Paper A Recall Lecture Notes

Neuropharmacology: Mechanism of Action and Drug Properties

  • Buspirone MOA: A partial agonist at 5−HT1A5-HT_{1A} receptors (serotonin-1A), resulting in an anxiolytic effect without significant sedation.
  • Atomoxetine MOA: A selective norepinephrine reuptake inhibitor (NRI) that increases noradrenaline levels in the prefrontal cortex.
  • Diazepam MOA: Acts as a positive allosteric modulator of the GABAAGABA_{A} receptor, which enhances GABA binding and increases CNS inhibition.
  • Guanfacine (ADHD Drug):
    • Category: Selective Alpha-2A adrenergic receptor agonist.
    • Uses: Primarily for ADHD (especially in children) and occasionally for hypertension.
    • MOA: Stimulates central α2A\alpha_{2A} receptors to reduce sympathetic outflow, leading to decreased blood pressure and improved attention regulation.
    • Common Side Effects: Postural hypotension, sedation, bradycardia, dizziness, and dry mouth.
  • Receptor Binding Definitions:
    • Agonist: Activates the receptor to increase activity.
    • Antagonist: Blocks the receptor; has no effect alone but prevents activation by other substances.
    • Inverse Agonist: Binds to a site and reduces receptor activity below its baseline level.
  • Hyperprolactinemia Management: To decrease hyperprolactinemia caused by Risperidone (a D2D_{2} antagonist that increases prolactin), Aripiprazole (a D2D_{2} partial agonist) can be added to lower prolactin levels.
  • Pharmacokinetics: Time to Peak Concentration (TmaxT_{max}):
    • Quetiapine (IR): ∼1.5\sim 1.5\ hours (quickest peak among the listed drugs).
    • Olanzapine: ∼5−8\sim 5-8\ hours.
    • Risperidone: ∼1−2\sim 1-2\ hours.
    • Aripiprazole: ∼3−5\sim 3-5\ hours.
    • Haloperidol (oral): ∼2−6\sim 2-6\ hours.
    • Clozapine: ∼2.5\sim 2.5\ hours.
  • Receptor Occupancy and Concentration:
    • If a drug has a 50%50\% binding capacity at 10 mg/L10\,mg/L (the KdK_d value), and we want to reach higher capacities:
    • 10 mg/L=50%10\,mg/L = 50\%
    • 20 mg/L≈67%20\,mg/L \approx 67\%
    • 30 mg/L=75%30\,mg/L = 75\%
    • 90 mg/L≈90%90\,mg/L \approx 90\%
  • Elimination Half-Lives:
    • It takes 55\ half-lives to eliminate over 96%96\%\ of a drug (specifically 96.875%96.875\%).
    • 1 Half-life: 50%50\%\ remaining, 50%50\%\ eliminated.
    • 2 Half-lives: 25%25\%\ remaining, 75%75\%\ eliminated.
    • 3 Half-lives: 12.5%12.5\%\ remaining, 87.5%87.5\%\ eliminated.
    • 4 Half-lives: 6.25%6.25\%\ remaining, 93.75%93.75\%\ eliminated.
    • 5 Half-lives: 3.125%3.125\%\ remaining, 96.875%96.875\%\ eliminated.
    • 6 Half-lives: 1.56%1.56\%\ remaining, 98.4%98.4\%\ eliminated.
  • Fluoxetine Half-life: 4−64-6\ days; its active metabolite, Norfluoxetine, stays up to 1616\ days.
  • Citalopram Half-life: 1−21-2\ days; steady state reached in approximately 11\ week.
  • Paroxetine Half-life: 2121\ hours.
  • Antibiotic-Clozapine Interactions:
    • Co-trimoxazole: Avoid; can cause or worsen neutropenia.
    • Ciprofloxacin: Strong CYP1A2 inhibitor; can increase clozapine levels.
    • Erythromycin/Clarithromycin: CYP3A4 inhibitors; can increase clozapine levels.
    • Levofloxacin: Risk of QT prolongation.
    • Metronidazole: Potential interaction; QT risk.
    • Linezolid: Risk of serotonin syndrome when combined with certain psychotropics.
  • Mirtazapine and Nausea: Anti-nausea effects are mediated through 5−HT35-HT_{3} receptor antagonism.
  • Cariprazine MOA: Partial agonist at D2D_{2} and D3D_{3} receptors with a higher affinity for D3D_{3}.
  • Nicotinic Receptors: Varenicline (Champix) is a partial agonist at α4β2\alpha 4 \beta 2\ nicotinic acetylcholine receptors used to reduce smoking cravings.
  • Propranolol MOA: Non-selective β1/β2\beta_{1}/\beta_{2}\ antagonist (does not block β3\beta_{3}).
  • Methylphenidate MOA: Catecholamine reuptake inhibition; increases dopamine and noradrenaline in the prefrontal cortex.
  • REM Suppression: Bupropion has the least effect on REM sleep compared to others like Venlafaxine or Fluoxetine.
  • Postural Hypotension: Primarily caused by Alpha-1 adrenergic antagonism, common in low-potency typicals, Clozapine, Quetiapine, and Trazodone.

Clinical Neurology and Movement Disorders

  • Gait Descriptions:
    • Huntington’s Disease: Dystonic, dancing gait with irregular, uncoordinated movements (chorea) and sudden lurching steps.
    • Parkinson’s Disease: Shuffling, festinating gait with small steps, stooped posture, reduced arm swing, and difficulty with initiation and turning.
    • Cerebellar Lesion: Ataxic gait; wide-based, unsteady, staggering walk where the patient veers side to side and has trouble with tandem walking.
  • Stupor Definition (1994 Standards): "A state of unresponsiveness in which the person can be aroused only briefly by vigorous and repeated stimuli."
  • Basal Ganglia Anatomy: Includes the Putamen, Caudate nucleus, Globus pallidus, Subthalamic nucleus, and Substantia nigra.
  • Huntington’s Disease Molecular Basis:
    • Gene: Huntingtin gene on chromosome 4p134p13.
    • Pathology: CAG trinucleotide repeat encoding glutamine.
    • Ranges: Normal is <26< 26\ repeats; disease range is >36> 36\ repeats.
    • Cell Type Affected: Medium spiny neurons; changes in GABA.
    • Motor Treatment: Tetrabenazine.
  • Alzheimer’s Disease (AD) Biomarkers in CSF:
    • Amyloid-$\beta_{42}$: Decreased (due to deposition in plaques).
    • Total tau: Increased.
    • Phosphorylated tau (p-tau): Increased.
    • Protective/Harmful Enzymes: α\alpha-secretase is protective (prevents amyloid formation); β\beta-secretase and γ\gamma-secretase promote harmful beta-amyloid formation.
  • Frontotemporal Dementia (FTD) Pathology:
    • FTD-tau: Tau-positive (e.g., Pick bodies in Pick’s disease).
    • FTD-TDP: Tau-negative, TDP-43 positive (assoc. with GRN and C9orf72 mutations).
    • FTD-FUS: FUS positive.
    • Genes: MAPT (17q21.3117q21.31), GRN (17q21.3117q21.31), C9orf72 (9p219p21).
  • Frontal Lobe Damage: Associated with perseveration (tested by the Wisconsin Card Sorting Test/WCST).
  • Chronic Traumatic Encephalopathy (CTE): Characterized by hyperphosphorylated tau pathology.
  • Insula Function: Damage leads to reduced emotional awareness, impaired interoception, and empathy.
  • Williams Syndrome Neuroimaging: Profound visuospatial deficits (Parietal/Occipital volume reduction) despite preserved verbal/social drive (preserved Frontal/Temporal volume). Amygdala shows abnormal reactivity to social stimuli.

Psychopathology and Clinical Psychiatry

  • Mania à Potu: Mania triggered by alcohol use or withdrawal; commonly associated with chronic alcohol dependence rather than primary bipolar mania.
  • Serotonin Syndrome (SS):
    • Trigger: Combining SSRIs (like Citalopram) with drugs that increase serotonin, such as Tramadol (weak opioid + SNRI action).
    • "Base temperature": A slight, persistent increase in body temperature early in SS.
    • Symptoms: Tremor, hyperreflexia, confusion, progressing to seizures/fever.
    • Clonus: A clinical features that distinguishes SS from Neuroleptic Malignant Syndrome (NMS).
  • Sleep Disturbances:
    • Modafinil can lead to sleep paralysis, hypnagogic/hypnopompic hallucinations, and insomnia due to disruption of REM regulation.
    • SSRIs, SNRIs, and TCAs can also disrupt REM sleep architecture.
  • Complex PTSD (ICD-11): Includes standard PTSD symptoms plus affective dysregulation, negative self-beliefs (low self-esteem), and interpersonal difficulties.
  • Personality Traits (ICD-11): Moves away from traditional types to qualifiers: Negative affectivity, Detachment, Disinhibition, Dissociality, and Anankastia.
  • Delirium: The core clinical feature is a disturbance in attention and awareness (not just agitation).
  • Eating Disorders:
    • Anorexia Nervosa Endocrine Signs: Low LH, Low FSH, Low GnRH (LHRH), low T3T_3, and high cortisol.
    • Binge/Purge Signs: Parotid gland swelling (hypertrophy).
    • Laxative Use Findings: Colonic slowing (melanosis coli).
    • ARFID: Avoidant/Restrictive Food Intake Disorder is not affected by body image distortion.
  • Schizophrenia Research and Models:
    • Prepulse Inhibition (PPI): Measures sensory gating (ability to filter stimuli). PPI is impaired in schizophrenia and restored by antipsychotics.
    • CATIE Study: Olanzapine had the lowest dropout rate. Approximately 31−40%31-40\%\ (average 35%35\%\ ) of male patients had metabolic syndrome.
    • DSM-5 Classification: Schizophrenia no longer categorized by subtypes.
  • NMDA Encephalitis: Often associated with ovarian teratomas.
  • LGI1 Autoimmune Encephalitis: Most commonly seen in the 55−6455-64\ age range.
  • Dissociative Disorders:
    • Dissociative Fugue: Suddenly forgetting identity and location.
    • Depersonalization: Loss of awareness of one's own body.
    • Sense of Presence: Feeling someone is in the room without sensory input.
  • Apophenia: The tendency to perceive connections/patterns that are not real, common in psychosis.

Human Development and Psychological Theory

  • Vygotsky vs. Piaget:
    • Vygotsky: Social interaction and support (scaffolding) guide development; continuous and context-based; language is crucial to thought.
    • Piaget: Development occurs in defined stages; biologically driven; language develops after cognition; key concepts are schemas, assimilation, and accommodation.
  • Bowlby Theories:
    • Attachment Phases: Protest, Despair, Detachment.
    • Grief Theory: Numbness, Yearning, and Reorganization.
  • Stages of Attachment (Ainsworth):
    • Anxious-Avoidant (~15%): Indifferent to presence/absence; easier to be comforted by strangers.
    • Secure (~70%): Mother is a secure base; distressed when she leaves; comforted upon return.
    • Anxious-Resistant (~15%): Intense distress; ambivalent on mother's return.
  • Critical Phase/Imprinting: Described by Konrad Lorenz; rapid, irreversible learning during a time-sensitive period (e.g., ducklings).
  • Developmental Milestones:
    • Stranger anxiety occurs at 99\ months.
    • Delayed gratification predicts long-term school achievement.
  • Identity Statuses:
    • Identity Achievement: Exploration and commitment present.
    • Moratorium: Exploration present, commitment absent (often high distress).
    • Foreclosure: Commitment present without exploration.
    • Identity Diffusion: Neither exploration nor commitment.
  • Piaget's Concrete Operational Stage: Development of conservation (liquid weight, mass), seriation (ordering by size), and reversibility.
  • Piaget's Formal Operational Stage: Ability to test hypotheses (hypothetico-deductive reasoning) and think about abstract concepts (justice, morality).
  • Moral Development (Kohlberg/Eisenberg): Sequence moves from self-interest to social order and then internal ethics.
  • Erikson's Psychosocial Stages: Midlife crisis corresponds to "Generativity vs. Stagnation."

Therapy, Ethics, and Sociology

  • Therapeutic Modalities:
    • Systemic Family Therapy (Milan): Focuses on social discourse, reflection groups, and family systems.
    • Structural Family Therapy (Salvador Minuchin): Emphasizes hierarchy and boundaries.
    • Narrative Therapy: Explores personal/cultural stories and re-authoring life stories.
    • Mentalisation: Technique to understand and imagine the intentions of others.
    • CBT/Phobia (Implosion): Imagining a horrible situation in the head to reach extinction.
  • Ethical Principles:
    • Paternalism: Doctor withholding information (e.g., cancer diagnosis) to "protect" the patient.
    • Utilitarianism: Maximizing benefit for the majority (e.g., funding a service used by many over early intervention for few).
    • Non-maleficence: "Do no harm"; stopping a drug (e.g., Clozapine) due to agranulocytosis.
  • Group Dynamics: "Group think" reduction occurs through open debate, appointing a devil's advocate, and anonymous feedback.
  • Criminology (Left Realism): Hypothesizes that crime results from social inequality, relative deprivation, and marginalization.
  • Maslow’s Hierarchy of Needs (1945): Physiological, Safety, Love/Belonging, Esteem (one of the options), and Self-actualization.
  • Social Sociology: Emil Durkheim hypothesized that suicide is due to social reasons rather than purely individual ones.
  • Culture: Integration occurs when an individual practices their host culture while also joining groups in the new culture.

Neuroanatomy, Genetics, and Physiological Processes

  • Action Potential Mechanism:
    • Depolarization: Na+Na^{+} (Sodium) flows into the cell.
    • Hyperpolarization: K+K^{+} (Potassium) continues to leave the cell, making it more negative than the resting potential.
  • Genetics and Development:
    • NMDA gene GRIN1: Associated with neurodevelopmental disorders.
    • DiGeorge Syndrome (22q11.222q11.2\ deletion): High risk of schizophrenia (25−30%25-30\%); associated with heart defects and cleft palate.
    • ADHD: Associated with the DRD4 gene.
    • Microarray: Test used to check for small to moderate copy number variations in DNA.
    • Heritability: A concept that applies to the population level, not to individuals.
  • Brain Structures and Arousal:
    • Orexin: Released from the lateral hypothalamus to promote wakefulness; loss leads to narcolepsy.
    • Adenosine: Receptor site for caffeine's effect on sleep.
    • Psilocybin: Partial agonist at 5−HT2A5-HT_{2A} receptors.
    • Appetite Modulation: Neuropeptide Y is released from the hypothalamus; Leptin is released from adipose tissue.
    • Gut-Brain Axis: Microglia are the cells most affected by the gut microbiome.
  • Brain Research Tools:
    • PET Scan: Measures neurotransmitters in vivo (e.g., [11C^{11}C]-raclopride for D2D_{2} occupancy).
    • Brain Organoids: Harvested from 2nd-trimester human fetal tissue; a major limitation is the lack of vasculature.

Psychological Assessment and Sleep Architecture

  • MADRS Assessment: Measures items such as Lassitude (physical/mental tiredness), sadness, inner tension, and anhedonia.
  • Sleep Stages:
    • Stage 1 (Theta waves)
    • Stage 2 (Sleep spindles and K-complexes)
    • Stages 3 and 4 (Delta waves)
    • REM (Beta waves + sawtooth waves)
  • Neuropsychological Tests:
    • National Adult Reading Test (NART): Tests premorbid intelligence.
    • Rey-Osterrieth Complex Figure: Tests visuospatial construction, planning, and visual memory.
    • Stroop Test: Measures selective attention and inhibition (color-word conflict).
    • Digit Span: Measures working memory.
    • Similarities (WAIS): Tests abstraction.
  • Scaling and Statistics:
    • Likert Scale: Based on an ordinal scale assumption (ranked order with unequal intervals).
    • Cross-Sectional Study: Conducted at a single point in time.