Psychiatric profile and attention deficits in postural tachycardia syndrome

Abstract

Patients with postural tachycardia syndrome (POTS) often appear anxious and report inattention. Patients with POTS were formally assessed for psychiatric disorders and inattention and compared with patients with attention deficit hyperactivity disorder (ADHD) and control subjects.
Patients with POTS (n = 21), ADHD (n = 18) and normal control subjects (n = 20) were assessed for DSM-IV psychiatric disorders and completed a battery of questionnaires that assessed depression, anxiety and ADHD characteristics.
Patients with POTS did not have an increased prevalence of major depression or anxiety disorders, including panic disorder, compared with the general population. Patients with POTS had mild depression. They scored as moderately anxious on the Beck Anxiety Inventory but did not exhibit a high level of anxiety sensitivity. Patients with POTS scored significantly higher on inattention and ADHD subscales than control subjects. These symptoms were not present during childhood.
Patients with POTS do not have an increased lifetime prevalence of psychiatric disorders. Although they may seem anxious, they do not have excess cognitive anxiety. They do experience significant inattention which may be an important source of disability.

Full text

PSYCHIATRIC PROFILE AND ATTENTION DEFICITS IN
POSTURAL TACHYCARDIA SYNDROME
Vidya Raj, MB ChB1, Kirsten L. Haman, PhD1, Satish R. Raj, MD MSCI2,3, Daniel Byrne,
MS4, Randy D. Blakely, PhD1,3,6, Italo Biaggioni, MD2,3, David Robertson, MD2,3,5,6, and
Richard C. Shelton, MD1,3
1Department of Psychiatry, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
2Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
3Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee,
USA.
4Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
5Department of Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
6Center for Molecular Neuroscience, Vanderbilt University School of Medicine, Nashville,
Tennessee, USA.
Abstract
Objectives—Patients with postural tachycardia syndrome (POTS) often appear anxious and report
inattention. We formally assessed patients with POTS for psychiatric disorders and inattention and
compared them to patients with attention deficit hyperactivity disorder (ADHD) and control subjects.
Methods—Patients with POTS (N=21), ADHD (N=18) and normal control subjects (N=20) were
assessed for DSM-IV psychiatric disorders and completed a battery of questionnaires that assessed
depression, anxiety and ADHD characteristics.
Results—Patients with POTS did not have an increased prevalence of major depression or anxiety
disorders, including panic disorder, compared to the general population. Patients with POTS had
mild depression. They scored as moderately anxious on the Beck Anxiety Inventory, but did not
exhibit a high level of anxiety sensitivity. Patients with POTS scored significantly higher on
inattention and ADHD subscales than control subjects. These symptoms were not present during
childhood.
Conclusions—Patients with POTS do not have an increased lifetime prevalence of psychiatric
disorders. Although they may seem anxious, they do not have excess cognitive anxiety. They do
experience significant inattention, which may be an important source of disability.
Search Terms
Postural tachycardia syndrome (POTS); Orthostatic Intolerance; Attention; Depression; Anxiety
Corresponding Author & Address for Reprints: Richard C. Shelton MD, Department of Psychiatry, Vanderbilt University School of
Medicine, 1500 21st Ave., South, Suite 2200, Nashville, TN 37212, USA. Tel: (615) 343-9669 Fax: (615) 343-7868 Email:
Richard.Shelton@vanderbilt.edu.
COMPETING INTERESTS
None.
NIH Public Access
Author Manuscript
J Neurol Neurosurg Psychiatry. Author manuscript; available in PMC 2010 March 1.
Published in final edited form as:
J Neurol Neurosurg Psychiatry. 2009 March ; 80(3): 339–344. doi:10.1136/jnnp.2008.144360.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

INTRODUCTION
Postural tachycardia syndrome (POTS), a disorder that affects an estimated 500,000 people
(~0.18%) in the United States alone, is an important source of disability in young adults.[1] It
shows a strong predilection for females, typically between the ages 20–50 years.[2] POTS is
a form of orthostatic intolerance characterized by an excessive increase in heart rate (>30 bpm)
on assuming the upright position associated with orthostatic symptoms, but in the absence of
orthostatic hypotension.[2–5] Their symptoms of dizziness, nausea, tremor, chronic fatigue
and exercise intolerance make even simple activities of daily living such as walking and bathing
exhausting prospects.[6]
Although the role of noradrenergic dysfunction is unclear, there is significant evidence of
central dysregulation of the noradrenergic system in POTS and an association between
dysregulation of norepinephrine (NE) homeostasis and psychiatric disorders, including
depression, panic disorder and attention deficit hyperactivity disorder (ADHD). [7–9]
Centrally acting drugs that inhibit the pre-synaptic norepinephrine transporter (NET) (e.g.
tricyclic antidepressants, duloxetine, reboxetine, amphetamines and cocaine) produce the
clinical features of POTS.[10–13] Peripheral plasma norepinephrine (NE) is frequently raised
in patients with POTS, particularly when upright, and many clinical features of POTS such as
tachycardia, palpitations, shortness of breath, chest discomfort and tremor mimic the
hyperadrenergic features of a panic attack. In one family, the POTS phenotype segregated with
a heterozygous missense mutation in NET effecting >98% loss of function and elevated plasma
norepinephrine levels. The mutation tracked with POTS characteristics and the probands
complained of inattention.[10] While stimulants used to treat ADHD enhance alertness,
attention and working memory, very high levels of catecholamines disrupt these higher
cognitive functions. This effect can be reversed by α2–adrenoreceptor agonists which reduce
NE release.[9] Together, these findings suggest that the correct balance of central NE activity
is required to maintain normal attention and this could be impaired in POTS.
This cross-sectional controlled study assessed attention, mood, and anxiety symptoms in
patients with POTS and contrasted them with ADHD subjects and psychiatrically normal
control subjects. We tested the following hypotheses:
1. Patients with POTS will report a higher lifetime prevalence of depression and anxiety
disorders, and a higher magnitude of current depression and anxiety symptoms, than
controls and the prevalence will be comparable to subjects with ADHD.
2. Patients with POTS will show significant inattention relative to controls, and similar
to levels shown by subjects with ADHD.
METHODS
Patients and Study Design
The study was approved by the Vanderbilt University Institutional Review Board and all
participants provided written informed consent prior to the study. Patients with POTS (N=23),
aged 18–65 years, were admitted as research subjects to the Vanderbilt Clinical Research
Center between January 2003 and December 2004. They were referred to Vanderbilt due to a
clinical suspicion of POTS or had received a clinical diagnosis. The diagnosis of POTS was
confirmed with current criteria, which include (1) symptoms of orthostatic intolerance and an
increase in heart rate of ≥30 beats per minute within 10 minutes of standing from a supine
position, but in the absence of orthostatic hypotension (fall in blood pressure of ≥20/10 mm
Hg);[2–4] (2) symptoms with standing that improved with recumbence; (3) symptoms had
occurred for at least 6 months; and (4) symptoms had occurred in the absence of other major
medical co-morbidity or another obvious cause of tachycardia (such as acute dehydration).
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None of the subjects were receiving medications which could affect autonomic function during
their admission, including psychotropic drugs. Subjects participated in the seated position and
were not acutely symptomatic during the testing.
Patients with POTS were matched by age, gender and race with 20 psychiatrically healthy
control subjects, who formed a comparison group for the self-report questionnaires used in the
study. They were free of current or lifetime history of DSM-IV [14] Axis I psychiatric disorders
as assessed by the Structured Clinical Interview for DSM-IV Axis I Disorders (SCID).[15]
Age-matched adults with ADHD (n=18) formed a second comparison group with the POTS
patients, in particular regarding symptoms of inattention and chronic psychiatric illness. All
ADHD patients had been previously diagnosed and treated for ADHD by a psychiatrist or
psychologist. To ensure they currently met criteria, we re-evaluated patients using DSM-IV
diagnostic criteria as recommended by Barkley.[16] All control and ADHD subjects were free
of medical co-morbidities and were not taking psychotropic agents. The control and ADHD
subjects did not receive formal autonomic function testing, but none complained of autonomic
symptoms on screening by a medical doctor (VR), and ADHD subjects did not meet POTS
criteria on testing supine and standing heart rate and blood pressure.
For data on DSM IV axis I diagnoses, subjects with POTS were compared with subjects with
ADHD and data from a large population of respondents (n=9282) to the National Comorbidity
Survey Replication (NCS population norms).[17] Similarly, data on Anxiety Sensitivity Index
score was also compared to published general population normative data.[18]
Measures
Subjects were assessed by a trained research assistant for current and lifetime history of axis
I psychiatric disorders using the SCID. Psychiatric diagnoses were made only if not accounted
for by the presence of a medical disorder. Any diagnostic questions were resolved based on
the consensus opinion of the project clinicians (KLH, RCS). Subjects completed the following
self-report questionnaires (further details are in a supplemental file):
1. The Beck Depression Inventory Second Edition (BDI-II) - a well validated screening
questionnaire for depression.[19,20]
2. The Beck Anxiety Inventory (BAI) – a commonly used measure of anxiety severity.
[21]
3. The Anxiety Sensitivity Index (ASI) - assesses fear of anxiety-related symptoms.
[22]
4. The Connors Adult ADHD Rating Scale long form (CAARS-L) - rates items in four
factor domains including inattention/memory problems and hyperactivity/
restlessness.[23]
5. The ADHD Behavior Checklist for Adults (ABC-A) - measures the specific
inattentive and hyperactive-impulsive symptoms that comprise the DSM-IV criteria
for ADHD.[24]
Statistical Analysis
Differences among the groups were assessed using Fisher’s exact test for categorical variables
and one-way analysis of variance (ANOVA) for continuous variables, with a post-hoc Scheffe
multiple comparisons procedure used for pair-wise comparisons. Spearman’s test was
performed to analyze for bivariate correlations. A general linear model with inattention as the
dependent variable and gender, anxiety and depression as fixed factors was used to test for the
influence of potential confounding variables. All tests were two-sided and results were
considered significant if P<0.05. Data were analyzed with SPSS for Windows software, version
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14.0 (SPSS Inc.), and GraphPad Prism software, version 4 (GraphPad Software, San Diego,
Calif.). Results presented are means and standard deviations unless otherwise specified.
RESULTS
Patient Characteristics
One POTS patient declined to participate, reporting she felt too symptomatic. Data collected
on 2 of the 23 patients with POTS were not analyzed due to co-morbid ADHD that pre-dated
the diagnosis of POTS. One control subject was excluded after meeting criteria for a past
diagnosis of major depressive disorder. No ADHD volunteers were excluded. However, 3 of
23 initial subjects failed to participate and 2 subjects failed to complete the study so their data
could not be included. ADHD subjects could not be closely gender-matched with the POTS
patients due to the male bias of ADHD compared to the strong female predominance of POTS.
POTS patients reported mean length of illness from self-reported onset of symptoms as 6.9
±9.2 years. Characterizing data in the POTS subjects is presented in table 1 and baseline
demographic data for each patient group is compared in Table 2:
Groups did not differ significantly in age and education level and there was no difference in
gender distribution between the POTS and control groups. There were more men in the ADHD
group compared with the control group (P=0.027) reflecting the male predominance of ADHD.
All subjects were Caucasian, with the exception of one African-American patient with POTS
who was matched with an African-American control subject.
Prevalence of Mental Disorders
Lifetime prevalence of DSM-IV axis I psychiatric disorders in POTS patients and ADHD
subjects are presented in Table 3.
The lifetime prevalence of anxiety disorders in patients with POTS was not significantly greater
than NCS population norms (P=0.83) and did not differ significantly from subjects with ADHD
(P=0.34). Subjects with ADHD had a non-significant trend toward a higher prevalence of
anxiety disorders than NCS population norms (P=0.08), including panic disorder (P=0.066).
Amongst anxiety disorders, the prevalence of panic disorder in patients with POTS did not
differ from NCS population norms (P=0.99) or subjects with ADHD (P=0.32).
There was no difference in the lifetime prevalence of major depressive disorder in patients with
POTS compared to NCS population norms (P=0.99). However, there was a higher prevalence
of major depressive disorder in subjects with ADHD compared to patients with POTS
(P=0.024) or NCS population norms (P<0.001).
Finally, the prevalence of substance abuse or dependence in patients with POTS did not differ
significantly from NCS population norms (P=0.73), but was significantly less than in subjects
with ADHD (P=0.025).
Prevalence of Depression Symptoms
The BDI-II score compared the magnitude of current depression symptoms in patients with
POTS, subjects with ADHD and control subjects free of DSM-IV axis I disorders. Patients
with POTS scored as mildly depressed (4.8±8.5). Overall, BDI-II scores differed significantly
among the groups (P< 0.001). Post-hoc analysis showed a significantly higher score in patients
with POTS compared to control subjects (14.8±8.5 vs. 1.4±1.5; P<0.001), and in ADHD
subjects compared to controls (10.7±9.8 vs. 1.4±1.5; P<0.001), but there was no significant
difference between the POTS and ADHD groups (P=0.239). For patients with POTS, there
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was a significant inverse correlation between length of illness and BDI-II score (rs=−0.47,
p=0.04). There was no significant correlation of supine, upright or delta NE with BDI-II score
in the POTS group.
Prevalence of Anxiety Symptoms
The BAI compared the magnitude of current anxiety symptoms in the three groups (Figure 1
top). Patients with POTS scored as moderately anxious (22.5±9.8). Overall, BAI scores
differed significantly among the groups (P<0.001). Post-hoc analysis showed a significantly
higher score in patients with POTS compared to control subjects (1.3±1.6; P<0.001), and in
patients with POTS compared to subjects with ADHD (5.9±5.7; P<0.001), but there was no
significant difference between the ADHD and control groups (P=0.115). In the POTS group,
there was no significant correlation between length of illness and BAI score (rs =−0.40,
P=0.09). There was also no significant correlation of supine, upright or delta NE with BAI
score in the POTS subjects. The 5 BAI items scoring with highest frequency in the POTS group
compared to the other groups were heart pounding and racing (2.3±0.6), feeling dizzy and
lightheaded (1.8±0.9), numbness and tingling (1.6±0.8), feeling unable to relax (1.5±0.8) and
feeling unsteady (1.5±0.9).
The ASI compared the magnitude of current fear of anxiety-related symptoms in the three
groups (Figure 1 bottom). Overall, ASI scores differed significantly between the groups
(P=0.001). Post-hoc analysis showed a significantly higher ASI score for the POTS patients
(15.4±9.8) than the control group (4.6±4.5; P=0.001), and in subjects with ADHD (11.8±9.7)
compared to controls (P=0.031), but there was no significant difference between the POTS and
ADHD groups (P=0.504). ASI scores for the 3 groups were also compared to the published
general population normative data of 19.1±9.11 (obtained from 12 non-clinical samples
comprising >4500 participants).[18] Patients with POTS experienced a trend toward lower
anxiety sensitivity than the general population (P=0.07), while subjects with ADHD
experienced higher anxiety sensitivity than the general population (P=0.001). As expected, our
psychiatrically normal control subjects experienced significantly less anxiety sensitivity than
the general population (P<0.001).
Among POTS patients, there was a significant inverse correlation between length of illness
and ASI score (rs =−0.56, P=0.01).There was no significant correlation of supine, upright or
delta NE with ASI score in the POTS subjects.
Prevalence of Inattention Symptoms
Significant group differences were noted on all 8 CAARS-L subscales. Post-hoc analysis
showed that patients with POTS did not differ significantly from the controls for hyperactivity
(P=0.170), impulsivity (P=0.064), self-concept (P=0.196) and DSM-IV hyperactivity
(P=0.060) subscales, but both groups scored significantly lower than the ADHD group.
Patients with POTS experienced significantly more symptoms than the controls on three
CAARS-L subscales: Inattention/Memory problems (P=0.033), the CAARS-L “DSM-IV
Inattention” score (P<0.001) and the “DSM-IV ADHD” score (P=0.003) (Table 4). They also
scored significantly higher than the controls on the ADHD index (P=0.027). The ADHD group
scored significantly higher than either of the other groups on all CAARS-L subscales.
A general linear model analysis using gender, BDI score and ASI score was used to test for a
possible confounding influence by gender, current depression symptoms and current anxiety
sensitivity on inattention scores. First, using Connors DSM-IV inattention as the dependent
variable, the model showed no statistically significant effect of gender (P=0.307). There was
a statistically significant effect of BDI score (P=0.021) and ASI score (P=0.019), but group
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remained a statistically significant driver of the CAARS-L DSM-IV inattention score
(P<0.001) even when BDI and ASI scores were taken into account. Second, using CAARS-L
ADHD score as the dependent variable, the model showed no statistically significant effect of
gender (P=0.444) or ASI score (P=0.155). There was a statistically significant effect of BDI
score (P=0.005), but group remained a statistically significant driver of the CAARS-L ADHD
score (P<0.001) even when BDI score was taken into account.
In the POTS group, there were statistically significant inverse correlations between length of
illness and the following CAARS-L subscales: inattention/memory score (rs =−0.46, P=0.05),
self concept score (rs =−0.47, P=0.04), Connors DSM-IV hyperactivity score (rs =−0.53,
P=0.02), DSM-IV ADHD score (rs =−0.49, P=0.04) and ADHD index (rs =−0.52, P=0.02).
There was no significant correlation of supine, upright or delta NE with any of the CAARS-L
subscale scores in subjects with POTS.
Prevalence of ADHD Symptoms in Childhood and Adulthood
Scores on the four ABC-A subscales were compared between the three groups, and data on
inattention are presented graphically in Figure 2. There were significant overall group
differences on all subscales (attention problems in childhood: P<0.001; hyperactivity in
childhood: P<0.001; inattention over the past 6 months: P<0.001; hyperactivity over the past
6 months: P<0.001).
For inattention in childhood, post-hoc analysis showed that patients with POTS (4.8±5.4) had
significantly less childhood symptoms than ADHD subjects (20.2±7.0; P<0.001) and did not
differ significantly from control subjects (2.9±2.6; P=0.499). However, for inattention over
the past six months, patients with POTS (10.7±7.8) had significantly more symptoms than
control subjects (2.2±2.1; P<0.001), but less than ADHD subjects (16.7±7.7; P=0.021).
For hyperactivity in childhood, post-hoc analysis showed that patients with POTS (5.7±6.2)
had significantly less childhood symptoms than ADHD subjects (18.8±9.3; P<0.001) and did
not differ significantly from control subjects (2.5±2.2; P=0.281). For hyperactivity over the
past six months, patients with POTS (7.9±6.6) had significantly more symptoms than control
subjects (1.8±2.0; P=0.007), but less than ADHD subjects (13.7±7.7; P=0.015).
DISCUSSION
Several studies have reported that patients with POTS have co-morbid psychiatric symptoms,
particularly anxiety and panic disorder.[8,25] Using the Structured Clinical Interview for DSM-
IV Axis I Disorders, we found that there was no significant difference in lifetime prevalence
of major depressive disorder in patients with POTS compared to a general population sample.
[17] Patients with POTS do, however, score as mildly depressed on quantitative measures of
current depression symptoms (BDI). This may reflect living with a chronic medical illness
rather than a phenomenon specific to POTS, as medical illness is commonly associated with
an increased frequency of depressive disorders.[26–28] Certainly, patients with POTS show
limitations across multiple domains of quality of life in common with other chronic medical
illnesses including chronic obstructive pulmonary disease and heart failure.[6] Interestingly,
there is a significant reduction in depressive symptoms (BDI score) as POTS progresses. This
could reflect a reduction in symptom burden over time, or indicate the psychological adjustment
of patients to living with a chronic illness.
Patients with POTS did not experience a significantly increased lifetime prevalence of anxiety
disorders (including panic disorder) compared to a general population sample [17] or subjects
with ADHD. For current anxiety symptoms, patients with POTS scored significantly higher
than controls and ADHD subjects on the BAI, and within the moderate anxiety range. However,
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when using the cognitively focused ASI, patients with POTS did not score higher than the
general population (they actually had a trend toward a lower score), although they still scored
higher than control subjects free of axis I psychiatric disorders. This is supported by the findings
of Masuki et al. who reported that ASI scores in 14 patients with POTS were significantly
higher than in control subjects, but within the limits of published general population data.
[29]
The contrast between the BAI score (moderate anxiety) and the ASI score (comparable to the
general population) in the POTS group is striking. A major difference between the BAI and
ASI is that the former measures both somatic symptoms and subjective anxiety and panic
symptoms on factor analysis, while the latter measures sensitivity to anxiety-provoking stimuli
but not somatic symptoms. Since the orthostatic symptoms experienced by patients with POTS
are similar to the somatic criteria required for the diagnosis of panic attacks or other anxiety
disorders (e.g. palpitations), it is likely that these symptoms, rather than psychological factors,
elevate the BAI scores. Unlike subjects with panic disorder, patients with POTS show several
important clinical differences that can be used to distinguish between the two disorders. These
include predictable precipitants for the onset of somatic symptoms in subjects with POTS (e.g.
dehydration and standing) while patients with panic disorder experience repeated episodes
without a clear precipitant. Further, patients with POTS experience a significant worsening of
somatic symptoms on adoption of the upright position while subjects with panic disorder
typically do not.[30] It is therefore likely that the somatic symptoms in POTS patients do not
represent panic disorder, which is appropriately reflected in the lower ASI score. This finding
is supported by two recent studies. Masuki et al. showed that excessive increase in heart rate
in patients with POTS in response to orthostatic stress is not caused by anxiety.[29] Kharuna
collected data on anxiety and somatic symptoms in response to anxiety-provoking stimuli and
found that symptoms of POTS were distinguishable from symptoms of panic disorder.[31]
Taken together, the evidence suggests that clinically observed anxiety in patients with POTS
is caused by biological rather than psychological factors.
As POTS progresses, there is a significant decrease in ASI score but no significant change in
BAI score. This suggests that there is a diminution in cognitive anxiety symptoms with time,
but not in somatic symptoms.
Our data suggest that patients with POTS experience inattention of a magnitude that is greater
than in controls but less severe than in adult ADHD subjects. Unlike ADHD subjects, patients
with POTS did not report more inattention during childhood. This could indicate a causal role
for POTS in attention difficulties, or suggest that the two problems share common antecedents.
Moreover, this might suggest common genetic underpinnings since noradrenergic gene
products regulate sympathetic tone, cardiac output, and attention. Interestingly, there is a
significant perceived reduction in the magnitude of inattention and ADHD symptoms as POTS
progresses. This could reflect patient adaptations or an improvement in POTS symptoms over
time.
Study Limitations
First, the sample size in this study is relatively small, although it does compare favorably to
other clinical research studies in POTS. It is possible that with a much larger cohort, some of
our non-significant trends might have become significant. Second, whereas psychiatric
diagnoses were evaluated using the gold standard of a structured interview, data on attention
was collected by subjective self-rated questionnaires. While these tools have been well
validated, future studies might benefit from using more objective outcome measures.
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Conclusions
Patients with POTS do not have a higher than normal prevalence of anxiety disorders. While
they register with moderate anxiety using somatic assessment tools like the BAI, they have no
more anxiety than the general population using cognitive tools such as the ASI. Similarly,
patients with POTS do not have a significantly increased prevalence of major depression, but
do exhibit mild depressive symptoms. The main abnormality noted in patients with POTS was
difficulty with maintaining attention. These attention difficulties develop later in life, in
contrast to ADHD patients. Further investigation is required in order to identify the etiology
of these problems, and therefore guide clinicians in the selection of targeted treatments.
Supplementary Material
Refer to Web version on PubMed Central for supplementary material.
ACKNOWLEDGEMENTS
We acknowledge the professional assistance of the staff of the Vanderbilt Clinical Research Center and the research
subjects whose participation made this work possible.
FUNDING
This work was supported by National Institutes of Health (Bethesda MD, USA) grants 2P01 HL56693, RO1
NS055670, K23 RR020783, M01 RR00095 & UL1 RR024975.
References List
1. Robertson D. The epidemic of orthostatic tachycardia and orthostatic intolerance. Am.J.Med.Sci
1999;317:75–77. [PubMed: 10037110]
2. Low PA, Opfer-Gehrking TL, Textor SC, et al. Postural tachycardia syndrome (POTS). Neurology
1995;45:S19–S25. [PubMed: 7746369]
3. Raj SR, Black BK, Biaggioni I, et al. Acetylcholinesterase inhibition improves tachycardia in postural
tachycardia syndrome. Circulation 2005;111:2734–2740. [PubMed: 15911704]
4. Raj SR, Biaggioni I, Yamhure PC, et al. Renin-aldosterone paradox and perturbed blood volume
regulation underlying postural tachycardia syndrome. Circulation 2005;111:1574–1582. [PubMed:
15781744]
5. Grubb BP, Kanjwal Y, Kosinski DJ. The postural tachycardia syndrome: a concise guide to diagnosis
and management. J Cardiovasc.Electrophysiol 2006;17:108–112. [PubMed: 16426415]
6. Benrud-Larson LM, Dewar MS, Sandroni P, et al. Quality of life in patients with postural tachycardia
syndrome. Mayo Clin.Proc 2002;77:531–537. [PubMed: 12059122]
7. Harro J, Oreland L. Depression as a spreading adjustment disorder of monoaminergic neurons: a case
for primary implication of the locus coeruleus. Brain Res.Brain Res.Rev 2001;38:79–128. [PubMed:
11750928]
8. Esler M, Alvarenga M, Pier C, et al. The neuronal noradrenaline transporter, anxiety and cardiovascular
disease. J Psychopharmacol 2006;20:60–66. [PubMed: 16785272]
9. Biederman J, Spencer T. Attention-deficit/hyperactivity disorder (ADHD) as a noradrenergic disorder.
Biol.Psychiatry 1999;46:1234–1242. [PubMed: 10560028]
10. Shannon JR, Flattem NL, Jordan J, et al. Orthostatic intolerance and tachycardia associated with
norepinephrine-transporter deficiency. N.Engl.J Med 2000;342:541–549. [PubMed: 10684912]
11. Robertson D, Flattem N, Tellioglu T, et al. Familial orthostatic tachycardia due to norepinephrine
transporter deficiency. Ann.N.Y.Acad.Sci 2001;940:527–543. [PubMed: 11458707]
12. Vincent S, Bieck PR, Garland EM, et al. Clinical assessment of norepinephrine transporter blockade
through biochemical and pharmacological profiles. Circulation 2004;109:3202–3207. [PubMed:
15184278]
Raj et al. Page 8
J Neurol Neurosurg Psychiatry. Author manuscript; available in PMC 2010 March 1.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

13. Schroeder C, Tank J, Boschmann M, et al. Selective norepinephrine reuptake inhibition as a human
model of orthostatic intolerance. Circulation 2002;105:347–353. [PubMed: 11804991]
14. Diagnostic and Statistical Manual of Mental Disorders DSM-IV. American Psychiatric Association;
1994.
15. First, MB.; Gibbon, M.; Spitzer, RL.; Williams, JBW. User's Guide for the Structured Interview for
DSM–IV Axis I Disorders – Research Version (SCID-I, version 2.0, February 1996 final version).
New York: Biometrics Research; 1996.
16. Barkley, RA. Attention-Deficit Disorder: A Handbook for Diagnosis and Treatment. New York:
Guilford Press; 1998.
17. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-
IV disorders in the National Comorbidity Survey Replication. Arch.Gen.Psychiatry 2005;62:593–
602. [PubMed: 15939837]
18. Peterson, RA.; Reiss, S. Anxiety Sensitivity Index Revised test manual. Worthington, OH: IDS
Publishing Corporation; 1993.
19. Beck, AT.; Steer, RA.; Brown, GK. BDI-II manual. San Antonio: The Psychological Corporation;
1996.
20. Nezu, AM.; Ronan, GF.; Meadows, EA.; McClure, KS. Practitioner's guide to empirically based
measures of depression. Springer: 2000.
21. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety: psychometric
properties. J Consult Clin Psychol 1988;56:893–897. [PubMed: 3204199]
22. Peterson, RA.; Reiss, S. Anxiety Sensitivity Index Manual. Worthington, OH: International
Diagnostic Systems; 1992.
23. Conners CK. Rating scales in attention-deficit/hyperactivity disorder: use in assessment and treatment
monitoring. J Clin Psychiatry 1998;59:24–30. [PubMed: 9680050]
24. Barkley, RA. ADHD behavior checklist for adults; The ADHD Report. 1995. p. 16
25. Benrud-Larson LM, Sandroni P, Haythornthwaite JA, et al. Correlates of functional disability in
patients with postural tachycardia syndrome: preliminary cross-sectional findings. Health Psychol
2003;22:643–648. [PubMed: 14640863]
26. Burvill PW, Johnson GA, Jamrozik KD, et al. Prevalence of depression after stroke: the Perth
Community Stroke Study. Br.J.Psychiatry 1995;166:320–327. [PubMed: 7788123]
27. Beck DA, Koenig HG. Minor depression: a review of the literature. Int.J.Psychiatry Med
1996;26:177–209. [PubMed: 8877487]
28. Lindeman S, Hamalainen J, Isometsa E, et al. The 12-month prevalence and risk factors for major
depressive episode in Finland: representative sample of 5993 adults. Acta Psychiatr.Scand
2000;102:178–184. [PubMed: 11008852]
29. Masuki S, Eisenach JH, Johnson C, et al. Excessive Heart Rate Response to Orthostatic Stress in
Postural Tachycardia Syndrome is Not Caused by Anxiety. J Appl Physiol 2006;102:1136–1142.
30. Kanjwal Y, Kosinski D, Grubb BP. The postural orthostatic tachycardia syndrome: definitions,
diagnosis, and management. Pacing Clin.Electrophysiol 2003;26:1747–1757. [PubMed: 12877710]
31. Khurana RK. Experimental induction of panic-like symptoms in patients with postural tachycardia
syndrome. Clin Auton Res 2006;16:371–377. [PubMed: 16915526]
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Figure 1.
The Beck Anxiety Inventory (BAI) scores (top panel) and the Anxiety Sensitivity Index (ASI)
scores (bottom panel) are shown for the healthy control subjects (normals; solid black), patients
with postural tachycardia syndrome (POTS; hashed lines), patients with attention deficit
hyperactivity disorder (ADHD; open bar), and published population norms (dark gray). The
overall P value is measured using an analysis of variance (ANOVA) for the 3 study groups
(not including the published population norms) and paired P values were performed using a
post-hoc Scheffe test. Data are presented as mean ± standard error. The differences between
the 2 anxiety tools may reflect the inclusion of somatic anxiety symptoms in the BAI, whereas
the ASI scores only for cognitive anxiety.
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Figure 2.
The ADHD Behavior Checklist for Adults Inattention scores are presented for the 3 groups (as
outlined earlier) during their childhood (left) and during the last 6 months (right). The overall
P value is measured using an analysis of variance (ANOVA) for the 3 groups and paired P
values were performed using a post-hoc Scheffe test. Data are presented as mean ± standard
error.
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Table 1
Characterizing Data in Patients with POTS
Characteristic Supine Standing
Heart rate (bpm*)75±12 128±19 bpm
Blood pressure (mm Hg**)108/65±11/8 118/73±19/12 mmHg
NE (pg/ml***)267±98 962±720 pg/ml
POTS – Postural Tachycardia Syndrome. Data are presented as mean ± standard deviation.
*bpm = beats per minute
**mmHg = millimeters Mercury
***pg/ml = picograms per milliliter.
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Table 2
Demographic Data for Patients with POTS, Normal Controls and ADHD Patients
Characteristic Normals
(N = 20) POTS
(N = 21) ADHD
(N = 18) P value
Age (years) 36.6±11.5 35.9±10.9 41.8±9.1 0.117*
Female, N (%) 18 (90%) 18 (86 %) 10 (56%) 0.022**
Race/Ethnicity – Caucasian N
(%) 19 (95%) 20 (95%) 18 (100%) 0.634**
Education (years) 16.4±3.4 14.3±2.8 14.8±2.6 0.090*
POTS – Postural Tachycardia Syndrome; ADHD – Attention Deficit Hyperactivity Disorder. Data are presented as mean ± standard deviation.
*P value based on one way ANOVA assessing for difference between the groups.
**P value based on Fisher’s exact test for difference between the groups.
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Table 3
Lifetime Prevalence of Axis I Psychiatric Disorders in POTS Patients and ADHD Subjects
POTS (N=21) ADHD (N=18) Population** (N=9282)
None 8 (38.1%) 5 (25%)*
Major Depressive Disorder 4 (19.0%) 10 (50%) 1541 (16.6%)
Anxiety Disorders 7 (33.3%) 9 (45%) 1639 (28.8%, N=5692)
- Panic Disorder 1 (4.8%) 3 (15%) 436 (4.7%)
Substance abuse/dependence 2 (9.5%) 8 (40%) 1355 (14.6%)
POTS – Postural Tachycardia Syndrome; ADHD – Attention Deficit Hyperactivity Disorder.
*For ADHD subjects, no other psychiatric disorder.
**Population data from National Comorbidity Survey replication data on the lifetime prevalence of DSM-IV axis I disorders.[17]
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Table 4
CAARS-L Subscale Scores
Subscale Controls
(N=20) POTS
(N=21) ADHD
(N=18) P value*
(POTS vs.
Controls)
P value*
(POTS vs.
ADHD)
Inattention/Memory 43.4±5.4 52.3±11.1 67.5±13.2 0.033 <0.001
DSM-IV Inattention 41.1±7.4 57.7±15.8 73.8±14.5 <0.001 0.001
DSM-IV ADHD 38.1±6.0 52.6±16.1 70.4±15.5 0.003 0.001
ADHD Index 38.9±4.3 46.5±10.3 62.4±12.0 0.027 <0.001
CAARS-L – Conners’ Adult ADHD Rating Scales-Long version; POTS – Postural Tachycardia Syndrome; ADHD – Attention Deficit Hyperactivity Disorder; DSM-IV – Diagnostic and Statistical
Manual of Mental Disorders 4th Edition. Data are presented as mean ± standard deviation.
*P values based on post-hoc Scheffe multiple comparisons procedure. P values <0.05 are in bolded text.
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