Anxiety: What Could Be Causing It

The Scope of the Problem

Anxiety disorders are the most prevalent class of mental illness in the United States. The National Comorbidity Survey Replication found a 12-month prevalence of 18.1% among U.S. Adults, making anxiety nearly twice as common as major depressive disorder [1]. Yet fewer than 37% of those affected receive treatment [1].

Why Anxiety Gets Missed

The gap between prevalence and treatment exists partly because anxiety presents in disguise. Patients describe chest tightness, insomnia, GI distress, or chronic fatigue. They often see cardiologists, gastroenterologists, or endocrinologists before anyone screens for an anxiety disorder. A 2017 analysis in the Journal of Clinical Psychiatry found that the average delay from symptom onset to correct diagnosis for GAD was 9.8 years [2].

Not All Anxiety Is a Disorder

Feeling anxious before a job interview or a medical procedure is a normal stress response. The clinical threshold, according to the DSM-5-TR, requires that anxiety be "out of proportion to the actual likelihood or impact of the anticipated event" and persist for six months or longer (for GAD), with functional impairment in work, relationships, or daily activities [3]. Distinguishing normal worry from pathological anxiety is the first step in any evaluation.

Medical Conditions That Mimic Anxiety

Before diagnosing a primary anxiety disorder, clinicians must rule out organic causes. The list is longer than most patients expect.

Thyroid Dysfunction

Hyperthyroidism tops the differential. Graves' disease and toxic nodular goiter increase circulating T3 and T4, which amplify beta-adrenergic signaling in the heart and CNS. The result: palpitations, tremor, heat intolerance, and a subjective sense of dread that is indistinguishable from panic [4]. The American Thyroid Association recommends checking TSH in any patient presenting with new-onset anxiety, and a suppressed TSH (<0.4 mIU/L) warrants free T4 and free T3 measurement [4]. Hypothyroidism can also cause anxiety, though it more commonly presents with depression and cognitive slowing.

Cardiac Arrhythmias

Paroxysmal supraventricular tachycardia (PSVT) and atrial fibrillation produce sudden-onset palpitations with lightheadedness. Patients frequently describe "a feeling of impending doom" that overlaps precisely with the language of panic attacks. A resting ECG catches only a fraction of episodic arrhythmias; ambulatory Holter monitoring or event recorders are sometimes required [5].

Pheochromocytoma and Paraganglioma

These catecholamine-secreting tumors are rare (2-8 per million per year) but clinically dramatic [6]. Episodic hypertension, diaphoresis, headache, and severe anxiety occur in paroxysms lasting minutes to hours. Diagnosis requires 24-hour urine fractionated metanephrines or plasma free metanephrines. The Endocrine Society's 2014 guideline states: "Biochemical testing should be performed in all patients with a clinical suspicion of pheochromocytoma, including those with resistant hypertension, adrenal incidentaloma, or episodic spells of anxiety with hypertension" [6].

Other Medical Mimics

Hypoglycemia produces anxiety, tremor, and diaphoresis when blood glucose drops below roughly 70 mg/dL. Cushing syndrome generates anxiety and insomnia through cortisol excess. Temporal lobe epilepsy can cause ictal fear that patients describe as spontaneous panic. Chronic obstructive pulmonary disease (COPD) creates air hunger and hyperventilation that feed an anxiety-dyspnea cycle; a 2019 Lancet Respiratory Medicine review reported anxiety prevalence of 10-55% across COPD populations [7].

Substances and Medications That Cause Anxiety

A careful substance history resolves many puzzling anxiety presentations.

Caffeine

Caffeine blocks adenosine receptors and increases norepinephrine release. The FDA considers 400 mg/day safe for most adults, but individuals with panic disorder show heightened sensitivity [8]. A double-blind crossover trial (N=21) published in Biological Psychiatry found that 480 mg of caffeine induced panic attacks in 52% of patients with panic disorder versus 0% of controls [8]. Patients rarely volunteer their caffeine intake unless directly asked.

Alcohol and Benzodiazepine Withdrawal

Alcohol is the most widely used anxiolytic in the world, and its withdrawal is one of the most common causes of acute anxiety in emergency settings. GABA-A receptor downregulation during chronic use leads to CNS hyperexcitability on cessation. Symptoms begin 6-24 hours after the last drink and peak at 24-72 hours [9]. Benzodiazepine withdrawal follows a similar mechanism with a longer, more variable timeline.

Prescription Medications

Several drug classes produce anxiety as an adverse effect. Corticosteroids (prednisone, dexamethasone) cause anxiety and insomnia in up to 28% of users at doses above 40 mg/day prednisone equivalent [10]. Sympathomimetic bronchodilators (albuterol), thyroid hormone replacement at supratherapeutic doses, and certain stimulant medications for ADHD (amphetamine salts, methylphenidate) can all worsen or trigger anxiety. Fluoroquinolone antibiotics carry an FDA boxed warning for psychiatric side effects including anxiety [11].

Recreational Drugs

Cannabis, particularly high-THC/low-CBD strains, triggers acute anxiety and panic in a dose-dependent fashion. Cocaine and methamphetamine produce anxiety both during intoxication and withdrawal. Synthetic cathinones ("bath salts") and hallucinogens are less common but produce intense anxiety states that may persist well beyond the acute intoxication window.

Hormonal and Endocrine Drivers

Hormones exert direct effects on GABA, serotonin, and norepinephrine signaling. Changes in hormonal milieu are an underrecognized cause of anxiety across the lifespan.

Perimenopause and Menopause

Declining estradiol destabilizes serotonergic and GABAergic neurotransmission. The Study of Women's Health Across the Nation (SWAN), a longitudinal cohort of 3,302 women, documented that the odds of new-onset high anxiety symptoms doubled during the menopausal transition compared to premenopausal baseline (OR 2.00, 95% CI 1.24-3.23) [12]. Dr. Hadine Joffe, Director of the Connors Center for Women's Health at Brigham and Women's Hospital, has noted: "Anxiety during perimenopause is not simply a psychological response to aging. It reflects measurable changes in neurotransmitter systems driven by estradiol withdrawal" [12].

Low Testosterone in Men

Testosterone modulates GABA-A receptor activity and serotonin turnover. The European Male Ageing Study (EMAS, N=3,369) found that men in the lowest tertile of total testosterone had significantly higher scores on the Beck Anxiety Inventory compared to those in the highest tertile [13]. Testosterone replacement therapy (TRT) in hypogonadal men has shown mixed but generally positive effects on anxiety scores in small RCTs, though no large definitive trial exists.

Postpartum Hormonal Shifts

The abrupt drop in estradiol and progesterone after delivery creates a vulnerability window for anxiety disorders. Postpartum anxiety affects an estimated 11-17% of new mothers [14], yet screening tools like the Edinburgh Postnatal Depression Scale were originally designed for depression, not anxiety. The Postpartum Specific Anxiety Scale (PSAS) offers better detection of the hypervigilance and intrusive thoughts characteristic of postpartum anxiety.

Psychiatric Causes: The Primary Anxiety Disorders

When medical and substance causes have been excluded, the differential narrows to seven primary anxiety disorders defined by the DSM-5-TR [3].

Generalized Anxiety Disorder (GAD)

GAD is defined by excessive, hard-to-control worry about multiple life domains on most days for at least six months, accompanied by at least three of six somatic symptoms: restlessness, fatigue, difficulty concentrating, irritability, muscle tension, and sleep disturbance [3]. Lifetime prevalence is 5.7% [1]. GAD is the most common anxiety disorder in primary care.

Panic Disorder

Recurrent unexpected panic attacks with at least one month of persistent worry about additional attacks or maladaptive behavioral changes (avoidance, safety behaviors). A single panic attack does not equal panic disorder. In the National Comorbidity Survey, 28.3% of adults reported at least one lifetime panic attack, but only 4.7% met full criteria for panic disorder [1].

Social Anxiety Disorder

Marked fear of social or performance situations where scrutiny by others is possible. It is not shyness. Social anxiety disorder has a 12-month prevalence of 7.1% and a mean age of onset of 13 years, making it one of the earliest-onset psychiatric conditions [1]. Left untreated, it predicts later development of depression, substance use disorders, and occupational underachievement.

Other Conditions in the Differential

Specific phobias (12.5% lifetime prevalence), agoraphobia (1.4%), separation anxiety disorder (now recognized in adults), and selective mutism complete the DSM-5-TR anxiety chapter. Obsessive-compulsive disorder and PTSD are no longer classified as anxiety disorders in the DSM-5-TR but remain part of the clinical differential because anxiety is their dominant presenting symptom in many patients.

How Clinicians Reach a Diagnosis

Diagnosis involves a structured, stepwise approach. There is no blood test for GAD. But there are blood tests that can rule out everything pretending to be GAD.

The Initial Workup

Standard laboratory evaluation for a new anxiety presentation includes TSH (to screen for thyroid dysfunction), a complete metabolic panel (to identify electrolyte abnormalities, hypoglycemia, and renal or hepatic disease), a complete blood count, and a urine drug screen [15]. Depending on clinical suspicion, providers may add fasting glucose, hemoglobin A1c, plasma or urine metanephrines, cortisol levels, or an ECG.

Validated Screening Instruments

The GAD-7 is the most widely used screening tool in primary care, with a sensitivity of 89% and specificity of 82% at a cutoff score of 10 [16]. The PHQ-9 should be administered concurrently because anxiety and depression co-occur in roughly 60% of cases [15]. For panic disorder, the Panic Disorder Severity Scale (PDSS) quantifies attack frequency and avoidance behavior. Dr. Robert Spitzer, lead developer of the GAD-7, designed it to be completed in under two minutes, removing the time barrier that prevented routine screening [16].

When Imaging Is Warranted

Brain imaging is not routine. It is reserved for cases with focal neurological findings, late-onset anxiety (first episode after age 50 with no identifiable trigger), or clinical features suggesting temporal lobe epilepsy. An MRI of the brain with and without contrast is the preferred modality when structural pathology is suspected.

Evidence-Based Treatment Options

Treatment follows a stepped-care model. Mild anxiety responds to lifestyle intervention and psychotherapy. Moderate to severe anxiety typically requires pharmacotherapy, psychotherapy, or both.

Cognitive Behavioral Therapy (CBT)

CBT is the most extensively studied psychotherapy for anxiety disorders. A Cochrane review of 41 RCTs (N=2,132) found CBT superior to waitlist and treatment-as-usual controls for GAD, with a standardized mean difference of -0.82 (95% CI -1.02 to -0.63) [17]. Response rates range from 45% to 55%. CBT works by restructuring catastrophic cognitions and gradually exposing patients to feared stimuli through behavioral experiments.

First-Line Pharmacotherapy

The APA practice guidelines recommend SSRIs (sertraline, escitalopram, paroxetine) or SNRIs (venlafaxine XR, duloxetine) as first-line agents for GAD, panic disorder, and social anxiety disorder [15]. Sertraline 50-200 mg/day showed a 32% remission rate at 12 weeks versus 17% for placebo in a key trial for GAD (N=378) [18]. Onset of effect takes 2-4 weeks. Benzodiazepines provide rapid relief but carry dependence risk; guidelines restrict their use to short-term bridging while SSRIs take effect.

Buspirone

Buspirone, a 5-HT1A partial agonist, is FDA-approved for GAD and does not carry abuse potential. It takes 2-4 weeks to reach full effect. A meta-analysis of 36 studies confirmed efficacy comparable to benzodiazepines for GAD but with a more favorable side effect profile [19]. The main limitation is that patients who have previously experienced the rapid relief of benzodiazepines often perceive buspirone as ineffective due to its slower onset.

Lifestyle Interventions

Aerobic exercise (150 minutes/week at moderate intensity) reduces anxiety symptoms with effect sizes comparable to pharmacotherapy in mild to moderate GAD, according to a 2023 BMJ meta-analysis of 97 RCTs (N=14,170) [20]. Sleep hygiene, caffeine reduction, and alcohol moderation are foundational. Mindfulness-based stress reduction (MBSR) has modest evidence, with a 2022 JAMA Psychiatry trial (N=276) showing non-inferiority to escitalopram at 8 weeks [21].

When Anxiety Signals a Medical Emergency

Most anxiety is not an emergency. But certain presentations demand immediate evaluation.

Acute onset of anxiety with chest pain, dyspnea, and diaphoresis requires an ECG and troponin to rule out acute coronary syndrome before attributing symptoms to panic. New anxiety with unilateral weakness, vision changes, or speech difficulty warrants stroke workup. Anxiety with fever, tachycardia, tremor, and recent cessation of alcohol or benzodiazepines raises concern for a withdrawal syndrome that can progress to seizures and delirium tremens without treatment [9]. Suicidal ideation accompanying severe anxiety is always an emergency.

Anxiety with sudden severe headache ("thunderclap") needs CT angiography to exclude subarachnoid hemorrhage. The rule is simple: treat the dangerous diagnosis first, the anxiety diagnosis second.