American Journal of Therapeutics 20, 279–291 (2013)

A Review of the Etiology, Asssociated Comorbidities, and

Treatment of Orthostatic Hypotension

Lawrence C. Perlmuter,1 Garima Sarda,2 Vanessa Casavant,1

and Aron D. Mosnaim3*

The magnitude of increase in systolic blood pressure in response to the shift from supine to upright
posture is considered to reflect the adequacy of orthostatic regulation. Orthostatic integrity is largely
maintained by the interaction between the skeletal muscle pump, neurovascular compensation,
neurohumoral effects, and cerebral blood flow regulation. Various physiological states and disease
conditions may disrupt these mechanisms as seen in vasovagal syncope, dysautonomic orthostatic
intolerance, and postural orthostatic tachycardia syndrome. Orthostatic hypotension (OH) and
decreased cerebral blood flow are strongly related. Even subclinical OH has been associated to
different degrees with impaired cognitive function, decreased effort, reduced motivation, increased
hopelessness, and signs of attention-deficit hyperactivity disorder and dementia, diabetes mellitus,
and Parkinson disease. Furthermore, subclinical levels of inadequate blood pressure regulation in
response to orthostasis have been linked to increased depression and anxiety and intergenerational
behavioral sequelae between mother and child. Identifying causes of subclinical and clinical OH is
critical in improving quality of life for both children and older adults. A better understanding of the
underlying causes responsible for the etiology of OH could lead to a rational design of novel effective
therapeutic regimens for the treatment of this condition and associated comorbidities.

Keywords: blood pressure regulation, cerebral blood flow, cognition, panic and affective disorders,
orthostasis, orthostatic intolerance, subclinical orthostatic hypotension, treatment of orthostatic
hypotension

INTRODUCTION diagnosed as clinical OH when SBP declines at least

Orthostatic hypotension (OH), broadly defined as
a measurable drop in systolic blood pressure (SBP)
after changing from supine to upright posture, is
1
Department of Psychology, Rosalind Franklin University of
Medicine and Science, North Chicago, IL; 2Chicago Medical
School, Rosalind Franklin University of Medicine and Science,
North Chicago, IL; and 3Department of Cellular and Molecular
Pharmacology, Chicago Medical School, Rosalind Franklin Uni-
versity of Medicine and Science, North Chicago, IL.
The authors have no conflicts of interest to declare.
*Address for correspondence: Professor, Department of Cellular
and Molecular Pharmacology, Chicago Medical School, Rosalind
Franklin University of Medicine and Science, 3333 Green Bay Rd,
North Chicago, IL 60064. E-mail: aron.mosnaim@rosalindfranklin.edu
1075–2765 Ó 2013 Lippincott Williams & Wilkins
20 mm Hg within a minute of standing. This change
may be accompanied by a decrease in diastolic blood
pressure (DBP) of about 10 mm Hg.1 Similarly, to
many other pathological processes such as prediabetes
and glucose intolerance, there are likely to be subclinical
patterns of OH expression, resulting in measurable
sequelae.
Orthostatic intolerance (OI), that is, symptomatic
changes associated with orthostasis, widely viewed as
a disorder of the autonomic nervous system, affects
more women than men with a ratio of at least 4:1 and
usually starts under the age of 35 years. It occurs when
an individual moves from a supine to an upright posi-
tion, as standing up is a fundamental stressor requiring
rapid and effective circulatory and neurologic compen-
sation to maintain blood pressure (BP), cerebral blood
flow (CBF), and consciousness.2 Individuals suffering
www.americantherapeutics.com
280 Perlmuter et al

from OI exhibit a deficit in the basic mechanisms that
compensate for the above changes; these deficits seem to
be related to alterations in the “normal” physiological
interplay between blood volume control, the cardiovas-
cular system, the autonomic nervous system, and local
circulatory mechanisms responsible for regulating the
functioning of these basic biological processes. Response
to a subclinical (,20 mm Hg change) reduction in SBP
may vary from one of little relevance to the onset of
symptoms ranging in severity from lightheadedness to
confusion, dizziness, or even syncope.2–4 Subclinical
changes in OH may be manifested in a variety of
behavioral and emotional sequelae that may not be
innocuous.5
OH is an increasingly important topic in the bio-
medical and psychological fields as certain medica-
tions, particularly agents routinely used to control
high BP and diabetes mellitus, increase one’s risk of
OH. Furthermore, OH is commonly associated with
other frequent medical and behavioral conditions
such as depression and anxiety.3 The successful treat-
ment of patients with OH is a challenge faced by
many clinicians due to the variety of its underlying
causes, symptoms, side effects of drug, and associated
comorbidities, which will be discussed in detail below
(Tables 1–3).18
A primary focus of this article is to discuss whether
a seemingly minor or asymptomatic response to an ortho-
static challenge can be considered benign with respect to
the “usual” outcomes of OH. There is evidence indicating
that a measurable but asymptomatic response to OH
may be associated with a variety of negative behavioral
and affective consequences. Thus, this article will also
review the autonomic, neurohumoral, and cardiovascular
mechanisms associated with orthostasis; examine the re-
lationships between subclinical OH and cognition and
affective disorders; and briefly identify treatment modal-
ities and clinical implications of subclinical OI.
We have already published parts of this article,
including Figure 1 (see Perlmuter et al19). In the pres-
ent submission, we have, among other information,
added new Tables 1–3 and a discussion on the current
treatment of OH.
MECHANISM OF ORTHOSTASIS
Heart function, neurovascular compensation, selective
release of neurotransmitters and hormones, and CBF
regulation are primary processes responsible for main-
taining normal orthostatic blood distribution.2 In
assuming an upright posture, about 500 to 700 mL of
blood is redistributed. This may produce pooling in the
lower extremities, splanchnic bed, and pulmonary cir-
culation, resulting in decreased venous return to the
heart and decreased cardiac output,3 thus activating
a skeletal muscle pump that functions to force blood
from the legs and gluteal muscles to the heart through
the venous system and thus increasing the venous
return pressure in the dependent limbs.2 The neurovas-
cular adjustments, initiated by the arterial baroreceptor
reflex, include pressure-sensing areas in the carotid
sinus, intima of the aortic arch, and heart chambers.
The ensuing significant drop in BP triggers an increase
in the firing of the arterial baroreceptors, ultimately lead-
ing to norepinephrine (NE) release, alpha-adrenergic
receptor stimulation, and vasoconstriction6 and leading
to a rapid change in lower extremities and splanchnic
beds vessel tone enhancing venous emptying.4 Under
“normal physiological” conditions, vasoconstriction in
the periphery causes blood to shift toward the central
venous system increasing blood flow into the left ven-
tricle. The baroreceptor reflex, along with complex
events involving muscle sensors, high- and low-pressure
receptors, and changes in circulating catecholamine lev-
els cause the heart rate to increase in response to

Table 1. Neurogenic causes of autonomic dysfunction and OH4,6–13

Neurogenic Causes of OH (Partial List, in Alphabetical Order)

Primary Secondary

Autonomic neuropathy More frequent: Less frequent:

Dementia with Lewy Amyloidosis Some enzyme deficiencies: aromatic L-amino decarboxylase,
body dopamine beta-hydroxylase, monoamine oxidase
Multiple system atrophy Diabetes mellitus Human immunodeficiency virus
PD Familial dysautonomia Holmes-Adie syndrome
POTS Paraneoplastic Nerve growth factor deficiency and some neurotoxins
syndromes
Pure autonomic failure Stroke Pernicious anemia, porphyria, transverse myelitis

American Journal of Therapeutics (2013) 20(3) www.americantherapeutics.com

Orthostatic Hypotension 281

Table 2. Drugs that may cause OH6,13–16 orthostasis.4 Vasopressin release from the posterior
pituitary in response to minimal changes in blood vol-
Pharmacologic Agents (Partial List, Alphabetical Order) ume is initiated by stimulation of the atrial stretch
Alcohol receptors and arterial baroreceptors.6 Figure 1 pro-
Antidepressant drugs vides an overview of the orthostasis mechanisms.
Selective serotonin receptor reuptake inhibitors, With these defense mechanisms, cerebral regulation,
monoamine oxidase inhibitors, tricyclic estimated to occur within seconds after orthostasis, is
antidepressants designed to maintain CBF in response to the change
Antihypertensive drugs: guanadrel, reserpine from supine to standing. Cerebral regulation protects
Antiparkinsonism drugs: levodopa, pramipexole, the brain by causing increased or decreased cerebral
ropinirole resistance in response to high or low BP, respectively.
Antipsychotic drugs: olanzapine, risperidone
Beta-blocker drugs: propranolol
Diuretic drugs: hydrochlorothiazide, furosemide
CAUSES AND CONTRIBUTORS TO
Vaccines: Gardasil THE DEVELOPMENT OF OH
Hypoglycemic drugs: insulin
There are a variety of medical conditions, of both neu-
Muscle relaxant drugs: tizanidine
rogenic and nonneurogenic origin, with widely differ-
Narcotic analgesic drugs: morphine
ent etiologies and associated pathophysiologies that
Sedatives
have been shown to increase the risk for both subclin-
Vasodilator drugs: hydralazine, nitroglycerin
ical and clinical OH. Some conditions are typically
Calcium channel blockers
chronic or nonreversible such as cardiac failure, diabe-
tes mellitus, Parkinson disease (PD), adrenal insuffi-
ciency, pure autonomic failure, and multiple system
orthostasis.6 The normal immediate physiological atrophy,3 whereas others are acute or reversible such
response to hypotension is tachycardia (heart rate . as dehydration, certain medications, or deconditioning.
100 beats/minute).20,21 Neurogenic causes of OH (Table 1) could be of pri-
Hormonal response to orthostasis includes changes
mary or secondary origin.4,22,23 Side effects arising from
in the renin–angiotensin–aldosterone system, enhanc-
the use of certain drugs (Table 2) include autonomic
ing sodium and water retention ultimately increasing
dysfunction, which can also result in OH. These agents
blood volume, and the release of other peptides and
can be classified as secondary neurogenic causes4 and
active neuroamines such as vasopressin and epineph-
may act by interrupting autonomic function directly
rine (EPI) whose effects are seen within minutes of
(beta-blocking agents) or they may produce a neuropa-
thy, resulting in OH or syncope exacerbation.
Table 3. Nonneurogenic causes of autonomic dysfunc- Nonneurogenic causes of autonomic dysfunction
tion and OH3,17 (Table 3) associated with OH may be cardiovascular,
Nonneurogenic Causes of OH (Partial List, Alphabetical
endocrine, or renal in origin. OH may also result from
Order) alterations in venous pooling and reduced intravascu-
lar volume.3
Cardiac pump failure Deficient blood volume In addition, there is evidence that relatively tall in-
Aortic stenosis Adrenal insufficiency dividuals with poorly developed musculature or
Bradyarrhythmia/ Burns those suffering from anorexia nervosa may also
tachyarrhythmia exhibit inadequate postural adjustment. Furthermore,
Constrictive Dehydration OH is often seen during pregnancy or after various
pericarditis nonrelated events such as rigorous physical exertion,
Myocardial infarction Diabetes mellitus space flight, prolonged bed rest, gastrectomy, and
Myocarditis Heavy lifting, hemorrhage, marijuana use.
renal salt loss
Last, and very importantly, OH is associated with
Venous pooling aging, partly because the autonomic nervous system
Alcohol, postprandial splanchnic expansion, may become less functional.6 The effects of aging on
prolonged standing/lying, sepsis, and vigorous
the autonomic nervous system and the mechanism of
exercise
orthostasis will be discussed later.
www.americantherapeutics.com American Journal of Therapeutics (2013) 20(3)
282
FIGURE 1. The figure has been already published in Perlmuter et al19 and is included “with kind permission of Springer
Business Media.”
MECHANISM OF OH AND OI
A number of physiological changes and seemingly
unrelated medical conditions associated with increas-
ing age, such as abnormal sympathetic activity, altered
hormone levels, and denervation, impact the ability of
the body to compensate for an orthostatic challenge
and may lead to the development of OI and OH.
In the younger population, OH has been found to be
associated with diminished sympathetic outflow and
relative deficits in the regulation of vasoconstrictive
mechanisms; individuals who developed OH after
standing generally exhibited a decrease in circulating
NE levels and systemic arterial pressure and reduced
pulse rate. In contrast, these 3 measures increased in
the control group used for comparison, suggesting that
the observed decrease in NE levels reflects a with-
drawal of sympathetic nervous tone to the vasculature
American Journal of Therapeutics (2013) 20(3)
Perlmuter et al
thus causing hypotension during a vasodepressor
reaction or vasovagal syncope, one of the main condi-
tions associated with OH.24
A literature review shows increased circulating EPI
levels in individuals with OI.25 Young subjects experi-
encing orthostatic dysregulation and reductions in
mean arterial pressure exhibited a 2- to 8-fold increase
in circulating levels of this amine. It is unclear whether
altered EPI levels are a cause or the result of OH; how-
ever, it has been suggested that EPI contributes to OI
by causing peripheral vasodilation and activation of
cardiac vagal fibers.25
The mechanism of orthostasis is also disrupted in
individuals presenting primary chronic autonomic
failure such as pure autonomic failure, multiple system
atrophy, and autonomic failure associated with PD.
These patients often express reduced sympathetic
activity during orthostasis, so their reflexive increases
www.americantherapeutics.com
Orthostatic Hypotension
in sympathetic action are not sufficient, and fail to
compensate for the decreased venous return to the
heart that occurs upon standing.26 Although the mech-
anism linking OH and most of the conditions listed
above are not yet well known, the etiology and path-
ophysiology of PD is reasonably well understood and
includes a degeneration of nigrostriatal dopaminergic
neurons, preventing proper regulation of basal ganglia
outflow.27 In addition, evidence suggests that patients
with PD and OH have diffuse sympathetic innervation
throughout the left ventricle of the heart that could
potentially cause or contribute to the OH.26
There is an increase in OH prevalence from 15% to
26% with advancing age (65–69 to 85 years or older),3
resulting in more falls, partly due to a decline in auto-
nomic function.6,28 Because the baroreceptor response be-
comes impaired with age, upon standing, older patients
may experience a large decrease in blood volume along
with inadequate cardiovascular compensation.3 Aging is
also associated with generalized neuronal loss, fewer beta
receptors with decreased functionality, and a weaker
response to catecholamines, all of which are factors con-
tributing to the development of OH.6
TYPES OF OI
Vasovagal syncope, dysautonomic OI, and postural
orthostatic tachycardia syndrome (POTS) reflect 3 main
types of OI. Acute OI typically presents as syncope.2
Although the etiology of syncope is not always of
orthostatic origin,21 about 90% of this condition in chil-
dren could be considered vasovagal syncope (classic
simple faint, neurogenic syncope, or neurally mediated
syncope).2,4 Furthermore, this condition is observed
most commonly in young people whose symptoms
include lightheadedness, weakness, pallor, blurred
vision, and impaired hearing.4
Vasovagal syncope
Whereas the pathophysiology of this condition is not
well understood, it is generally accepted that the
mechanism of syncope includes a “paradoxical” left
ventricular stretch reflex.2 Upon standing, the baror-
eceptors detect a decrease in BP due to venous pool-
ing followed by a fall in ventricular volume and an
increase in efferent sympathetic activity. This
increase in sympathetic tone, along with an under-
filled ventricle, activates ventricular afferents, which
then stimulate vagal tone and decrease sympathetic
activity leading to hypotension, bradycardia, and
fainting.
However, some research disputes that an increase in
sympathetic tone occurs before syncope. A study using
www.americantherapeutics.com
283
tilt testing found that muscle sympathetic nerve activity
increased less in those who repeatedly suffer from vaso-
vagal syncope and it fully ceased with fainting. In addi-
tion, these investigators reported that individuals with
vasovagal syncope exhibited an attenuation of the max-
imal increase in circulating NE and less effective sym-
pathetic baroreflex responses compared with controls. It
was strongly suggested that several different peripheral
and/or central mechanisms may be involved in the var-
ious sympathetic responses to orthostasis and may ulti-
mately lead to fainting.29 Other possible explanations
for the occurrence of syncope include a large increase
in the bioavailability of EPI and renin and a decrease in
vasopressin and/or changes in the circulating levels of
various vasoactive substances such as serotonin, NE,
neuropeptide Y, and substance P.24 Thus, abnormalities
in the central nervous system, baroreflex functioning,
peripheral mechanisms, and/or amount of neurotrans-
mitter may lead to OI.
Dysautonomic OI
Patients with this condition, which is rarely seen in
children,2 may also present with OH. In this condition,
which may be drug induced or result from autonomic
failure,2 the normal baroreflex response to hypoten-
sion or tachycardia does not occur.
POTS, also known as chronic OI or hyperadrenergic
OH, is the most frequent cause for medical referral in
adults with OH. Symptoms include upright tachycardia
and signs of OI. In contrast to patients suffering from
vasovagal syncope, POTS patients face consequences of
their condition on a daily basis21; postural orthostatic
tachycardia; POTS has also been observed in children
with chronic fatigue syndrome, which has been shown
as the most damaging form of this condition in pediat-
ric patients.30
Postural orthostatic tachycardia syndrome
Individuals suffering from this disease usually have
an abnormal amount of blood pooling in their legs,
leading to OI. This observation suggests that patients’
inability to properly respond to orthostasis may
result from inadequate innervation of the veins
and/or defective venoconstriction.21 These authors
found some evidence that POTS results from dener-
vation of the legs, a condition also known as the long
tract syndrome, and that the arms are also involved
as these patients tend to present decreased resistance
in the forearm at rest. They suggested that a wide-
spread vasoconstrictor defect is present in POTS that
is exacerbated during an orthostatic challenge and
suggested that this deficit could account for altered
venous filling and the inappropriate vasoconstriction
that occurs in response to the orthostatic challenge.
American Journal of Therapeutics (2013) 20(3)
284
Additional supporting studies, along with a number
of different theories, suggest that local vasoconstric-
tive, mechanical, central neurologic, or genetic factors
could be responsible for the observed vasoconstric-
tive defect.30
A faulty muscle pump could also partly account for
the pathophysiology of POTS. Although it functions
adequately in most individuals with this condition,
muscle pump activity is insufficient in patients exhib-
iting decreased blood flow and reduced venous return,
especially in the legs.21 One-way venous valves nor-
mally increase the efficiency of the muscle pump by
preventing blood flow from flowing back into the legs.
Therefore, one may suggest that POTS patients with
decreased flow may have dysfunctional venous valves
or even lack valves from birth, resulting in genetically
determined OI.21
Most POTS patients also suffer from peripheral auto-
nomic autoimmune neuropathy that may help to
explain the etiology of their OI.21 Although it mostly
affects the legs, this neuropathy damages peripheral
vasculature and leads to alpha-1 adrenergic receptor
denervation hypersensitivity. These patients express
an increased adrenergic tone at rest and an increased
postganglionic sympathetic response to orthostasis, yet
their plasma catecholamine levels remain normal or are
only slightly higher when standing.2,21 Decreased beta-
1 adrenergic receptor sensitivity and alpha-1 adrenergic
receptor supersensitivity have been suggested as addi-
tional explanations for the abnormal pooling or swell-
ing in the dependent limbs of those with POTS.2
Individuals with POTS may also present with hyper-
adrenergic neuropathy and consequently an intact or
exaggerated autonomic reflex response. These individ-
uals show increased NE levels when upright.21 Muta-
tions in the NE transporter protein, which could lead to
irregular vascular structure and/or muscle tone result-
ing in abnormal vascular regulation and altered veno-
constriction, may play a role in the development of
POTS and OI.21
In summary, studies of vasovagal syncope, dysau-
tonomic OI, and POTS provide some insight into the
mechanisms that may be involved in the development
of OH. Altered sympathetic tone or response, changes
in neurotransmitter levels, drug effects, autonomic fail-
ure, impaired innervation, vasoconstrictive defect,
faulty muscle pump, autoimmune neuropathy, irregu-
lar receptor sensitivity, hyperadrenergic neuropathy,
and NE transporter protein deficiency are among the
reasons for the OI associated with the above condi-
tions. Less is known regarding the underlying pro-
cesses causing vasovagal syncope, dysautonomic OI,
and POTS and consequently of the relationship of
these conditions to OH and OI.
American Journal of Therapeutics (2013) 20(3)
Perlmuter et al
CEREBRAL BLOOD FLOW
CBF regulation is one of the ways the body compen-
sates for orthostasis, as there is evidence for a strong
relationship between orthostatic stress and a disruption
in CBF, leading to cerebral hypoperfusion. In response
to changes in CBF caused by the orthostatic stress head
upright tilt syncope, patients with recurrent syncope
experienced vasoconstriction in the middle cerebral
artery, instead of the normal vasodilation occurring
when blood flow to the brain is reduced.31 These find-
ings suggested that as a result of an abnormal barore-
ceptor response, CBF regulation is disrupted, resulting
in vasovagal syncope.31 Research on OI indicates that
the symptoms of hypotension seen during tilt testing are
associated with a decrease in CBF and an increase in
cerebrovascular resistance. Furthermore, neurocognitive
defects associated with chronic OI seem to be correlated
with cerebral malperfusion in patients with POTS.21
Recent evidence shows a possible association
between OH and changes in CBF, with flow levels
significantly increased in the cerebellar vermis and
visual cortical areas of the brain of healthy individuals
during orthostatic stress. These areas, which are
important for motor coordination and control over
voluntary standing, would be especially relevant to
balance and falls in the elderly. CBF in the frontal
and parietal cortices tends to decrease as subjects
move from a supine to a standing position.32 Similar
results had been reported using a transcranial doppler
ultrasound flow in patients with OH.33 These authors33
also found that postural cerebral hypoperfusion in
patients with OH was localized to the frontal areas
of the brain as a result of an inadequate vascular
response during orthostasis.
Current literature on brain perfusion and cognitive
performance indicates that BP in individuals with
chronic hypotension is inadequate at maintaining perfu-
sion of a large part of the brain despite autoregulation.34
Consequently, blood flow of the middle cerebral artery,
in particular, is substantially reduced in hypotensive
subjects. To maintain cognition, the middle cerebral
artery supplies regions that are directly related to sub-
cortical areas and large fractions of the frontal and pari-
etal lobes and the temporal lobes. These authors34
suggest that chronically low BP is accompanied by
decreased cognitive performance, especially concerning
attention and memory tasks.
Not only does brain hypoperfusion cause temporary
symptoms associated with OH but also can result in
lesions to periventricular white matter, basal ganglia,
and hippocampus with lasting effects.35 As a result of
decreased blood flow, the supply of glucose and
www.americantherapeutics.com
Orthostatic Hypotension
oxygen to the brain can no longer support normal cell
metabolism, resulting in ischemia-associated injuries. In
the elderly, one of the most important reasons for cere-
bral hypoperfusion is OH. Additionally, their blood
vessels become narrow, calcified, elongated, and tortu-
ous, thereby preventing effective vasodilation and cur-
tailing cerebral perfusion, especially in periventricular
white matter, basal ganglia, hippocampus, and regions
of the brain that have more than one source of blood
supply. When these areas develop lesions, the prefrontal–
basal ganglia circuits may become disrupted impairing
cognition and memory, thereby increasing the likeli-
hood of vascular dementia.35
OH AND COGNITION
The relationship between cognition and BP regulation
has been the subject of extensive research; however,
the nature, mechanism, and extent of their association
need further investigations. Although most studies
have found a correlation between OH and cognitive
decline, variability of reported findings may reflect,
among other factors, the difficulties in finding suitable
patient populations and comparable controls and com-
paring results obtained from various cognitive tests.
Although some authors36 have proposed a curvilin-
ear relationship between OH and cognition within
a small maximal range, others have suggested that
the changes in cognitive functioning observed after
postural changes are rather unpredictable. In a 2½-year
follow-up study of prospective memory among elderly
with and without OH, this condition was not associ-
ated with significant alterations in cognitive perfor-
mance.37 However, the cognitive test data was based
on scores from the Mini Mental Status Exam in which
a difference of a single point determines the level of
cognitive functioning. One author38 reported a lack of
correlation between neurocognitive functioning and
cognitive performances with postural change; how-
ever, greatly increased supine systolic pressure was
associated with reduced executive cognitive function.
Even so, cognitive impairments are widely accepted
as recognizable patterns and symptoms of OH.39 Sig-
nificantly, impaired speed, attention, and executive
functioning among patients with pure autonomic fail-
ure suggest that these findings may be consequences
of cerebral hypoperfusion via systemic hypotension.40
Román35 similarly credited hypoperfusion to the risk
of cognitive impairments among elderly with OH,
elaborating that anatomical changes in the aging brain
leave certain regions, such as the basal ganglia and
hippocampus more susceptible to ischemic hypoperfu-
sion that in turn can impact cognitive and memory
www.americantherapeutics.com
285
functioning. In addition to reduced CBF, a decrease
in the rate of neurotransmitter synthesis, and receptor
density, the elderly have an increased likelihood of
brain tissue and neuronal loss, formation of neurofi-
brillary tangles, and an increased size of the ven-
tricles.41 In a study of asymptomatic community
dwelling elderly, participants with poor orthostatic
BP regulation exhibited significantly inferior scores
on measures of neurobehavioral functioning and activ-
ities of daily living relative to normotensive partici-
pants.42 Whereas some elderly patients with either
postural hypotension or hypertension had more
advanced leukoaraiosis and/or periventricular hyper-
intensities,42 others showed leukoaraiosis-associated
cognitive and motor impairments43 and poor progno-
sis among individuals with cerebrovascular disease.44
Although the majority of literature focuses on clinical
OH and cognitive impairments, there are a few studies
that have specifically examined the effect of subclinical
levels of OH. In a controlled study involving 181 type 2
diabetes mellitus patients and 43 sex-matched, age-
comparable, drug-free individuals, the presence of
asymptomatic subclinical OH was positively correlated
with diminished cognitive performance and a decreased
systolic response to orthostatic challenge was consis-
tently associated with poorer learning, memory, and
slower reaction times in patients and controls.5
Among children, less effective BP regulation in
response to orthostatic challenge was reflective of poorer
performances on several neuropsychological measures.45
Along with SBP regulation, pulse pressure can also be
used as an indicator of OH. Because pulse pressure is the
difference between SBP and DBP, a smaller pulse pres-
sure increase is indicative of poorer compensation after
an orthostatic challenge.45 Thus, smaller increases in SBP
or pulse pressure after orthostasis were predictive of
decreased verbal memory scores or poor prospective
memory, respectively.45 On the other hand, improved
BP compensation after a postural change (increases in
SBP, even subclinical) was associated with enhanced
cognitive execution.45 A controlled study with preschool
aged Hispanic Americans also showed improved perfor-
mance on language and cognitive tests as SBP increased
upon standing.46 In a double-blind study, teachers’ year-
long evaluations of effort in 45 students positively corre-
lated with adequate BP regulation.47 Similarly, children
with untreated orthostatic dysregulation showed signif-
icantly smaller amplitudes in early, late, and total con-
tingent negative variation, which is a measurement
associated with cognitive processes and is used to assess
attention and motivation/hypodynamia.48
Patients diagnosed with various types of dementia
showed an increased OH prevalence, most likely due
to impaired autonomic function.49 OH was reported in
American Journal of Therapeutics (2013) 20(3)
286
69% of Lewy body patients with dementia and in 42%
of Alzheimer disease dementia patients compared with
only 13% of controls.50 Elderly women who developed
dementia during a 5-year longitudinal study tended to
have a larger drop in BP during an orthostatic challenge
and a lower state of active awareness compared with
participants who remained dementia free.51
A study showing OH contributing to significant
declines in sustained attention, visual memory, and
visual perception led to suggestions that this condition
might also contribute to cognitive decline among
patients with PD who also suffer from dementia.52 In
a related work, it was reported that OH, frequent among
PD patients with dementia, exhibited exacerbated atten-
tion problem.53 Comparing brain perfusion among PD
patients with or without OH suggests that bilateral
activity in the anterior cingulate gyrus played a role in
autonomic failure, as this brain area was significantly
less perfused in the participants with OH.54 It is gener-
ally accepted that reduced CBF may account for the
increased prevalence of OH among patients with
dementia. Furthermore, it has been suggested that the
neurocardiovascular instability caused by hypotension
commonly observed among dementia patients may
exacerbate their cognitive decline.55
Various reports point to potential connections
between areas of the brain, cognitive functioning, and
OH. Dushek et al34 suggested that hypotension affects
cortical activity via the cardiovascular system and the
prefrontal cortex, a connection that can be further under-
stood after reviewing neurological structures involved
in the regulation of the autonomic nervous system. Mat-
sui et al54 observed that the autonomic nervous system
is controlled by the hypothalamus, which in turn is con-
trolled by limbic structures including the cingulate
gyrus, and that the degeneration of the anterior cingu-
lated gyrus provokes hypothalamic dysfunction, which
projects to various cortical and subcortical structures
contributing to autonomic effects evident in various dis-
orders. Our results, obtained from well-validated cogni-
tive screening tests in a group of young (3 and 4 year
old) Hispanic American children, show that measures of
concept skills and language competence are in direct
relation to the strength of the SBP response to an ortho-
static challenge (L.C.P., et al, unpublished data, 2013).
OH AND AFFECTIVE DISORDERS
Depression and anxiety disorders have been strongly
associated with cardiovascular morbidity and impaired
autonomic functioning.56,57 Depression is associated
with altered autonomic regulation as evidenced by
reduced heart rate variability.56,58 Mood states, such
American Journal of Therapeutics (2013) 20(3)
Perlmuter et al
as increased depressive symptoms, have been found
to be related to greater vascular resistance, and even
subclinical levels of depression may have deleterious
effects on cardiovascular functioning.57
Children with subclinical BP dysregulation or
a decreased pulse pressure in response to orthostatic
challenge exhibited elevated anxiety and/or increased
depression, poor mood, lowered self-esteem, and per-
ceived lack of competence.45 Additionally, reports of
depressive states were negatively correlated with SBP
changes after orthostasis.45 In a similar study, failure to
maintain BP regulation upon postural change predicted
depression scores among adults. Association of OI with
significantly elevated scores on depression tests and
activities of daily living have been reported.5,59
Recent studies have shed some light on the nature of
orthostatic responses to a variety of anxiety disorders
including panic disorder, general anxiety, and social
phobias. In a preliminary study, Lorenz et al60 reported
a positive relationship between mother and child anxi-
ety scores and BP regulation in response to orthostatic
challenge. That is, as mother’s trait anxiety increased,
children exhibited poorer SBP responses to orthostasis.
This is the first study to suggest that anxiety not only is
associated with poor SBP regulation but also has an
intergenerational impact on nonclinical samples.
In comparison to anxiety patients, panic disorder
patients showed a greater DBP overshoot immediately
after standing, which supports the suggestion of an
increased sympathetic baroreceptor function, which
in turn can have significant negative health effects.61
Using an isometric handgrip test, which measures
strength and effort while raising BP and heart rate,
Yeragani et al62 measured BP during postural change.
Results suggested that the increase in adrenergic tone
among panic disorder patients was significantly ele-
vated compared with controls. In related studies, a sig-
nificantly higher heart rate has been reported in
response to an orthostatic challenge among panic dis-
order patients compared with healthy controls and
social phobics. This latter group of individuals had
increased circulating NE levels during the supine
and standing position when compared with controls
and panic disorder patients,63 further emphasizing
previous suggestions that BP regulation plays signifi-
cant differential roles in the response to orthostasis
among the spectrum of anxiety disorders.
Presence of OH is associated with autonomic changes
that may be reflected as dizziness, palpitations, anxiety,
fear, and catastrophic cognitions, a constellation of
symptoms referred to as the “multiplex model of panic
attack.” In patients suffering from orthostatic panic,
a recently described phenomenon observed primarily
in Southeastern Asian refugees, catastrophic cognitions
www.americantherapeutics.com
Orthostatic Hypotension
occurring after a change from supine to standing posi-
tion include fear of a “heart attack, a weak heart, dan-
gerous body weakness, increased BP that will snap the
cerebral blood vessels, an invasion of the skin pores by
an exterior wind, and excessive tension on the brain
nerves that may cause snapping.” In addition to cul-
tural-specific somatic worries, participants also experi-
enced orthostatic-induced flashbacks.64,65
Changes in CBF and circulating NE levels may con-
tribute to, and help explain, the association between
affect (including anxiety and depression) and BP regu-
lation. There is some evidence supporting a relationship
between the presence of panic disorder and regulation
of blood flow to the brain; when compared with healthy
controls, panic disorder patients, either of recent onset
or in full remission, exhibited decreased blood velocity
in the middle cerebral artery and presented with sudden
drops in CBF after a change in position from supine to
standing. When compared with controls or unipolar
depressed patients, circulating supine NE levels were
lower in bipolar patients. However, after an orthostatic
challenge, amine levels increased significantly for both
depressed patient groups (close to 100% over controls).66
Related reports showed that depressed and panic disor-
der individuals as having significantly increased circulat-
ing NE levels during supine and standing position,
whereas bipolar patients had significantly lower amine
levels during supine posture.67 Higher plasma NE levels
were positively related to self-reported anxiety,68 and
combat veterans have been described as displaying
“hemodynamic abnormalities” of the NE system.69
Many have suggested an important link between NE
and affective disorders and BP regulation, but other neu-
rotransmitters such as serotonin and acetylcholine may
also play a significant role.70
It is generally accepted that there is an association of
OH with the presence of a variety of behavioral and
emotional disorders. Attention-deficit hyperactive disor-
der, presenting with impulsive behavior, lack of concen-
tration, and extreme hyperactivity, was recently shown
to be associated with a poorer SBP regulation in a non-
clinical sample.71 In another study with a nonclinical
sample, increased hopelessness was related to subclini-
cal levels of change in SBP in response to an orthostatic
challenge.72 In at least one study, birth weight was
shown to predict subclinical OH. As birth weight
increased from 4 to 10 lb, the effectiveness of the SBP
response to an orthostatic challenge also increased.73
After reviewing the research literature, one could sug-
gest that early identification of factors that may alter BP
regulation, such as birth weight, may help in monitoring
for signs of various affect problems. Even in nonclinical
samples, when OH is subclinical, decreased mood, poor
self-esteem, decreased self-efficacy, somatic complaints,
www.americantherapeutics.com
287
worry, fatigue, and pessimism have all been linked to
orthostatic BP inadequacy in response to orthostatic
challenge among children and adults across various cul-
tures and seemingly generate measurable sequelae, irre-
spective of the presence of comorbidities.
TREATMENT
Extensive basic and clinical research has yet to identify
reliable biological markers to assess the presence and/or
severity of OH. Thus, the diagnostic criteria for this
condition continue to be mostly based on the symp-
toms associated with OI, information obtained from
patient’s physical examination, and medical history
(Tables 1–3), clearly hindering the practitioner’s ability
to optimize and follow the patient’s response to treat-
ment protocols and holding back the discovery and
implementation of new therapeutic modalities. As it
could be expected, various classes of endogenous
and exogenous chemical substances with significantly
distinct biological activity and widely different chem-
ical structure have been proposed as possible media-
tors in the etiology and/or pathophysiology of OH
and in the comorbidities associated with this condi-
tion. They include, but are not limited to, various mono-
amine neurotransmitters, hormones, nitrate, and other
drugs regulating BP (Table 2). Prognosis for the treat-
ment of OH varies greatly as it depends on successfully
addressing the underlying causes and associated factors
responsible for this multifaceted condition.3 Patients
with OH respond best to pharmacotherapy, including
the widely used mineralocorticoids such as fludrocorti-
sone acetate, which expand plasma volume by retaining
salt and water at the expense of increasing potassium
excretion. It may also work by enhancing alpha-1
adrenergic receptor response and blocking vasodilata-
tion.2 This class of drugs should be used cautiously,
particularly in older patients, because they can be
poorly tolerated and cause excessive fluid retention. In
one such study, elderly individuals diagnosed with
hypotensive disorders, including OH, experienced side
effects of long-term usage of fludrocortisones such as
hypertension, cardiac failure, edema, and depression.74
Alpha-1 adrenergic receptor agents, such as mido-
drine, are also used to treat OI, specifically vasovagal
syncope and POTS.2 These drugs are specific arteriolar
constrictors used to help prevent pooling upon stand-
ing via increased venous vasomotor tone.75 They sig-
nificantly increase standing SBP, reduce feelings of
dizziness and lightheadedness, and limit occurrence
of syncope.76 Midodrine, which is effective for condi-
tions characterized by a failure in sympathetic release
of NE at the alpha-1 adrenergic receptor, is however
American Journal of Therapeutics (2013) 20(3)
288
contraindicated if the patient has a serious heart dis-
ease, acute renal disease, pheochromocytoma, thyro-
toxicosis, heart blocks, or urinary retention.2,3
Some clinicians recommend the use of selective beta-
adrenergic receptor blocking agents for the treatment of
OH, particularly for those patients suffering from vaso-
vagal syncope, as they blunt the action of catechol-
amines.2 However, in recent studies, these drugs have
been shown ineffective for younger vasovagal syncope
patients and of only limited benefits for older patients
with this condition.77 Although they may be useful for
treating some types of syncope by decreasing the release
of EPI and renin, beta-blockers may not help patients
with POTS who have already maximized their sympa-
thetic compensatory mechanisms.2,4
Additional pharmacological treatment options for
OH include the use of dihydroergotamine (a potent
vasoconstrictor that improves venous return without
increasing arterial pressure), erythropoietin (erythropoi-
esis-stimulating hormone that increases hemoglobin
synthesis and blood volume), and octreotide (a somato-
statin analogue and peptide release inhibitor that causes
vasoconstriction and improves cardiac output). Pyridos-
tigmine, an acetylcholinesterase inhibitor, is also an
increasingly accepted option as it improves sympathetic
ganglionic transmission and thereby enhances vascular
tone without exacerbating supine hypertension.78 At
least one anecdotal report79 suggests that glycyrrhizic
acid–containing preparations (licorice) may relieve
symptoms of postural hypotension caused by diabetic
autonomic neuropathy. Additionally, pacemakers can
be used to treat OH in patients with bradycardia.3
Recent reports indicate an association between estro-
gen replacement therapy and efficient orthostatic BP
regulation. The increased SBP exhibited by women on
estrogen replacement therapy in response to orthosta-
sis is correlated with improved cellular integrity and
central nervous system activity. Estrogen replacement
therapy was also indicated as beneficial because it in-
creases CBF, alleviates depressive symptoms, im-
proves mood, and could be a possible treatment for
cognitive impairments80; however, its use is limited
as estrogens are mitogenic for benign and cancerous
breast epithelial cells.81
Non–drug therapies recommended for OH treat-
ment include the maintenance of appropriate fluid
intake and increased salt consumption if the patient
is not hypertensive, eating small meals often, avoid
standing up suddenly postprandially, and avoid or
limit alcohol use, saunas, and hot showers. Fitted elas-
tic hose or compression stockings may help to prevent
excessive pooling of venous blood in the legs, and
exercising the lower body (especially by isometric
exercise) increases the effectiveness of the muscle
American Journal of Therapeutics (2013) 20(3)
Perlmuter et al
pump and venous tone in the legs.2,3 OH can also be
successfully treated by combining certain medications
and nonpharmacological therapies. It should be noted
that successful treatment of OH usually requires a care-
fully designed personalized treatment, taking into full
account the different underlying causes of OI. Thus,
research leading to the development of sensitive spe-
cific tests for the differential diagnoses of OI should be
vigorously encouraged.
CLINICAL RELEVANCE
OH afflicts patients of all ages, and its occurrence is asso-
ciated with a variety of diseases of widely different eti-
ologies. In fact, diabetes mellitus and various conditions
affecting the cardiovascular and central nervous system
are known to increase the risk for developing OH,
emphasizing the need for a better understanding of the
relationship between these conditions and BP regulation
as it may help to elucidate the processes leading to OH
and OI.3 It is hoped that additional research on vasovagal
syncope, dysautonomic OI, POTS, and the mechanisms
relating OH to cognition and affective disorders will pro-
vide physicians and other health practitioners with new
tools for better treatment of these patients.
Although OH is not commonly recognized, chronic
OI is an increasing reason for primary care referrals as
its severity and impact on daily life can be disabling
and patients are often unable to hold jobs or attend
school. Fainting also poses the risk of fractures and skull
injuries, especially in the elderly.30,82 Additionally, OH
and BP dysregulation has been connected with altered
affective states including anxiety and depression, thus
significantly reducing the quality of life.
FINAL COMMENTS
Even though this review of the literature is not exhaus-
tive, we examined the mechanisms involved in the
development of orthostasis and OH in some detail.
We further emphasize the generally accepted notion
that OI can be manifested as a variety of symptoms
and conditions and that OH has many implications
including decreased cognitive function, attention defi-
cits, increased incidence of depression, and heightened
feelings of anxiety. Although most of the research in
this area has focused on clinical OH, the subclinical
manifestation of this condition is becoming an increas-
ingly important area of interest, especially in children,
as OH measurements are generally overlooked in the
clinical setting. Orthostatic measurements should be
implemented into routine physical examinations to
not only prevent the progression of subclinical OH
www.americantherapeutics.com
Orthostatic Hypotension
but also identify insidious influences on cognitive and
affective disorders and to design rational behavioral
and pharmacotherapeutic treatments for this condition.
ACKNOWLEDGMENTS
Some material in this review, including Figure 1, has
been already published in Perlmuter et al19 and is
included “with kind permission of Springer Business
Media.”
REFERENCES
1. Consensus Committee of the American Autonomic Soci-
ety and the American Academy of Neurology. Consensus
statement on the definition of orthostatic hypotension,
pure autonomic failure, and multiple system atrophy.
Neurology. 1996;46:1470.
2. Stewart JM. Orthostatic intolerance in pediatric. J Pediatr.
2002;140:404–411.
3. Sclater AS, Alagiakrishnan K. Orthostatic hypotension:
a primary care primer for assessment and treatment.
Geriatrics. 2004;59:22–27.
4. Hermosillo AG, Márquez MF, Jáuregui-Renaud K, et al.
Orthostatic hypotension. Cardiol Rev. 2001;9:339–347.
5. Perlmuter LC, Greenberg JJ. Do you mind standing?
Cognitive changes in orthostasis. Exp Aging Res. 1996;
22:325–341.
6. Schatz IJ. Orthostatic Hypotension. F.A. Davis Company
Philadelphia, PA; 1986.
7. Bacon PJ, Smith SE. Cardiovascular and sweating dys-
function in patients with Holmes-Adie syndrome.
J Neurol Neurosurg Psychiatry. 1993;56:1096–1102.
8. Freeman R. Neurogenic orthostatic hypotension. N Engl J
Med. 2008;358:615–624.
9. Grubb BP, Karas B. Clinical disorders of the autonomic
nervous system associated with orthostatic intolerance:
an overview of classification, clinical evaluation and
management. Pacing Clin Electrophysiol. 1999;22:798–810.
10. Kalita J, Misra UK. Postural hypotension in a patient
with acute myelitis. Postgrad Med J. 1996;72:180–182.
11. Kong K, Chou AM. Incidence and outcome of orthostatic
hypotension in stroke patients undergoing rehabilitation.
Arch Phys Med Rehabil. 2003;84:559–562.
12. Low PA. Prevalence of orthostatic hypotension. Clin
Auton Res. 2008;18:8–13.
13. Robertson D. The pathophysiology and diagnosis of ortho-
static hypotension. Clin Auton Res. 2008;18(suppl 1):
2–7.
14. Figueroa JJ, Basford JR, Low PA. Preventing and treating
orthostatic hypotension: as easy as A, B, C. Cleve Clin
J Med. 2010;77:298–306.
15. Goldstein DS, Sharabi Y. Neurogenic orthostatic hypo-
tension: a pathophysiological approach. Circulation. 2009;
119:139–146.
www.americantherapeutics.com
289
16. Mosnaim AD, Abiola R, Wolf ME, et al. Etiology and risk
factors for developing orthostatic hypotension. Am
J Ther. 2010;17:86–91.
17. Grubb BP, McMann MC. The Fainting Phenomenon:
Understanding Why People Faint and What Can Be Done
About It. Futura Publishing Company New York, NY;
2001.
18. Ejaz AA, Haley WE, Wasiluk A, et al. Characteristics of
100 consecutive patients presenting with orthostatic
hypotension. Mayo Clin Proc. 2004;79:890–894.
19. Perlmuter LC, Sarda G, Casavant V, et al. A review of
orthostatic blood pressure regulation and its associa-
tion with mood and cognition. Clin Auton Res. 2012;
22:99–107.
20. Mayo Clinic Staff. Tachycardia. Available at: http://www.
mayoclinic.com/health/tachycardia/DS00929. Accessed
June 1, 2007.
21. Stewart JM, Medow MS. Orthostatic intolerance: an over-
view. In: Pediatrics: Cardiac Disease and Critical Care Medi-
cine. Vol 1. 2007. Department of Pediatrics, New York
Medical College, Valhalla, NY. Available at: http://
www.emedicine.com/ped/topic2860.htm. Accessed June
10, 2008.
22. Miller VM, Kalaria RN, Hall R, et al. Medullary micro-
vessel degeneration in multiple system atrophy. Neuro-
biol Dis. 2007;26:615–622.
23. Miller VM, Kenny RA, Slade JY, et al. Medullary auto-
nomic pathology in carotid sinus hypersensitivity. Neu-
ropathol Appl Neurobiol. 2007;34:403–411.
24. Ziegler MG, Echon C, Wiler KD, et al. Sympathetic ner-
vous withdrawal in the vasodepressor (vasovagal) reac-
tion. J Auton Nerv Syst. 1986;17:273–278.
25. Gabbett T, Gass G, Gass E, et al. Norepinephrine and
epinephrine responses during orthostatic intolerance in
healthy elderly men. Jpn J Physiol. 2000;50:59–66.
26. Goldstein DS, Pechnik S, Holmes C, et al. Association
between supine hypertension and orthostatic hypoten-
sion in autonomic failure. Hypertension. 2003;42:136–142.
27. Weintraub D, Comella C, Horn S. Part 1: pathophysiology,
symptoms, burden, diagnosis, and assessment. Am J Manag
Care. 2008;14:S40–S48.
28. Rutan GH, Hermanson B, Bild DE, et al. Orthostatic
hypotension in older adults. The Cardiovascular Health
Study. CHS Collaborative Research Group. Hypertension.
1992;19:508–519.
29. Mosqueda-Garcia R, Furlan R, Fernandez-Violante R,
et al. Sympathetic and baroreceptor reflex function in
neurally mediated syncope evoked by tilt. J Clin Invest.
1997;99:2736–2744.
30. Stewart JM, Weldon A. The relation between lower limb
pooling and blood flow during orthostasis in the pos-
tural orthostatic tachycardia syndrome of adolescents.
J Pediatr. 2001;138:512–519.
31. Grubb BP, Gerard G, Roush K, et al. Cerebral vasoconstric-
tion during head-upright tilt-induced vasovagal syncope.
A paradoxic and unexpected response. Circulation. 1991;
84:1157–1164.
American Journal of Therapeutics (2013) 20(3)
290
32. Ouchi Y, Okada H, Yoshikawa E, et al. Absolute changes
in regional cerebral blood flow in association with
upright posture in humans: an orthostatic PET study.
J Nucl Med. 2001;42:707–712.
33. Hayashida K, Nishiooeda Y, Hirose Y, et al. Maladaption
of vascular response in frontal area of patients with
orthostatic hypotension. J Nucl Med. 1996;37:1–4.
34. Dushek S, Meinhardt J, Schandry R. Reduced cortical
activity due to chronic low blood pressure: an EEG
study. Biol Psychol. 2006;72:241–250.
35. Román GC. Brain hypoperfusion: a critical factor in vas-
cular dementia. Neurol Res. 2004;26:454–458.
36. Wharton W, Hirshman E, Merritt P, et al. Lower blood
pressure correlates with poorer performance on visuospa-
tial attention tasks in younger individuals. Biol Psychol.
2006;73:227–234.
37. Viramo P, Luukinen H, Koski K, et al. Orthostatic hypo-
tension and cognitive decline in older people. J Am Geriatr
Soc. 1999;47:600–604.
38. Kuo H, Sorond F, Iloputaife I, et al. Effects of blood
pressure on cognitive functions in elderly persons.
J Gerontol A Biol Sci Med Sci. 2004;59:1191–1194.
39. Low PA, Opfer-Gehrking TL, McPhee BR, et al. Prospec-
tive evaluation of clinical characteristics of orthostatic
hypotension. Mayo Clin Proc. 1995;70:617–622.
40. Heims HC, Critchley HD, Martin N, et al. Cognitive
functioning in orthostatic hypotension due to pure auto-
nomic failure. Clin Auton Res. 2006;16:113–120.
41. Knight J, Nigam Y. Exploring the anatomy and physiol-
ogy of ageing. Part 5: the nervous system. Nurs Times.
2008;35:18–19.
42. Matsubayashi K, Okymiya K, Wada T, et al. Postural
dysregulation in systolic blood pressure is associated
with worsened scoring on neurobehavioral function tests
and leukoaraiosis in the older elderly living in a commu-
nity. Stroke. 1997;28:2169–2173.
43. Pantoni L, Garcia JH. The significance of cerebral white
matter abnormalities 100 years after Binswanger’s report:
a review. Stroke. 1995;26:1293–1301.
44. Gorter JW, Algra A, van Gijn J, et al, on behalf of the
SPIRIT Study Group. SPIRIT: predictors of anticoagu-
lant-related bleeding complications in patients after cere-
bral ischemia [abstract]. Cerebrovasc Dis. 1997;7:3.
45. Stress M, Mayefsky J, Perlmuter LC. Blood pressure reg-
ulation, cognition, and depression in responses to ortho-
static challenge in African American children: an initial
investigation. Behav Med. 2003;29:27–32.
46. Casavant V, Spivak A, Wiltse J, et al. Orthostatic blood
pressure regulation correlates with cognitive function in
Hispanic American Head Start children. Vulnerable Child
Youth Stud. 2010;5:188–195.
47. Carapetian S, Siedlarz M, Jackson S, et al. Orthostatic
blood pressure regulation predicts classroom effort in
children. Int J Psychophysiol. 2008;68:70–74.
48. Torigoe K, Numata O, Ogawa Y, et al. Contingent neg-
ative variation in children with orthostatic dysregulation.
Pediatr Int. 2001;43:469–477.
American Journal of Therapeutics (2013) 20(3)
Perlmuter et al
49. Allan LM, Ballard CG, Allen J, et al. Autonomic dysfunc-
tion in dementia. J Neurol Neurosurg Psychiatry. 2007;78:
671–677.
50. Andersson M, Hansson O, Minthon L, et al. The period
of hypotension following orthostatic challenge is prolonged
in dementia with Lewy bodies. Int J Geriatr Psychiatry.
2008;23:192–198.
51. Elmstahl S, Rosen I. Postural hypotension and EEG var-
iables predict cognitive decline: results from a 5-year
follow-up of healthy elderly women. Dement Geriatr Cogn
Disord. 1997;8:180–187.
52. Allcock LM, Kenny RA, Mosimann UP, et al. Orthostatic
hypotension in Parkinson’s disease: associations with cog-
nitive decline? Int J Geriatr Psychiatry. 2006;21:778–783.
53. Peralta C, Stampfer-Kountchev M, Karner E, et al. Ortho-
static hypotension and attention in Parkinson’s disease
with and without dementia. J Neural Transm. 2007;114:
585–588.
54. Matsui H, Udaka F, Miyoshi T, et al. Brain perfusion
differences between Parkinson’s disease and multiple
system atrophy with predominant parkinsonian features.
Parkinsonism Relat Disord. 2005;11:227–232.
55. Kenny RA, Kalaria R, Ballard C. Neurocardiovascular
instability in cognitive impairment and dementia. Ann
N Y Acad Sci. 2002;977:183–195.
56. Carney R, Blumenthal J, Stein P, et al. Depression, heart
rate variability, and acute myocardial infarction. Circula-
tion. 2001;104:2024–2028.
57. Matthews SC, Nelesen RA, Dimsdale JE. Depressive
symptoms are associated with increased systemic vascu-
lar resistance to stress. Psychosom Med. 2005;67:509–513.
58. Carney RM, Rich MW, Jaffe AS. The relationship
between heart rate, heart rate variability and depression
in patients with coronary heart disease. J Psychosom Res.
1988;32:159–164.
59. Bendini C, Angelini A, Salsi F, et al. Relation of neuro-
cardiovascular instability to cognitive, emotional
and functional domains. Arch Gerontol Geriatr. 2007;44:
69–74.
60. Lorenz N, Stress M, Smith M, et al. Blood pressure regula-
tion and anxiety in African American and Caucasian youth.
Paper presented at: the Midwestern Psychological Associa-
tion Seventy-Seventh Annual Meeting; 27 May 2005;
Chicago, IL.
61. Coupland NJ, Wilson SJ, Potokar JP, et al. Increased sym-
pathetic response to standing in panic disorder. Psychia-
try Res. 2003;118:69–79.
62. Yeragani VK, Meiri PC, Pohl R, et al. Heart rate and
blood pressure changes during postural change and iso-
metric handgrip exercise in patients with panic disorder
and normal controls. Acta Psychiatr Scand. 1990;81:9–13.
63. Stein MB, Tancer ME, Uhde TW. Heart rate and plasma
norepinephrine responsivity to orthostatic challenge in
anxiety disorders. Comparison of patients with panic
disorder and social phobia and normal subjects. Arch
Gen Psychiatry. 1992;49:311–317.
64. Hinton DE, Hinton L, Tran M, et al. Orthostatically
induced panic attacks among Vietnamese refugees:
www.americantherapeutics.com
Orthostatic Hypotension
associated psychopathology, flashbacks and catastrophic
cognitions. Depress Anxiety. 2006;23:113–115.
65. Hinton DE, Chhean D, Hofmann SG, et al. Dizziness and
palpitations predominant orthostatic panic: physiology,
flashbacks, and catastrophic cognitions. J Psychopathol Be-
hav Assess. 2008;30:100–110.
66. Rudorfer MV, Ross R, Linnoila M, et al. Exaggerated
orthostatic responsivity of plasma norepinephrine in
depression. Arch Gen Psychiatry. 1985;42:1186–1192.
67. Roy A, Pickar D, Linnoila M, et al. Plasma norepineph-
rine level in affective disorders. Arch Gen Psychiatry.
1985;42:1181–1185.
68. Roy-Byrne P, Cowley DS, Stein MB, et al. Cardiovascular
and catecholamine response to orthostasis in panic and
obsessive compulsive disorder and normal controls: effects
of anxiety and novelty. Depress Anxiety. 1997;6:159–164.
69. Strawn JR, Ekhator NN, Horn PS, et al. Blood pressure
and cerebrospinal fluid norepinephrine in combat-
related posttraumatic stress disorder. Psychosom Med.
2004;66:757–759.
70. Voss A, Schulz BV, Bar KJ. Linear and nonlinear meth-
ods for analyses of cardiovascular variability in bipolar
disorders. Bipolar Disord. 2006;8:441–452.
71. Casavant V, Chae C, Sherwali A, et al. Subclinical ortho-
static pulse pressure confirms mothers’ ratings of ADH
in preschoolers. Psychophysiology. 2012;49:708–12.
72. Czajkowska J, Ozhog S, Smith E, et al. Cognition and
hopelessness in association with subsyndromal ortho-
static hypotension. J Gerontol A Biol Sci Med Sci. 2010:
65A;873–79.
www.americantherapeutics.com
291
73. Sachman JL, Mayefsky JH, Ozhog S, et al. Birth weight
predicts subclinical orthostatic hypotension in children.
Hum _Ontogenet. 2009;3:13–17.
74. Hussain RM, McIntosh SJ, Lawson J, et al. Fludrocorti-
sone in the treatment of hypotensive disorders in the
elderly. Heart. 1996;76:507–509.
75. Gilden JL. Midodrine in neurogenic orthostatic hypoten-
sion: a new treatment. Int Angiol. 1993;12:125–131.
76. McClellan KJ, Wiseman LR, Wilde MI. Midodrine. A
review of its therapeutic use in the management of ortho-
static hypotension. Drugs Aging. 1998;12:76–86.
77. Tan MP, Parry SW. Vasovagal syncope in the older pa-
tients. J Am Coll Cardiol. 2008;51:599–606.
78. Low PA, Singer W. Update on management of neurogenic
orthostatic hypotension. Lancet Neurol. 2008;7:451–458.
79. Basso A, Paola LD, Erle G, et al. Licorice ameliorates
postural hypotension caused by diabetic autonomic neu-
ropathy. Diabetes Care. 1994;17:1356.
80. Canada SA, Hofkamp M, Gall EP, et al. Estrogen replace-
ment therapy, subsyndromal depression, and orthostatic
blood pressure regulation. Behav Med. 2003;29:101–105.
81. Seeger H, Wallwiener D, Mueck AO. Effects of estradiol
and progestogens on tumor-necrosis factor-alpha-induced
changes of biochemical markers for breast cancer growth
and metastasis. Gynecol Endocrinol. 2008;24:576–579.
82. Chang N, Yang N, Chou P. Incidence, risk factors and
consequences of falling injuries among the community-
dwelling elderly in Shihpai, Taiwan. Aging Clin Exp Res.
2009;22:70–77.
American Journal of Therapeutics (2013) 20(3)