Lecture 7
Anxiety Disorders: Etiology
Biological Factors
Lecture Outline
I. Introduction
II. Biological Factors
A. Neurobiology
1. Benzodiazepine
2. Other neurotransmitters
B. Genetics
C. Preparedness
D. Physiology
1. Mitral Valve Prolapse
2. Hyperventilation
III.Conclusions
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I. Introduction
Today we continue our discussion of Anxiety Disorder etiology with
an examination of the role of biological factors: neurobiology,
genetics, biological predispositions, and physiology.
II. Biological Factors
A. Neurobiology
A promising area of research has been the study of the brain
in an attempt to discover neurological mechanisms that may underlie
anxiety responses. This research goes hand in hand with
developments in drug treatments for anxiety: If a drug can be
found that inhibits anxiety, and if it can be determined how that
drug works in the brain, then we've learned something about the
neurobiology of anxiety. Similarly, work with brain damaged
individuals sheds light on this neurobiology: We can see how the
damage effects the person's behavior, and thus learn what that part
of the brain does in a normal individual.
1. Benzodiazepine: A major class of antianxiety drugs (eg:
librium, xanax). Although its antianxiety effects have been
known since the 60's, it's only recently that benzodiazepines
have been vigorously investigated (Agras, 1985). These
investigations were largely spurred on by the discovery of
specific receptor sites in the brain that are set up to react
to benzodiazepines.
Before we continue, let's review some of the basics of
neurobiology and the functioning of the brain (see Grebb,
Reus & Freimer, 1988 for much more detail).
The brain is made up of billions of neurons (or nerve
cells). These cells bring information to the brain, store
memories, process information, and send out directions for
responses. This information is carried as electrical
impulses along each neuron (see Handout 7-1). This impulse
moves down the axon, to the nerve terminals (terminal but-
tons), where it stimulates the release of chemical sub-
stances called neurotransmitters (of which there may be over
200! [Snyder, 1980]). These chemicals flow out into the
space existing between every neuron - the synaptic cleft -
and activate the nearby neurons "telling" them to fire an
electrical impulse.
The manner in which these chemicals do their job is
unique: Like a key into a lock, only a neurotransmitter
with the proper molecular shape will fit into the receptor
sites of the adjacent neuron. Each neurotransmitter must
seek out the receptor sites specifically attuned to it.
Once found, the chemical will stimulate an electrical
impulse in this adjacent neuron, and the message continues
on. Thus, information flows through the nervous system as
electrical impulse, transformed to a chemical, back to an
impulse, and so.
Specific receptor sites have been found for benzo-
diazepines. This had the fascinating implication that there
might be naturally occurring substances in the brain with
anti-anxiety effects. These chemicals have only recently been
discovered (Greist & Jefferson, 1988). Such substances may
have important implications for future developments in anxiety
treatment techniques.
How benzodiazepines work: The benzodiazepines cause the
secretion of a neurotransmitter called Gamma Aminobutyric Acid
(GABA) which inhibits anxiety responses (Agras, 1985),
especially those associated with Generalized Anxiety (Barlow,
1988). Research indicates that the region of the brain known
as the septo-hippocampal region (a very old part of the brain)
receives the messages from the benzodiazepine sites (Agras,
1985).
We thus know what part of the brain is responsible (at
least in part) for anxiety responses. This finding is
supported by experiments where this region of the brain is
directly stimulated or damaged. It appears that
oversensitivity of this region will result in anxiety
responses and symptoms.
2. Other Neurotransmitters have also been found to play an
important role in anxiety, especially noradrenalin and
serotonin. These chemicals increase when a person is under
stress and are especially associated with panic (Barlow,
1988). Like the benzodiazepines, they seem to effect the
older part of the brain.
B. Genetics
Genetic studies suggest that certain people inherit autonomic
nervous system traits that make them vulnerable to anxiety (eg:
overly responsive, reactive, strong alarm tendencies, overly
emotional) (eg: Eysenck, 1967; McGuffin & Reich, 1984; Rose &
Chesney, 1986). It is possibly because of this inherited
vulnerability that even minor events trigger anxiety. In other
words, the person is predisposed to anxiety. But such a
predisposition won't be realized without there also being a
sufficient amount of stress to activate it (Selye, 1976):
Environmental conditions + Inherited vulnerable nervous
(stress) system
= ANXIETY
This should look familiar, it is the diathesis stress model we
discussed in the third lecture
Despite the fact that some genetic factor seems to be present
(Carey & Gottesman, 1981; Barlow, 1988, for reviews), it remains to
be seen to what degree and in what specific manner genetics plays a
role. It's much more complex than simply passing on an "anxiety
gene".
C. Preparedness (Barlow, 1988; McNally, 1987; Mineka, 1985; Ohman,
1986; Ohman, Dimberg & Ost, 1985; Ohman, Erixon & Lofburg, 1975;
Seligman & Hager, 1972):
There is some evidence that what we learn may be controlled in
part by our inherited biology: We seem to be "prepared" to
associate certain stimuli with aversive events/stimuli. That is,
it is easier to learn to be afraid of a snake than a flower. This
"preparedness" seems to be "hard-wired" into us - an evolutionarily
selected predisposition to learn certain fears. A predisposition
doesn't mean we will necessarily develop the fear, only that if the
conditions are right we are likely to do so.
Research by Ohman: Shock (US) associated with two classes of
CS: (i) snakes, spiders, (ii) flowers, geometric shapes. The
association was made much quicker with (i), often with a
single pairing. In addition, the CR to (i) was highly
resistent to extinction, just like actual phobias. If guns
(and other modern-day threats) were substituted for the snakes
and spiders, the effect was lost. And if a nonaversive
stimulus replaced the shock, spiders and snakes did not show
preparedness.
Looking at all the research in this area, this resistance to
extinction most strongly suggests biological preparedness
(McNally, 1987). The first finding, that certain associations
are made more easily, doesn't have quite the same level of
support.
Nevertheless, this all suggests that at some level we may be
innately set up to make certain associations that (at one time)
were evolutionarily advantageous (eg: fear of snakes that might be
poisonous). We aren't biologically prepared to be afraid of guns
because they're too new in our evolutionary history. And fear of
flowers would never have been selected for (no survival advantage).
In summary: We may be vulnerable to develop certain fears which
once developed are clearly resistent to extinction.
D. Physiology
In general, very few reliable physiological differences which
would help explain the etiology of anxiety disorders have been
found between normals and anxiety disorder patients (Barlow, 1988).
We will discuss some of the physiological factors that have gained
the most attention in recent years and that seem most promising.
1. Mitral Valve Prolapse:
Although many people suffering panic attacks fear they have
heart disease, this fear is usually unfounded. Nevertheless,
the connection has been suspected to be real for some people.
A high incidence of the heart disease known as mitral valve
prolapse has been reported in some patients (eg: agoraphobics,
Kantor, Zitrin & Zeldis, 1980). Mitral valve prolapse is an
abnormality in one of the valves separating the chambers of
the heart - the mitral valve fails to close properly,
interfering with the heart's ability to empty when it
contracts (see Handout 7-2). The symptoms of this disorder
include chest pain, headaches, breathlessness and dizziness,
all very similar to anxiety symptoms. For a number of years
it was thought that this could be a major organic cause of
Anxiety Disorders. The results of more recent studies bring
this into some doubt (eg: Dager, Comess, Saal & Dunner, 1986),
where the correlation between mitral valve prolapse and
anxiety tends to be weak. Nevertheless, such a heart disorder
may account for some anxiety sufferers. For example, Agras
(1985) reviewed the research in this area, and concluded that
as many as 40% of patients with panic have mitral valve
prolapse, whereas only about 10% of people without panic have
this heart abnormality.
2. Hyperventilation:
i) Introduction: An increasing amount of attention is being
placed on the possible role that abnormal respiration plays in
the etiology of Anxiety Disorders, especially Panic Disorder
(eg: Clark, Salkovskis & Chalkley, 1985; Ley, 1985, 1987).
First, we shall begin with some background on respiration:
The purpose of respiration is to remove CO2 and take in
oxygen. But when hyperventilation or "overbreathing" occurs,
the amount of air breathed exceeds the body's demand. The
results:
a) Too much CO2 is lost, which has two consequences:
1) blood pH level increases (pH is a measure of how
acidic a solution is; when pH increases, it means
the solution is less acidic - So, in this case the
blood is becoming less acidic than it should be).
The body is a very fine-tuned mechanism - for the
body to make the most efficient use of the oxygen
available to it, the pH level of the blood must
remain in a very particular range (around 7.2 - 7.6
- although this depends on activity level). But as
the pH level increases, the metabolism of the oxygen
in the blood is impaired. As a result, less oxygen
becomes available to the body.
2) the pressure of the CO2 in the arteries
decreases.
The finely tuned mechanism is also upset by this
increased pressure. For the body to receive the
necessary amounts of blood for its various organs, a
particular pressure of CO2 must be present in the
arteries. When this level drops, the result is an
impeded flow of blood to the body.
b) The result of all this is that the heart must pump
faster and harder to compensate. In addition, CO2 plays an
important role in triggering respiration: when a certain
amount accumulates in the body, respiration reflexively
occurs (hold your breath and you will eventually experience
this reflex). But because too much CO2 has been lost
through hyperventilation, this reflex is impaired,
resulting in shortness of breath or difficulty breathing
(dyspnea).
What should readily stand out is that increased heart rate,
inability to breathe, and many of the other effects of
hyperventilation are the same symptoms associated with
panic (see Barlow, Vermilyea, Blanchard, Vermilyea,
DiNardo, Cerny, 1985). See Handout 7-3.
ii) A hyperventilation theory of panic:
a) The DSM-III-R lists these somatic complaints as
symptoms of Panic Disorder. The definition for "Symptom"
is "an observable manifestation of a disorder". That is,
if you have disorder X, then you will eventually manifest
certain symptoms, or in other words, the symptoms arise
because you have the disorder. To say that the somatic
complaints as listed in the DSM-III-R are symptoms implies
that they are a consequence of anxiety: fear is primary,
the symptoms arise from the fear. This is the basis of
what has been called the "Fear of Fear hypothesis" (eg:
Jacob & Rapport, 1984; Stampler, 1982). This hypothesis
states: Panic Disorder is caused by the person fearing the
sensations that accompany the fear. The process works this
way: There is a sudden onset of anxiety ---> unexplainable
somatic sensations ---> fear of sensations (eg: feel like
you're going crazy, having a heart attack) ---> fear
increases ---> somatic sensations increase...and so on, in
a viscous circle, until a panic attack occurs.
b) Problem with Fear of Fear Hypothesis: "symptoms" are
often experienced prior to the experience of fear (Ley,
1985). That is, the somatic sensations occur first. This
seems to indicate that the fear is a consequence to the
sensations, not the other way around. To explain this, a
Hyperventilation theory of Panic Disorder has been
suggested (eg: Ley, 1987):
1) Initiation of panic attacks are caused by the
unexpected and unexplainable sensations that accompany
hyperventilation. This results in misattributions
(danger, death, insanity) which further increases
hyperventilation; and so on.
2) Certain people are chronic hyperventilators, through
faulty respiratory behavior (caused by, for example,
chronic stress, mouth breathing, physical disorder of
the nasal passages, drug intoxication). This chronic
condition does not mean they are always panicking, but
that they are always "ready" to do so.
There is a "threshold of tolerance" (Ley, 1987)
below which we can tolerate increases in blood pH and
decreases in CO2 pressure (the effects of hyper-
ventilation) without experiencing anxiety. Chronic
hyperventilators are closer to this threshold, so even
a mildly arousing event or "false alarm" (Barlow, 1988)
can "push them over" the threshold into panic (recall
that panic attacks seem to come out of the blue).
Handout 7-4 illustrates this.
In sum: The tendency to hyperventilate may predispose
certain people, or put them at risk, for developing
Panic Disorder.
iii) Lactate: Although often presented as an alternative
explanation, support for the hyperventilation theory comes
from "Lactate Models" of Panic Disorder (eg: Carr & Sheehan,
1984; Rainey, Frohman, Freedman, Pohl, Ettedgui & Williams,
1984).
a) Early studies (eg: Jones & Mellersh, 1946): It was
found that anxiety increases in Anxiety Disorder patients
when they exercise. When you exercise, blood lactic acid
increases.
b) Later studies (eg: Liebowitz, Fyer, Gorma, et al., 1984;
Pitts & McClure, 1967): Injections of lactate frequently
lead to panic in patients, but not in nonpatients: 50 -
90% patients respond with panic, 0 - 25% nonpatients
respond with panic (Ley, 1987). This has lead some
researchers to suggest that abnormal blood lactate levels
may cause panic in some individuals.
c) Lactate and hyperventilation: The hyperventilation
theory can incorporate these findings - hyperventilation,
among its many other effects, produces lactate (Grosz &
Farmer, 1972), as well as makes an individual more
susceptible to the anxiety producing effects of lactate
(Ley, 1987).
iv) The Final Result: Chronic hyperventilators are highly
susceptible to anxiety. The anxiety can be triggered by even
mild events. The chronic hyperventilator is primed and ready
to panic.
III. Conclusions
The more comprehensive theories of anxiety recognize that the
etiology of anxiety is a complex psycho-biological process. These
theories (eg: Lang, 1979) combine cognition, biology, predispositions,
and learning.
It's important to understand that it is very unlikely that the
cause(s) of anxiety will be found to be a simple linear (straight line)
process (where one thing leads to the next and so on like a one
direction chain of events). Rather, to speak of causation we will
undoubtedly need to explore complex, interactive, reciprocal processes.
Handout 7-1
Diagram of neuron
Handout 7-2
A drawing of the heart illustrating its structure,
including the location of the mitral valve
[To be added]
Handout 7-3
Some Symptoms of Hyperventilation*
Cardiovascular - palpitations, chest pain
Neurological - dizziness, numbness, tingling
Respiratory - shortness of breath, dryness of mouth
Gastrointestinal - stomach pains, gas
Musculoskeletal - muscle pains, cramps, tremors
Psychological - anxiety, insomnia, nightmares
*(Adapted from Ley, 1987, p. 197)
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Some DSM-III-R Symptoms of Panic Disorder
Palpitations or accelerated heart rate, chest pain
Dizziness, numbness, tingling
Shortness of breath or smothering sensations
Nausea, abdominal distress
Trembling or shaking
Fear of going crazy, fear of dying
Handout 7-4
Death ...............................³0
³
³
Coma ............................ ³
. ³
Panic . ³ CO2
. ³
Threshold .................... . ³
. . ³
. . ³
Tolerance . . ³
. . ³40
. . ³
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7.4 7.8
Blood pH
Note: This is a very sensitive process, indeed! The
difference between a pH of 7.4 and 7.8 is quite slight. Water
has a pH of 7.0, laboratory acids are on the order of 1.0,
milk, ammonia, lye ***** [values to be added]