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

• Lactate and Respiratory Hypotheses• Noradrenergic Hypothesis• Serotonergic Dysfunction Hypothesis• Adenosinergic Dysfunction Hypothesis• Benzodiazepine Receptor Sensitivity Hypothesis• Neuroendocrine Hypotheses• Sleep and Panic Disorder• Neuroimaging Studies