BMS150 Wk 6

MDD: Diagnostic Criteria DSM-5

• Impaired ability to think, concentrate, or make decisions
• Recurrent thoughts of death, suicide ideation, or attempts
• Additional diagnostic requirements:
  • Symptoms must cause significant distress or impair social, occupational, or other important areas of function
  • Symptoms are not due to direct physiological effects of a substance or medical condition
  • Patient has never experienced a manic or hypomanic episode
  • Condition is not better explained by schizophrenia spectrum or other psychotic disorders

MDD: Neuropathology and Neurochemistry

• Multifactorial disease with various causes and triggers
  • Psychosocial causes
  • Genetics
  • Nutritional deficiencies
  • Pollution/environment
  • Gut-brain axis
• Leading biomedical theories:
  • Monoamine hypothesis
  • Stress-induced depression hypothesis
  • Neurotrophic/neuroplasticity hypothesis
  • Cytokine hypothesis/neuroinflammation hypothesis
  • Circadian hypothesis of depression
  • GABA-glutamate-mediated depression hypothesis

Monoamine Hypothesis

• Altered levels of monoamine neurotransmitters (serotonin, noradrenaline, and dopamine) cause depression
• Based on antidepressant therapies that increase the presence/function of one or more neurotransmitters, resulting in reduced depression
• Criticisms:
  • Abruptly decreasing serotonin and/or dopamine doesn't cause depression in a healthy person
  • Other neurochemicals are implicated in depression beyond these

Stress-induced Depression Hypothesis

• Chronic stress leads to dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis
• Prolonged, moderate stress is the problem, versus minor daily stresses or one strong stressor
• Examples of chronic stress:
  • Maternal stress
  • Maternal smoking
  • Early grave loss
  • Child abuse
• Early trauma may have a more significant impact than in adult life (impact on HPA development in utero)
• Chronic HPA activation leads to:
  • Excess cortisol secretion
  • Pro-inflammatory agents that damage glia and neurons
  • Interference with neurogenesis and reduced glutamate and GABA

Bipolar Disorders - DDX

• Bipolar Disorder 2:
  • No/never experienced episode of mania
  • Exclusion of/not better explained by schizophrenia, delusional or psychotic disorder, or unspecified schizophrenia spectrum
  • Clinically significant distress from symptoms
  • Hypomania episode

Hypomania Episode (DSM-5)

• Elevated, expansive, or irritable mood with persistently increased activity or energy
• 4+ days, most of the day, nearly every day
• 3 or more additional mania symptoms
• Episode is different from patient's regular non-symptomatic experience
• Observers can note change in mood and function
• Not severe enough to impair functioning or necessitate hospitalization (no psychotic features)
• Episode is not triggered by substance (drug, medication, or other treatment)

Pathophysiology of Bipolar Disorders

• Circadian Rhythm Dysfunction
• Metabolic Dysfunction
• Mitochondria Dysfunction
• Glutamate Excitotoxicity

Circadian Rhythm Dysfunction

• During mania, there is a reduced need for sleep
• Observations in patients with bipolar disorders:
  • Changes in melatonin levels
  • Changes in melatonin receptor expression with CNS
  • Changes in cortisol profiles (patterns of release)
  • Sleep deprivation as well as light therapy have been effective as adjunct in some cases of bipolar disorder
• Correlation between polymorphism in CLOCK genes and positive response to lithium therapy

Metabolic Dysfunction

• Various metabolic abnormalities have been found in patients with bipolar disorder, such as:
  • Increased risk of obesity, type 2 diabetes, and reduced longevity due to increased cardiovascular problems
  • Increased amount of leptin secreted in obese patients with bipolar compared to obesity alone
• Leptin regulates appetite and sleep duration
• Hypothesis: body is forced to compensate for the high metabolic demand of the brain during manic states, leading to:
  • Reduced appetite
  • Reduced sleep
  • Increased energy expenditure

Mitochondria Dysfunction

• Impairment in mitochondrial function resulting in brain metabolism shifting towards glycolysis
• Observations:
  • Polymorphisms within mitochondrial DNA linked to BD
  • Reduced levels of phosphocreatine within frontal cortex

Main Classes of Antidepressants

• SNRI's (Serotonin & Norepinephrine Reuptake Inhibitors):
  • Examples: TCA's (tricyclic antidepressants), venlafaxine
• SSRI's (Selective Serotonin Reuptake Inhibitors):
  • Example: fluoxetine
• Other:
  • MAOI's (monoamine oxidase inhibitors)
  • Trazodone
  • Bupropion

Objectives

• Compare and contrast general anxiety disorder, phobia disorders, agoraphobia, social anxiety disorder, and panic disorder
• Describe the clinical features of post-traumatic stress disorder (PTSD) and obsessive-compulsive disorder (OCD)
• Describe the clinical features of eating disorders and their risk factors
• Explain the general neurobiological mechanisms underlying anxiety and OCD
• Discuss the use of benzodiazepines (BDZ) as anxiolytics and hypnotics, their therapeutic mechanism of action, and adverse effects

Anxiety

• Anxiety is a wide range of symptoms and signs that everyone experiences to some degree
• Anxiety becomes "pathologic" when it is out of proportion to the risk or severity of the threat, lasts beyond the duration of the threat, becomes generalized to other situations, or impairs social or occupational functioning
• 17% of adults report a lifetime history of one of the major anxiety disorders

Anxiety Disorders

• "True" anxiety disorders: panic disorder, agoraphobia, specific phobia, and generalized anxiety disorder
• "Anxiety-like" disorders: OCD, PTSD (no longer strictly considered part of the anxiety disorder spectrum)

Panic Disorder

• Characterized by recurrent panic attacks
• To be diagnosed, need at least 1 month history of avoidance or fear of another panic attack
• The panic cannot be due to a particular phobia or another anxiety-related disorder
• The panic symptoms cannot be due to an underlying medical disorder

Panic Attacks

• Four or more of the following features:
  • Palpitations, pounding heart, or accelerated heart rate
  • Sweating
  • Trembling or shaking
  • Sensations of shortness of breath or smothering
  • Feelings of choking
  • Chest pain or discomfort
  • Nausea or abdominal distress
  • Feeling dizzy, unsteady, light-headed, or faint
  • Chills or heat sensations
  • Paresthesias (numbness or tingling sensations)
  • Derealization (feelings of unreality) or depersonalization (being detached from oneself)
  • Fear of losing control or "going crazy"
  • Fear of dying

Generalized Anxiety Disorder

• Characterized by generalized worry that occurs more days than not, disproportionate to the severity of the event that is feared
• Common, with a prevalence of 3-8%
• Can be difficult to treat
• Often anxiety reduces with age
• Diagnostic criteria:
  • Excessive anxiety for more days than not for 6 months
  • Individual has difficulty controlling the anxiety
  • Accompanied by typical symptoms (restlessness, feeling "keyed up" or on edge, being easily fatigued, difficulty concentrating, irritability, muscle tension, and sleep disturbance)

Agoraphobia

• Characterized by unreasonable fear of being out-of-doors or being in a crowd or being in a place where they can't escape from or may suffer embarrassment
• Anxiety and symptoms are typically present almost all of the time, even when the patient is somewhere comfortable
• Avoidance is prominent
• Very common, with a rough estimate of about 1% of the population

Agoraphobia Symptoms

• Examples of situations that cause worry or fear:
  • Using public transportation
  • Being in open spaces or enclosed spaces
  • Standing in line, being in a crowd, or being in other social situations
  • Being outside of the home
• These situations should almost always provoke fear or anxiety
• The fear or anxiety needs to be present for > 6 months and cause significant distress or impairment in social or occupational function

Specific Phobias

• Fears of specific objects or situations that go beyond the true threat of the stimulus and cause avoidance and functional impairment
• Surprisingly common, with a prevalence of 12-16%
• Diagnostic criteria:
  • Exposure to stimulus provokes an immediate fear/anxiety response
  • Phobic object/situation is actively avoided or endured with intense anxiety
  • Fear/anxiety is out of proportion to actual danger/sociocultural context
  • Person recognizes fear as excessive or unreasonable
  • Significant distress or impact on daily routine, occupational/social functioning, and/or marked distress

Social Anxiety Disorder

• Characterized by marked and persistent fear of social or performance situations in which:
  • One is exposed to unfamiliar people or to possible scrutiny by others
  • One is afraid of fearing they will act in a way that may be humiliating or embarrassing
  • Out-of-proportion fear that they will be harshly judged by their interpersonal interactions
• Very common, with a prevalence of 2-7%

Post-Traumatic Stress Disorder

• When does it happen?
  • Exposure to actual death, threatened death, physical or sexual violence, serious injury
  • Can occur in people who are repetitively exposed to disturbing or violent events
• Examples of situations that cause worry or fear:
  • Exposure to actual death, threatened death, physical or sexual violence, serious injury
  • Witnessing or receiving the violent act
  • Can occur in people who are repetitively exposed to disturbing or violent events

Obsessive Compulsive Disorder

• Additional criteria:
  • Obsessions and compulsions must take > 1 hour/day or cause significant distress or impairment in social, occupational, or other areas of function
• Patients are usually aware that obsessions and compulsions are illogical and not based in fact
• Other disorders may share a similar neurobiology with OCD, including hoarding disorder, skin-picking or trichitomania disorders, and body dysmorphic disorder

Neurobiology of Anxiety Disorders

• General concepts in fear and anxiety:
  • Fear response: activation of the locus coeruleus (LC), a midbrain nucleus that contains neurons that release norepinephrine (NE) at the presynaptic terminal
  • Activation of the LC !release of norepinephrine (NE) !activation of the amygdala – emotional "fear" responses
  • Activation of the hypothalamus – activation of the sympathetic nervous system and cortisol release
  • Activation of the reticular activating system in the brainstem – increased arousal
• The networks involved in anxiety-type disorders are complex

Benzodiazepine Adverse Effects

• Selected adverse effects (most common with hypnotic use):
  • Hangover effects
  • Early morning rebound insomnia
  • Tolerance
  • Dependence
  • Withdrawal symptoms
• Withdrawal symptoms:
  • Mild symptoms: extra-sensory awareness, muscle twitching or tremors, rebound excitation
  • Severe symptoms: increased blood pressure, temperature, and pulse, rage, hallucinations, and paranoia, seizures
• Use of BDZs more than 14-21 nights in a row makes tolerance/dependence/several withdrawal symptoms more likely

Microbial Disorders of the Nervous System

Bacterial Meningitis

• Inflammatory bacterial infections of the meninges (pia and arachnoid mater)
• Causes meningial swelling, restricting CSF flow, and putting pressure on organs
• Symptoms: nausea, pain, vomiting, reduced brain function, stiff neck, and motor control reduction
• Testing: cloudy CSF and positive meningitis test through lumbar puncture

Causative Bacteria

• Opportunistic members of normal microbiota
• Regular disease-causing bacteria: Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis (~90% of cases)
• Other bacteria: Listeria monocytogenes, Staphylococcus aureus, Streptococcus pyogenes, and Klebsiella pneumoniae

Neisseria Meningitidis

• Causes meningicoccal meningitis
• Virulence factors: fimbriae, polysaccharide capsules, lipooligosaccharide (with Lipid A/Endotoxin), and factors to prevent digestion in phagocytes

Streptococcus Pneumoniae

• Leading cause of meningitis
• Virulence factors: capsule, secretory IgA protease, pneumolysin, and phosphorylcholine (attachment to cells of lungs, meninges, and blood vessels)

Listeria Monocytogenes

• Gram-positive coccobacillus found in soil, water, and many animals (no endospores)
• Obtained through contaminated food/drink
• Causes meningitis in immunocompromised individuals, but only mild flu in healthy adults
• Avoids immune system detection by dividing inside macrophages and epithelial cells

Pathogenesis of Bacterial Meningitis

• N.meningitidis, H.influenzae, S.pneumoniae – inhaled in respiratory droplets
• Listeria – unpasteurized milk, cheese, meat
• Bacteria spread to meninges from infections of lungs, sinuses, or inner ear
• Head or neck trauma may expose meninges directly
• Bacteria ferment glucose in CSF for energy

Prevention

• Susceptible individuals should avoid undercooked veggies, unpasteurized milk, undercooked meat, and soft cheese
• People living in dormitories should receive vaccinations

Hansen's Disease (Leprosy)

• Causative agent: Mycobacterium leprae
• Optimal growth at 30°C – in peripheral nerve endings, earlobes, nose, tips of fingers and toes
• Signs of disease may not be present for 10-30 years

Botulism

• Causative agent: Clostridium botulinum toxin (not an infection)
• 3 types: foodborne, infant, and wound botulism
• Symptoms: paralysis of all voluntary muscles, blurred vision, nausea (death from respiratory paralysis)

Tetanus

• Causative agent: Clostridium tetani
• Portal of entry: endospores enter through breaks in skin
• Signs/symptoms: tightening of jaw and neck muscles, difficulty swallowing, fever, spasms
• Treatment: aggressive treatment of wound, antibiotics
• Prevention: Vaccination

West Nile Fever

• Absent from N. America until 1999
• Virus infects 100s of bird, 37 mosquito, 18 other vertebrate species
• Transmitted by mosquito bite
• Incubation period: 3-14 days
• 20-30% get flu-like illness, 80% - no symptoms
• 1/150 experience neuroinvasion: headache, ocular manifestations, muscle weakness, cognitive impairment, and polio-like flaccid paralysis

Poliomyelitis (Polio)

• Humans are the only known reservoir
• Spread by fecal-oral transmission
• Peaks during warm months in temperate climates
• Complication: post-polio syndrome
• 30-40 year interval, 25-40% affected
• Not an infectious process

This quiz covers the diagnostic criteria for Major Depressive Disorder (MDD) according to the DSM-5, including symptoms and additional requirements. Test your knowledge of MDD diagnosis!