Drugs and Behavior III:
Anxiety Disorders
Anxiety Disorders
• The Anxiety Disorders are a diverse group of psychiatric
illnesses that have abnormal fear as their unifying
characteristic. Anxiety as a symptom and Anxiety Disorders
are common. 10-15% of general medical outpatients and
10% of inpatients experiences significant anxiety.
• Of the healthy population, 25% of individuals are anxious at
some time in their lives and 7.5% of these have a
diagnosable anxiety disorder during a given month. Primary
psychiatric disorders may be associated with anxiety, which
may be prominent or even the presenting complaint. About
70% of depressed patients also have symptoms of anxiety
and 20-30% of cases of anxiety disorder have an underlying
depression.
Anxiety Disorders
• Depressed patients with a family history of anxiety are
more likely to experience anxiety and depression than
patients with a family history of depression alone. Anxiety
may present as an early symptom of impending psychosis
or an organic mental syndrome.
• The psychological symptoms of anxiety are: apprehension,
worry, fear and anticipation of misfortune; sense of doom
or panic; hypervigilance; irritability; fatigue; insomnia;
predisposition to accidents; derealization;
depersonalization; and difficulty concentrating.
Anxiety Disorders
• The somatic complaints associated with anxiety are
headache; dizziness and lightheadedness; palpitations and
chest pain; upset stomach and diarrhea; frequent urination;
lump in the throat; motor tension or restlessness, shortness
of breath, paresthesias, and dry mouth.
• The physical signs of anxiety are diaphoresis; cool,
clammy skin; tachycardia and arrhythmias; flushing and
pallor; hyperreflexia, trembling; and easy startling and
fidgeting.
Panic Disorder: DSM-IV Criteria
• Both of the following:
• Recurrent and unexpected panic attacks
• At least one of the attacks has been followed by 1 month or more of
– Persistent concern about having additional attacks
– Worry about the implication of the attack or its consequences (e.g.
having a heart attack, “going crazy”)
– Significant change in behavior related to the attacks
• Not due to the direct physiological effects of a substance or a general
medical condition.
• Agoraphobia may or may not be present
Neurobiology of Panic Disorder
Sari Gilman Aronson. M.D.
Panic Disorder
• A syndrome rather than a singular
biological phenomenon
• A heterogeneous group of
nueropathological susceptibilities
• Numerous hypotheses, not mutually
exclusive
Lactate Hypothesis
• Sodium lactate is a potent respiratory
stimulant
• Infusions of sodium lactate elicit panic
attacks in 50-70% individuals and 10%
controls
Role of Carbon Dioxide
Patients with panic disorder may have
a heightened behavioral sensitivity
and irregular respiratory rhythm in
response to carbon dioxide
Issues With Respiratory Control
• Do patients with panic disorder have a
biologically based hypersensitive respiratory
control system operating at the level of brainstem
chemoreceptors?
• Do patients with panic disorder have a tendency to
be frightened by and intolerant of physical
sensations of shortness of breath induced by either
sodium lactate or carbon dioxide?
Noradrenergic Hypothesis
Dysregulation of norepinephrine,
primarily with regard to function of
the locus ceruleus (considered to be
the “panic button” in primates)
Serotonergic Hypothesis
• Patients with panic disorder are more
sensitive to the anxiety producing effects of
serotonin receptor stimulation with
serotonin agonists
• However, antidepressant medications which
elevate serotonin in the brain are used to
treat panic disorder
Caffeine and Panic Disorder
• Patients with panic disorder are more
sensitive to the anxiogenic effects of
caffeine
• Caffeine influences the adenosine receptor
• Is there an andenosinergic dysfunction in
panic disorder?
Benzodiazepine Receptor
• The GABA (gamma-amino butyric acid)benzodiazepine receptor complex plays a
central role in the mediation of anxiety
• Altered benzodiazepine receptor sensitivity
has been noted in panic disorder
Neuroendocrine Hypotheses
• There is some evidence for dysregulation of
the hypothalamic-pituitary axis in panic
disorder
• Patients with panic disorder have a blunted
growth hormone response to clonidine
Sleep and Panic Attacks
• Patients with panic disorder (without the
presence of clinical depression) generally
have normal sleep architecture
• Panic attacks occur in the transition
between stages 2 and 3 of NREM sleeps
End
Anxiety Disorders Case: Panic Disorder (1)
Connie is a 24 year old graduate student in engineering who came for psychiatric evaluation
and possible medication treatment at the urging of her psychotherapist. She said, “I feel
terrible.” She had a 1 year history of problems that began with trouble sleeping. She woke up
around 3 in the morning feeling sweaty, frightened, and short of breath. Connie though she
may have had a nightmare, but couldn’t remember any dream content. About 8 months ago,
she had a terrifying experience. She was driving her car on the freeway and began to feel
pressure in her chest, shortness of breath, sweaty, and lightheaded, so she pulled her car over
to the side of the road. Connie was terrified that she might be dying, and was worried that her
asthma had gotten worse. Her boyfriend, Jason, called 911 on her cell phone. Connie was
taken to the Emergency Department at a local hospital for evaluation. She felt better within 1
hour and was relieved that her physical examination, chest x-ray, EKG, and labs (including
cardiac enzymes, hemoglobin, and TSH) were all normal. The physician told her to “take it
easy…you may have had a panic attack”. Connie had about 10 more episodes like this over
the ensuing 4 months. She stopped driving and began to feel frightened about going out of
her apartment (although she did force herself to go to class). Jason was very kind, and spent
time with her, encouraging her to not withdraw. Jason became very concerned about 8 weeks
ago, when he thought Connie might be getting worse. She had episodes of crying, talked
about the hopelessness of her situation and how she “could not go on like this”. Connie said
she couldn’t eat, couldn’t concentrate on her work, didn’t feel like doing anything, and felt
“totally worthless”. Jason suggested that she begin some counseling, which she started 4
weeks prior to her first psychiatric visit.
Anxiety Disorders Case: Panic Disorder (2)
Connie had never experienced anything like this before. She said she was always a
bit shy and uncomfortable with new people, but never had these terrifying episodes
of fear, and had never felt this badly before. She had always done well in school and
was able to make friends and keep them. Her mother tended to be a “worrier”, and
her maternal aunt had been treated for “nerves” at age 38. Her father’s father had a
drinking problem, but stopped drinking when he was in his late 20s. Connie is the
youngest of 3 children and grew up in what she described as a “very supportive and
loving family”. She had talked with one of her sisters about how she had been
feeling, and her sister decided to come for a visit “just so we can be together for a
while”. Connie was very grateful.
Connie was healthy except for a history of exercise-induced asthma and mild
reactive airways. These problems were well managed by use of an albuterol inhaler
prn. The inhaler did not help during her episodes.
Mental Status Evaluation
Connie was dressed in shorts and a T-shirt, and looked tired. She
looked down throughout most of the interview, but did make eye
contact with the examiner when she was describing her episodes. She
fidgeted in the chair. Her speech was fluent and soft. Connie
described her mood as “bad and scared”. Her affect showed
apprehensiveness and thoughtfulness, but no tearfulness or irritability.
She said she was “worried about everything, especially if I will be
kicked out of graduate school”. Her thinking was logical yet she
tended to see the negative side of issues. Although she could believe
that she might feel better, she was worried that she would continue to
“feel like this forever, and that I couldn’t take”. She denied
hallucinations. She did not want to die or harm herself. Her cognitive
functions were grossly intact with excellent memory. Her judgement
and insight were good.
Treatment
Connie was started on nortriptyline, a tricyclic antidepressant, at 25
mg hs. Her dose was gradually increased to 125 mg. She had 80%
relief of symptoms: her panic attacks stopped, her baseline anxiety
level decreased, her symptoms of depression improved, and she
began to look forward to things in her life. However, she continued to
have trouble concentrating and noted that her mood would drop
around the time of her menses. Her nortriptyline blood level was 140
ng/ml. Lithium carbonate, 600 mg per day, was added. She had
complete remission of symptoms within 3 weeks. Her lithium blood
level was 0.5 meq/L. Connie stayed on medication and continued
psychotherapy for 1 ½ years. She had to work diligently on her
agoraphobia and fear of driving. During her treatment, her social
anxiety was addressed as well.
Questions and Discussion Points
• What psychiatric problem is Connie experiencing?
• What symptoms is Connie experiencing?
• What do we know about the neurobiology of this
disorder?
• What are the biological bases of Connie’s
symptoms?
• What would be the features of a medication that
would help with these problems?
• What kind of psychotherapy is necessary for
Connie to have a full recovery?
The Neurobiology of Panic Disorder
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Lactate and Respiratory Hypotheses
Noradrenergic Hypothesis
Serotonergic Dysfunction Hypothesis
Adenosinergic Dysfunction Hypothesis
Benzodiazepine Receptor Sensitivity Hypothesis
Neuroendocrine Hypotheses
Sleep and Panic Disorder
Neuroimaging Studies