PATHOPHYSIOLOGY

• Noradrenergic model. This model suggests that the autonomic nervous system of
anxious patients is hypersensitive and overreacts to various stimuli. The locus
ceruleus may have a role in regulating anxiety, as it activates norepinephrine release
and stimulates the sympathetic and parasympathetic nervous systems. Chronic
noradrenergic overactivity downregulates α2-adrenoreceptors in patients with generalized
anxiety disorder (GAD) and posttraumatic stress disorder (PTSD). Patients
with social anxiety disorder (SAD) appear to have a hyperresponsive adrenocortical
response to psychological stress.
• γ-Aminobutyric acid (GABA) receptor model. GABA is the major inhibitory neurotransmitter
in the central nervous system (CNS). Many antianxiety drugs target the
GABAA receptor. Benzodiazepines enhance the inhibitory effects of GABA, which
regulates or inhibits serotonin (5-hydroxytroptamine; 5-HT), norepinephrine, and
dopamine activity. Anxiety symptoms may be linked to underactivity of GABA
systems or downregulated central benzodiazepine receptors. In patients with GAD,
benzodiazepine binding in the left temporal lobe is reduced. Abnormal sensitivity
to antagonism of the benzodiazepine-binding site and decreased binding occurs in
panic disorder. In generalized SAD there may be abnormal central GABAB receptor
function. Abnormalities of GABA inhibition may lead to increased response to stress
in PTSD.
• 5-HT model. GAD symptoms may reflect excessive 5-HT transmission or overactivity
of the stimulatory 5-HT pathways. Patients with SAD have greater prolactin response
to buspirone challenge, indicating an enhanced central serotonergic response. The
role of 5-HT in panic disorder is unclear, but it may be involved with development
of anticipatory anxiety. 5-HT and dopamine systems may also be involved in the
pathophysiology of generalized SAD.
• Patients with PTSD hypersecrete corticotropin-releasing factor, but have subnormal
levels of cortisol at the time of trauma and chronically. Dysregulation of the hypothalamic-
pituitary-adrenal axis may be a risk factor for eventual development of PTSD.
• Neuroimaging studies support the role of the amygdala, anterior cingulate cortex,
and insula in the pathophysiology of anxiety. In GAD, there is an abnormal increase
in the brain’s fear circuitry and increased activity in the prefrontal cortex. Patients
with panic disorder have abnormalities of midbrain structures. Patients with SAD
have greater activity in the amygdala and insula. In PTSD, the amygdala plays a role
in the persistence of traumatic memory.

CLINICAL PRESENTATION

POSTTRAUMATIC STRESS DISORDER

• In adults and children older than 6, there is exposure to actual or threatened death,
serious injury, or sexual violence, either directly, or by witnessing the event(s) happening
to others, learning about the event(s) happening to someone close, or experiencing
repeated or extreme exposure to details of the event(s).
• Duration of intrusive, avoidance, cognitive, and arousal/reactivity symptoms
(Table 66–4) must be present longer than 1 month and cause significant distress
or impairment. PTSD co-occurs with mood, anxiety, and substance use disorders
DIAGNOSIS

• Evaluation of the anxious patient requires a physical and mental status examination;
complete psychiatric diagnostic exam; appropriate laboratory tests; and a medical,
psychiatric, and drug history.
• Anxiety symptoms may be associated with medical illnesses (Table 66–5) or drug
therapy (Table 66–6), and they may be present in several major psychiatric illnesses
(eg, mood disorders, schizophrenia, organic mental syndromes, and substance
withdrawal).

POSTTRAUMATIC STRESS DISORDER

• Goals of Treatment: The goals are to decrease core symptoms, disability, and comorbidity
and improve quality of life.
• Immediately after the trauma, patients should receive treatment individualized to
their presenting symptoms (eg, nonbenzodiazepine hypnotic or short courses of
CBT). Brief courses of CBT in close proximity to the trauma can help prevent PTSD.
• If symptoms persist for 3 to 4 weeks, and there is social or occupational impairment,
patients should receive pharmacotherapy or psychotherapy, or both.
• Psychotherapies for PTSD include stress management, eye movement desensitization
and reprocessing (EMDP), and psychoeducation. Trauma-focused CBT (TFCBT)
and EMDP are more effective than stress management or group therapy to reduce
PTSD symptoms.
• Figure 66–3 shows an algorithm for the pharmacotherapy of PTSD.
• The SSRIs and venlafaxine are first-line pharmacotherapy for PTSD (Table 66–14).
• Sertraline and paroxetine are approved for acute treatment of PTSD, and sertraline
is approved for long-term management.
• Antiadrenergics and atypical antipsychotics can be used as augmenting agents.
• The SSRIs are believed to be more effective for numbing symptoms than other drugs.
About 60% of sertraline-treated patients showed improvement in arousal and avoidance/
numbing symptoms.
• Mirtazapine was effective in doses up to 45 mg/day and is a second-line agent.
Amitriptyline and imipramine, are also second-line drugs. Phenelzine is a thirdline
drug.
• If there is no improvement in the acute stress response 3 to 4 weeks following trauma,
SSRIs should be started in a low dose with slow titration upward toward antidepressant
doses. Eight to 12 weeks is an adequate duration of treatment to determine
response.
• Responders to drug therapy should continue treatment for at least 12 months. When
discontinued, drug therapy should be tapered slowly over 1 month or more to reduce
the likelihood of relapse.
• Prazosin, in daily doses of 1 to 4 mg, can be useful in some patients with PTSD.
• Risperidone, quetiapine, α1-adrenergic antagonists, antidepressants, mood stabilizers,
and anticonvulsants may be used as augmenting agents in partial responders.
• See patients frequently for the first 3 months, then monthly for 3 months. In months
6 to 12, patients can be seen every 2 months. Monitor for symptom response, suicidal
ideation, disability, side effects, and treatment adherence.