Methylphenidate Reduces State Anxiety During a Continuous Performance Test That Distinguishes Adult ADHD Patients From Controls

Abstract

Objective: We hypothesized that patients with ADHD were typified by distress more than by functional difficulties. Thus, a decline in state anxiety while performing a cognitive task when taking methylphenidate would discriminate between ADHD patients and controls. Method: State anxiety and cognitive performance on a continuous performance test were assessed in ADHD patients and controls with and without taking methylphenidate. Results: State anxiety and cognitive performance improved from baseline in 36 ADHD adults after taking methylphenidate. In 25 controls, cognitive performance improved, but state anxiety did not abate after a recess. In two additional studies, 5 controls were evaluated at baseline and after receiving methylphenidate, and showed improvement in cognitive assessment but not in state anxiety. Five ADHD adults were assessed at baseline and after a recess, and showed no improvement. Conclusion: Our results support the hypothesis that adult ADHD patients are characterized by distress and the relief of this distress under effective therapy as expressed by a decline in state anxiety while they perform a cognitive task.

Keywords

methylphenidate adult ADHD anxiety assessment

Introduction

ADHD is a common neurobehavioral disorder in which the clinical manifestations are thought to evolve from difficulties in attention and executive functions. Laboratory tests such as the continuous performance tests (CPTs) that assess continuous attention show difficulties in ADHD patients when compared with controls. These tests do not show a recognizable deficit in more than 15% of ADHD patients (Bloch et al., 2012; Willcutt, Doyle, Nigg, Faraone, & Pennington, 2005). Approximately 10% to 30% of the controls share difficulties with ADHD patients (Willcutt et al., 2005). Recent studies support a similarity in neurocognitive findings in ADHD patients and their first-degree relatives (Gau & Shang, 2010), substantiating the doubts about their specificity and pathophysiological role. Studies that focus on the phenomenology, clinical course, and prognosis demonstrate the considerable functional and emotional burden that this disorder places on patients’ lives (Kessler et al., 2006; Wilens et al., 2009). For many patients, methylphenidate therapy ameliorates both the symptoms and the deficits found in CPTs (Swanson, Baler, & Volkow, 2011). Recently, evidence has accumulated showing that methylphenidate might have a nonspecific enhancing effect on attention in controls as well (Nandam et al., 2011). This evidence sharpens both research and clinical questions related to the understanding of ADHD. Thus, the cognitive findings exemplify only one aspect of the difficulties endured by patients suffering from ADHD. Beyond the high prevalence (up to 47%) of anxiety disorders among adult ADHD patients (Kessler et al., 2006; Wilens et al., 2009), recent studies have implicated the role of trait anxiety on attention (Basten, Stelzel, & Fiebach, 2011). There is some evidence pointing to a correlation between ADHD and test anxiety as a form of state anxiety and it’s correlation with self-esteem (Dan & Raz, 2015). Distress related to the demands of a cognitive task is a closer phenomenon to clinical symptomatology than cognitive performance per se. This distress is partially related to the cognitive performance. The possibility that anxiety has a crucial role in this phenomenology has not been studied systematically. We hypothesized that state anxiety while performing a cognitive task is a more reliable measure of the cognitive-related distress that typifies ADHD patients. Thus, a decline in state anxiety during the performance of a CPT while being treated with methylphenidate is a more specific marker of ADHD patients than the improvement in cognitive function.

The following series of small-scale studies were carried out to investigate a possible unique effect of methylphenidate on state anxiety in adult patients suffering from ADHD while performing a CPT task.

Method

Tools

Adult ADHD Self-Report Scale (ASRS)

The ASRS comprises 18 items that relate to ADHD symptoms in adults (Adler et al., 2006; Kessler et al., 2005).

Wender-Utah Adult ADHD Scale (WUAAS)

The WUAAS is a 61-item self-administered scale for rating frequencies of ADHD childhood symptoms retrospectively on a 5-point scale, from 0 = not at all or slightly to 4 = very much. The subscale Wender-Utah Rating Scale (WURS)-25 provides a total sum score (range 0-100) by putting together those 25 items, which best discriminate between ADHD and controls (Ward, Wender, & Reimherr et al., 1993). A cutoff score of 36 is 96% sensitive and specific for identifying childhood ADHD among the general population (Ward et al., 1993).

The use of these scales helps to combine the history of childhood symptoms (WUAAS) with the current difficulties typifying adults with ADHD (ASRS). Both scales are standard tools in clinical practice.

The Brief Symptom Inventory (BSI)

The BSI is a brief psychological self-report symptom scale adapted from its longer parent instrument, the Symptom Checklist-90–Revised (SCL-90-R). It is well-validated and commonly used to identify general psychopathology (Derogatis & Melisaratos, 1983).

The Spielberger State-Trait Anxiety Inventory (STAI)

The STAI is a well-known 40-item instrument, measuring transient and enduring levels of anxiety. Strong psychometric support is available for the STAI with young adults (Spielberger, Gorssuch, Lushene, Vagg, & Jacobs, 1983). A cutoff point of 39 to 40 is normally used for clinically significant symptoms of a state of anxiety (Forsberg & Bjorvell, 1993; Knight, Waal-Manning, & Spears, 1983).

The Rapid Visual Processing (RVP) Task From the Cambridge Neuropsychological Test Automated Battery (CANTAB)

The RVP is a CPT that measures sustained attention. It is a cognitive measure commonly used both in research and in clinical practice of ADHD (Riccio, Reynolds, Lowe, & Moore, 2002). The most significant variables are the A′ representing the participants’ ability to detect the target sequence, and the latency representing the speed of response.

Procedure

In the following studies, patients were recruited through advertisements and through the outpatient clinic. The diagnosis of ADHD was based on thorough clinical interviews conducted by a psychiatrist experienced in adult ADHD diagnosis and assisted by the ASRS and the WUAAS. Thirteen of all the ADHD patients recruited were previously diagnosed with ADHD, and methylphenidate treatment was recommended (six in childhood, and seven as adults). Four additional patients admitted to have used nonprescribed methylphenidate at least once. Three participants used methylphenidate regularly, they did not take their medications on the day of the study. Ten patients had a diagnosis of dyslexia or dyscalculia (six of them without a prior diagnosis of ADHD). No other active diagnosis was present because exclusion criteria included history of head trauma, epilepsy, mental retardation, psychotic or bipolar disorder, current substance abuse, current depression or anxiety disorder, and any current regular use of a psychoactive medication.

The diagnosis of the control group was based on the BSI and a brief interview.

The study was approved by the local institutional review board (IRB), and after signing an informed consent form, all participants underwent two identical evaluations, separated by a 2-hr recess.

The evaluations were performed via questionnaires, computerized cognitive tests, and voice analyses (results of the latter were analyzed separately). Specifically, all participants filled out a well-validated self-report questionnaire to evaluate anxiety (STAI) and performed a CPT (RVP) from the CANTAB (Robbins et al., 1998).

Study 1

The participant group comprised 36 patients with ADHD (M age = 30.72 years, SD = 5.14) of which 14 were females. At baseline evaluation, the ASRS total was 61.28 (SD = 11.4), hyper was 28.28 (SD = 6.3), and WURS was 44.78 (SD = 16.47). The anxiety trait was 48.09 (SD = 13.3). In addition, 25 controls with no mental disorder (M age = 26.84 years, SD = 5.5) were recruited, of which 22 were females (average BSI = 1.53, SD = 0.54; M anxiety trait = 35.64, SD = 10.21). The difference in trait anxiety was significant, t(50) = −3.75, p < .001.

The participants in the ADHD group repeated all the evaluations 2 hr after taking 10 mg of methylphenidate.

The control group repeated all evaluations after a 2-hr recess.

Statistical analyses included a two-way ANOVA with repeated measure, between groups, ADHD versus control, and within-participant between the two assessments.

Results

The ADHD group displayed lower performance on measures of sustained attention (RVP A′ M = 0.89, SD = 0.05; RVP mean latency M = 521.65, SD = 136.22) compared with the control group (RVP A′ M = 0.92, SD = 0.03; RVP mean latency M = 463.09, SD = 69.09). The group differences were significant: RVP A′, t(58) = 2.28, p < .05; RVP mean latency, t(58) = 2.19, p < .05.

After administration of methylphenidate, the ADHD group performed significantly better on the sustained attention test (Table 1): RVP A′, t(35) = 6.78, p < .001; RVP mean latency, t(35) = 2.66, p < .05.

Table 1.

Sustained Attention and State Anxiety.

	ADHD (N = 36)		Control (N = 25)		Statistics
Measures	Test 1	Test 2	Test 1	Test 2	ADHD (t1-t2)	Control (t1-t2)	ADHD × Control
RVP A′	0.89 (0.05)	0.94 (0.04)	0.92 (0.03)	0.94 (0.04)	t(35) = −6.78***	t(23) = −5.5***	F(1,58) = 5.89*
RVP mean latency	521.6 (136.2)	462.6 (82.9)	463.1 (69.1)	424.2 (54.1)	t(35) = 2.66*	t(23) = 3.1**	F(1,58) = 0.48
Anxiety state	39.5 (9.96)	30.9 (7.89)	31.0 (9.09)	30.5 (9.58)	t(35) = 6.93***	t(24) = 0.52	F(1,59) = 21.2***

Note. RVP = rapid visual processing.

Significant at level .05. **Significant at level .01. ***Significant at level .001.

However, the control group showed a similar pattern after a 2-hr recess. They too performed significantly better on the second sustained attention test (see Table 1): RVP A′, t(23) = 5.5, p < .001; RVP mean latency, t(23) = 3.08, p < .01. The improvement in performance of the ADHD group was significantly higher in RVP A′ but not in RVP mean latency. This difference was exemplified in the significant interaction between the two assessments and the groups, RVP A′, F(1,58) = 5.89, p < .05.

After administration of methylphenidate, the ADHD group showed a significant decline in state anxiety scores (see Table 1), t(35) = 6.93, p < .001. By contrast, no difference was found in state anxiety before and after a 2-hr recess in the control group, t(24) = 0.52 (ns). There was a significant interaction between the groups and the two anxiety state assessments. This interaction was related to a significant difference between the groups in anxiety state at baseline, t(59) = 3.38, p < .01. State anxiety was higher in the ADHD group (M = 39.51, SD = 9.97) compared with the control group (M = 31.04, SD = 9.09).

We wanted to investigate whether methylphenidate-related improvement in state anxiety is a true feature of ADHD, present beyond variability in baseline anxiety. Because the groups differed significantly in baseline state anxiety, we evaluated these findings after matching the groups for baseline state anxiety (18 ADHD and 18 control participants). The pattern described above both for the cognitive measures and for state anxiety remained the same. Both groups performed significantly better in the second cognitive evaluation, RVP A′, F(1,33) = 43.34, p < .001; RVP mean latency, F(1,33) = 8.35, p < .01, while only marginal interaction was found for the RVP A′, p = .06.

The decline in state anxiety of the ADHD patients remained significant, t(17) = 6.89, p < .001. No such decline was demonstrated in the control group (see Figure 1). It is important to note that after matching, there was no significant difference in trait anxiety between the groups (p > .1).

Figure 1.

Comparison of attention and anxiety before and after methylphenidate (ADHD group) or recess (control group), Group × Tests interaction.

To verify that the decline in anxiety in the methylphenidate-treated ADHD group was relevant even when the level of state anxiety was low, we looked at the five ADHD patients with the lowest trait anxiety. Surprisingly, state anxiety declined significantly, from 24.1 (SD = 1.8) at baseline to 20.8 (SD = 1.3), t(4) = 4.3, p < .05, while there was no significant change in RVP A′ and mean latency (p > .1).

Study 2

To verify that the methylphenidate effect on state anxiety during a cognitive task performed by patients with ADHD was not a nonspecific effect of methylphenidate, the IRB committee approved the recruitment of five additional control participants who, after an informed consent process, underwent the same procedure as the ADHD patients, that is, receiving 10 mg of methylphenidate between the two assessments (M age = 32 years, SD = 5.3). All were male.

The results of this control group when comparing evaluations at baseline to evaluations performed 2 hr after taking methylphenidate were as follows:

On the CPT, RVP A′ changed significantly—.95 (SD = 0.03), .99 (SD = 0.01), t(4) = −3.7, p < .05—but mean latency did not (p > .1).

State anxiety did not change: 27.4 to 25.6 (ns).

Study 3

To verify that the methylphenidate effect on state anxiety during a cognitive task performed by patients with ADHD was not a nonspecific effect of training of ADHD patients and not related to methylphenidate therapy, the IRB committee approved the recruitment of five additional ADHD participants who, after an informed consent process, underwent the same procedure as the control patients, that is, repeating the test after a recess without taking methylphenidate (M age = 29.8 years, SD = 4.8 years). Four of them were females.

The results of this group when comparing evaluations at baseline to evaluations performed after a 2-hr recess were as follows:

On the CPT, there was no significant change after a recess on the RVP A′ or in the mean latency (p > .1 for both tests).

For the measure of anxiety, there was a trend toward deterioration: 29 (SD = 5.2), 32.2 (SD = 7.9), t(4) = −2.5, p = .067.

Discussion

The central finding of the current study is that while the positive effect of methylphenidate on continuous attention is not specific to patients with ADHD, the effect on state anxiety close to the time of performing the cognitive task is unique to patients with ADHD. Baseline state anxiety is expected to have personal variability and to be affected by multiple factors. We consider the effect methylphenidate has on state anxiety for the same patient while performing the same task a more reliable feature of the relation between ADHD and anxiety. In accord with this line of thought, the effect on state anxiety was not explained by the fact that at baseline, ADHD patients were more anxious. Rather, it was evident both when the control and ADHD groups were matched, and also when we examined the least anxious subgroup of the ADHD patients. It is important to note that these patients after matching would not have been considered clinically anxious because their state anxiety was in the normal range (below 40); nevertheless, the decline in anxiety was still significant. Because these findings were significant even in the group of the five least anxious ADHD patients, we performed two small complementary studies to verify the specificity of our findings. Control patients after receiving methylphenidate were more accurate on the CPT (RVP A′)—again supporting the effect even in a small group—but their anxiety did not decline. In ADHD patients, repeating the task without methylphenidate did not cause a decline in anxiety (there was even a trend toward an incline in anxiety).

One possible explanation for the presented results would be that patients with ADHD are at the lower end of capabilities related to attention. Attention is a dimensional and not a categorical feature. Thus, it is not surprising that the attention of control participants benefited from methylphenidate as well, but to a lesser degree. Patients with ADHD suffer from higher levels of state anxiety when confronted with a task demanding attention. Because attention is a central obstacle in their functioning, improving attention, which is related to methylphenidate, typically reduces their state anxiety. It should also be stated that—as opposed to this ADHD “learned cognitive task anxiety” hypothesis—it is possible that there is an inherent connection between networks related to anxiety and those related to attention. The role of the catecholamine neurotransmitters dopamine and norepinephrine in state anxiety (Carrasco & Van de Kar, 2003) and in ADHD, and in the effect stimulants have on them (Swanson et al., 2011) would support a possible shared biology in these pathologies.

Our findings are in accord with some of the imaging studies that have been carried out with ADHD patients. These studies demonstrate changes in brain regions typically connected to anxiety: the limbic system and specifically the amygdala (Frodl & Skokauskas, 2012; Volkow et al., 2007). A recent meta-analysis of these findings even raised support for a protective effect of prolonged methylphenidate therapy on the anterior cingulated cortex and the amygdala (Frodl & Skokauskas, 2012).

It is important to stress the study’s limitations: a placebo was not administered, the study included only adult referrals and the majority of them not treated regularly before being studied, the sample was small and relevant confounders, including gender difference or differences in ADHD subtypes, could not be evaluated. These limitations must be stressed when relating to the two small continuation studies especially because four of the five ADHD with no methylphenidate recruits were females.

These preliminary findings call for future larger-scale placebo-controlled studies intended to study possible interactions between state anxiety and ADHD, including the effect of methylphenidate on state anxiety in patients suffering from ADHD.

Footnotes

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) received no financial support for the research, authorship, and/or publication of this article.

Author Biographies

Yuval Bloch, MD, is the director of the child and adolescent psychiatric outpatient clinic and a senior researcher in the cognitive-emotion research lab in Shalvata Mental Health Center. He is a lecturer in Tel-Aviv University medical school. Central fields of interest include brain stimulation, and cognitive and emotional assessment in different mental disorders especially ADHD.

Shai Aviram, MA, is a student in cognitive psychology at Haifa University. He is a research assistant and statistical consultant at the cognitive-emotion research lab, Shalvata Mental Health Center.

Aviv Segev, MD, is a psychiatry resident at Shalvata Mental Health Center. He studies the interactions of psychopathology and computer games, as well as biological correlates of schizophrenia and other severe mental disorders.

Uri Nitzan, MD, works as a senior psychiatrist in the day department and in the brain stimulation unit of the hospital. His central fields of interest are resistant depression, placebo effect, and adherence to treatment.

Yechiel Levkovitz, MD, is the director of the day department and of the cognitive-emotion research lab in Shalvata Mental Health Center. He is a full professor of psychiatry in Tel-Aviv University medical school. Central fields of interest include brain stimulation, mood disorders, and cognitive and emotional assessment in different mental disorders

Yoram Braw has a PhD in clinical-rehabilitation psychology (Bar-Ilan University, Israel). He is currently the chairman of the Behavioral Sciences Department, Ariel University Center of Samaria (Israel). His current research focuses on the cognitive functioning of psychiatric patients (mainly patients with affective disorders).

Aviva Mimouni Bloch, MD, is the director of the pediatric neurology and developmental unit of Loewenstein Rehabilitation Hospital in Raanana, Israel, and a lecturer in Sackler medical school of Tel-Aviv University. Central fields of interest include genetic aspects of neurodevelopmental disorders and ADHD.

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