Anxiety Disorders

Genetic and temperamental (non-modifiable)

• Heritability: Twin and family studies show moderate heritability for GAD and panic disorder, with first-degree relatives at substantially increased risk; the genetic liability is largely shared across anxiety disorders and major depression rather than disorder-specific.
• Behavioral inhibition: The classic childhood temperament of withdrawal from novelty and stranger wariness predicts later social anxiety disorder — the single developmental antecedent examiners most often plant in a pediatric stem.
• Female sex: Anxiety disorders are roughly twice as common in women, attributed to gonadal steroid modulation of amygdala reactivity and HPA tone plus reporting/help-seeking differences.
• Age: Onset is typically childhood to early adulthood (specific phobia and separation anxiety earliest, social anxiety in adolescence, panic disorder in the twenties to thirties). New-onset anxiety after age 40 should raise suspicion for an organic or substance cause.

Environmental and psychosocial (partly modifiable)

• Childhood adversity: Abuse, neglect, parental loss, and overprotective/controlling parenting sensitize the HPA axis and impair prefrontal fear-extinction circuitry.
• Stressful life events: Job loss, bereavement, trauma, and chronic illness commonly precipitate a first episode in a genetically loaded patient (diathesis–stress framing).
• Conditioning and modeling: A single aversive pairing (dog bite, elevator entrapment) plus subsequent avoidance-driven negative reinforcement produces and maintains specific phobia.

Modifiable substance and medical contributors

• Stimulants: Caffeine, nicotine, cocaine, amphetamines, and decongestants (pseudoephedrine) drive noradrenergic arousal and can reproduce panic symptoms exactly.
• Withdrawal states: Alcohol, benzodiazepine, and opioid withdrawal cause rebound noradrenergic surge; anxiety here is a withdrawal sign, not a primary disorder.
• Medications: Corticosteroids, thyroid hormone excess, albuterol, and levodopa.
• Medical mimics: Hyperthyroidism, pheochromocytoma, arrhythmia, hypoglycemia, and asthma/COPD — the APA and DSM-5-TR require exclusion of a medical or substance etiology before a primary anxiety diagnosis is assigned.

• GABAergic hypoactivity: Decreased inhibitory neurotransmission via gamma-aminobutyric acid (GABA) in the amygdala and prefrontal cortex results in diminished suppression of fear responses and excessive amygdala reactivity to perceived threats.

• Serotonergic dysfunction: Reduced serotonin (5-HT) transmission in key circuits (dorsolateral prefrontal cortex, anterior cingulate cortex) impairs fear extinction and emotional regulation, contributing to persistent anxiety and worry.

• Noradrenergic hyperactivity: Excessive norepinephrine signaling in the locus coeruleus increases arousal, hypervigilance, and startle responses; this directly mediates physical symptoms of panic (tachycardia, tremor, diaphoresis).

• HPA axis dysregulation: Chronic activation of the hypothalamic-pituitary-adrenal axis leads to sustained cortisol elevation, which perpetuates hypervigilance and impairs hippocampal-mediated fear extinction and memory processing.

• Amygdala-prefrontal cortex imbalance: The amygdala shows exaggerated responsiveness to threat cues while the prefrontal cortex demonstrates reduced capacity for top-down inhibition, impairing cognitive regulation of fear.

• Altered threat detection: Enhanced salience processing causes misinterpretation of neutral or ambiguous stimuli as dangerous, maintaining a cycle of anxiety and avoidance behavior.

• Generalized Anxiety Disorder (GAD): Excessive worry about multiple domains (work, health, finances, relationships) occurring more days than not for ≥6 months; accompanied by at least 3 of: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, or sleep disturbance. Worry is difficult to control and causes functional impairment.

• Panic Disorder: Recurrent, unexpected panic attacks (discrete periods of intense fear with ≥4 of: palpitations, diaphoresis, tremor, dyspnea, chest pain, nausea, dizziness, derealization/depersonalization, fear of dying or losing control) followed by ≥1 month of persistent worry about future attacks or avoidance behavior.

• Agoraphobia: Anxiety about being in situations where escape is difficult or help is unavailable (crowds, open spaces, enclosed spaces, public transit). Patients may become housebound in severe cases. Can occur with or without panic disorder.

• Social Anxiety Disorder: Intense fear of social/performance situations involving potential scrutiny or judgment; patient recognizes fear is excessive. Manifests as blushing, trembling, nausea, or avoidance of public speaking, eating in public, or social gatherings.

• Specific Phobia: Excessive, irrational fear triggered by a specific object or situation (animals, heights, blood, needles, flying). Immediate anxiety response occurs reliably upon exposure; avoidance is prominent.

• Separation Anxiety Disorder: Developmentally inappropriate anxiety about separation from attachment figures; can persist into adulthood. Includes worry about harm befalling the figure or feared situations preventing reunion.

• Selective Mutism: Failure to speak in specific social situations (e.g., school) despite speaking normally in other settings; reflects underlying social anxiety in children.

• Important clinical pearls:
• Autonomic arousal symptoms (tremor, tachycardia, diaphoresis, shortness of breath) are hallmark features across anxiety disorders and distinguish them from depression.
• Anxiety often precedes and underlies depression—always screen for anxiety in depressed patients.
• Avoidance behavior is reinforcing; anxiety temporarily decreases when the feared stimulus is avoided, perpetuating the anxiety disorder.

• Clinical interview and DSM-5 criteria: Diagnosis is primarily clinical, based on symptom duration (typically ≥6 months for GAD, ≥1 month for panic disorder), frequency, severity, and functional impairment. Use DSM-5 diagnostic criteria as the gold standard; always rule out medical causes and substance use.

• Screening instruments:
• GAD-7 (7-item Generalized Anxiety Disorder scale): Scores ≥10 suggest moderate anxiety; ≥15 suggest severe anxiety. Useful for monitoring treatment response.
• PANIC DISORDER SEVERITY SCALE (PDSS) and Panic and Agoraphobia Scale (PAS) quantify panic severity.
• Social Phobia Scale (SPS) and Social Interaction Anxiety Scale (SIAS) for social anxiety disorder.

• Medical workup to exclude organic causes:
• Thyroid function tests (TSH, free T4) to rule out hyperthyroidism.
• Cardiac evaluation (ECG, troponin) if chest pain or palpitations are prominent, especially in first presentation.
• Glucose, electrolytes, calcium to exclude metabolic derangements.
• Urine drug screen for stimulant use (cocaine, amphetamines, excessive caffeine).
• Consider imaging if neurological symptoms present.

• Important diagnostic considerations:
• Anxiety can be a symptom of medical conditions (hyperthyroidism, pheochromocytoma, cardiac arrhythmias, COPD, pulmonary embolism, asthma) or medication side effects (stimulants, decongestants, corticosteroids, caffeine).
• Substance withdrawal (alcohol, benzodiazepines, opioids) produces severe anxiety and physical symptoms mimicking panic disorder.
• Distinguish generalized anxiety from worry (which is normal); anxiety must be excessive, uncontrollable, and impairing.
• Comorbidity is common: ~80% of patients with anxiety disorders have a comorbid psychiatric condition (depression, substance use, other anxiety disorders).

First-line pharmacotherapy

• SSRIs (Selective Serotonin Reuptake Inhibitors): Gold standard for all anxiety disorders. Examples:
• Sertraline: Starting 25-50 mg daily, titrate to 50-200 mg daily. Onset of effect 2-4 weeks.
• Paroxetine: 10-20 mg daily, titrate to 20-60 mg daily (FDA-approved for panic disorder, social anxiety, GAD).
• Escitalopram: 5-10 mg daily, titrate to 10-20 mg daily.
• Fluoxetine: 10-20 mg daily, titrate to 20-80 mg daily.
• Wait ≥4-6 weeks at therapeutic dose before judging efficacy; full response may take 8-12 weeks.

• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors): Equally effective as SSRIs, particularly beneficial when fatigue/anhedonia coexist.
• Venlafaxine: 37.5 mg daily, titrate to 75-225 mg daily. Monitor blood pressure (can elevate BP at higher doses).
• Duloxetine: 30-60 mg daily, effective for GAD and anxiety with depression.

First-line psychotherapy

• Cognitive-Behavioral Therapy (CBT): Gold standard psychological treatment; 12-20 sessions typically needed. Components include psychoeducation, cognitive restructuring (challenging catastrophic thoughts), and exposure therapy (gradual, repeated exposure to feared stimuli until anxiety naturally decreases—principle of extinction).
• Exposure and Response Prevention (ERP): Particularly effective for panic disorder and phobias; patient confronts feared situation/stimulus while refraining from avoidance/safety behaviors.
• **Acceptance and Commitment Therapy (ACT

Complications of untreated disease

• Major depressive disorder: The most common sequela; chronic HPA activation and demoralization from avoidance-related functional loss convert anxiety into depression. Screen every anxious patient for depression and suicidality.
• Suicide risk: Anxiety disorders — panic disorder in particular — independently raise suicidal ideation and attempt risk, and the risk multiplies with comorbid depression or alcohol use. Active suicidal ideation with plan or intent is an emergency requiring immediate safety assessment.
• Substance use disorder: Self-medication with alcohol or benzodiazepines relieves anxiety acutely but produces tolerance and rebound anxiety, a self-perpetuating cycle.
• Progressive avoidance and disability: Agoraphobic avoidance can render a patient housebound; look for school refusal in children with separation anxiety.
• Medical morbidity and overuse of care: Repeated emergency visits, serial cardiac catheterizations for noncardiac chest pain, and cumulative radiation from repeat imaging.

Complications of treatment

• Early activation/jitteriness with SSRIs and SNRIs: Paradoxical worsening of anxiety in the first 1–2 weeks; prevented by starting at half the usual antidepressant dose and titrating slowly.
• Serotonin syndrome: Hyperthermia, clonus (lower extremity > upper), hyperreflexia, agitation, and diarrhea after adding a second serotonergic agent (triptan, linezolid, tramadol, MAOI). This is an emergency — stop all serotonergic drugs, provide supportive care and benzodiazepines; cyproheptadine for refractory cases.
• Discontinuation syndrome: Flu-like symptoms, dizziness, "brain zaps" on abrupt stop of short-half-life agents (paroxetine, venlafaxine); taper rather than stop.
• SSRI-associated hyponatremia (SIADH) in older adults, and increased bleeding risk with concurrent NSAIDs or anticoagulants via impaired platelet serotonin uptake.
• QT prolongation: The FDA limits citalopram dosing, with a lower maximum in patients over 60, hepatic impairment, or CYP2C19 inhibition.
• Suicidality boxed warning: FDA-mandated for all antidepressants in patients under 25 — monitor closely early in treatment.
• Benzodiazepine harms: Tolerance, dependence, cognitive impairment, and falls/fractures/delirium in the elderly (listed as potentially inappropriate by the AGS Beers Criteria). Abrupt withdrawal causes autonomic instability and withdrawal seizures — an emergency. The FDA carries a boxed warning against combining benzodiazepines with opioids because of fatal respiratory depression.

• The best next step after a first panic attack is a targeted medical workup, not reassurance alone: TSH, ECG, glucose, and urine drug screen. Once negative and criteria are met, first-line therapy is an SSRI plus CBT — combination beats either alone.
• USPSTF screening: The USPSTF recommends screening for anxiety disorders in adults 64 and younger, including pregnant and postpartum patients, and in children and adolescents ages 8–18. The GAD-7 is the workhorse instrument.
• Benzodiazepines are a bridge, not a plan: Reasonable for a few weeks while an SSRI takes effect, then taper. Avoid entirely in patients with alcohol or opioid use disorder and in the elderly. Do not give flumazenil to a chronic benzodiazepine user — it precipitates withdrawal seizures.
• Buspirone is a 5-HT1A partial agonist with no dependence, no sedation, and no withdrawal, but a delayed onset of about two weeks — so it is useless as PRN rescue and is not effective for panic disorder. Classic exam use: GAD in a patient with a substance use history.
• Propranolol treats the autonomic periphery (tremor, tachycardia) of performance-only social anxiety before a speech or recital. It does not treat generalized social anxiety disorder or panic disorder — a frequent distractor.
• Specific phobia is treated with exposure therapy, not medication — systematic desensitization is the answer. Blood-injection-injury phobia is the exception with a vasovagal faint; teach applied tension.
• Hyperventilation physiology: Acute respiratory alkalosis lowers ionized calcium, producing perioral paresthesias and carpopedal spasm — a panic finding, not hypocalcemia from a parathyroid disorder.
• Pheochromocytoma is the medical mimic examiners love: episodic headache, palpitations, diaphoresis, and sustained or paroxysmal hypertension. Panic attacks are typically normotensive-to-mildly-hypertensive with prominent fear of dying.
• Pregnancy: SSRIs and CBT remain the treatments of choice; ACOG advises against paroxetine given fetal cardiac malformation concerns.