Affective Disorders and Alzheimer's Disease Clinical Pharmacology

Patient Case Study and Clinical Observations

  • Vignette #1 (Mrs. Smith):
    • Patient Profile: 56-year-old female.
    • Presenting Complaints: Bouts of crying, grief, chest pain, severe fatigue, loss of appetite, and suicidal ideation.
    • Clinical History: Symptoms emerged following the death of her husband 6 months ago. She has a prior history of similar symptoms when younger.
    • Previous Medications: Successfully treated in the past with Amitriptyline (Elavil) and Fluoxetine (Prozac).
    • Current Severity: Reports never feeling this "low" before and expresses a specific intent to end her life by suicide.

Introduction to Affective Disorders

  • Definition: Affective disorders are primarily characterized by a disturbance in mood.
  • Distinctions from Other Disorders:
    • Schizophrenia: Characterized by a disturbance of thought.
    • Parkinsonism: Characterized by a disturbance in movement.
  • General Symptoms of Depression:
    • Emotional state: Feelings of sadness, anxiety, emptiness, hopelessness, worry, helplessness, worthlessness, guilt, irritability, or restlessness.
    • Functional impacts: Loss of interest in previously pleasurable activities (anhedonia), changes in appetite (loss of appetite or overeating), and cognitive difficulties (problems concentrating, remembering details, or making decisions).

Common Depressive Syndromes and Treatments

  • Major Depression (Typical):
    • Criteria: Depressed mood or loss of interest plus four other depressive symptoms.
    • Treatment: Antidepressants and psychotherapy.
  • Atypical Depression:
    • Criteria: Overeating and weight gain, oversleeping, rejection sensitivity, and mood reactivity.
    • Treatment: Selective Serotonin Reuptake Inhibitors (SSRIs), Monoamine Oxidase Inhibitors (MAOIs), and Tricyclic Antidepressants (TCAs).
  • "Anxious" Depression:
    • Criteria: Prominent anxiety symptoms in addition to meeting major depressive criteria.
    • Treatment: SSRIs and MAOIs.
  • Seasonal Depression:
    • Criteria: Fall onset and spring offset; recurrent patterns.
    • Treatment: SSRIs.
  • Dysthymia:
    • Criteria: Chronic depressive illness lasting for 22 or more years; symptoms are fewer and less severe than Major Depression.
    • Treatment: SSRIs.
  • Bipolar Depression:
    • Criteria: Prior history of mania; mixed episodes may occur.
    • Treatment: Mood stabilizers are preferred (e.g., Lithium, Valproate, Carbamazepine).

Comprehensive List of Antidepressant Agents

  • Common Agents (A-Z):
    • Anafranil (clomipramine)
    • Asendin (amoxapine)
    • Aventyl (nortriptyline)
    • Celexa (citalopram hydrobromide)
    • Cymbalta (duloxetine)
    • Desyrel (trazodone HCl)
    • Elavil (amitriptyline)
    • Effexor (venlafaxine HCl)
    • Emsam (selegiline)
    • Etrafon (amitriptyline)
    • Fluvoxamine maleate
    • Lexapro (escitalopram)
    • Limbitrol (amitriptyline)
    • Ludiomil (maprotiline)
    • Marplan (isocarboxazid)
    • Nardil (phenelzine sulfate)
    • Nefazodone HCl
    • Norpramin (desipramine HCl)
    • Pamelor (nortriptyline)
    • Parnate (tranylcypromine sulfate)
    • Pexeva (paroxetine mesylate)
    • Paxil (Paroxetine)
    • Prozac (fluoxetine HCl)
    • Remeron (mirtazapine)
    • Sarafem (fluoxetine HCl)
    • Seroquel (quetiapine)
    • Sinequan (doxepin)
    • Surmontil (trimipramine)
    • Symbyax (olanzapine/fluoxetine)
    • Tofranil (imipramine)
    • Tofranil-PM (imipramine pamoate)
    • Triavil (amitriptyline)
    • Vivactil (protriptyline)
    • Wellbutrin (bupropion HCl)
    • Zoloft (sertraline HCl)
    • Zyban (bupropion HCl)
  • FDA Warning: The U.S. Food and Drug Administration (FDA) has issued black box warnings for many antidepressant agents.

Tricyclic Antidepressants (TCAs)

  • Representative Drugs:
    • Amitriptyline (Elavil)
    • Clomipramine (Anafranil): Noted as the first-line treatment for Obsessive-Compulsive Disorder (OCD).
    • Desipramine (Norpramin)
    • Imipramine (Tipramine)
    • Doxepin
    • Protriptyline
  • Indications:
    • Depression
    • Enuresis (bedwetting)
    • Migraine and Chronic Pain
    • Neurological Pain
    • Panic disorders and OCD
    • Eating disorders (specifically Bulimia nervosa)
    • ADHD
    • Sleep disorders: Somnambulism (sleepwalking) and night terrors.
  • Mechanism of Action:
    • Short-term effects: Non-selective reuptake inhibition of Norepinephrine (NE), Serotonin (5HT), and Dopamine (DA). This increases synaptic concentration and increases stimulation of pre- and post-synaptic receptors.
    • Clinical Lag: It takes 2−3 weeks2-3\,\text{weeks} for clinical effects to manifest.
    • Long-term effects: Decrease in the uptake of all neurotransmitters and down-regulation of presynaptic autoreceptors.
  • Pharmacokinetics:
    • Absorption/Distribution: Incomplete absorption; significant first-pass metabolism. High protein binding, high lipid solubility, and a large volume of distribution.
    • Metabolism: Extensively metabolized into active and inactive metabolites.
      • Amitriptyline $\rightarrow$ Nortriptyline (Aventyl)
      • Imipramine $\rightarrow$ Desipramine (Norpramin)
    • Half-life: TCAs and active metabolites have long half-lives ranging from 1818 to 70 hours70\,\text{hours}.
  • Adverse Effects:
    • Drowsiness and Sedation.
    • Sympathomimetic effects: Tremors and insomnia.
    • Anticholinergic effects: Blurred vision, constipation, dry mouth.
    • Cardiovascular: Orthostatic hypotension, reflex tachycardia, arrhythmias.
    • Psychiatric: Withdrawal syndrome.
    • Neurological: Lowering of the seizure threshold.
    • Metabolic-endocrine: Weight gain and sexual disturbance.
  • Drug Interactions:
    • CNS depressants (e.g., alcohol): Additive effects.
    • Sympathomimetics: May cause arrhythmias.
    • QT Interval Prolongation: Interaction with azole antifungals and macrolide antibiotics can cause fatal Torsades de pointes.
    • Antihypertensives: Additive hypotensive effects.

Selective Serotonin Reuptake Inhibitors (SSRI)

  • Representative Drugs:
    • Fluoxetine (Prozac)
    • Fluvoxamine (Luvox)
    • Paroxetine (Paxil)
    • Sertraline (Zoloft)
    • Citalopram (Celexa)
    • Escitalopram (Lexapro)
  • Mechanism of Action: Selectively blocks the reuptake of Serotonin (5HT). These drugs are well absorbed and extensively metabolized by Cytochrome P450 enzymes.
  • Adverse Effects:
    • Lower incidence of anticholinergic effects and sedation compared to TCAs.
    • Nervousness, dizziness, and insomnia.
    • Male sexual dysfunction.
    • Suicidal tendencies (particularly in early treatment).
    • Safety in Overdose: Seldom cause cardiac arrhythmias or seizures compared to TCAs.
  • Drug Interactions:
    • CNS depressants.
    • Cytochrome P450 Inhibition:
      • Inhibition of CYP2D6 isoenzyme: Increases serum concentrations of antipsychotics and Dextromethorphan.
      • Inhibition of CYP2C and CYP3A4 isoenzymes: Increases serum concentrations of Benzodiazepines, Carbamazepine, and Phenytoin.
    • MAO-Inhibitors: Concurrent use precipitates Serotonin Syndrome. A washout period of 2−5 weeks2-5\,\text{weeks} is required when switching between these classes.
  • Indications:
    • Depression and Eating disorders (Bulimia/Anorexia nervosa).
    • Anxiety disorders (Panic, Phobic, OCD).
    • Fibromyalgia, Autism, and Premenstrual syndrome.

Serotonin Syndrome

  • Mechanism: Result of excessive serotonin levels.
  • Cognitive Effects: Headache, agitation, hypomania, mental confusion, hallucinations.
  • Autonomic Effects: Shivering, sweating, hyperthermia, hypertension, tachycardia, nausea, diarrhea.
  • Somatic Effects: Myoclonus, hyperreflexia.

Atypical Antidepressants (Heterocyclics) and SNRIs

  • Second Generation: Amoxapine (Asendin), Maprotiline (Ludimil).
  • TCA-Related: Trazodone (Desyrel), Bupropion (Wellbutrin).
  • Third Generation: Nefazodone (Serzone), Mirtazapine (Remeron).
  • SNRIs (Serotonin Norepinephrine Reuptake Inhibitors): Venlafaxine (Effexor), Duloxetine (Cymbalta).
  • Bupropion (Wellbutrin, Zyban):
    • Mechanism: Weak uptake inhibitor of DA, NE, and 5HT.
    • Profile: Few anticholinergic effects, little sedation, rare cardiovascular or sexual dysfunction.
    • Unique Use: Employed in smoking cessation.
  • Nefazodone (Serzone):
    • Mechanism: Inhibits 5-HT2 receptors.
    • Profile: Little to no anticholinergic, antiadrenergic, or antihistamine activity. Not associated with sexual dysfunction.
  • Venlafaxine (Effexor):
    • Mechanism: Structurally unique SNRI; blocks reuptake of both NE and serotonin.
    • Profile: Minimal sedative or cardiovascular effects; does not inhibit Muscarinic, adrenergic, or histamine receptors.
  • Trazodone:
    • Mechanism: Selectively inhibits serotonin reuptake.
    • Profile: High sedation and orthostatic hypotension; minimal anticholinergic/cardiac conduction effects.
  • Mirtazapine (Remeron):
    • Mechanism: Alpha-2 antagonist; blocks presynaptic alpha-2 receptors to increase amine release from presynaptic nerve endings.

Bipolar Mood Disorder

  • Characterization: Alternation between mania and depression.
  • Subtypes:
    • Bipolar I: Full manic episodes.
    • Bipolar II: Hypomanic episodes.
    • Cyclothymia: Chronic "moodiness" (fluctuations between up and down).
  • Clinical Presentation of Mania ("The High"):
    • Inflated self-esteem, severe insomnia.
    • Excessive talkativeness, racing thoughts, distractibility.
    • Excess activities (e.g., spending money) and risky behaviors.
  • Clinical Presentation of Depression ("The Low"):
    • Loss of interest, changes in appetite/weight.
    • Sleep pattern changes, loss of energy.
    • Cognitive trouble, repeated thoughts of suicide.

Pharmacology of Lithium

  • Overview: Mood stabilizer that reduces both manic and depressive symptoms; greater efficacy against manic symptoms.
  • Mechanism of Action (Multiple):
    • Effects on electrolyte and ion transport.
    • Effects on neurotransmitters and receptor binding.
    • Signaling pathways: Suppresses the formation of Inositol triphosphate (IP3) and Diacylglycerol (DAG), which are essential for amine neurotransmission.
  • Pharmacokinetics:
    • Absorption: 95−100%95-100\% orally well absorbed.
    • Distribution: High levels in the thyroid, bone, and specific brain areas.
    • Metabolism: Not metabolized; half-life is 24 hours24\,\text{hours}.
    • Excretion: Excreted in urine; extensively reabsorbed. Sodium competes for renal tubular reabsorption.
  • Clinical Management:
    • Narrow therapeutic window requiring blood level monitoring.
    • Pregnancy: Lithium clearance is increased.
    • Initial phase: May require neuroleptics or benzodiazepines until lithium takes effect.
  • Adverse Effects:
    • Drowsiness, weight gain.
    • Fine hand tremor: Can be controlled by β\beta-adrenergic antagonists.
    • Polyuria: Lithium interferes with ADH (Antidiuretic Hormone), making the kidney resistant to ADH and unable to concentrate urine.
    • Thyroid enlargement/dysfunction and salivary gland hyposecretion.
  • Drug Interactions:
    • NSAIDs and Thiazide Diuretics: Reduce lithium clearance by 25%25\%.
    • Antipsychotics: Can produce severe extrapyramidal syndromes (except Clozapine).

Alzheimer’s Disease (AD)

  • Epidemiology: Most common form of dementia. Affects 55 million55\,\text{million} people worldwide (as of 2025 data/projections); predicted to affect 11 in 8585 people globally by 2050.
  • Neuropathology:
    • Neuronal loss in the cerebral cortex and subcortical regions.
    • Gross atrophy: Degeneration of temporal and parietal lobes and parts of the frontal cortex.
    • Amyloid Plaques: Dense, insoluble deposits of beta-amyloid peptide and cellular material outside and around neurons.
    • Neurofibrillary Tangles: Aggregates of microtubule-associated protein Tau inside nerve cell bodies.
  • Hypotheses:
    • Cholinergic hypothesis: Decreased levels of Acetylcholine production.
    • NMDA hypothesis: Increased NMDA activity in the grey matter.
    • Tau hypothesis: Hyperphosphorylated tau pairs with other tau threads to form tangles.
  • Anti-Alzheimer Agents:
    • Acetylcholinesterase (AChE) Inhibitors: Tacrine, Rivastigmine, Galantamine, Donepezil.
      • Note: Donepezil is the only approved drug for advanced AD.
    • NMDA Receptor Antagonist: Memantine (Akatinol). Originally an anti-influenza agent; blocks NMDA receptors to inhibit overstimulation by glutamate.