Anxiety Disorders
Anxiety Disorders
Everyone experiences anxiety, which includes awareness of physiologic sensations (e.g., palpitations, sweating) and feeling nervous or frightened.
Anxiety is a diffuse, unpleasant sense of apprehension, usually with autonomic symptoms.
Anxiety differs from fear: it is a response to an impending danger, not an overt one.
Both fear and anxiety are normal, adaptive responses to potential danger, preparing us for fight, flight, or freezing.
Psychology research focuses on understanding normal anxiety, but this discussion concentrates on pathologic anxiety: inappropriately triggered and maladaptive anxiety disorders.
Anxiety disorders are the most prevalent psychiatric syndromes in the U.S.
Nearly 20% of adults report a lifetime history of a major anxiety disorder.
1 in 10 adults currently suffer from an anxiety disorder.
Anxiety disorders are associated with social impairment and can interfere with healthy development in childhood, impacting later social and occupational functioning.
Worldwide, anxiety disorders are the sixth most significant contributor to nonfatal health loss.
They explain 10% of disability-adjusted life years for mental, neurologic, and substance use disorders, second only to major depression.
Clinical Presentation of Anxiety
Anxious patients have a variety of symptoms, particularly cognitive and physical.
Autonomic symptoms are observable and quantifiable, making objective measures and research more straightforward.
Physical manifestations of anxiety:
Commonly affects the autonomic system: headache, perspiration, palpitations, tightness in the chest, and mild stomach discomfort.
Motor symptoms: restlessness, inability to sit or stand still for long.
The specific symptoms vary among individuals.
Anxious individuals may describe themselves as "nervous" or "frightened."
Mood is frequently observable, especially during panic attacks: fearful expression with eyes and mouth open, eyebrows raised.
Chronic anxiety may present with a more blunted affect, akin to depression.
Thoughts may be more rapid and disorganized in severe anxiety, leading to difficulty in thinking clearly.
During panic attacks, patients may ruminate or stammer.
In acute anxiety, thoughts focus on the perceived cause of anxiety.
Patients may catastrophize and overestimate danger.
During panic attacks, somatic concerns of death from cardiac or respiratory problems may be the primary focus.
Patients may believe palpitations and chest pain indicate imminent death.
Up to 20% of such patients have syncopal episodes during panic attacks.
Patients may present in emergency departments insisting they are about to die from a heart attack, despite being young and physically healthy.
As anxiety becomes chronic, thoughts may take the form of more negative thinking.
Hallucinations are rare, but patients with severe anxiety may have distortions in perception of time, space, persons, and the meanings of events.
Anxiety can help attention by increasing alertness and focusing attention; however, in excess, it can impair cognition.
Cognitive Impact of Severe Anxiety
Patients with severe anxiety can become confused.
They can have difficulty focusing their attention, leading to trouble with recall.
Anxiety usually does not significantly affect insight or judgment.
Patients can become selective in their interpretation of the environment, focusing on specific aspects to justify their reactions.
Although patients do not tend to talk about suicidal ideation, they are at increased risk of committing suicide.
Some studies have found that the lifetime risk of suicide in persons with panic disorder is higher than it is in persons with no mental disorder.
Presentation in Special Populations
Anxiety disorders can present differently in different populations.
Children or the elderly may present more with somatic symptoms.
Certain cultural groups may have unique syndromes related to culturally specific understandings of their body.
Examples: fear of “wind attacks” in Cambodians, or Ataque de Nervios (attack of nerves) in Puerto Rican and Dominican patients.
In most cases, anxiety symptoms do not differ from those in other cultures; however, the emphasis may be on specific ones relevant to beliefs about the underlying cause.
A full history and examination can often elucidate the problem.
Cultural consultation can be helpful for understanding particular syndromes.
Broad overgeneralizations about different ethnic or cultural groups often reflect bias and are usually not helpful.
Diagnosis of Anxiety Disorders
Several disorders fall within the anxiety category, including:
Panic disorder (with and without agoraphobia).
Agoraphobia (without a history of panic disorder).
Specific phobia.
Social phobia.
Generalized anxiety disorder.
Panic Disorder
Panic disorder is an acute intense attack of anxiety (a panic attack) accompanied by feelings of impending doom.
The anxiety occurs during discrete periods of intense fear that can vary from several attacks during 1 day to only a few attacks during a year.
Patients with panic disorder present with several comorbid conditions, most commonly agoraphobia, which refers to a fear of or anxiety regarding places from which escape might be difficult.
A panic attack is a sudden period of intense fear or apprehension that may last from minutes to hours.
It is a symptom, and many disorders and situations besides panic disorder can cause panic attacks.
Case Example: Mrs. K, a 35-year-old woman, experienced difficulty breathing, dizziness, tachycardia, shakiness, and a feeling of terror that she was going to die of a heart attack while at work. Medical evaluation revealed no sign of cardiovascular, pulmonary, or other illness. She had experienced similar episodes over the past month and worried about being perceived as crazy if she sought medical treatment without ongoing symptoms.
Panic Disorder:
Panic attacks include somatic, cognitive, and mood symptoms.
Patients can feel physical symptoms in many organs and systems, including cardiorespiratory, gastrointestinal, and otoneurologic systems.
Panic attacks can occur as part of another mental disorder, particularly phobias and PTSD.
They may or may not be associated with an identifiable situational stimulus, and unexpected panic attacks are not uncommon.
Situationally predisposed panic attacks may or may not occur when encountering a specific trigger or may occur either immediately after exposure or after a considerable delay.
In DSM-5, to be diagnosed with panic disorder, a patient must have recurrent, unexpected attacks to help distinguish the disorder from phobias and other causes of panic attacks.
Agoraphobia
Agoraphobia refers to a fear of or anxiety regarding places from which escape might be difficult.
Agoraphobia can be the most disabling of the phobias because it can significantly interfere with a person’s ability to function in work and social situations outside the home.
Although agoraphobia often coexists with panic disorder, in that patients are afraid to leave the safety of home lest they have a panic attack in a public place, DSM-5 considers agoraphobia a separate condition that may or may not be comorbid with panic disorder.
Often patients with agoraphobia alone still have some measure of anxiety, “panic-like” symptoms, although those symptoms may not reach the level of an actual panic attack.
Patients with agoraphobia rigidly avoid situations in which it would be challenging to obtain help.
They prefer to be accompanied by a friend or a family member when leaving home, especially if their destination is crowded or closed-in.
Severely affected patients may simply refuse to leave the house.
Patients may be terrified that they are going “crazy.”
Several situations that might cause anxiety include:
Confining spaces (public transportation, elevators, stores).
Open spaces (parks, shopping centers).
Crowds.
Common to all is the fact that a person is away from home and safety and cannot quickly return to it.
Specific Phobia
The term phobia refers to excessive fear of a specific object, circumstance, or situation.
A specific phobia is an intense, persisting fear of an object or situation, considered dangerous.
The fear should be out of proportion to the actual threat.
The diagnosis of specific phobia requires the development of intense anxiety, even to the point of panic, when exposed to the feared object.
Persons with specific phobias may anticipate harm, such as being bitten by a dog, or may panic at the thought of losing control; for instance, if they fear elevators, they may also worry about fainting after the door closes.
There are many possible objects of fear, including:
Animals.
Environments (storms, dark rooms).
Situations (driving, flying, blood injections).
What they have in common is the irrational fear that the object of one’s fear is harmful or dangerous.
In each case, the anxiety usually occurs immediately after exposure to the object or situation.
The result is either avoidance or painful endurance.
It should last for at least 6 months.
Social Anxiety Disorder
Social anxiety disorder (also referred to as social phobia) involves the fear of social situations, including situations that involve scrutiny or contact with strangers.
The term social anxiety reflects the distinct differentiation of social anxiety disorder from a specific phobia, which is the intense and persistent fear of an object or situation.
Persons with social anxiety disorder are fearful of embarrassing themselves in social situations (i.e., social gatherings, oral presentations, meeting new people).
They may have specific fears about performing specific activities such as eating or speaking in front of others, or they may experience a vague, nonspecific fear of “embarrassing oneself.”
In either case, the fear in social anxiety disorder is of the embarrassment that may occur in the situation, not the situation itself.
Many people feel anxiety in social situations, and it is rare to find the person who feels no anxiety over speaking in public or attending a party where they will not know anyone.
The key feature in social anxiety disorder is that this anxiety is significant to the point of being disabling, meaning that it is sufficient to cause clinically significant distress or impairment.
It also occurs while one is scrutinized and includes a fear of negative judgment.
Furthermore, DSM-5 emphasizes that the fear should occur in situations in which the individual is under scrutiny and that the fear is of being “negatively evaluated” (embarrassed or rejected).
Generalized Anxiety Disorder
Generalized anxiety disorder is defined as excessive anxiety and worries about several events or activities most of the time for at least 6 months.
The worry is difficult to control and is associated with somatic symptoms, such as muscle tension, irritability, difficulty sleeping, and restlessness.
The worry usually involves a broad swath of everyday life, such as simple daily activities, timeliness, finances, or health.
These are ordinary worries for many people; however, patients with generalized anxiety disorder worry about them to the point where catastrophe seems possible, likely, and imminent.
Another feature is that these concerns cannot be prioritized or put aside to deal with more pressing matters that may pop up.
This inability to prioritize is a key feature that contributes to the pathologic effect that this disorder has on functioning.
Objective Rating Scales
There are many scales for measuring anxiety, such as:
Beck Anxiety Inventory (BAI).
Hospital Anxiety and Depression Scale (HADS).
Generalized Anxiety Disorder scale (GAD-7).
Some scales measure anxiety per se, while others help to identify a specific disorder.
Scales may also differentiate between state and trait anxiety, which is situational anxiety versus anxiety that seems characteristic for a person and independent of the situation.
An example is the State-Trait Anxiety Inventory.
Differential Diagnosis: Distinguishing Between the Anxiety Disorders
Anxiety disorders have overlapping symptoms.
Sometimes it is difficult to distinguish between panic disorder and specific and social phobias.
Some patients who experience a single panic attack in a specific setting (e.g., an elevator) may go on to have long-lasting avoidance of the specific setting, regardless of whether they ever have another panic attack. These patients meet the diagnostic criteria for a specific phobia, and clinicians must use their judgment about what is the most appropriate diagnosis.
In another example, a person who experiences one or more panic attacks may then fear to speak in public. Although the clinical picture is almost identical to the clinical picture in social anxiety disorder, we would not diagnose a social anxiety disorder because the avoidance of the public situation is based on fear of having a panic attack rather than on fear of the public speaking itself.
Differential Diagnosis: Other Psychiatric Disorders
The differential diagnosis for agoraphobia includes all the psychiatric disorders that can cause anxiety or depression.
A panic disorder is the most common cause of agoraphobia, and a separate diagnosis of agoraphobia is not necessary.
Other disorders include major depressive disorder, schizophrenia, paranoid personality disorder, avoidant personality disorder, and dependent personality disorder.
Differential Diagnosis: Medical Disorders
Many medical disorders can cause anxiety or have symptoms that overlap with anxiety disorders.
Several medical conditions produce symptoms that are similar to panic disorder.
Panic attacks are associated with a variety of endocrinologic disorders, including both hypo- and hyperthyroid states, hyperparathyroidism, and pheochromocytomas.
Episodic hypoglycemia associated with insulinomas can also produce panic-like states, as can primary neuropathologic processes, including seizure disorders, vestibular dysfunction, neoplasms, or the effects of both prescribed and illicit substances on the CNS.
Finally, disorders of the cardiac and pulmonary systems, including arrhythmias, chronic obstructive pulmonary disease, and asthma, can produce autonomic symptoms and accompanying crescendo anxiety that can be difficult to distinguish from panic disorder.
Clues of an underlying medical etiology to panic-like symptoms include the presence of atypical features during panic attacks, such as ataxia, alterations in consciousness, or bladder dyscontrol, onset of panic disorder relatively late in life, and physical signs or symptoms indicative of a medical disorder.
Comorbidity
Depressive symptoms are often present in panic disorder, and in some patients, a depressive disorder coexists with panic disorder, and depression can complicate the symptom picture in anywhere from 40 to 80 percent of all patients, as estimated by various studies.
In addition to agoraphobia, other phobias and OCD can coexist with panic disorder.
Alcohol and other substance use disorders occur in about 20 to 40 percent of all patients, and OCD may also develop.
Course of Anxiety Disorders
Panic attacks, by definition, have a sudden onset and relatively short duration.
The first panic attack is often completely spontaneous, although panic attacks occasionally follow excitement, physical exertion, sexual activity, or moderate emotional trauma.
The attack often begins with 10 minutes of rapidly increasing symptoms.
The significant mental symptoms are extreme fear and a sense of impending death and doom.
Patients usually cannot name the source of their fear; they may feel confused and have trouble concentrating.
The physical signs often include tachycardia, palpitations, dyspnea, and sweating.
Patients often try to leave whatever situation they are in to seek help.
The attack generally lasts 20 to 30 minutes and rarely more than an hour.
Panic disorder usually has its onset in late adolescence or early adulthood, although onset during childhood, early adolescence, and midlife do occur.
Some data implicate increased psychosocial stressors with the onset of panic disorder, although in most cases, there are no identifiable psychosocial stressors.
Panic disorder is a chronic disorder, although its course is variable, both among patients and within a single patient.
About 30 to 40 percent of patients seem to be symptom-free at long-term follow-up, about 50 percent have symptoms that are sufficiently mild not to affect their lives significantly, and about 10 to 20 percent continue to have significant symptoms.
After the first one or two panic attacks, patients may be relatively unconcerned about their condition; with repeated attacks, however, the symptoms may become a significant concern.
Between attacks, patients may have anticipatory anxiety about having another attack.
Patients may attempt to keep the panic attacks secret and thereby cause their families and friends concern about unexplained changes in behavior.
The frequency and severity of the attacks can fluctuate.
Panic attacks can occur several times in a day or less than once a month.
Excessive intake of caffeine or nicotine can exacerbate the symptoms.
When agoraphobia is part of a panic disorder, improving panic symptoms often also improves agoraphobia. For rapid and complete reduction of agoraphobia, behavior therapy is useful.
Agoraphobia without a history of panic disorder is often incapacitating and chronic, and depressive disorders and alcohol use disorder often complicate its course.
The presence of comorbid disorders, particularly alcohol and substance use disorders, complicates the course of anxiety disorders.
Patients with good premorbid functioning and symptoms of brief duration tend to have a favorable prognosis.
Most of the other anxiety disorders also have long-term courses with multiple relapses.
Overall these are all chronic disorders.
Generalized anxiety disorder commonly has multiple relapses, although some may occur long after the initial episode, sometimes giving a false sense of security. Clinicians should regularly monitor the symptoms.
Most of these disorders also have an increased risk of suicide, and clinicians should monitor this as well.
Treatment Approach
With treatment, most patients exhibit dramatic improvement in their anxiety symptoms.
Treatments include pharmacologic, psychologic, and combined treatments for all anxiety disorders.
Meta-analyses generally suggest that pharmacologic treatment has the largest effect size of the various options.
However, depending on the anxiety disorder, there are many pharmacologic, psychotherapeutic, and combined options available.
Hospitalization
Patients rarely require hospitalization unless they need a diagnostic workup, for example, to rule out a medical cause.
Also, we may hospitalize patients with comorbid disorders such as substance use or those who are suicidal.
Pharmacotherapy
Among the medication options, selective serotonin reuptake inhibitors are the first-line agents for most anxiety disorders, including panic disorder, generalized anxiety disorder, and social anxiety disorder.
Some non-SSRIs are also useful, for example, venlafaxine for panic disorder, generalized anxiety disorder, and social anxiety disorder.
Tricyclic antidepressants are useful for panic disorder as well, although less popular due to their side effects.
Many clinicians consider mirtazapine to be useful for anxiety disorders, owing to its sedative effect. However, there are few studies of its use for anxiety disorder.
Benzodiazepines remain one of the most popular medications used for anxiety disorder, perhaps the most popular.
Most treatment guidelines suggest that they be mostly limited to short-term use, either as an adjunct to SSRIs during the initial treatment phase or for acute use during exacerbations of the anxiety.
Generally, most guidelines recommend that we should only consider long-term benzodiazepines for patients who do not respond or cannot tolerate the SSRIs. The main concerns are the potential for dependence, as well as the cognitive and other side effects. Tolerance to the anxiolytic effects does not seem to develop.
Antipsychotics and anticonvulsants are not recommended as initial therapy but may have some role for treatment-resistant patients. Among them, quetiapine is popular and may be useful as a second-line treatment for generalized anxiety disorder.
Buspirone is an azapirone and is effective for the treatment of generalized anxiety disorders. It is given in three divided doses during the day. The time to effect is similar to that for antidepressants, several weeks, and may take as long as several months. It may be useful as an adjunct to antidepressants for other anxiety disorders; however, most of the evidence is anecdotal.
β-Blockers, such as propranolol, are sometimes used for anxiety disorders, particularly social anxiety disorder. However, the available evidence does not support this use. Anecdotally, many consider it useful for social anxiety, particularly performance anxiety. The presumed mechanism is the drug’s ability to block many of the physiologic symptoms of anxiety. However, there is little data to support this, and at least one study showed no effect. One study concluded it might be useful for performance anxiety— specifically musical performances—however, it also had significant side effects that could impair performance.
Antihistamines, such as hydroxyzine, are also used, particularly as alternatives to benzodiazepines for acute treatment. It has some evidence for its use in generalized anxiety disorder. We know little about its long-term effect.
For most anxiety disorders, a conservative approach is to begin with an SSRI. Benzodiazepines are most useful when a patient requires rapid control of severe anxiety symptoms. In those cases, a short-term benzodiazepine, such as lorazepam or alprazolam, is helpful in the short term. Concurrently, an SSRI should be started and slowly increased.
For panic disorder, SSRIs or the serotonin–norepinephrine reuptake inhibitor (SNRI) venlafaxine are first-line options. Tricyclic antidepressants or MAOIs are effective but less preferably given their side effects. Other agents, such as mirtazapine, are other second-line options. As mentioned, the benzodiazepines are effective options but mainly used for short-term use or exacerbations. Long-term antidepressant therapy is useful for preventing relapse, with studies suggesting that the beneficial effects last for up to 1 to 3 years. When appropriate, maintenance therapy should be discontinued very slowly.
For generalized anxiety disorder, the approach is similar, with SSRIs and SNRIs being the first-line treatments. Reasonable alternatives if those are not effective include agomelatine, pregabalin, buspirone, and quetiapine.
For social anxiety disorder, the approach is similar to those already described, with SSRIs and SNRIs being the first-line choice. Pregabalin and clonazepam also have strong evidence, although the same caveats for other benzodiazepines apply to clonazepam. Phenelzine is effective as well but is rarely used because of the side effects. Tricyclic antidepressants, buspirone, and quetiapine are not recommended owing to their side effects. As noted above, β-blockers may be useful for performance anxiety. However, their use does not appear to generalize to other types of social anxiety.
Pharmacotherapy of Anxiety Disorders
MAOIs: Not generally recommended due to insufficient evidence.
RIMAs (e.g., Moclobemide): Second-line option but with insufficient evidence.
Other Psychotropics: Agomelatine, Buspirone, and Mirtazapine are considered second-line treatments.
Benzodiazepines: Second-line option.
Atypical Antipsychotics (e.g., Quetiapine): Second-line for some conditions but not recommended for others due to insufficient evidence.
Anticonvulsants (e.g., Pregabalin): Second-line option with varying levels of evidence.
Beta-Adrenergic Blocking Agents: Recommended only for performance anxiety.
Specific Phobia: Psychotherapy, especially behavioral therapies, is the first-line treatment. SSRIs may be helpful, although research is limited.
Agoraphobia: Pharmacotherapy focuses on treating comorbid panic attacks. Research on medications for "pure" agoraphobia is limited.
Psychosocial Therapies
Strong support exists for psychosocial therapies, including:
Cognitive-Behavioral Therapy (CBT)
Behavioral Therapies
Interpersonal Therapy
CBT Benefits:
Generalized Anxiety Disorder
Panic Disorder
Social Anxiety Disorder
Note: Evidence tempered by concerns about treatment bias in studies.
Individual CBT is often considered a first-line treatment for social anxiety disorder.
Group psychotherapy, mainly using CBT techniques, is also useful for social anxiety disorder.
In vivo exposure therapy is the treatment of choice for specific phobia.
Cognitive Therapy for Panic Disorder
Focuses:
Addressing false beliefs.
Providing information about panic attacks.
False Beliefs: Patients often misinterpret mild bodily sensations as signs of impending panic, doom, or death.
Information on Panic Attacks: Explanations that panic attacks are time-limited and not life-threatening.
Key Pointers for Pharmacotherapy of Anxiety Disorders
SSRIs as First-Line:
SSRIs are the first-line option.
Start low and go slow.
Routine increase to higher doses not recommended, but a subgroup might benefit.
Benzodiazepines:
Concomitant benzodiazepines as initial therapy in the short term may be useful.
Assessment of Efficacy:
8–12 weeks of pharmacotherapy at optimum doses may be needed to assess efficacy.
Maintenance Treatment:
Good evidence for the benefit of maintenance treatment at least up to 6 months.
Behavioral Therapies
Underlying assumption: Change can occur without psychologic insight.
Techniques:
Positive and negative reinforcement
Systematic desensitization
Flooding
Implosion
Graded exposure
Response prevention
Thought stopping
Relaxation techniques
Panic control therapy
Self-monitoring
Hypnosis
Specific Phobias: Gradual exposure to the feared stimulus while practicing relaxation techniques.
Interpersonal Psychotherapy
There is good evidence for interpersonal psychotherapy, particularly interpersonal skills training for social anxiety disorder.
Assumption: Patients have interpersonal deficits that contribute to their anxiety.
Result: Patients experience more punishments and fewer rewards from social interactions.
Virtual Therapy
Computer programs treat anxiety disorders such as agoraphobia, specific phobia, and social anxiety disorder.
Example: Virtual environments for agoraphobia patients (e.g., a supermarket).
Benefits: Useful for situations hard to reproduce in a clinician’s office (i.e., flying).
Supportive Psychotherapy
Involves psychodynamic concepts and a therapeutic alliance to promote adaptive coping.
Adaptive defenses are encouraged, and maladaptive ones are discouraged.
The therapist assists in reality testing and may offer behavioral advice.
Lacks empirical support but is frequently used as an adjunct to medication.
Insight-Oriented Psychotherapy
Goal: Increase patient insight into psychologic conflicts that manifest as symptomatic behavior.
Assumption: Anxiety represents an underlying psychodynamic conflict.
Evidence: Some studies show it can decrease anxiety symptoms and may have lasting effects, but studies have methodologic problems.
Epidemiology of Anxiety Disorders
Anxiety disorders are one of the most common groups of psychiatric disorders.
National Comorbidity Study:
One in four persons met diagnostic criteria for at least one anxiety disorder.
12-month prevalence rate of percent.
Panic Disorder:
12-month prevalence between and percent.
Lowest reported rate: percent (Nigeria).
Highest reported rate: percent (Italy).
Median: percent.
Generalized Anxiety Disorder:
12-month prevalence between about and percent in the United States.
Ranges from percent (Nigeria) to percent (Germany).
Social Anxiety Disorder:
12-month prevalence varies widely.
Highest rates: United States ( percent).
Lowest rates: China ( percent).
Median: about percent to percent.
Cultural differences may influence these rates.
Agoraphobia:
12-month prevalence is mostly consistent across regions.
Range: 0 (China) to percent (U.S.).
Exception: South Africa ( percent).
Specific Phobias:
Rates vary widely.
Range: percent (China) to percent (U.S.).
Sex Differences
Women have higher rates of almost all anxiety disorders than men (twofold difference for most disorders).
Exception: Social anxiety disorder (ratio is about equal).
Most evident during early and mid-adulthood.
Age of Onset
Anxiety disorders have one of the earliest onsets of all psychiatric disorders.
Most disorders begin in childhood or adolescence; the median age is .
Phobic disorders are the most stable over time.
Panic and generalized anxiety disorder have exacerbations and remissions, similar to major depressive disorder.
Sociocultural and Ethnic Variables
Anxiety disorders appear to be common in persons of lower socioeconomic status and educational level.
Complex relationships exist.
Some studies reported higher rates in African Americans and lower rates in Hispanics.
Neurobiology of Anxiety Disorders
Anxiety disorders are complex disorders.
Animal models have informed research on genetics and other aspects.
Studies of Inheritance Patterns
Family studies support familial aggregation of major anxiety disorders, including panic disorder, generalized anxiety disorder, phobias, and agoraphobia.
Familial risk for panic disorder was highest for early-onset panic disorder.
For social anxiety disorder, it was strongest for the generalized subtype.
Twin studies demonstrate higher inheritance for monozygotic than dizygotic twins, suggesting a genetic component.
Genetic contribution appears to be about percent or more, perhaps as high as percent for the phobias.
Genetic Studies
Linkage studies have had inconsistent results.
Association studies rely on candidate genes, usually chosen for their relevance to the disorder or prior studies.
Most studied are genes for neurotransmitter systems and stress response. Results have been inconsistent.
Genome-wide studies (GWAS) do not require the same a priori assumptions or degree of penetrance.
Limitation: Large sample sizes needed.
Panic Disorder:
One study found support for immune-related involvement.
Another study found two associated single nucleotide polymorphisms (SNPs), later replicated.
The genes are involved in mRNA expression in the frontal cortex.
Psychiatric Genetics Consortium has found several possible novel risk genes, but these results are tentative.
Limited data on gene–environment interactions, which are an essential area for investigation.
Limited but compelling evidence for the role of epigenetics in anxiety disorders.
Neuroimaging Studies
Preclinical data on fear circuitry has guided the search for neuroanatomical associations with anxiety.
Areas Studied:
Amygdala
Frontoamygdala connections (perirhinal cortex, ventrolateral prefrontal cortex (vlPFC), and anterior insula)
Hippocampus
Posterior and lateral orbitofrontal cortex (OFC)
Increased neurophysiologic activity in these areas in patients with phobias.
Neurochemical systems: Central noradrenergic, serotonergic, dopaminergic, and GABA systems.
Studies of fear conditioning in healthy humans confirm that the fear circuitry is conserved across species.
Amygdala, ventromedial PFC (vmPFC), and hippocampus implicated in both PET and fMRI studies.
Panic Disorder:
Abnormalities both when patients are at rest and during an acute panic attack.
Resting state: Hippocampal and parahippocampal areas implicated.
During panic: Associations in the insular and striatal regions, with reduced activity in the PFC.
MRI Studies:
Abnormalities of gray matter volume in the parahippocampal and temporal regions.
Exaggerated response to hypocapnia, suggesting a suffocation response.
Receptor-binding studies show abnormalities in GABA and serotonergic, particularly 5-HT1A, binding.
Specific Phobias:
Activation of anterior paralimbic regions and sensory association cortices.
Hypersensitivity to specific threat-related cues.
Amygdala implicated.
Social Anxiety Disorder:
Exaggerated response to social stimuli, particularly in the medial temporal lobe structures.
Amygdala hyperresponsivity to social threats.
Generalized Anxiety Disorder:
Does not show clear findings of amygdala hyperactivity.
Emotional dysregulation, with disruptions of functional connections between the anterior cingulate and the amygdala, as well as the uncinate fasciculus.
Weaker frontoamygdala connectivity and fear overgeneralization.
Effective treatments target these areas, including CBT and pharmacotherapies.
Psychological Studies
Behavioral scientists study the psychology of fear and anxiety through animal and human studies.
Conditioning:
Neutral stimulus (conditioned stimulus) paired with an aversive stimulus (unconditioned stimulus) leads to a conditioned response.
Extinction occurs when the conditioned stimulus is presented without the unconditioned stimulus.
Conditioning is not forgotten but is competing with a new memory.
Etiology
Biologic Theories
Neurochemicals and the Fight-or-Flight Reaction:
Stress activates neurotransmitters and neuropeptides, resulting in the fight-or-flight reaction.
Overgeneralization of this response can be disabling and underlies many anxiety disorders.
Chronic activation can cause alterations in various systems.
Early-life stressors can predispose individuals to anxiety disorders later in life.
Neurochemical Systems:
Monoamines
Hypothalamic–pituitary–adrenal (HPA) axis
Corticotropin-releasing hormone (CRH)
Patients with anxiety disorders have symptoms suggesting an exaggerated noradrenergic system output, along with increased autonomic and sympathetic activation.
Neurochemical Systems Involved in Anxiety Disorders and Related Treatment Approaches
Noradrenergic System:
Brain Regions: Locus coeruleus, amygdala, hippocampus, hypothalamus, prefrontal cortex
Association with Anxiety Disorders: Unrestrained, excessive system activation
Treatment Approaches: SNRIs (first-line), propranolol for performance anxiety
Hypothalamic–Pituitary–Adrenal (HPA) Axis:
Brain Regions: Hippocampus, amygdala, hypothalamus, prefrontal cortex
Association with Anxiety Disorders: Dysregulated HPA axis function (excessive cortisol release, abnormal feedback) in some studies
Treatment Approaches: Cortisol administration (under study for SAD and spider phobia), mifepristone (under study for GAD and PD)
Corticotropin-Releasing Hormone (CRH):
Brain Regions: Prefrontal and cingulate cortices, amygdala, hippocampus, hypothalamus, bed nucleus of stria terminalis, nucleus accumbens, periaqueductal gray matter, locus coeruleus, dorsal raphe nuclei
Association with Anxiety Disorders: Persistently increased CRH concentration
Treatment Approaches: CRH-1 receptor antagonists (failed to demonstrate efficacy in clinical trials)
Neurosteroids:
Brain Regions: Hippocampus, amygdala, cortex
Association with Anxiety Disorders: Abnormal peripheral levels of neurosteroids in PD; possibly also in GAD and SAD (inconsistent findings)
Treatment Approaches: Paroxetine (found to increase peripheral levels of allopregnanolone in one study of PD patients, but not in a second study), synthetic analogs under development
Arginine Vasopressin (AVP):
Brain Regions: Paraventricular nucleus of hypothalamus, septum, hippocampus, cortex
Association with Anxiety Disorders: Single nucleotide polymorphism in AVP V1b receptor gene linked to PD
Treatment Approaches: AVP V1b receptor antagonist (SSR149415) failed to demonstrate efficacy for GAD in a clinical trial. New AVP V1b receptor antagonists currently under study
Dopaminergic System:
Brain Regions: Amygdala, nucleus accumbens, prefrontal cortex
Association with Anxiety Disorders: Excessive mesocortical dopamine release, persistently high levels of dopamine in prefrontal cortex
Treatment Approaches: Bupropion (NDRI used primarily to treat depression, sometimes adjunct for anxiety disorders)
Serotonergic System:
Brain Regions: Dorsal raphe nuclei, amygdala, hippocampus, prefrontal cortex
Association with Anxiety Disorders: Low activity of postsynaptic 5-HT1A receptors in PD and SAD
Treatment Approaches: SSRIs and SNRIs (first-line for anxiety disorders)
γ-Amino Butyric Acid (GABA):
Brain Regions: Substantia nigra, globus pallidus, hypothalamus, periaqueductal gray matter, hippocampus, amygdala, anterior cingulate
Association with Anxiety Disorders: Reduced GABA-A and benzodiazepine binding in PD; reduced GABA levels in PD, possible imbalance between tonic GABAergic inhibition and glutamate-mediated excitation
Treatment Approaches: Tiagabine (selective GABA reuptake inhibitor) and vigabatrin (inhibitor of GABA transaminase) are potential treatments; topiramate (block voltage-sensitive sodium channels, potentiates GABA) mixed findings in PD; compounds selective for specific GABA-A receptor subtypes under development Note: Gabapentin and pregabalin although structurally related to GABA do not act on GABA receptors.
Glutamate:
Brain Regions: Amygdala, hippocampus, frontal and cingulate cortices
Association with Anxiety Disorders: Possible imbalance between tonic GABAergic inhibition and glutamate-mediated excitation in PD
Treatment Approaches: Efficacy of DCS as adjunct to exposure therapy for acrophobia, SAD, and PD; glycine transporter inhibitors under study; metabotropic receptor modulators under study; NMDA receptor antagonism as potential anxiolytic—preliminary efficacy of riluzole for GAD
Neuropeptide Y (NPY):
Brain Regions: Amygdala, hippocampus, brainstem, nucleus accumbens, locus coeruleus, hypothalamus
Association with Anxiety Disorders: Low NPY levels in PTSD, less well studied in anxiety disorders
Treatment Approaches: Intranasal administration may reduce anxiety, under investigation; Y1 and Y2 receptors potential target for treatment
Galanin:
Brain Regions: Prefrontal cortex, amygdala, hippocampus, locus coeruleus
Association with Anxiety Disorders: Very few studies in patients with anxiety disorders; galanin gene polymorphism associated with PD, only in women
Treatment Approaches: Potential of galanin modulators as future approach, no known studies
Cholecystokinin (CCK):
Brain Regions: Cerebral cortex, hippocampus, amygdala, caudate, putamen, thalamus, hypothalamus
Association with Anxiety Disorders: Lower CSF levels of CCK in PD
Treatment Approaches: To date, CCK-B receptor antagonists have failed to demonstrate efficacy for GAD or PD
Oxytocin:
Brain Regions: Hypothalamus, ventral tegmental area, amygdala
Association with Anxiety Disorders: Oxytocin gene receptor polymorphism associated with increased risk for anxiety in individuals with early life stress
Treatment Approaches: Intranasal oxytocin administration beneficial for SAD, under study; potential benefit for GAD
Endocannabinoid System:
Brain Regions: Prefrontal cortex, hypothalamus, amygdala, hippocampus
Association with Anxiety Disorders: Dysregulation of endocannabinoid signaling
Treatment Approaches: Cannabidiol reduced anxiety in patients with SAD during public speaking, under study; studies of FAAH inhibitors as potential treatment under way for PTSD (no longer classified as anxiety disorder), needed in anxiety disorders
Preclinical Studies of Fear Learning
Researchers study anatomical correlates of fear and anxiety using conditioned models of fear in animals.
Stimulus Processing:
A stimulus, collected through afferent systems, is processed and evaluated to assess aversiveness.
This assessment involves previous experiences and environmental contexts.
Results in a fear or anxiety response, which employs behavioral, endocrine, and autonomic responses.
Brain Regions Involved:
Amygdala:
Lateral Nucleus (LA): Primary interface for visual, auditory, and somatic sensory information from the thalamus and cortex. Connections between the thalamus and this nucleus are central to fear conditioning.
Basal (BA) Nuclei: Involved in forming the long-lasting traces for fear conditioning.
Central Nucleus: Outputs to motor, autonomic, and neuroendocrine systems involved in expressing fear, including the hypothalamus, midbrain, and medulla.
Hippocampus: Critical role in fear learning and extinction and helps in the development of emotional responses associated with fear.