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Anxiety Disorders: Sources, Signs and Solutions

Examining Anxiety’s Underpinnings

“Stress or trauma early in life, when the brain is still developing, may permanently alter the structure and function of the brain,” said Christine
M. Heim, PhD, Assistant Professor, Department of Psychiatry and Behavioral Sciences, Emory University School of Medicine, Atlanta.

“Such ‘biological scars’ may set the stage for later anxiety disorders,” she said. Stress in general precedes and aggravates anxiety disorders. In addition, childhood abuse and neglect have been found to predict later onset of several anxiety disorders. Patients with generalized anxiety disorder and panic disorder report more childhood abuse compared to controls.

“There are also indirect relationships between childhood stress and anxiety disorders,” said Dr. Heim, “because stress early in life might induce sensitization to the effects of stress later in life, decreasing the threshold for anxiety disorders.” She added that there also is evidence for a moderate genetic basis for anxiety disorders.

The etiology of anxiety disorders may include increased activity of the hypothalamic pituitary adrenal (HPA) axis, as well as the alteration of neurotransmitter systems as a basis for neurobiological changes, according to Dr. Heim.

Various brain regions control the activity of the HPA axis. The hippocampus and prefrontal cortex inhibit the HPA axis. Input from the amygdala and the brain stem nuclei activate the HPA axis. Glucocorticoids have feedback effects on all of these brain regions and control the HPA axis.

Corticotropin-releasing factor (CRF) integrates information relevant to stress at the hypothalamic level, and it is found throughout the brain, including the amygdala, cortical regions, and in brain stem nuclei, which are brain regions involved in emotional processing and control of autonomic and endocrine responses to stress.

“When injected into the brain of animals, CRF produces an array of effects that closely parallel signs of depression, anxiety, and stress,” said Dr. Heim. These effects are believed to be mediated in a circuit that connects the amygdala and the hypothalamus with the locus ceruleus and the brain stem.

CRF and norepinephrine form a forward cascade in that circuit that regulates fear, anxiety, vigilance and alerting behavior, and autonomic and endocrine control. Several other neurotransmitters interact to block this cascade.

“Disruptions in these circuits of CRF and the associated neurotransmitters as a consequence of early life stress might lead to a lower threshold for anxiety disorders,” said Dr. Heim.

In studies with rats, stress in early life—induced by separating pups from their mothers—resulted in a reorganization of brain circuits involved in endocrine regulation, regulation of alerting and vigilance behavior, and autonomic control.

In studies with humans who have a history of childhood abuse, various neuroendocrine, autonomic, neurochemical, and neuroanatomical abnormalities have been found. “Some of the findings, particularly in children, are conflicting in terms of the direction of the changes,” said Dr. Heim.

She described her own study of neuroendocrine and autonomic stress responses in adult women who had been exposed to childhood abuse, both with and without current major depression (JAMA. 2000;284:592-597). Stress was induced by having the women speak in public.

The women with a history of abuse showed markedly increased ACTH responses to the stress test. The abused women with depression had the most pronounced change of ACTH sensitization, and they had an 80% to 90% comorbidity with anxiety disorders.

Abused women without depression showed surprisingly low cortisol concentrations. “We now believe that such hypocortisolism might be a counter-regulatory adaptation to the central sensitization, which might pose a risk for the development of anxiety in individuals when they are exposed to further stressors,” said Dr. Heim, adding that “the low cortisol may induce a disinhibition of the central stress response that leads to enhanced responses whenever the person is stressed, ultimately leading to depression and anxiety.”

A sustained increase in CRF and norepinephrine might then lead to increased arousal and imprinting of emotional memories and facilitate fear conditioning, which may eventually evolve into anxiety disorders.

Anxious Body, Anxious Self, Anxious Psychiatrist

“Most anxiety disorders have associated somatic complaints,” began Mack Lipkin, Jr., MD, Director, Division of Primary Care, New York University School of Medicine, New York. Diag-nosis and treatment of anxiety disorders forces psychiatrists to manage patients’ often intense somatic concerns, which may evoke anxiety in the psychiatrist as well, who may wonder “Do I reassure this person with chest pain or call an ambulance?”

Some of the most common physical symptoms of anxiety disorders are chest pain or discomfort, palpitations, shortness of breath or feeling smothered, choking or tight feeling in the throat, nausea, abdominal distress, sweating, chills or hot flushes, trembling, paresthesias, and feeling dizzy or light-headed.

The linchpin in the neurobiological mechanism is the locus ceruleus, which has noradrenergic neurons, releasing norepinephrine. It relates in efferent pathways to the amygdala, hippocampus, prefrontal cortex, and spinal cord.

The amygdala mediates key anxiety responses, such as fear and panic, and it gives feedback to the locus ceruleus, which produces adrenergic arousal and increased blood pressure and heart rate, parabrachial respiratory stimulation, and HPA axis CRF release.

Turning to the epidemiology of symptoms, Dr. Lipkin noted that women experience about one symptom every 3 days, and the duration of the symptom is, on average, 1.6 days. Men experience one symptom every 2.2 to 2.4 days, but they last about 2 days. In one study of 1,000 illness episodes, 75% of patients improved without treatment within 2 weeks.

“About one-third of symptoms are unexplained medically in primary care,” said Dr. Lipkin. He noted that ghost explanations—an explanation that can be neither confirmed nor denied objectively—abound. Examples include chronic fatigue syndrome, candidiasis, sero-negative Lyme disease, chemical hypersensitivity, and Gulf War syndrome.

When evaluating anxious patients with physical symptoms, Dr. Lipkin recommended considering these questions: is the symptom immediately dangerous? Is there a medical explanation in the patient’s history or presentation? What is the patient concerned about? Does the symptom persist? Is there an explanation for the symptom at this time, such as a new life event?

In the absence of acute danger, Dr. Lipkin advised following the patient rather than performing a work-up. The symptom may go away spontaneously. Psychiatrists should involve a psychosocially-attuned primary care physician, who can perform the physical and order lab tests.

Facing Up to Social Anxiety Disorder

“People with social anxiety disorder (SAD) are worried about embarrassing themselves when exposed to scrutiny by others,” said Murray B. Stein, MD, Professor of Psychiatry, University of California, San Diego.

“Many people with SAD have other mental health problems, including depression or an anxiety disorder,” he said. SAD typically starts early in life, and major depression can be considered a complication, resulting from demoralization and social isolation. Studies have shown that early onset anxiety disorder is a risk factor for developing depression later on. Therefore, when considering treatment, this comorbidity should be taken into account.

In terms of the etiology of SAD, Dr. Stein noted that twin studies have revealed that the heritability of the disorder is about 50%. “There’s good evidence for a moderate to strong genetic basis for inheriting the kind of temperament that would lead to social anxiety disorder,” he said.

He explained that there is some evidence for inheriting “general phobia proneness,” but there also may be specific genes that influence what type of phobia a person is likely to develop.

One of the genes being studied in this realm is a serotonin transporter. The short (s) allele of this polymorphism appears to be associated with anxiety-related personality traits. The long (l) allele was found to be associated with shyness in one study.

In neuroimaging studies, people with the short allele had a more pronounced amygdala response to pictures of faces with fearful expressions.

An imaging study that used PET scanning found an increase in regional cerebral blood flow in the left amygdaloid hippocampal region in social phobic subjects prior to public speaking (Arch Gen Psychiatry. 2002;59:425-433). When these individuals were treated with cognitive behavioral therapy or the SSRI citalopram, there was a bilateral reduction in amygdala cerebral blood flow.

“So, the treatments that work for social phobia seemed to reduce the increase in neuronal activity in the regions that we think are important for the illness,” said Dr. Stein.

The drugs with FDA approval for SAD are the SSRIs paroxetine and sertraline, but other SSRIs are likely to work as well. The dual reuptake inhibitor venlafaxine also has FDA approval for SAD.

Generalized Anxiety Disorder: Beneath the Surface

“One of the best descriptions of generalized anxiety disorder was put forth by Mark Twain who said ‘I have lived a terrible life, most of which never happened,’” began Jonathan R.T. Davidson, MD, Professor, Department of Behavioral Sciences, Duke University Medical Center, Durham, North Carolina.

“This is often the experience of chronic incessant worriers,” he continued. “Sometimes they have good reasons to worry and it gets grossly magnified, but much of the time what they worry about does not take place.”

According to the DSM-IV, the diagnostic criteria for generalized anxiety disorder (GAD) is the following: “excessive anxiety and worry for more days than not for 6 months or longer, about many subjects. Worry is difficult to control, and anxiety, worry, and physical symptoms impair social, occupational, and other functioning.”

“The long-term prognosis of untreated GAD is not very good,” Dr. Davidson remarked. One year after an episode, the chance of recovering is only 15% and five years later it’s only 38%. GAD causes both psychic and somatic symptoms. Psychic symptoms include worry, insomnia, fatigue, irritability, a feeling of being “on edge,” and poor concentration. The somatic symptoms, which more often prompt patients to seek treatment, include muscle tension, nausea or diarrhea, sweating, urinary frequency, and palpitations.

In addition to the vague symptoms associated with the condition itself, patients with GAD have a higher rate of chest pain, irritable bowel syndrome, hypertension, diabetes, heart disease, peptic ulcer disease, hospitalization, and emergency admissions. People with GAD also have a high rate of impaired performance or lost time from work.

People with GAD have a four-fold greater risk for suicide, and the odds go up to eight-fold for people with both GAD and depression.

The neurobiological basis for GAD has been hypothesized to involve serotonergic, noradrenergic, and benzodiazepine systems. “A study done over 15 years ago showed a reduction of platelet benzodiazepine-binding sites in GAD,” said Dr. Davidson (Eur J Pharmacol. 1987;138:289-292). When patients were treated with a benzodiazepine drug, the level was raised slightly higher than the controls, providing evidence for GABA-related abnormalities.

“There’s also evidence that noradrenergic systems and the regulation thereof are faulty in GAD,” Dr. Davidson added. Giving yohimbine, which is a noradrenergic challenge, to controls causes an increase of norepinephrine and the breakdown product 3-methoxy-4-hydroxyphenylglycol (MHPG). However, when GAD patients are similarly challenged the response is much less.

This may explain why drugs that influence noradrenergic systems, like venlafaxine and tricyclic antidepressants, are helpful for GAD. The other neurotransmitter involved is serotonin; there is reduced serotonin transporter activity in GAD patients compared to controls.

The goals of treatment for GAD are to reduce core symptoms (both psychic and somatic), reduce disability, reduce comorbidity, improve quality of life, and achieve remission.

A study from 1993 showed that diazepam produced an early impressive effect, but no further gain took place (Arch Gen Psychiatry 1993;50:884-895). With imipramine, on the other hand, there was a steady reduction of symptoms which at 6 weeks was, in some respects, superior to diazepam.

This was followed by studies looking at venlafaxine, which produced improvement beginning as early as week 1 and increasing by 3 or 4 months. Venlafaxine was the first antidepressant to be approved for treatment of GAD, followed by paroxetine.

Escitalopram has also been studied for GAD. “A series of studies have all demonstrated superior effect of escitalopram over placebo for GAD,” said Dr. Davidson. The positive effects are seen with both psychic and somatic dimensions. Dr. Davidson expects the drug to be FDA approved for GAD by the end of the year. “SSRIs and SNRIs are the first-line choice for managing most patients with chronic GAD,” said Dr. Davidson. He recommended continuing treatment for at least 12 months, and possibly longer, to prevent relapse and achieve remission.


The Neurobiology of Panic Disorder and Obsessive Compulsive Disorder

“Panic disorder (PD) and obsessive compulsive disorder (OCD) are subclasses of anxiety disorders, both commonly treated with SSRIs,” said Stephen M. Stahl, MD, PhD, Chairman, Neuroscience Education Institute, University of California, San Diego.

The neurotransmitters most prominently linked to PD and OCD are serotonin and gamma aminobutyric acid (GABA). Because drugs that act on serotonin have established efficacy in treating anxiety disorders, there is likely to be an association between anxiety and serotonin. In addition, mice with genes for serotonin receptors knocked out have increased anxiety, further bolstering the evidence of a link.

The association with GABA has been made because PD patients have decreased GABA levels in the cortex. “The benzodiazepines, which act on anxiety, act on GABA receptors,” said Dr. Stahl. The subunits of GABA–particularly the GABAA receptor, which is linked to chloride channels and is where benzodiazepines act–have three major subgroups: alpha, beta, and gamma.

The alpha1 subunit is sedative while the alpha2 and alpha3 subunits are anxiolytic.

Other neurotransmitters linked to symptoms of anxiety are norepinephrine, CRF, acetylcholine, and glutamate. Dr. Stahl emphasized that “we’re no longer talking about just neurotransmitters in the brain; we must consider circuits that have neurotransmitters in them.”

“The amygdala is the panic button in the brain,” he continued. “If you have an automatic fear, it comes from the thalamus as a conditioned response and it goes right to the amygdala.”

When the panic response is turned on, there are four major outputs from the amygdala: a motor output through the periaqueductal grey, which is the fight, flight, or freeze response; an endocrine output through the hypothalamus, which raises cortisol; a breathing output, controlled by the brain stem; and a heart rate output, from the locus ceruleus. “The autonomic outputs are accompanied by the subjective sense of fear,” said Dr. Stahl.

He noted that the important question is: what’s the difference between fear and anxiety disorder? In panic disorder, the amygdala is activated falsely, and it triggers a full blown fear response. This results in activation of the autonomic outputs and the subjective sense of fear.

Currently, serotonergic antidepressants (SSRIs and SNRIs) are the first-line treatment for panic disorder, and benzodiazepines are second line. FDA-approved agents for panic disorder are paroxetine, sertraline, alprazolam, clonazepam, and alprazolam XR.

Escitalopram has been approved for depression and is being considered for approval for anxiety. “It’s the most selective of the SSRIs and is well tolerated,” said Dr. Stahl.

Dr Stahl indicated that combining antidepressants with benzodiazepines has some advantages. The combination provides early onset and it treats residual anxiety in people with incomplete responses. “If you add two drugs that work on different neurotransmitters in the same circuit you can have an output that is therapeutically greater than the sum of the parts,” said Dr. Stahl.

The neurobiology of OCD appears to be different from PD, Dr. Stahl continued. Instead of the amygdala fear circuit, the cortico-striatal-thalamic-cortical (CSTC) circuits are implicated. CSTC circuits may be hyperactive in OCD and increase further when symptoms are provoked.

Hoarding behavior may activate a ventral prefrontal limbic pathway, and may not respond as well to SSRIs than other OCD symptoms. Checking behavior may activate a dorsal prefrontal pathway, and excessive washing may activate both.

Pharmacological treatment options for OCD include clomipramine and all of the SSRIs. OCD can also be treated with psychosurgery (cingulotomy or capsulotomy), which may improve symptoms in patients refractory to SSRIs and behavioral therapy.


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