11.4 Anxiety, Stress-Related & Obsessive-Compulsive Disorders
Key Takeaways
- Obsessive-compulsive disorder, phobias, post-traumatic stress disorder, generalized anxiety disorder and panic disorder are the enumerated anxiety topics.
- Selective serotonin reuptake inhibitors combined with cognitive behavioral therapy are first-line for essentially all anxiety disorders.
- Benzodiazepines are avoided for long-term management because of tolerance, dependence, cognitive impairment and fall risk.
- Obsessive-compulsive disorder often requires higher antidepressant doses and longer trials than depression.
- Medical mimics of anxiety include hyperthyroidism, pheochromocytoma, arrhythmia, hypoglycemia, and stimulant or withdrawal states.
Last updated: August 2026
2. Valproic Acid / Divalproex Sodium
- Mechanism: Increases brain GABA concentrations, blocks voltage-gated sodium channels and T-type calcium channels.
- Therapeutic Serum Level: 50 to 125 mcg/mL (draw 12-hour trough level).
- Key Clinical Utility: Highly effective for acute manic episodes, mixed episodes, and rapid-cycling bipolar disorder.
- Adverse Effects & Black Box Warnings:
- Hepatotoxicity / Fatal Hepatic Failure: Most common in first 6 months; monitor baseline and periodic Liver Function Tests (LFTs).
- Acute Pancreatitis: Can occur at any point in therapy; severe abdominal pain, elevated amylase/lipase; mandates immediate permanent discontinuation.
- Thrombocytopenia & Coagulopathy: Dose-dependent bone marrow suppression (especially at levels >100 mcg/mL); monitor baseline and periodic CBC with platelet count.
- Hyperammonemic Encephalopathy: Can present with lethargy, vomiting, and cognitive worsening with normal or near-normal LFTs; check serum ammonia; treated with L-Carnitine and Lactulose.
- Severe Teratogenicity: High incidence of Neural Tube Defects (Spina Bifida, Anencephaly: 1-2% risk), craniofacial anomalies, cardiovascular defects, and lower childhood IQ scores. Strongly avoid in women of childbearing potential unless absolutely refractory to other agents.
- Weight gain, alopecia, fine tremor, polycystic ovarian syndrome (PCOS).
3. Atypical Antipsychotics in Bipolar Disorder
- Bipolar Depression (FDA-Approved First-Line Options):
- Quetiapine (Seroquel): 300 mg at bedtime (dual 5-HT2A and D2 antagonism + active metabolite norquetiapine inhibits NE transporter; adverse effects: sedation, weight gain, metabolic syndrome, orthostasis).
- Lurasidone (Latuda): 20 to 120 mg/day (high 5-HT7 and D2 affinity; low metabolic risk; MUST be administered with a meal containing at least 350 calories to ensure absorption; minimal weight gain; EPS/akathisia risk).
- Cariprazine (Vraylar): 1.5 to 3 mg/day (D3/D2 partial agonist; effective for mania and depression; low metabolic risk; akathisia).
- Olanzapine-Fluoxetine Combination (Symbyax): Effective for treatment-resistant bipolar depression; high metabolic risk (weight gain, dyslipidemia, diabetes).
- Lumateperone (Caplyta): 42 mg daily.
- Acute Manic Episodes: Aripiprazole, Risperidone, Olanzapine, Quetiapine, Ziprasidone, or Haloperidol (rapid onset of antimanic action, often combined with Lithium or Valproate for severe mania).
- Lamotrigine (Lamictal): Approved for bipolar maintenance therapy and prevention of depressive relapses (ineffective for acute mania). Black Box Warning for Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN). Mandates strict slow dose titration (25 mg daily for 2 weeks, 50 mg daily for 2 weeks, 100 mg daily for 1 week, target 200 mg daily). Critical Drug-Drug Interaction: Valproate strongly inhibits lamotrigine glucuronidation and doubles lamotrigine blood levels (starting dose must be halved to 12.5-25 mg every other day); Carbamazepine and phenytoin induce glucuronidation and halve lamotrigine blood levels.
1. Anxiety, Stress-Related & Obsessive-Compulsive Disorders
Anxiety disorders represent a spectrum of conditions characterized by excessive, irrational fear, autonomic hyperarousal, and maladaptive avoidance behaviors.
Clinical Comparison of Anxiety & Stress Disorders
| Disorder | Core Diagnostic Criteria & Duration | First-Line Pharmacotherapy | First-Line Psychotherapy | Second-Line / Adjunctive Options & Contraindications |
|---|---|---|---|---|
| Generalized Anxiety Disorder (GAD) | Excessive, uncontrollable anxiety and worry about multiple daily domains for >= 6 months, accompanied by >=3 of 6 somatic symptoms (restlessness/on edge, easy fatigability, difficulty concentrating, irritability, muscle tension, sleep disturbance); GAD-7 score >=10 | SSRIs (Escitalopram, Sertraline, Paroxetine) or SNRIs (Duloxetine, Venlafaxine XR) | Cognitive Behavioral Therapy (CBT) (cognitive restructuring, progressive muscle relaxation, worry exposure) | Buspirone (5-HT 1A partial agonist; 15-60 mg/day divided BID/TID; no sedation, zero abuse liability, 2-4 week onset; ineffective PRN); Hydroxyzine (antihistaminergic); Pregabalin; Avoid long-term benzodiazepines |
| Panic Disorder | Recurrent, unexpected panic attacks (abrupt surge of intense fear peaking within minutes with >=4 somatic/cognitive symptoms: palpitations, sweating, trembling, SOB, choking sensation, chest pain, nausea, dizziness, chills/heat, paresthesias, derealization, fear of dying) followed by >=1 month of persistent worry about further attacks or maladaptive behavioral changes (avoidance) | SSRIs (Sertraline, Paroxetine, Fluoxetine) or SNRIs (Venlafaxine XR); start at half standard dose to avoid initial jitteriness | CBT with Interoceptive Exposure (deliberately inducing somatic panic sensations to extinguish catastrophic misinterpretations) | Short-term Benzodiazepine bridging (Clonazepam 0.5-1 mg/day or Lorazepam 0.5-1 mg BID) reserved strictly for severe acute disabling distress during initial 2-4 weeks of SSRI titration, then tapered off; avoid chronic use |
| Social Anxiety Disorder (SAD) | Marked, persistent fear or anxiety about one or more social situations in which the individual is exposed to possible scrutiny by others (conversations, eating in public, public speaking) lasting >= 6 months | Generalized Subtype: SSRIs (Sertraline, Paroxetine) or SNRIs (Venlafaxine XR)<br/>Performance-Only Subtype: Oral Propranolol 10 to 40 mg (or Atenolol 25-50 mg) taken 30 to 60 minutes prior to the performance event | CBT with In Vivo Social Exposure and video feedback | Propranolol blunts peripheral beta-adrenergic hyperactivity (palpitations, vocal/hand tremors, diaphoresis); Contraindications to Propranolol: Active reactive airway disease / asthma, severe bradycardia, second/third-degree AV block, decompensated HF |
| Obsessive-Compulsive Disorder (OCD) | Presence of Obsessions (recurrent, persistent intrusive thoughts, urges, or images causing marked anxiety) and/or Compulsions (repetitive behaviors [hand washing, checking, ordering] or mental acts [counting, repeating words silently] performed to neutralize anxiety according to rigid rules); time-consuming (>1 hour/day) or causing severe impairment | High-Dose SSRIs: Sertraline (up to 200 mg/day), Fluoxetine (up to 80 mg/day), Fluvoxamine (up to 300 mg/day), Paroxetine (up to 60 mg/day). (Note: Higher doses and longer durations [10-12 weeks] are required compared to MDD) | Exposure and Response Prevention (ERP) (gold-standard specialized behavioral therapy: systematic exposure to obsession-provoking cues while strictly refraining from performing compulsions) | Second-line: Clomipramine (potent serotonergic TCA; monitor anticholinergic effects, QTc, and seizure threshold); Augmentation with atypical antipsychotics (Aripiprazole, Risperidone) |
| Post-Traumatic Stress Disorder (PTSD) | Exposure to actual or threatened death, serious injury, or sexual violence. Symptoms persist for > 1 month across 4 clusters:<br/>1. Intrusion (flashbacks, nightmares, intrusive memories)<br/>2. Avoidance (trauma reminders, thoughts)<br/>3. Negative alterations in mood/cognition (amnesia, emotional detachment, excessive guilt)<br/>4. Hyperarousal (hypervigilance, exaggerated startle, insomnia, irritability) | SSRIs (Sertraline, Paroxetine) or SNRI (Venlafaxine XR) | Trauma-Focused Psychotherapy: Prolonged Exposure (PE), Cognitive Processing Therapy (CPT), or Eye Movement Desensitization and Reprocessing (EMDR) | Prazosin (centrally acting alpha-1 adrenergic antagonist, 1 to 15 mg at bedtime; crosses BBB and inhibits central noradrenergic hyperactivation; proven to reduce trauma-related nightmares and sleep disturbance; monitor for orthostasis); BENZODIAZEPINES ARE STRICTLY CONTRAINDICATED (worsen PTSD symptoms, prevent trauma processing, high abuse liability) |