Biologic Therapies in Psychiatry

ANTI-DEPRESSANTS: GENERAL PRINCIPLES AND INDICATIONS

• Treatment Overview and Remission Rates:

  • Antidepressants (ADs) with Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) activity may produce higher remission rates.

  • Selective Serotonin Reuptake Inhibitors (SSRIs) remain the first-line treatment due to superior tolerability.

  • $50\%$ of patients who respond poorly to one SSRI will respond favorably to another. It is recommended to try other agents within the same SSRI class before switching to a different class.

• Suicide Risk and Age Factors:

  • Studies show no significant difference in the rates of suicidal thoughts and behaviors between ADs and placebos in children and teenagers.

  • Adults, particularly geriatric patients, show an age-dependent decrease in suicidal thoughts and behaviors when taking ADs compared to placebo.

  • Across all age groups, the severity of depression (and consequently, suicide risk) decreased with medication use.

  • Monitoring during Initiation: Initial anxiety or agitation can aggravate suicidal ideation in already depressed patients. Close monitoring is required; short-term Benzodiazepines (BZDs) may be used.

• Population-Specific Considerations:

  • Elderly: SSRIs are generally safe. Paroxetine has anticholinergic activity that can affect cognition and cause constipation. Clinicians should monitor for bleeding, subtle cognitive effects, and hyponatremia.

  • Children: Fluoxetine has the most consistent evidence for efficacy in pediatric depression. Sertraline combined with Cognitive Behavioral Therapy (CBT) is used for Social Anxiety Disorder (SAD).

• Indications for SSRIs:

  • Impulse Control Disorders: OCD, trichotillomania, skin picking, Non-Suicidal Self-Injury (NSSI), gambling, and compulsive buying.

  • OCD Dosage: Adults (>18 years) use Fluoxetine, Fluvoxamine, Sertraline, or Paroxetine. Children ($6\text{--}17$ years) use Fluoxetine, Fluvoxamine, or Sertraline. OCD often requires higher doses and longer duration for effect. Second-generation antipsychotics (e.g., Risperidone) may be added.

  • Anxiety Disorders: Panic disorder (Paroxetine, Fluoxetine, Sertraline). General Anxiety Disorder (GAD) and PTSD are other indications.

  • Eating Disorders: Fluoxetine ($60\,mg/day$) is used for Bulimia. In Anorexia, psychotherapy is primary; SSRIs are used only for comorbid conditions.

  • Premenstrual Dysphoric Disorder (PMDD): Fluoxetine, Fluvoxamine, Sertraline, and Paroxetine are used. Fluoxetine and Sertraline are effective whether given throughout the cycle or only during the luteal phase ($2$ weeks between ovulation and menstruation).

  • Off-label Uses: Premature ejaculation, paraphilias (obsessive sexual thoughts), and autism.

PHARMACOLOGY OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

• Fluoxetine (Prozac):

  • Half-life: $4\text{--}6\,days$; active metabolite half-life is $7\text{--}9\,days$.

  • Characteristics: Highly protein-bound; interacts with $5HT2C$ receptors.

  • Dosing: MDD initial $10\text{--}20\,mg/day$ (Max: $80\,mg/day$). Bulimia: $60\,mg/day$.

  • Notes: Activating/stimulating (dose in AM). Side effects include anorexia and weight loss (peaks at week $20$). High risk for headache and anxiety.

• Paroxetine (Paxil):

  • Half-life: $21\,hours$.

  • Characteristics: Highly protein-bound; binds to NO synthase; high anticholinergic activity.

  • Dosing: $10\text{--}20\,mg/day$ (Max: $50\,mg/day$). Take with food.

  • Notes: Sedating (dose in PM). Pregnancy Category D (septal defects). Causes weight gain resistant to diet/exercise.

• Sertraline (Zoloft):

  • Half-life: $26\,hours$; active metabolite is $3\text{--}5\,days$.

  • Characteristics: Weakly inhibits Norepinephrine (NE) and dopamine reuptake.

  • Dosing: Initial $50\,mg/day$ (Max: $200\,mg/day$). Take with food.

  • Notes: Very low levels in breast milk. Causes intense GI side effects ($5HT3$ receptor).

• Citalopram (Celexa) and Escitalopram (Lexapro):

  • Half-life: Escitalopram ($27\text{--}32\,hours$); Citalopram ($35\,hours$).

  • Characteristics: Escitalopram is the least protein-bound and has the fewest drug-drug interactions.

  • Dosing: Citalopram ($20\text{--}40\,mg/day$); Escitalopram ($10\,mg/day$, max $20\,mg/day$).

  • Safety: Citalopram can cause QT prolongation (limit to $20\,mg/day$ for hepatic patients or those over $60$ years).

• Fluvoxamine (Luvox):

  • Half-life: $15\,hours$ (short $t_{1/2}$ causes discontinuation syndrome).

  • Interactions: Most drug-drug interactions (significant CYP interactions).

  • Indications: Strictly OCD (Adult and Pediatric).

• Vortioxetine:

  • Half-life: $66\,hours$ ($2.5\,days$).

  • Mechanism: Serotonin reuptake inhibitor with complex effects: Antagonist ($5HT3, 5HT1D, 5HT7$), Agonist ($5HT1A$), Partial agonist ($5HT1B$).

  • Dosing: Initial $10\,mg/day$ (Max $20\,mg/day$). Take AM.

ADVERSE EFFECTS AND DRUG INTERACTIONS OF SSRIs

• General Adverse Effects:

  • Sexual Dysfunction: Most common long-term side effect (consider switching to Mirtazapine or Bupropion).

  • QT Prolongation: Citalopram has the most pronounced effect ($20\,mg = 8.5\,ms$, $40\,mg = 12.6\,ms$, $60\,mg = 18.5\,ms$).

  • Others: Vivid dreams, yawning, rare akathisia (EPS), impaired platelet aggregation, hyponatremia/SIADH, and nocturnal sweating (treat with Terazosin).

• Serotonin Syndrome:

  • Signs: Hyperreflexia, fever, tremors/rigidity, autonomic instability, diarrhea, and diaphoresis.

  • Risk: Combining SSRIs with MAOIs or Lithium.

• SSRI Withdrawal (Discontinuation Syndrome):

  • Appears after at least $6\,weeks$ of treatment. Symptoms include nausea, headache, rebound anxiety/depression, insomnia, and upper respiratory symptoms.

  • Common with Paroxetine and Fluvoxamine (short $t_{1/2}$); rare with Fluoxetine.

  • Resolves spontaneously in $3\,weeks$.

• Drug-Drug Interaction Highlights (CYP450):

  • CYP 2D6 Inhibitors (High): Fluoxetine and Paroxetine. They increase levels of Carbamazepine, Diazepam, Phenytoin, and Warfarin.

  • CYP 1A2 Inhibitor (High): Fluvoxamine. Increases levels of Theophylline, Warfarin, Clozapine, and Propranolol.

  • Paroxetine + Tramadol: Risk of Serotonin Syndrome in the elderly.

OTHER ANTI-DEPRESSANTS: MIRTAZAPINE, TRAZODONE, AND SNRIs

• Mirtazapine:

  • Mechanism: $\alpha 2$ adrenergic antagonist (increases NE and $5HT$ firing); $5HT2$ and $5HT3$ antagonist; Histamine ($H1$) antagonist (sedation).

  • Usage: Depression, sedation, reducing SSRI-induced nausea (due to $5HT3$ blockade).

  • Side Effects: Sedation, dizziness, increased appetite (elevates Cholesterol and Triglycerides), orthostatic hypotension, and rare agranulocytosis.

• Trazodone:

  • Mechanism: Weak serotonin reuptake inhibitor; potent $5HT2a$ and $5HT2c$ blockade.

  • Usage: First-line for Insomnia ($25\text{--}100\,mg\,ODHS$), MDD ($250\text{--}600\,mg/day$), and erectile problems.

  • Side Effects: Extreme sedation, hypotension, and Priapism (painful erection >3\,hours).

• Nefazodone:

  • Mechanism: SNRI activity; $5HTA$ blockade; $\alpha 1$ antagonism.

  • Note: Associated with liver failure and "visual trails" (after-images).

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):

  • Venlafaxine: MDD, GAD, SAD, panic. Initial dose $75\,mg/day$; Max $225\text{--}375\,mg/day$. Nausea is the most common side effect. Can cause blood pressure (BP) elevations at doses >100\,mg/day.

  • Duloxetine: Approved for neuropathic pain in DM. Usual dose $60\,mg/day$. Monitor FBS/$Hba1c$. Avoid in hepatic or end-stage renal disease.

  • Milnacipran: FDA approved for Fibromyalgia.

  • Levomilnacipran: FDA approved for adult MDD. Side effects include urinary hesitation and erectile dysfunction.

TRICYCLIC ANTI-DEPRESSANTS (TCAs) AND MAOIs

• Tricyclic Anti-depressants (TCA):

  • Levels increased by: Antipsychotics and SSRIs (Fluoxetine, Paroxetine, Fluvoxamine).

  • Levels decreased by: Nicotine and Lithium.

• Monoamine Oxidase Inhibitors (MAOI):

  • Types: MAO-A (metabolizes NE, Epi, $5HT$); MAO-B (Dopamine and Tyramine).

  • Irreversible MAOIs: Tranylcypromine ($10\text{--}40\,mg/day$), Isocarboxazid ($10\text{--}50\,mg/day$), Phenelzine ($15\text{--}90\,mg/day$).

  • Reversible Inhibitors (RIMA): Moclobemide. Fewer side effects; tyramine-rich foods can be eaten $3\,days$ after the last dose.

  • Hypertensive Crisis: Caused by Tyramine. Symptoms treated with $\alpha$ adrenergic antagonists (Phentolamine, Chlorpromazine) or IV Nifedipine. Avoid tyramine-rich foods for $2\,weeks$ after irreversible MAOIs.

• Novel Agents:

  • Ketamine/Esketamine: NMDA receptor antagonists for depression. Esketamine is intranasal; observe for $2\,hours$ post-dose for hypertension and sedation.

  • Brexanolone: GABA A modulator for postpartum depression. Requires continuous IV infusion for $60\,hours$.

MOOD STABILIZERS: LITHIUM

• Pharmacokinetics: Excreted unchanged by the kidneys ($t_{1/2} = 18\text{--}24\,hours$). Equilibrium reached in $5\text{--}7\,days$. Rapidly excreted during pregnancy.

• Indications: Bipolar I (mania prophylaxis), adjunct for severe MDD, reduces suicide risk ($6\text{--}7$ fold) in bipolar patients.

• Therapeutic Ranges and Toxicity:

  • Maintenance: $0.6\text{--}1.2\,mEq/L$ ($900\text{--}1200\,mg/day$).

  • Acute Mania: $1.0\text{--}1.5\,mEq/L$.

  • Mild Toxicity: $1.5\text{--}2.0\,mEq/L$.

  • Moderate Toxicity: $2.0\text{--}2.5\,mEq/L$.

  • Severe Toxicity: >2.5\,mEq/L. Hemodialysis required if >4.0\,mEq/L.

• Side Effects:

  • Renal: Polyuria (Diabetes Insipidus) and Interstitial Fibrosis (microcysts). Lithium antagonizes ADH.

  • Cardiac: Brugada syndrome revelation; ECG changes like hypokalemia ($T$ wave flattening); contraindicated in sick sinus syndrome.

  • Other: Hypothyroidism, weight gain, leukocytosis, acne, and Ebstein anomaly (tricuspid valve) in infants.

• Interactions:

  • Increase Lithium: Valproate, CBZ, Thiazide diuretics, NSAIDs (Ibuprofen, Naproxen), Metronidazole, CCBs (neurotoxicity).

  • Decrease Lithium: Caffeine, Acetazolamide, Alcohol, Sodium Bicarbonate.

MOOD STABILIZERS: VALPROATE AND LAMOTRIGINE

• Valproate (Depakote):

  • Mechanism: Enhances GABA and modulates Na channels.

  • Dosing: $20\text{--}30\,mg/kg/day$ (Target level: $50\text{--}100\,\mu g/mL$ or $125\,\mu g/mL$ for mania).

  • Side Effects: Hepatotoxicity (especially in children <3 years), Pancreatitis, Thrombocytopenia (more likely if levels >110\,\mu g/mL in females, >135\,\mu g/mL in males), PCOS, and weight gain.

  • Pregnancy: Neural tube defects ($1\text{--}4\%$ risk); supplement with $1\text{--}4\,mg/day$ Folic Acid.

• Lamotrigine (Lamictal):

  • Indication: Maintenance of bipolar depression (not for acute mania).

  • Titration Schedule: Missing $4$ days requires a restart.

    • Weeks $1\text{--}2$: $25\,mg/day$.

    • Weeks $3\text{--}4$: $50\,mg/day$.

    • Week $5+$: Increase to $100\text{--}200\,mg/day$.

  • Dermatologic Risk: Maculopapular rash, Stevens-Johnson Syndrome (SJS), or Toxic Epidermal Necrolysis (TEN). Risk increases with concomitant Valproate use (VA doubles Lamotrigine levels).

ANTICONVULSANTS: CARBAMAZEPINE AND OTHERS

• Carbamazepine:

  • Features: Similar to Imipramine. Half-life reduces from $26\,hours$ to $12\,hours$ due to autoinduction (after $2\text{--}3\,weeks$).

  • Indications: Trigeminal neuralgia, bipolar depression, rapid cycling, aggression in schizophrenia.

  • Side Effects: Rare agranulocytosis and aplastic anemia. Discontinue if WBC <3,000. Causes hyponatremia/SIADH (unlike Lithium's Diabetes Insipidus).

• Oxcarbazepine: Carbamazepine analog; no anti-manic effects; higher risk of hyponatremia.

• Other Agents:

  • Topiramate: Used for weight loss, bulimia, and binge eating. Risk of renal calculi.

  • Zonisamide: Blocks Na/Ca channels; blocks carbonic anhydrase. Risk of renal calculi and rash.

  • Gabapentin/Pregabalin: Used for neuropathic pain and anxiolysis. Pregabalin has $6\times$ higher binding affinity.

  • Phenytoin: Dyskinesia, gingival hyperplasia, and Vit K deficiency clotting factor issues.

ANTIPSYCHOTICS: TYPICAL (DRA) AND ATYPICAL (SDA)

• Dopamine Receptor Antagonists (DRA/Typical):

  • High Potency (Haloperidol): More neurological/EPS side effects.

  • Low Potency (Chlorpromazine): More weight gain, sedation ($H1$), cardiotoxicity, and hypotension ($\alpha 1$).

  • Efficacy: Requires $72\%$ $D2$ receptor occupancy.

  • Neuroleptic Malignant Syndrome (NMS): $20\text{--}30\%$ mortality. Treatment: Bromocriptine ($2.5\,mg\,BID/TID$), Amantadine ($200\text{--}400\,mg/day$), Dantrolene ($1\,mg/kg/day$).

• Serotonin-Dopamine Antagonists (SDA/Atypical):

  • Risperidone: Dose $2\text{--}4\,mg/day$; avoid exceeding $6\,mg/day$ to prevent EPS.

  • Olanzapine: High risk for weight gain (not dose-related).

  • Quetiapine: Half-life $7\,hours$. Best for Parkinson's psychosis. Risk for cataracts.

  • Ziprasidone: Must be taken with food. Risk of QTc prolongation.

  • Aripiprazole: Partial $D2$ agonist. Good metabolic profile.

  • Clozapine: For treatment-resistant cases. Risk of Agranulocytosis (<1\%). Discontinue if WBC <3,000 or ANC <1500. Side effects: Sialorrhea and sedation.

ANXIOLYTICS AND SLEEP MEDICATIONS

• Benzodiazepines (BZDs):

  • High Potency: Alprazolam, Clonazepam, Triazolam.

  • Long-acting: Diazepam (t_{1/2} > 100\,hours with metabolites).

  • Overdose: Flumazenil ($0.2\,mg$ IV initial; max $3\,mg$). Can precipitate seizures.

• Z-Drugs (Non-BZD): Zolpidem, Zaleplon, Eszopiclone. No tolerance to sedating effects; no muscle relaxant/anticonvulsant action.

• Other Sleep Aids:

  • Ramelteon: $MT1/MT2$ agonist. No affinity for GABA.

  • Melatonin: Synthesized from tryptophan. Inhibits fertility in both sexes.

  • Agomelatine: Agonist at $MT1/MT2$ and $5HT2C$ antagonist.

SUBSTANCE USE AND ADHD MEDICATIONS

• Disulfiram: Inhibits aldehyde dehydrogenase (acetaldehyde buildup). Avoid in cardiac patients. Risk of psychosis due to increased dopamine.

• Acamprosate: NMDA antagonist for alcohol dependence post-withdrawal. Contraindicated in severe renal insufficiency.

• Opioid Management:

  • Methadone: Pure $\mu$ agonist for addiction. Safe in pregnancy; causes neonatal withdrawal.

  • Buprenorphine: Mixed effect ($\mu$ agonist, $\kappa$ antagonist). Sublingual administration.

  • Naltrexone: Opioid antagonist; reduces alcohol and opioid cravings.

• ADHD Stimulants:

  • Methylphenidate: IR ($2\text{--}3\,hr\,t_{1/2}$) vs XR (Concerta, $12\,hr$ efficacy).

  • Lysdexamfetamine: Prodrug with less addictive potential.

  • Modafinil: Used for narcolepsy and adjunctive for depression medically ill.

• Atomoxetine: Non-stimulant for ADHD; selective NE reuptake inhibition. Dosing: Adults start $40\,mg/day$, max $100\,mg/day$. Risk of severe liver injury.

NEUROCOGNITIVE DISORDERS

• Cholinesterase Inhibitors:

  • Tacrine: First inhibitor but hepatotoxic; no longer used.

  • Donepezil: Long half-life ($70\,hours$). Central selectivity. Starting dose $5\,mg$.

  • Rivastigmine: Peripheral selectivity (GI). Not protein-bound.

• Memantine: NMDA antagonist for moderate-to-severe Alzheimer's. Prevents overexcitation by glutamate excess. Excreted unchanged in urine.