Psychopharmacology

Introduction to Psychopharmacology: Overview and Classification

• Definition & Evolution: Psychopharmacology involves the study and application of psychiatric drugs, often termed "psychotropic" medications. Early terminology used "tranquilizers" for antipsychotics, which later branched into "major" and "minor" (anxiolytics) tranquilizers.

• Primary Classification Systems:

  • By Application/Indication: Antidepressants, Antipsychotics, Mood stabilizers, Anxiolytics, Hypnotics, Cognitive enhancers, and Stimulants.

  • By Structure: Examples include tricyclic antidepressants (TCAs).

  • By Mechanism: Examples include monoamine oxidase inhibitors (MAOIs).

  • By Generation: Typically used for antipsychotics ($1^{\text{st}}$ vs. $2^{\text{nd}}$ generation) and antidepressants ($1^{\text{st}}$ gen TCAs/MAOIs vs. $2^{\text{nd}}/3^{\text{rd}}$ gen SSRIs and newer agents).

• Drug Selection Principles:

  • Overall efficacy across FDA-approved psychotropics is generally similar, with the notable exception of Clozapine, which is the only agent proven superior for treatment-refractory schizophrenia.

  • Selection is guided by side effect profiles, tolerability, patient-specific variables, and clinical judgment.

Pharmacokinetics and Pharmacodynamics

• Pharmacokinetics (PK): Defined as what the body does to the drug. It involves four processes: absorption, distribution, metabolism, and excretion (ADME).

  • Specific Interaction Example: Renal-related interactions where NSAIDs, ACEIs, and thiazides can increase lithium levels.

• Pharmacodynamics (PD): Defined as what the drug does to the body, focusing on biological activity and receptor binding.

• Mechanisms of Action:

  • Typical Mechanisms: Includes receptor agonism/antagonism (e.g., antipsychotics blocking $D_2$ receptors), reuptake inhibition (e.g., SSRIs), and enzyme inhibition (e.g., MAOIs).

  • Specific Examples:

    • Benzodiazepines enhance GABA via receptor complexes.

    • Lithium inhibits inositol-$1$-phosphatase.

  • Alternative Pathways: Ketamine acts as an NMDA antagonist for rapid antidepressant effects. Minocycline (an antibiotic) may have antidepressant effects via anti-inflammatory pathways.

• Pharmacogenetics: Study of genetic variants affecting drug metabolism (e.g., ultrarapid metabolizers resulting in low drug levels) and response.

Adverse Events and Movement Disorders

• Serious Adverse Events (SAEs): Includes agranulocytosis (clozapine), Stevens-Johnson Syndrome (lamotrigine), hepatic failure (nefazodone), and QTc prolongation (thioridazine).

• Medication-Induced Movement Disorders:

  • Parkinsonism: Characterized by rigidity, tremor, and shuffling gait. Onset is $5$-$90$ days. Treatment: benztropine or diphenhydramine.

  • Neuroleptic Malignant Syndrome (NMS): Characterized by rigidity, fever, and autonomic instability. Incidence is $0.01\%$-$0.02\%$. High mortality. Treatment: Discontinue antipsychotic, administer dantrolene or bromocriptine.

  • Acute Dystonia: Painful spasms, oculogyric crisis, or torticollis. Onset is hours to days. Risk group: young males. Treatment: IM benztropine or diphenhydramine.

  • Akathisia: Restlessness, pacing, and anxiety. Risk group: middle-aged females. Treatment: Propranolol or benzodiazepines.

  • Tardive Dyskinesia (TD): Involuntary perioral, limb, or trunk movements. Risk increases with long-term use, especially in women and the elderly. Treatment: Switch to clozapine or use valbenazine.

• General Side Effects:

  • Sexual Dysfunction: Affected by $35\%$-$75\%$ of patients on SSRIs.

  • Weight Gain: Common with clozapine and olanzapine.

  • Weight Loss: Linked to bupropion and topiramate.

  • Cardiovascular: QTc prolongation (ziprasidone) and myocarditis (clozapine).

Clinical Guidelines: Dosing, Monitoring, and Outcomes

• Dosing Principles: Guided by drug half-life and side effects. Sedating drugs are given at night; activating drugs during the day. Drug potency does not equal efficacy (e.g., haloperidol vs. chlorpromazine).

• Treatment Duration Phases: Initial trial (weeks), Continuation, and Maintenance. Long-term use is often required to reduce relapse risk.

• Therapeutic Index (TI): The ratio of toxic dose to effective dose ($TD_{50}/ED_{50}$). Lithium has a low TI (narrow margin), while haloperidol has a high TI.

• Laboratory Monitoring:

  • Blood levels are essential for low TI drugs like Lithium ($0.8$-$1.2\,mEq/L$ for mania; $0.4$-$0.8\,mEq/L$ for maintenance).

  • Clozapine requires weekly Neutrophil count (ANC). Discontinue if WBC < 3,000 or ANC < 1,500/mm^3.

• Outcomes:

  • Remission: Resolution of all symptoms (e.g., HAM-D $\le 7$).

  • Response: $\ge 50\%$ symptom reduction.

  • Tolerance: Reduced response over time.

  • Sensitization: Enhanced response to the same dose over time.

Second-Generation Antipsychotics (SGAs / SDAs)

• General Profile: Block $D_2$ and $5\text{-HT}_{2A}$ receptors. Lower EPS risk but higher metabolic risk (weight gain, glucose dysregulation, metabolic syndrome).

• Specific Agents:

  • Risperidone: FDA-approved for Schizophrenia and Bipolar Mania. Dose-dependent EPS risk above $6\,mg/day$. Increases prolactin.

  • Paliperidone: Active metabolite of risperidone. Monthly IM option (Sustenna). Safe in liver impairment.

  • Olanzapine: High risk of weight gain and diabetes. Requires observation for $3$ hours after long-acting injection (Relprevv) for PDSS risk.

  • Quetiapine: Low EPS risk; useful for Parkinson’s psychosis.

  • Ziprasidone: Must be taken with food ($500\,kcal$ minimum). Low weight gain but high QTc risk.

  • Aripiprazole: Partial $D_2$ agonist. Long half-life ($75\,hours$). Common side effect: akathisia.

  • Clozapine: Reserved for treatment-resistant schizophrenia. Induces sialorrhea (excessive drooling) and constipation. Risk of agranulocytosis ($0.73\%$ in year 1).

  • Lurasidone: Must be taken with food. Low metabolic risk.

Antidepressants: SSRIs, SNRIs, and Others

• Selective Serotonin Reuptake Inhibitors (SSRIs): Common agents include Fluoxetine, Sertraline, and Paroxetine.

  • Fluoxetine: Longest half-life ($4$-$6\,days$). Most data for children.

  • Paroxetine: High risk of withdrawal syndrome and anticholinergic effects. FDA category D for cardiac malformations.

  • Sertraline: Preferred in the elderly due to low drug interactions.

  • Citalopram: Max dose $20\,mg/day$ in elderly due to QTc prolongation.

• Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs):

  • Venlafaxine: Risk of hypertension at doses > 300\,mg/day. Meta-analysis suggests slight remission advantage over SSRIs.

  • Duloxetine: Used for depression and neuropathic pain. Avoid in hepatic insufficiency.

• Norepinephrine–Dopamine Reuptake Inhibitor (NDRI):

  • Bupropion: No sexual dysfunction, weight gain, or sedation. Contraindicated in seizure disorders and eating disorders (seizure risk is dose-dependent, max $150\,mg/dose$).

• Monoamine Oxidase Inhibitors (MAOIs):

  • Hypertensive Crisis: Caused by dietary tyramine (aged cheese, wine). Treatment involves phentolamine.

  • Serotonin Syndrome: Risk when combined with SSRIs/SNRIs. Signs include diarrhea, agitation, and seizures. Wait $5$ weeks when switching from fluoxetine to an MAOI.

Mood Stabilizers: Lithium and Anticonvulsants

• Lithium: First-line for Bipolar I. Most common long-term side effect is hypothyroidism. Polyuria treated with amiloride. Excreted renally; toxicity caused by low sodium or dehydration.

• Valproate: Therapeutic range $50$-$125\,\mu g/mL$. Black box warnings for hepatotoxicity and pancreatitis. Teratogenic: increases neural tube defects risk by $1$-$5\%$.

• Lamotrigine: Effective for the depressive phase of Bipolar, not acute mania. Risk of Stevens-Johnson Syndrome (SJS); titration must be restarted if $\ge 4$ days are missed.

• Carbamazepine: Autoinduces its own metabolism (CYP450). Good for rapid cycling. Serum level target $4$-$12\,\mu g/mL$. Increases risk of blood dyscrasias.

Special Populations and Regulatory Issues

• Children: higher metabolism often requires higher $mg/kg$ dosing.

• Pregnancy: No psychotropic is entirely safe. Teratogens to avoid: lithium (Ebstein anomaly), valproate/carbamazepine (neural tube defects), lamotrigine (oral clefts), and paroxetine (cardiac defects).

• Elderly: "Start low, go slow." Increased risk of SIADH and hyponatremia with SSRIs.

• FDA Labeling:

  • Black Box Warning: Strictest warning for severe adverse reactions (e.g., suicide risk in youth on SSRIs).

  • Off-Label Use: Legal and common (e.g., propranolol for performance anxiety). Requires clinical justification and documentation.

• Placebos: Approximately $30\%$ of patients with depression or anxiety improve on placebo. The "Nocebo effect" refers to placebos causing adverse effects.