33.1 Nervous System Pharmacology II: Antidepressants and Their Toxicity, Serotonin Syndrome, Anxiolytics and Hypnotics, Antipsychotics, EPS and NMS, Lithium and Mood Stabilizers, Sleep Disorders, Agitation and Alcohol Withdrawal

Why this area matters

The TOS covers drug treatment of:

• psychosis and schizophrenia;
• bipolar disorder;
• depression;
• anxiety;
• sleep disorders;
• psychiatric emergencies.

Psychotropic drugs have narrow margins (lithium, tricyclics), dangerous interactions (serotonergic combinations, MAO inhibitors) and serious idiosyncratic reactions (NMS, agranulocytosis). Overdose of psychiatric drugs is a common poisoning.

Antidepressant Pharmacology & Serotonergic Crises

Major Antidepressant Classes

• Selective Serotonin Reuptake Inhibitors (SSRIs: Fluoxetine, Sertraline, Paroxetine, Citalopram, Escitalopram):
  • Mechanism: Selectively block the presynaptic serotonin reuptake transporter (SERT), prolonging serotonin action in the synaptic cleft. First-line therapy for Major Depressive Disorder (MDD), Generalized Anxiety Disorder (GAD), Panic Disorder, OCD, and PTSD.
  • Adverse Effects: Sexual dysfunction ($30\text{--}50\%$: decreased libido, erectile failure, anorgasmia), gastrointestinal distress (nausea, diarrhea), insomnia, syndrome of inappropriate antidiuretic hormone secretion (SIADH) causing hyponatremia in the elderly, and an FDA boxed warning for increased suicidal ideation in children, adolescents, and young adults under 25 years. Paroxetine carries cardiac teratogenicity risks (ventricular septal defects).
• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs: Venlafaxine, Duloxetine, Desvenlafaxine):
  • Mechanism: Inhibit both SERT and the norepinephrine transporter (NET). Useful in comorbid depression with chronic neuropathic pain (diabetic peripheral neuropathy, fibromyalgia). Adverse effects include dose-dependent diastolic hypertension (noradrenergic peripheral vasoconstriction), diaphoresis, and tachycardia.
• Tricyclic Antidepressants (TCAs: Amitriptyline, Nortriptyline, Imipramine, Clomipramine):
  • Mechanism: Inhibit SERT and NET; simultaneously block muscarinic $M_1$, histaminergic $H_1$, and alpha-1 adrenergic receptors, as well as myocardial fast voltage-gated sodium channels ($Nav1.5$).
  • Overdose Presentation — "The 3 Cs":
    1. Convulsions: Seizures mediated by central GABA-A antagonism.
    2. Coma: Profound CNS sedation mediated by $H_1$ and central anticholinergic blockade.
    3. Cardiotoxicity: Fast sodium channel blockade slows Phase 0 ventricular depolarization, manifesting on ECG as QRS prolongation ($> 100\text{ ms}$), rightward terminal 40-ms axis shift (prominent R wave in lead aVR $> 3\text{ mm}$), PR and QT prolongation, and lethal ventricular arrhythmias (ventricular tachycardia, ventricular fibrillation, refractory hypotension).
  • Antidote / Treatment: Intravenous Sodium Bicarbonate ($\text{NaHCO}_3$). Boluses administered when QRS duration exceeds $100\text{ ms}$ or in the presence of ventricular arrhythmias and hypotension. Mechanism: provides an extracellular sodium load ($Na^+$) that outcompetes TCA binding to fast sodium channels, while extracellular alkalinization ($\text{pH } 7.50\text{--}7.55$) deprotonates the lipid-soluble amine TCA molecule, reducing its affinity for sodium channel receptor sites.
• Monoamine Oxidase Inhibitors (MAOIs: Phenelzine, Tranylcypromine, Isocarboxazid, Selegiline):
  • Mechanism: Irreversibly inhibit MAO-A (degrades serotonin, norepinephrine, dopamine) and MAO-B (degrades dopamine).
  • Tyramine Hypertensive Crisis: Dietary tyramine (found in aged cheeses, red wine, cured meats, draft beer, soy sauce) is normally degraded by intestinal and hepatic MAO-A. Under MAOI inhibition, absorbed tyramine enters systemic circulation, enters presynaptic adrenergic terminals via NET, and displaces vesicular norepinephrine into the synaptic cleft. The massive noradrenergic surge produces acute severe hypertension (BP $> 180/120\text{ mmHg}$, throbbing occipital headache, intracranial hemorrhage, acute myocardial infarction). Treated with IV phentolamine or nitroprusside.
  • Washout Period: When transitioning between an MAOI and another antidepressant, a strict 14-day (2-week) washout period is required to allow resynthesis of MAO enzymes. A 5-week washout is required when switching from fluoxetine to an MAOI due to fluoxetine's exceptionally long half-life and active metabolite (norfluoxetine, $t_{1/2} \approx 7\text{--}15\text{ days}$).

Serotonin Syndrome

Hyperstimulation of central and peripheral 5-$HT_{1A}$ and 5-$HT_{2A}$ receptors, triggered by combining serotonergic agents (SSRIs, SNRIs, TCAs, MAOIs, Tramadol, Meperidine, Dextromethorphan, Linezolid, MDMA, St. John's wort).

• Diagnostic Triad:
  1. Neuromuscular Hyperactivity: Spontaneous or inducible clonus, marked hyperreflexia (lower extremities $\gg$ upper), tremor, shivering.
  2. Autonomic Instability: Hyperthermia, diaphoresis, tachycardia, labile blood pressure, mydriasis, hyperactive bowel sounds with diarrhea.
  3. Altered Mental Status: Agitation, delirium, confusion.
• Management: Discontinue all serotonergic agents immediately; aggressive cooling and IV fluids; benzodiazepines for agitation; specific antidote is Cyproheptadine (a first-generation antihistamine with potent 5-$HT_2$ receptor antagonist activity).

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Anxiolytics, Hypnotics & Antidotes: Benzodiazepines vs. Barbiturates

Both drug classes bind the pentameric $\text{GABA}_A$ receptor-chloride channel complex, but via distinct allosteric binding sites and kinetic mechanisms.

PLE High-Yield Point (Flumazenil Danger): Routine administration of flumazenil in comatose overdose patients is dangerous. In patients with chronic benzodiazepine dependence or co-ingestion of proconvulsant drugs (especially TCAs), flumazenil precipitates refractory, life-threatening withdrawal seizures that cannot be stopped with benzodiazepines because their receptors are blocked.

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Antipsychotic Pharmacology: Extrapyramidal Symptoms vs. Metabolic Syndrome

Typical / First-Generation Antipsychotics (FGAs: Haloperidol, Fluphenazine, Chlorpromazine)

• Mechanism: High-potency antagonism of dopamine $D_2$ receptors in the mesolimbic pathway (reduces positive symptoms of schizophrenia). Simultaneous blockade of nigrostriatal $D_2$ receptors produces high rates of Extrapyramidal Symptoms (EPS):
  1. Acute Dystonia (hours to 5 days): Sudden, painful spasms of neck muscles (torticollis), ocular muscles (oculogyric crisis), tongue protrusion, or laryngospasm. Treatment: IV or IM anticholinergic (Diphenhydramine or Benztropine).
  2. Akathisia (days to weeks): Subjective, distressing motor restlessness and inability to sit still. Treatment: Beta-blockers (Propranolol), benzodiazepines, or dosage reduction.
  3. Parkinsonism (weeks to months): Bradykinesia, cogwheel rigidity, resting pill-rolling tremor, masked facies. Treatment: Anticholinergics (Benztropine) or dopamine agonists that do not worsen psychosis (Amantadine; avoid levodopa).
  4. Tardive Dyskinesia (months to years): Involuntary choreoathetoid movements of face, mouth, tongue (lip smacking, tongue darting), and limbs due to chronic dopamine receptor upregulation and supersensitivity. Often irreversible. Anticholinergics worsen tardive dyskinesia. Treatment: Switch to an atypical antipsychotic with low $D_2$ affinity (Clozapine or Quetiapine); vesicular monoamine transporter 2 (VMAT2) inhibitors (Valbenazine, Deutetrabenazine).
• Neuroleptic Malignant Syndrome (NMS): Life-threatening hyperpyrexic reaction to dopamine blockade. Mnemonic FALTER: Fever (severe hyperthermia $> 40^\circ\text{C}$), Autonomic instability (tachycardia, diaphoresis, labile BP), Leukocytosis, Tremor, Elevated creatine kinase (CK, from rhabdomyolysis), Rigidity ("lead-pipe" generalized rigidity). Distinguished from Serotonin Syndrome by lead-pipe rigidity and hyporeflexia (versus clonus/hyperreflexia). Treatment: Stop antipsychotic; intensive ICU cooling and hydration; pharmacotherapy with Dantrolene (ryanodine receptor blocker) and Bromocriptine (dopamine agonist).

Atypical / Second-Generation Antipsychotics (SGAs: Olanzapine, Quetiapine, Risperidone, Clozapine, Aripiprazole)

• Mechanism: Dual antagonists of 5-$HT_{2A}$ and $D_2$ receptors (Aripiprazole is a partial $D_2$ agonist). Lower risk of EPS, but carry high risk of Metabolic Syndrome (weight gain, dyslipidemia, hyperglycemia, new-onset diabetes; highest risk with Olanzapine and Clozapine; lowest with Aripiprazole and Ziprasidone).
• Risperidone: High affinity for $D_2$; causes highest incidence of Hyperprolactinemia (galactorrhea, amenorrhea, gynecomastia, sexual dysfunction).
• Clozapine:
  • Uniquely effective for treatment-resistant schizophrenia (failure of $\ge 2$ prior antipsychotic trials) and for reducing suicidal behavior in schizophrenia.
  • Major Adverse Effects:
    1. Agranulocytosis ($1\text{--}2\%$ risk): Potentially fatal bone marrow suppression. Requires mandatory baseline and frequent serial monitoring of the Absolute Neutrophil Count (ANC). Clozapine must be withheld if ANC drops $< 1,000/\mu\text{L}$ ($< 1.0 \times 10^9/\text{L}$) or permanently discontinued if $< 500/\mu\text{L}$.
    2. Myocarditis and cardiomyopathy (monitor troponin and CRP).
    3. Dose-dependent seizure risk (lowers seizure threshold).
    4. Severe gastrointestinal hypomotility (paralytic ileus).

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Mood Stabilizers & Antiepileptic Therapeutics

Lithium Pharmacology & Toxicity

• Mechanism: Inhibits inositol monophosphatase (depleting cellular inositol and dampening $IP_3/DAG$ signaling) and inhibits glycogen synthase kinase-3 (GSK-3). First-line mood stabilizer for acute mania and maintenance in Bipolar I Disorder; proven to reduce suicide risk.
• Renal Clearance Dynamics: Excreted almost entirely unchanged by the kidneys; handled identically to sodium in the renal proximal tubule. Any physiological state or medication that depletes sodium or decreases GFR causes compensatory increased proximal tubular lithium reabsorption, precipitating acute lithium toxicity. Classic precipitating drugs: Thiazide diuretics (highest risk), NSAIDs (reduce renal prostaglandin synthesis and GFR), and ACE inhibitors / ARBs.
• Narrow Therapeutic Window: $0.6\text{--}1.2\text{ mEq/L}$. Acute toxicity ($> 1.5\text{ mEq/L}$) manifests with coarse tremors, ataxia, slurred speech, confusion, and vomiting; levels $> 2.5\text{ mEq/L}$ cause seizures, coma, arrhythmias, and permanent neurological injury. Severe toxicity is managed with emergency hemodialysis.
• Chronic Adverse Effects:
  1. Nephrogenic Diabetes Insipidus (NDI): Lithium enters collecting duct principal cells via ENaC channels, uncoupling vasopressin $V_2$ receptor signaling and aquaporin-2 water channel insertion (polyuria, polydipsia; treated with Amiloride to block ENaC entry).
  2. Hypothyroidism & Goiter: Inhibits thyroid hormone synthesis and release (monitor serum TSH).
  3. Teratogenicity: Category D; causes Ebstein Anomaly (apical displacement of tricuspid leaflets with atrialization of the right ventricle).

Bipolar disorder, anxiety and insomnia

• Acute mania:
  • lithium, valproate or an atypical antipsychotic (olanzapine, quetiapine, risperidone, aripiprazole), with benzodiazepines short-term for agitation;
  • antidepressants alone can trigger mania in bipolar disorder.
• Maintenance: lithium (which also lowers suicide risk), valproate, lamotrigine (for bipolar depression) and quetiapine.
• Lithium monitoring:
  • levels 12 hours after a dose;
  • renal and thyroid function and calcium every 6 to 12 months;
  • teach patients to avoid dehydration and NSAIDs.
• Anxiety disorders (generalized anxiety, panic, social anxiety):
  • SSRIs or SNRIs plus CBT as first-line;
  • buspirone (a 5-HT1A partial agonist, not addictive, slow onset) for generalized anxiety;
  • benzodiazepines only short-term, because of dependence, falls and cognitive effects in older adults;
  • propranolol for performance anxiety.
• Insomnia:
  • sleep hygiene and CBT for insomnia first;
  • short courses of hypnotics if needed: Z-drugs (zolpidem), low-dose benzodiazepines, or melatonin in some patients;
  • avoid long-term sedatives, especially in older adults;
  • treat underlying depression, pain and sleep apnea.

Psychiatric emergencies

• Acute agitation or aggression:
  • de-escalation first;
  • rapid tranquilization if needed, with IM haloperidol with lorazepam (or midazolam), or IM olanzapine (not with parenteral benzodiazepines);
  • monitor airway, vital signs and ECG (QT);
  • look for medical causes: hypoglycemia, hypoxia, delirium, intoxication or withdrawal, head injury.
• Acute dystonia after antipsychotics: IM or IV diphenhydramine or benztropine.
• Alcohol withdrawal:
  • symptoms begin 6 to 24 hours after the last drink, with seizures at 12 to 48 hours and delirium tremens at 48 to 96 hours;
  • treat with benzodiazepines (diazepam, chlordiazepoxide, or lorazepam in liver disease), using symptom-triggered dosing (CIWA-Ar);
  • give thiamine before glucose;
  • correct electrolytes and magnesium.
• Opioid withdrawal: uncomfortable but rarely fatal. Methadone or buprenorphine maintenance treats opioid use disorder.
• Lithium toxicity: stop lithium, give IV fluids (normal saline), and use hemodialysis for severe toxicity (high levels with neurologic signs or renal failure).
• Suicide risk: prescribe limited quantities of drugs that are dangerous in overdose (tricyclics, lithium). Involve the family and follow up closely.