innovation Beyond Limits, 2007).

Statistical Analyses

The data were analyzed using the statistical software package SPSS, Version 16. Variables are presented as either the mean (SD) or frequency. Two-tailed p values of <.05 were considered statistically significant.

Numerous parameters of measures for ADHD were used in this study, posing the risk of Type I errors. To reduce this risk, the ADHD measures were condensed using principal components analysis (PCA) with a set of weights for a composite ADHD score for each participant. The factors yielding eigenvalues greater than 1.00 were retained for varimax rotation, and then the extent to which the composite ADHD score for each identified factor correlated with the salivary cortisol levels was further investigated.

Employment of a linear mixed model was the primary analytic strategy used to analyze the longitudinal data. Compared with more traditional approaches, this technique has been found to cope with missing data with greater efficacy (Jennrich & Schluchter, 1986). To examine the trends in cortisol levels and the measures of ADHD over 6 months, the changes in cortisol levels were set as the dependent variables using the linear mixed model. Use of this model accounted for potential correlations between cortisol levels and composite ADHD scores while controlling for the confounding effects of gender, age, MPH dosage based on body weight, and stressful events.

Results

A total of 50 patients with ADHD (40 boys and 10 girls) and 50 healthy controls (40 boys and 10 girls) of a mean age of 7.6 (1.6) and 7.8 (1.5) years, respectively, were examined in this study. Detailed data regarding the cortisol levels of patients with ADHD and the healthy controls at baseline were previously reported by these authors (Wang et al., 2011). No significant differences in demographic characteristics or in morning cortisol levels were found between the two groups. Among the patients with ADHD, cortisol levels were found to be significantly correlated with only one index of the CPT, the D′ of the CPT, and were not found to be significantly correlated with any score of social/behavioral competence.

Trends in Salivary Cortisol Levels

Of the 50 patients with ADHD who presented at V1, 42, 33, and 30 remained in the study at V2, V3, and V4, respectively, whereas all 50 healthy controls remained in the study until its conclusion. Figure 1 shows the trends in salivary cortisol levels over time for the patients with ADHD and the healthy controls. Among the patients with ADHD, the salivary cortisol levels were found not to change significantly during the 6-month treatment period (F = 1.63, p = .187). However, the results of post hoc testing indicated that salivary cortisol levels at V2 (Month 1) were significantly higher than those at V1 (pre-treatment; mean difference = 0.11, p = .046). No significant differences were found regarding other pairwise comparisons of variables between visits. Among the healthy controls, salivary cortisol levels were found not to change significantly during the 6-month observation period (F = 0.27, p = .844), and the results of post hoc testing did not indicate any significant differences in cortisol levels between visits.

Figure 1.

Trends in the morning salivary cortisol levels in patients with ADHD (n = 50) treated with MPH for 6 months and in healthy controls (n = 50) untreated and observed for 6 months.

Changes in Measures of ADHD Symptoms

Table 1 shows the weights for the measures of each of the four factors yielding eigenvalues greater than 1.00 that were retained for PCA. The resulting factors were labeled on the basis of their clinical meaning such that Factor 1 was labeled disruptive behavior, Factor 2 hyperactivity, Factor 3 inattention, and Factor 4 impulse control. These factors, which had eigenvalues of 2.98, 2.28, 1.55, and 1.04, respectively, were found to account for 78.65% of the total matrix variance.

Table 1.

The Factors Produced by Principal Components Analysis of ADHD Measures.

	Factor 1 (disruptive behavior)	Factor 2 (hyperactivity)	Factor 3 (inattention)	Factor 4 (impulse control)
ADHD-RS
Inattention	−0.05	−0.10	0.88	0.13
Hyperactivity	0.15	0.88	0.08	0.08
SNAP-IV
Inattention	0.24	0.27	0.73	0.16
Hyperactivity	0.09	0.84	0.28	0.15
Opposition	0.54	0.56	−0.02	−0.22
CBCL
Aggression	0.90	0.20	−0.07	−0.16
Delinquency	0.90	0.06	0.07	0.13
CPT
Omission	−0.15	0.29	0.68	−0.14
Commission	0.06	0.02	−0.07	0.97
Detectability (D′)	−0.15	0.11	0.22	0.89

Note. ADHD-RS = ADHD–Rating Scale; SNAP-IV = Swanson, Nolan, and Pelham–Version IV Scale; CBCL = Child Behavior Checklist; CPT = Continuous Performance Test. Rotation method is varimax with Kaiser Normalization. Absolute values of factor loadings greater than 0.50 are represented in boldface type.

Figure 2 shows the changes over time of these four composite factors in the patients with ADHD relative to the baseline. As can be observed, significant improvements in disruptive behavior (F = 9.89, p < .001), hyperactivity (F = 16.35, p < .001), inattention (F =8.02, p < .001), and impulse control (F = 17.76, p < .001) were found to have occurred during the 6-month treatment period.

Figure 2.

Changes in the composite symptom scores of patients with ADHD (n = 50) relative to baseline during 6 months of treatment with methylphenidate.

Relationship Between Salivary Cortisol Levels and ADHD Measures

After controlling for gender, age, MPH dosage based on body weight, and stressful events, salivary cortisol levels of the patients with ADHD were found to be independently and significantly correlated with impulse control (β = −.006, p = .003) but not with the other three factors during the 6-month treatment period. Table 2 shows the correlation between cortisol levels and ADHD patient characteristics, MPH dosage, and the ADHD measures of the factor scores over this period.

Table 2.

Relationships of Cortisol Levels, ADHD Patient Characteristics, MPH Dosage/Body Weight, and ADHD Symptom Composite Scores Over 6 Months.

Predictors	Estimate	df	t	p value
Gender (male vs. female)	−0.074	53.32	−1.10	0.276
Age	−0.006	54.48	0.34	0.734
Stressful events (yes vs. no)	0.005	123.40	0.09	0.932
MPH dosage/body weight	0.099	99.56	1.05	0.298
Factor 1 (disruptive behavior)	−0.001	78.38	−0.40	0.693
Factor 2 (hyperactivity)	−0.005	94.30	−0.89	0.375
Factor 3 (inattention)	0.002	101.35	0.50	0.618
Factor 4 (impulse control)	−0.006	85.95	−3.10	0.003

Note. MPH = methylphenidate; df = degrees of freedom. The dependent variable is salivary cortisol levels in linear regression analysis with mixed models.

Discussion

A major finding of this study was the differential effect of MPH administration on the morning salivary cortisol levels of patients with ADHD. Specifically, while the morning salivary cortisol level of patients with ADHD increased significantly during the first month of MPH treatment, the level subsequently dropped to an intermediate level that was not significantly different from either the baseline or 1-month level over the 6-month course of treatment. In contrast, the salivary cortisol levels of the healthy controls did not change during the 6-month observation period. Another major finding was that among the patients with ADHD, patients with higher morning cortisol levels were found to have better CPT performance compared with those with lower levels throughout the 6-month treatment period.

Changes in Salivary Cortisol Levels With MPH Treatment

The cortisol levels of both patients with ADHD (Weizman et al., 1987) as well as of normal adults (Joyce, Donald, Nicholls, Livesey, & Abbott, 1986) have been found to increase markedly with MPH administration, indicating that psychostimulant medications might be able to facilitate cortisol secretion in patients with ADHD (Kariyawasam, Zaw, & Handley, 2002). It has been hypothesized that MPH exerts therapeutic effects on patients with ADHD by promoting noradrenergic and dopaminergic enhancement (Wilens, 2008), as well as the deployment of pharmacological mechanisms that generate neuroendocrine effects (Lurie & O’Quinn, 1991). In addition to having direct effects on the secretion and feedback control of the HPA axis, MPH has also been hypothesized to influence cortisol levels indirectly by attenuating or potentiating the impact of environmental events and subjective experiences on HPA-axis activity (Hibel et al., 2007).

The cortisol levels of the children with ADHD examined in this study decreased after 1 month of MPH administration. This finding, which supports previous demonstration of acute tolerance to MPH in the treatment of children with ADHD (Swanson et al., 1999), suggests that the neuroendocrine effects of MPH decrease over time, likely due to the development of desensitization in postsynaptic dopamine receptors after long-term MPH treatment (Weizman et al., 1987). However, the association among the trend in cortisol levels, neurobiological mechanisms, and tolerance to MPH requires further clarification.

Relationship Between ADHD Measures and Cortisol Levels

All four factors investigated by PCA showed significant improvement over 6 months of treatment. Previous studies have shown that patients with ADHD who display disruptive or aggressive behaviors, which were termed Factor 1 (disruptive behavior) in this study and which included oppositional, delinquent, and aggressive behaviors, display reduced cortisol reactivity to stress (Stadler et al., 2011; Yang et al., 2007). Although several studies have also suggested an association between morning levels of cortisol and disruptive behavior (Alink et al., 2008; Pesonen et al., 2011; Young et al., 2011), the findings regarding this association have not been consistent. The results of this study do not support a correlation between morning levels of cortisol and the clinical symptom dimensions of ADHD in patients receiving MPH treatment.

A notable finding in this study is the identification of a positive correlation between morning salivary cortisol levels and CPT performance (Factor 4) over the course of 6 months of MPH treatment. The findings regarding the measures of ADHD indicated that a major component of Factor 4 is a patient’s ability to control impulses and to discriminate between targets and nontargets (Conners, 2004). Previous studies have indicated that morning cortisol levels are a manifestation of basal arousal levels, reflecting the motivation to increase arousal to a tolerable level by seeking out novel and stimulating experiences (Alink et al., 2008). Based on these previous findings, the findings of this study suggest that the patients with ADHD with higher morning cortisol levels had been able to maintain greater alertness and impulse-control ability during neuropsychological testing. Nevertheless, in a previous study by the authors of the present study (Wang et al., 2011), morning levels of cortisol were not found to correlate significantly with CPT performance in the drug-naïve state at baseline. Taken together, a possible explanation of these findings is that the HPA-axis functioning in ADHD patients is modified during the course of treatment with MPH. This speculation warrants examination in future studies.

Study Limitations and Advantages

This study faced four primary limitations that may limit the validity or generalizability of the findings. First, the saliva samples were collected from the patients with ADHD in a hospital but from the healthy controls in a school. As the patients with ADHD were waiting to take the CPT in the hospital, they might have been experiencing anticipation anxiety, which might have affected their cortisol levels and thus confounded the results. Second, although the results indicated a significant increment in cortisol levels after 1 month of MPH treatment, no measurements of the levels were made after baseline and during the first month of treatment. Thus, it could not be determined whether the cortisol levels changed significantly during this interval of the study. Third, although a previous study had reported that children with ADHD had lower cortisol-awakening responses compared with healthy controls (Blomqvist et al., 2007), the waking time of the participants in this study was not precisely identified. Therefore, the waking time of the individual patients might have affected their cortisol levels in a manner that confounded the study results. Finally, to avoid the possible confounding effects of comorbidity, patients with oppositional defiant disorder or conduct disorder were excluded from this study. However, application of this exclusion criterion might have limited the external validity of the study, as abnormalities in cortisol secretion have been implicated in children with severe disruptive behaviors in previous international studies (Stadler et al., 2011; Yang et al., 2007). Due to these limitations, the findings of this study cannot be generalized to healthy controls, nonmedicated patients with ADHD, or ADHD patients with comorbid conditions.

However, this study used several methods that increased the reliability and generalizability of the findings compared with similar studies. Specifically, its use of a longitudinal study design allowed for determination of the changes in the morning cortisol levels in patients with ADHD compared with healthy controls, while its assessment of a wide range of ADHD symptomatology and of neurocognitive performance allowed for greater elucidation of the effects of MPH treatment on patients with ADHD.

Conclusion

The results of this study indicate that treatment with MPH affects the HPA-axis functioning of patients with ADHD, as measured by changes in their morning salivary cortisol levels. As increased cortisol levels have been positively correlated with impulse-control ability, the results thus suggest that MPH treatment may be a means of controlling ADHD symptomatology. Nevertheless, this study also found that the beneficial neuropharmacological effects of MPH might diminish over time. However, these findings require confirmation and further investigation to determine whether they are specific to patients with ADHD. Moreover, the complex nature of the relationships among HPA-axis functioning, MPH effects, and neurocognitive functioning warrants further clarification.

Footnotes

Acknowledgements

The authors thank Professor Wei-Tsun Soong for granting the use of the Chinese version of the Kiddie Epidemiologic Version of the Schedule for Affective Disorders and Schizophrenia (K-SADS-E); Professor Shur-Fen Gau for granting the use of the Chinese version of the Swanson, Nolan, and Pelham–Version IV Scale (SNAP-IV); and Lezen Medical Laboratory and Proteomics Core Laboratory at Chang Gung University for testing the saliva samples.

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was sponsored by the Chang Gung Memorial Hospital Research Project (CMRPG270141).

Author Biographies

Liang-Jen Wang is an assistant professor and chief in the Department of Psychiatry, Chang Gung Memorial Hospital at Keelung. As the primary researcher and coordinator of this project, he recruited the participants, gathered the data, and wrote the first draft of the manuscript.

Yu-Shu Huang is an associate professor and chief in the Department of Child Psychiatry, Chang Gung Memorial Hospital at Linko. She was responsible for the study design and protocol development.

Cheng-Cheng Hsiao is a psychiatrist in the Department of Psychiatry, Chia-Yi Christian Hospital. His major research interests are psychoneuroendocrinology and women’s psychiatry. He assisted with the study design and literature review.

Chih-Ken Chen is a professor at the Chang Gung University School of Medicine. He served as the primary statistical consultant for the project and conducted the literature search and edited the submitted manuscript.

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