14.3 Anxiety Disorders, Substance Misuse & Psychotropic Side Effects

Anxiety & Stress-Related Disorders: Spectrum & Evidence-Based Management

Anxiety disorders represent the most prevalent class of psychiatric conditions worldwide. Clinicians must distinguish pathological, disabling anxiety from adaptive physiological fear and systematically address comorbid somatic manifestations.

1. Generalized Anxiety Disorder (GAD)

• DSM-5 Criteria: Characterized by excessive, pervasive anxiety and worry about a multitude of everyday events or activities, occurring more days than not for at least 6 months, which the patient finds difficult to control. Accompanied by at least 3 of the following 6 somatic/cognitive symptoms (only 1 required in children):
  1. Restlessness or feeling keyed up or on edge
  2. Being easily fatigued
  3. Difficulty concentrating or mind going blank
  4. Irritability
  5. Muscle tension (prominent neck, shoulder, or back stiffness)
  6. Sleep disturbance (difficulty falling or staying asleep, restless unsatisfying sleep)
• First-Line Therapy: First-line pharmacotherapy consists of SSRIs (sertraline, escitalopram) or SNRIs (venlafaxine, duloxetine). First-line psychotherapy is Cognitive Behavioral Therapy (CBT). Second-line agents include Buspirone (a 5-HT1A receptor partial agonist; advantages: no sedation, no cognitive impairment, zero abuse or dependence potential; disadvantage: delayed therapeutic onset of 2 to 4 weeks, ineffective for panic disorder) and pregabalin. Benzodiazepines are restricted strictly to 1 to 2 weeks for acute severe crisis relief during SSRI initiation.

2. Panic Disorder & Agoraphobia

• Panic Attack Phenomenology: An abrupt surge of intense fear or intense discomfort that peaks within minutes, accompanied by at least 4 of 13 somatic/cognitive symptoms: palpitations/tachycardia, diaphoresis, trembling/shaking, sensations of shortness of breath/smothering, feelings of choking, chest pain/discomfort, nausea/abdominal distress, dizziness/lightheadedness, chills/heat sensations, paresthesias (numbness/tingling), derealization/depersonalization, fear of losing control or 'going crazy', and fear of dying.
• Panic Disorder Diagnostic Criteria: Recurrent unexpected panic attacks, followed by at least 1 month of persistent concern or worry about having additional attacks, worry about the consequences of attacks (cardiac arrest, stroke), or significant maladaptive alterations in behavior designed to avoid attacks.
• Agoraphobia: Marked fear or avoidance of at least 2 of 5 situations: using public transportation, being in open spaces, being in enclosed spaces, standing in line or in a crowd, or being outside the home alone. The underlying fear is that escape might be difficult or help unavailable should panic-like or incapacitating symptoms emerge.
• Therapy: SSRIs/SNRIs combined with CBT (interoceptive exposure); short-term sublingual or oral benzodiazepines (lorazepam, alprazolam) may abort acute severe attacks, but long-term maintenance is avoided due to tolerance, cognitive blunting, and dependence.

3. Post-Traumatic Stress Disorder (PTSD)

• Etiological Precondition: Exposure to actual or threatened death, serious injury, or sexual violence through direct experience, witnessing, learning that it occurred to a close family member/friend, or repeated extreme exposure to aversive details (first responders).
• Core Symptom Clusters (Duration > 1 Month):
  1. Intrusion Symptoms: Recurrent, involuntary, distressing memories; traumatic nightmares; dissociative reactions (flashbacks in which the trauma feels recurring); intense physiological distress at reminders.
  2. Avoidance: Persistent avoidance of distressing memories, thoughts, feelings, or external reminders (people, places, conversations) associated with the event.
  3. Negative Alterations in Cognitions & Mood: Inability to remember key aspects of trauma (dissociative amnesia), persistent distorted blame of self or others, pervasive negative emotional state (fear, horror, guilt), detachment from others, anhedonia.
  4. Alterations in Arousal & Reactivity: Irritable behavior, angry outbursts, reckless self-destructive behavior, hypervigilance, exaggerated startle response, concentration deficits, sleep disturbances.
• Acute Stress Disorder: Requires at least 9 of 14 trauma-related symptoms across intrusion, negative mood, dissociation, avoidance and arousal, causing significant distress/impairment for 3 days to 1 month; duration alone does not establish the diagnosis.
• Treatment: Trauma-focused CBT (TF-CBT), Eye Movement Desensitization and Reprocessing (EMDR); first-line pharmacotherapy: SSRIs (sertraline, paroxetine). Prazosin (an alpha-1 adrenergic antagonist) is uniquely effective in reducing trauma-related nightmares and sleep fragmentation by suppressing central noradrenergic hyperactivation.

4. Obsessive-Compulsive Disorder (OCD)

• Phenomenology: Characterized by obsessions (recurrent, persistent, intrusive, unwanted thoughts, urges, or images causing marked anxiety) and/or compulsions (repetitive behaviors such as handwashing, checking, ordering, or mental acts like counting, praying, silently repeating words performed to neutralize obsession-induced anxiety according to rigid rules). Recognized as egodystonic (distressing and recognized as irrational by the patient, unlike egosyntonic obsessive-compulsive personality disorder).
• Treatment: First-line psychotherapy is Exposure and Response Prevention (ERP). First-line pharmacotherapy requires high-dose SSRIs (e.g., fluoxetine 60-80 mg daily, sertraline 200 mg daily). Second-line agent is the tricyclic antidepressant Clomipramine (a potent serotonin reuptake inhibitor).

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Substance Misuse & Acute Withdrawal in the Caribbean Context

Substance misuse poses severe public health challenges in the Caribbean. Alcohol remains the most pervasive drug of abuse, driving trauma and domestic morbidity. Crack cocaine and cannabis toxicity are frequent emergency room presentations.

Alcohol Withdrawal Syndrome: Neurobiology & Clinical Stages

• Pathophysiological Mechanism: Alcohol acutely enhances inhibitory GABA-A signalling and inhibits excitatory NMDA signalling. Prolonged exposure produces compensatory reduced GABA-A function and increased NMDA activity/receptor expression. Abrupt reduction or cessation unmasks this excitatory state, producing autonomic hyperactivity, tremor, seizures and delirium.

Timeline of Alcohol Withdrawal

1. Stage 1: Minor Withdrawal (6 to 12 Hours post-cessation): Tremulousness (fine hand tremor), insomnia, generalized anxiety, nausea, vomiting, diaphoresis, mild tachycardia, and systolic hypertension.
2. Stage 2: Alcoholic Hallucinosis (12 to 24 Hours post-cessation): Visual, auditory, or tactile hallucinations (seeing animals or insects, hearing voices). Critical Clinical Feature: The patient's sensorium remains clear and fully oriented, distinguishing this from delirium tremens.
3. Withdrawal Seizures (About 8 to 48 Hours post-cessation, peaking near 24 hours): Generalized tonic-clonic convulsions. Typically singular or a brief flurry of 2 to 3 seizures. Post-ictal period is brief; status epilepticus is rare (< 3%). These are acute symptomatic (provoked) seizures, not by themselves evidence of chronic epilepsy. Treat withdrawal with benzodiazepines; routine phenytoin is ineffective unless a separate seizure disorder requires it.
4. Stage 4: Delirium Tremens (DTs) (48 to 96 Hours post-cessation; can last up to 7 days): Life-threatening medical emergency with historically a 5% to 15% mortality rate. Characterized by severe disorientation, profound delirium, fluctuating consciousness, vivid hallucinations (zoopsia), marked agitation, and severe autonomic hyperarousal (fever > 38.5°C, profuse drenching diaphoresis, tachycardia > 120 bpm, labile hypertension, tachypnea).

Clinical Management: The CIWA-Ar Protocol & Pharmacotherapy

• The CIWA-Ar Scale: This 10-item scale supports symptom-triggered treatment in communicative patients without delirium; local treatment thresholds commonly start around 8–10. Assess prior seizures/DTs and other risk factors separately: a low current score does not exclude serious withdrawal risk. Do not use CIWA-Ar during delirium; use an objective protocol such as RASS/MINDS, close observation and individualized IV benzodiazepines.
• Benzodiazepine Regimen: Symptom-triggered dosing is preferred when reliable assessment and trained monitoring are available and can reduce medication exposure. Use an individualized fixed-dose or front-loading regimen when symptom scoring is unreliable/infeasible or severe withdrawal warrants it, with respiratory and sedation monitoring.
  • Long-Acting Benzodiazepines: Diazepam (10 to 20 mg PO) or Chlordiazepoxide (25 to 50 mg PO) repeated hourly until CIWA-Ar < 8. Long-acting active metabolites provide smooth self-tapering and protect against rebound seizures.
  • Hepatic Failure / Cirrhosis / Elderly: Use Lorazepam (1 to 2 mg PO/IV) or Oxazepam (15 to 30 mg PO) [Mnemonic: LOT – Lorazepam, Oxazepam, Temazepam]. These agents undergo direct hepatic glucuronidation without phase I cytochrome P450 oxidation, preventing toxic drug accumulation and hepatic encephalopathy.

Wernicke-Korsakoff Syndrome: Prompt Thiamine and Glucose Treatment

• Etiology: Severe thiamine (vitamin B1) deficiency resulting from chronic malnutrition, impaired gastrointestinal absorption, and reduced hepatic storage in alcohol-dependent patients. Thiamine is an indispensable cofactor for transketolase, pyruvate dehydrogenase, and alpha-ketoglutarate dehydrogenase in cerebral glucose metabolism. Deficiency causes selective necrosis of the mamillary bodies, periventricular nuclei, and dorsomedial thalamus.
• Clinical Triad of Acute Wernicke Encephalopathy:
  1. Acute Encephalopathy: Global confusion, apathy, disorientation, inattention.
  2. Gait Ataxia: Cerebellar vestibulocerebellar dysfunction presenting with a wide-based, staggering gait.
  3. Oculomotor Abnormalities: Bilateral horizontal nystagmus, bilateral abducens (cranial nerve VI) palsy, conjugate gaze palsies.
• Korsakoff Syndrome: The chronic, largely irreversible neuropsychiatric sequela occurring in untreated Wernicke's, characterized by severe anterograde and retrograde amnesia and confabulation (spontaneous fabrication of false memories without conscious intent to deceive).
• RESUSCITATION: Suspected Wernicke encephalopathy requires prompt high-dose parenteral thiamine (e.g. IV thiamine 200–500 mg every 8 hours, following the local protocol). In a hypoglycaemic patient, give glucose immediately and thiamine concurrently when available; do not withhold glucose while waiting for thiamine. Continue thiamine during nutritional treatment because untreated deficiency can cause persistent neurological injury. At-risk alcohol-dependent patients also need thiamine prophylaxis.

Cocaine Intoxication & Sympathomimetic Toxicity

• Mechanism: Blocks presynaptic reuptake of dopamine, norepinephrine, and serotonin, producing massive sympathetic nervous system hyperactivation.
• Clinical Features: Severe agitation, mydriasis, diaphoresis, hyperthermia, tachycardia, and severe hypertension.
• Life-Threatening Complications: Acute coronary vasospasm, myocardial infarction, aortic dissection, hemorrhagic/ischemic stroke, ventricular arrhythmias, and rhabdomyolysis.
• Emergency Management: High-dose intravenous benzodiazepines (lorazepam 2 to 4 mg IV) are first-line therapy to blunt central sympathetic outflow, reduce blood pressure, control heart rate, and relieve psychomotor agitation. Intravenous nitroglycerin or phentolamine (nonselective alpha-adrenergic antagonist) treats refractory coronary vasospasm or malignant hypertension.
• BETA-BLOCKER CAUTION: Avoid pure beta-blockers such as propranolol or metoprolol as initial treatment of acute cocaine-related hypertension/ischemia; coronary vasoconstriction may worsen. Benzodiazepines and vasodilators are preferred. This is not an absolute prohibition of every beta-blocker: ASAM/AAAP allows specialist consideration of an agent with alpha-1 blockade (e.g. labetalol) for persistent hyperadrenergic symptoms after initial treatment. Seek toxicology/cardiology advice; life-threatening cocaine vasospasm is treated with vasodilators, not beta-blockade.

Opioid Overdose & Acute Withdrawal

• Overdose Triad: Central nervous system depression (coma), pinpoint pupils (miosis), and severe respiratory depression (respiratory rate < 8-10 breaths/min). Note: Mydriasis may occur in late-stage severe cerebral hypoxia or with meperidine.
• Emergency Reversal: Intravenous, intramuscular, or intranasal Naloxone (pure competitive mu-opioid receptor antagonist). Titrate in small increments (0.04 to 0.4 mg) to restore adequate spontaneous respiration without precipitating acute severe withdrawal. Because naloxone has a short half-life (30 to 90 minutes) compared to many opioids (e.g., methadone half-life 24-36 hours), continuous monitoring for rebound respiratory depression is mandatory.
• Opioid Withdrawal: Diaphoresis, lacrimation, rhinorrhea, yawning, piloerection ('cold turkey'), pupil dilation, intense abdominal cramps, vomiting, diarrhea, and severe myalgias. Highly distressing but not intrinsically life-threatening.

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Life-Threatening Psychotropic Drug Emergencies & Extrapyramidal Side Effects

The Hunter Serotonin Toxicity Criteria

Serotonin Syndrome is diagnosed clinically using the validated Hunter Criteria. In the presence of a serotonergic agent, the patient must exhibit at least one of the following:

1. Spontaneous clonus
2. Inducible clonus PLUS agitation or diaphoresis
3. Ocular clonus PLUS agitation or diaphoresis
4. Tremor PLUS hyperreflexia
5. Hypertonia PLUS temperature > 38.0°C PLUS ocular or inducible clonus Diagnostic Pearl: Clonus (spontaneous, inducible, or ocular) is the single most sensitive and specific clinical differentiator of Serotonin Syndrome from NMS.

Extrapyramidal Side Effects (EPS): Timeline, Manifestations & Management

1. Acute Dystonic Reaction (Hours to Days): Sustained, involuntary, painful muscle contractions. Manifests as torticollis (spasmodic neck twisting), oculogyric crisis (fixed upward deviation of the eyes), trismus, retrocollis, and laryngeal dystonia (respiratory emergency). High risk with typical FGAs (haloperidol). Treatment: Immediate intravenous or intramuscular Anticholinergic / Antihistaminic therapy: Diphenhydramine (50 mg IV/IM) or Benztropine (1 to 2 mg IV/IM), producing rapid resolution within 10 to 15 minutes.
2. Akathisia (Days to Weeks): Subjective feeling of inner motor restlessness, severe anxiety, and an irresistible urge to move the limbs. Patients pace continuously, rock from foot to foot, or shift repeatedly in chairs. Frequently misdiagnosed as worsening psychotic agitation, leading to fatal increases in neuroleptic dose. Associated with heightened suicide risk. Treatment: First-line therapy is a centrally acting beta-blocker: Propranolol (10 to 40 mg PO three times daily); second-line: low-dose benzodiazepines or reducing antipsychotic dose.
3. Parkinsonism / Pseudoparkinsonism (Weeks to Months): Striatal D2 blockade mimicking Parkinson's disease: bradykinesia, resting pill-rolling tremor, cogwheel rigidity, masked facies, festinating gait, and sialorrhea. Treatment: Centrally acting anticholinergics (Benztropine 1 to 2 mg PO daily or Trihexyphenidyl 2 to 5 mg PO daily) or switching to an atypical antipsychotic. Dopamine precursors (levodopa) are contraindicated as they exacerbate underlying psychosis.
4. Tardive Dyskinesia (TD) (Months to Years): Potential consequence of chronic, long-term D2 receptor blockade, resulting in postsynaptic dopamine receptor upregulation and supersensitivity in the nigrostriatal pathway. Characterized by involuntary, repetitive, choreoathetoid movements of the face, tongue, and lips: tongue protrusion ('fly-catcher' tongue), lip smacking, puckering, chewing motions, grimacing, and choreiform movements of the extremities and trunk. Treatment: Discontinue typical antipsychotics or switch to Clozapine (which has minimal D2 affinity and does not worsen TD). Anticholinergic drugs must be strictly withdrawn because they worsen tardive dyskinesia. First-line pharmacotherapy for established TD utilizes VMAT2 Inhibitors (Valbenazine, Deutetrabenazine), which deplete presynaptic dopamine vesicles.