Comprehensive Biologic Therapies in Psychiatry Notes

ANTI-DEPRESSANTS: GENERAL PRINCIPLES AND INDICATIONS

• Treatment of Depression:

  • Remission Rates: Anti-depressants (ADs) with Serotonin-Norepinephrine Reuptake Inhibitor (SNRI) activity may produce higher remission rates.
  • First-Line Treatment: Selective Serotonin Reuptake Inhibitors (SSRIs) remain the first-line choice due to superior tolerability.
  • Response Variations: Approximately $50\%$ of patients who respond poorly to one SSRI will respond favorably to another. Clinical practice suggests trying other agents within the same SSRI class before shifting to a different class.

• Suicide Risk and Age Factors:

  • Youth (Children and Teens): Clinical studies have shown no significant difference in the rates of suicidal thoughts and behaviors between ADs and placebo in this demographic.
  • Adults and Geriatric Patients: There is an age-dependent decrease in suicidal thoughts and behavior when comparing ADs to placebo.
  • General Outcome: Across all age groups, the medical treatment of depression decreases overall suicide risk as the severity of the depression improves.
  • Initiation Phase: Initial anxiety or agitation upon starting medication can provoke or aggravate suicidal ideation in already depressed patients. Close monitoring is required; short-term Benzodiazepines (BZDs) may be used for management.

• Demographic Specifics:

  • Elderly: SSRIs are generally safe. Paroxetine has anticholinergic activity, which may result in cognition issues and constipation. Monitoring is required for bleeding risks, subtle cognitive effects, and hyponatremia.
  • Children: Fluoxetine has the most consistently demonstrated efficacy for childhood depression. Sertraline combined with Cognitive Behavioral Therapy (CBT) is used for Social Anxiety Disorder (SAD).

• Anxiety and Impulse Control Disorders:

  • Obsessive-Compulsive Disorder (OCD):
    • Adults (>18 y/o): Fluoxetine, fluvoxamine, sertraline, and paroxetine.
    • Children (6-17 y/o): Fluoxetine, fluvoxamine, and sertraline.
    • Notes: Higher doses and longer durations are often required for effect. Second-generation antipsychotics (SGAs) like Risperidone may be added as augmentation.
  • Panic Disorder: Paroxetine, fluoxetine, and sertraline are indicated. Initiate with smaller doses due to "initiation symptoms"; low-dose BZDs may be used temporarily.
  • Other Impulse Control Disorders: Trichotillomania, skin picking, Non-Suicidal Self-Injury (NSSI), gambling, and compulsive buying.
  • General Anxiety Disorders: GAD and Post-Traumatic Stress Disorder (PTSD).
  • Off-label uses: Premature ejaculation, paraphilias (treating obsessive sexual thoughts), and autism.

• Eating Disorders and PMDD:

  • Bulimia: Fluoxetine $60\,mg/day$ is the standard. CBT is initiated first; if no response after $3-6$ weeks, the SSRI is added.
  • Anorexia: Fluoxetine is primarily used to treat co-morbid psychiatric conditions, though psychotherapy is the major intervention for the eating disorder itself.
  • Pre-menstrual Dysphoric Disorder (PMDD): Fluoxetine, fluvoxamine, sertraline, and paroxetine are used. Fluoxetine and sertraline are effective whether given during the entire cycle or just the luteal phase ($2$ weeks between ovulation and menstruation). Fluoxetine may alter menstrual period duration by approximately $\pm 4$ days.

SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)

• Fluoxetine (Prozac/Sarafem):

  • Half-life: $4-6$ days; active metabolite (norfluoxetine) $7-9$ days.
  • Dosing (MDD): Initial $10-20\,mg/day$; Max $80\,mg/day$. Take with food in the morning (Activating).
  • Pharmacology: Highly protein bound; inhibits $5HT_{2C}$ receptors; inhibits CYP 2D6.
  • Side Effects: Anorexia and weight loss (peak at week $20$), headache, and anxiety.
  • Interactions: Increases levels of carbamazepine, diazepam, and phenytoin. Increases bleeding with Warfarin.

• Paroxetine (Paxil):

  • Half-life: $21$ hours.
  • Dosing: $10-20\,mg/day$; Max $50\,mg/day$. Take with food in the evening (Sedating).
  • Pharmacology: High anticholinergic activity; inhibits NO synthase; potent CYP 2D6 inhibitor.
  • Special Notes: Pregnancy Category D (septal defects in first $3$ months). Discontinuation syndrome is common due to short half-life.
  • Side Effects: Weight gain resistant to diet and exercise.

• Sertraline (Zoloft):

  • Half-life: $26$ hours; active metabolite $3-5$ days.
  • Dosing: Initial $50\,mg/day$; Max $200\,mg/day$. Take with food.
  • Pharmacology: Weakly inhibits NE and dopamine reuptake. Very low levels found in breast milk.
  • Side Effects: Most intense GI side effects due to $5HT_3$ receptor activity.

• Citalopram (Celexa) and Escitalopram (Lexapro):

  • Half-life: Escitalopram $27-32$ hours; Citalopram $35$ hours.
  • Dosing: Escitalopram $10\,mg/day$ (Max $20\,mg$); Citalopram $20-40\,mg/day$.
  • Citalopram Specifics: Can cause QT prolongation ($20\,mg$ increases QT by $8.5\,ms$, $60\,mg$ by $18.5\,ms$). Limits: $20\,mg/day$ for patients with hepatic impairment, those $>60$ y/o, or those on Cimetidine.
  • Escitalopram Specifics: Least protein bound and least drug-drug interactions.

• Fluvoxamine (Luvox):

  • Half-life: $15$ hours.
  • Indication: Primarily OCD (adult and pediatric). Not FDA approved for MDD in the US.
  • Pharmacology: Most drug-drug interactions (CYP 1A2, 2D6, 3A4, 2C19).

• Vortioxetine:

  • Half-life: $66$ hours ($2.5$ days).
  • Mechanism: Serotonin reuptake inhibitor with complex effects: Antagonist (5HT3, 5HT1D, 5HT7), Agonist (5HT1A), and Partial agonist (5HT1B).

ADVERSE EFFECTS OF SSRIs AND SEROTONIN SYNDROME

• Common/Long-term Effects:

  • Sexual Dysfunction: The most common long-term side effect. Management may involve shifting to mirtazapine or bupropion.
  • Other Effects: Vivid dreams, yawning, rare akathisia, hyponatremia/SIADH, and nocturnal sweating (treated with Terazosin).

• Serotonin Syndrome:

  • Symptoms: Hyperreflexia, fever, tremors/rigidity, autonomic instability, diarrhea, and diaphoresis.
  • Risk Factors: Occurs when SSRIs are combined with MAOIs or Lithium.

• SSRI Withdrawal (Discontinuation Syndrome):

  • Onset: Appears after at least $6$ weeks of treatment.
  • Symptoms: Nausea, headache, rebound depression/anxiety, insomnia, and upper respiratory symptoms.
  • Risk: High for Paroxetine and Fluvoxamine (short half-life); lowest for Fluoxetine.

OTHER ANTI-DEPRESSANTS (SNRI, MIRTAZAPINE, TRAZODONE)

• Mirtazapine:

  • Mechanism: $\alpha_2$ adrenergic Antagonist (increases NE and 5HT firing); $5HT_2$ and $5HT_3$ receptor Antagonist; Histamine ($H_1$) receptor Antagonist.
  • Benefits: Potent sedation (good for insomnia), reduces nausea/diarrhea (due to $5HT_3$ blockade).
  • Dose: $15\,mg$, $30\,mg$, or $45\,mg/day$.
  • Side Effects: Dizziness, increased appetite (elevates Cholesterol and TAGs), orthostatic hypotension, and a rare risk of agranulocytosis.

• Trazodone & Nefazodone:

  • Trazodone: Weak serotonin reuptake inhibitor and potent $5HT_{2A}$ and $5HT_{2C}$ receptor blockade. Used for MDD ($250-600\,mg/day$) and insomnia ($25-100\,mg$). Can treat erectile problems but may cause Priapism (painful erection $>3$ hours).
  • Nefazodone: SNRI and $5HT_A$ receptor blockade. Notable for causing severe Liver Failure (elevated enzymes) and visual trails (after-images).

• SNRIs (Serotonin-Norepinephrine Reuptake Inhibitors):

  • Venlafaxine: Therapy usually $75-150\,mg/day$; Max $225-375\,mg/day$. Side effects include nausea (most common) and BP elevations. Discontinuation may be treated with fluoxetine.
  • Duloxetine: Therapeutic/Max dose $60\,mg/day$. First drug approved for neuropathic pain in Diabetes Mellitus (DM). Side effects include nausea and minor BP elevation.
  • Milnacipran: $5\times$ more potent for NE reuptake than serotonin; FDA approved for Fibromyalgia.
  • Levomilnacipran: Adult MDD; side effects include urinary hesitation and erectile dysfunction.

MONOAMINE OXIDASE INHIBITORS (MAOIs)

• Classification:

  • MAO-A: Metabolizes NE, Epinephrine, and Serotonin.
  • MAO-B and MAO-A: Metabolize Dopamine and Tyramine.

• Agents:

  • Irreversible: Tranylcypromine, Isocarboxazid, Phenelzine. Single doses can last $2$ weeks.
  • Reversible (RIMA): Moclobemide, Befloxatone.

• Hypertensive Crisis: Induced by Tyramine. Patients must avoid tyramine-rich foods for $2$ weeks after the last dose of irreversible MAOIs. Treated with $\alpha$-adrenergic antagonists (phentolamine, chlorpromazine), IV furosemide, or nifedipine.

• Side Effects: Hypotension (treat with fludrocortisone), insomnia (treat with trazodone), and Paresthesia (MAOI-induced pyridoxine deficiency).

NOVEL ANTI-DEPRESSANT AGENTS

• Ketamine & Esketamine:

  • Ketamine: An anesthetic; antidepressant effect involves sigma receptors.
  • Esketamine: FDA-approved enantiomer for depression. Administered intranasally; observe for $2$ hours post-administration for hypertension, sedation, and confusion.

• GABA-A Allosteric Modulators:

  • Brexanolone (Allopregnanolone): Used for post-partum depression. Positively modulates $GABA_A$. Requires a continuous IV infusion for over $60$ hours.

LITHIUM

• Kinetics: Excreted unchanged by the kidneys; half-life $18-24$ hours. Equilibrium reached in $5-7$ days. Excretion increases during pregnancy and decreases after delivery.
• Indications: Bipolar I (better for mania than depression), MDD adjunct, schizoaffective disorder augmentation. Reduces suicide risk $6-7$ fold in bipolar patients.
• Dosing & Levels:
  • Usual Dose: $900-1200\,mg/day$.
  • Maintenance Level: $0.6$ to $1.2\,mEq/L$.
  • Acute Mania Level: $1.0$ to $1.5\,mEq/L$ ($1800\,mg/day$).
  • Toxicity: Mild $1.5-2.0$; Moderate $2.0-2.5$; Severe $>2.5$. Hemodialysis required if $>4.0$.
• Adverse Effects:
  • Cardiac: T-wave flattening/inversion; contraindicated in Sick Sinus Syndrome and Ebstein anomaly.
  • Renal: Polyuria (Diabetes Insipidus) is most common; Interstitial fibrosis and increased creatinine are most serious.
  • Endocrine: Hypothyroidism, weight gain, thirst.
  • Dermatologic: Acne.
  • Hematologic: Leucocytosis (increased WBC).
• Interactions: Drugs that increase Lithium include Diuretics (Thiazides), NSAIDs (Ibuprofen, Naproxen), and CCBs (fatal neurotoxicity). Caffeine and Alcohol decrease Lithium. Stop Lithium $2$ days prior to ECT to prevent delirium.

ANTICONVULSANT MOOD STABILIZERS

• Valproate (Valproic Acid):

  • Mechanism: Enhances GABA and modulates voltage-gated Sodium channels.
  • Dosing: $20-30\,mg/kg/day$. Target concentration $50-125\,\mu g/mL$.
  • Side Effects: Hepatotoxicity (common in children $<3$ y/o), Pancreatitis, Hyperammonemia, and PCOS. Neural tube defects ($1-4\%$ risk); supplement with $1-4\,mg/day$ Folic acid. Zinc/Selenium for hair loss.

• Lamotrigine:

  • Indication: Maintenance of bipolar depression (not acute mania). Biopavailability $98\%$.
  • Serious Risk: Stevens-Johnson Syndrome (SJS) or Toxic Epidermal Necrolysis (TEN). Risk increases with concomitant Valproate use (which doubles Lamotrigine levels).
  • Titration: Weeks 1-2 ($25\,mg/day$); Weeks 3-4 ($50\,mg/day$); thereafter $100-200\,mg/day$. Restart titration if missing for $4$ consecutive days.

• Carbamazepine:

  • Metabolism: Autoinduction occurs within $2-3$ weeks (requiring dose increase). Active metabolite is $10,11$ epoxide.
  • Range: Anticonvulsant range $4-12 \mu g/mL$.
  • Side Effects: No weight gain. Rare agranulocytosis and aplastic anemia (discontinue if WBC $<3,000$). SIADH-like hyponatremia.
  • Interactions: Increases Carbamazepine: Erythromycin, Valproate (increases epoxide), and Grapefruit juice. Decreases Oral Contraceptives.

• Topiramate: Used for obesity, binge eating, and migraines. Risk of Renal Calculi; avoid with Acetazolamide.

ANTIPSYCHOTICS: DOPAMINE RECEPTOR ANTAGONISTS (DRA)

• First Generation (Typical):

  • Mechanism: Effective if $72\%$ of $D_2$ receptors are occupied.
  • High Potency (Haloperidol, Fluphenazine): More neurological Extrapyramidal Symptoms (EPS). Haloperidol $10\,mg$ leads to $80\%$ occupancy.
  • Low Potency (Chlorpromazine, Thioridazine): More Histamine ($H_1$) and Alpha-1 blockade, leading to weight gain, sedation, and hypotension. Thioridazine is associated with sudden death and cardiotoxicity.

• Adverse Effects:

  • Neuroleptic Malignant Syndrome (NMS): Evolving over $1-3$ days with high mortality ($20-30\%$). Treated with Bromocriptine ($2.5\,mg$ bid-tid), Amantadine ($200-400\,mg/day$), and Dantrolene ($1\,mg/kg/day$).
  • Anticholinergic Crisis: Constipation, dry mouth, urinary retention. Excess treated with Physostigmine.
  • Dermatologic: Blue-gray discoloration and ocular deposits with Chlorpromazine.

ANTIPSYCHOTICS: SEROTONIN-DOPAMINE ANTAGONISTS (SDA)

• Second Generation (Atypical):
  • Risperidone: $2-4\,mg/day$ (don't exceed $6\,mg$ due to EPS). Causes hyperprolactinemia.
  • Olanzapine: $5-20\,mg/day$. Significant weight gain (not dose-related).
  • Quetiapine: Lowest risk for EPS. Best for Parkinson's psychosis. Take XR version without food.
  • Ziprasidone: Must be taken with food. Almost no weight gain or prolactin release; QTc prolongation risk.
  • Aripiprazole: Partial agonist at $D_2$; good metabolic profile. Side effects: Akathisia and insomnia.
  • Clozapine: Gold standard for refractory cases. No EPS. Fatal risk of Agranulocytosis ($<1\%$); discontinue if WBC $<3,000$ or ANC $<1,500$. Side effects include Sedation and Sialorrhea.

BENZODIAZEPINES (BZDs)

• Pharmacology: Actions determined by lipid solubility rather than half-life. Rapidly absorbed within $30\text{ mins to }2\text{ hours}$.
• Specific Agents:
  • Lorazepam: Preferred for acute catatonia ($5-12\,mg$).
  • High Potency: Alprazolam, Clonazepam, Triazolam (shortest half-life: $2-3$ hours).
  • Long-acting: Diazepam and Chlordiazepoxide (metabolized to desmethyldiazepam, half-life $120$ hours).
• Overdose Treatment: Flumazenil. Dose: $0.2\,mg$ IV, then $0.3\,mg$, then $0.5\,mg$ every minute up to $3\,mg$ (total $5\,mg$ max). Risk of precipitating seizures.
• Z-Drugs for Insomnia: Zolpidem, Zaleplon, Eszopiclone. No tolerance to sedating effects; no muscle relaxant/anticonvulsant properties.

SUBSTANCE USE AND OTHER MEDICATIONS

• Alcohol Dependence:

  • Disulfiram: Inhibits aldehyde dehydrogenase, leading to acetaldehyde buildup. Should not exceed $500\,mg/day$.
  • Acamprosate: NMDA antagonist; CI in severe renal insufficiency.

• Opioid Use:

  • Methadone: Pure $\mu$-opioid agonist. Used in pregnancy Despite causing neonatal withdrawal.
  • Buprenorphine: Mixed effect ($\mu$ agonist, $\kappa$ antagonist). Sublingual delivery. $4\,mg$ Buprenorphine $\approx 40\,mg$ Methadone.
  • Naltrexone: Potent $\mu$ receptor antagonist; associated with nausea ($\mu$ receptor anti-emetic effect blockade).

• ADHD Medications:

  • Methylphenidate: IR (half-life $2-3$ hours); XR/Concerta (effective for $12$ hours; Max $40-60\,mg/day$).
  • Lysdexamfetamine: Prodrug formulation (L-lysine + D-amphetamine) with less addictive potential.
  • Atomoxetine: Non-stimulant NE transporter inhibitor. Initial $40\,mg/day$ for adults; weight-based for children ($0.5\,mg/kg/day$). Risk of severe liver injury (jaundice).

NEUROCOGNITIVE AND MOVEMENT AGENTS

• Donepezil (Aricept): Cholinesterase inhibitor for Alzheimer's; half-life $70$ hours.
• Memantine: NMDA antagonist for moderate to severe Alzheimer's; max dose $20\,mg/day$.
• Amantadine: Used for Parkinsonism and Rabbit Syndrome. Notable side effect: Livedo reticularis (purplish skin discoloration).
• Melatonin: Synthesized from tryptophan to serotonin to melatonin. Produced by the pineal gland. Short half-life ($0.5-6\text{ minutes}$). May reduce fertility in men and women.