Behavioural Genetics GENE3733
Chapter 60:
Neurobiology of Severe Mood and
Anxiety Disorders
Basic Neurochemistry 8th Ed.
Principles of Molecular, Cellular and Medical Neurobiology
Brady, Siegel, Albers & Price, 2012
Mood disorders
• Most common
• Major depressive disorder (MDD) à 16.6%
• Dysthymia à less severe but more chronic
• Bipolar disorder à 3.9%
• Women à higher risk
• Episodic and recurrent in 80% of the cases
• Likelihood of recurrence increase with each successive episode
• Recurrent episodes à long-term alterations in neurobiological
function
• Variability àsensitive to state-dependent factors
Serotonergic system
• Indoleamine hypothesis
• Vulnerability to depression à Low 5HT activity à Less 5HT release / fewer 5HT
receptors / impaired 5HT receptor –mediated signal transduction
• Suicidal behaviour, impulsivity, aggression, eating disorders, OCD,
anxiety disorders, personality disorders, SAD, alcohol use disorders
• Indicators:
• Depletion by TPH inhibition à depression recurs after
• SSRI à dependent on continuous enhancement of 5HT function
• Linkage & association studies à 5HTTLPR
• Hypofunction & compensatory alterations! à to increase deficient
5HT transmission
• More 5HT2A receptor binding in frontal cortex
• Fewer 5HT1A autorecepters in brainstem
• Fewer SERT in the cortex
Noradrenergic system
• Less clear
• Studies show inconsistent results
• Greater sympathetic nervous system activity à lower CNS
noradrenergic activity
• Sensitivity to stress!! à greater likelihood of noradrenergic depletion
after prolonged stress
• Adverse childhood experiences à greater risk for noradrenergic
depletion in adulthood à fewer noradrenergic neurons
• Inconsistencies à not a simple model of increased or decreased
activity
• Effects
• Pathogenesis of mood disorders
• Nonspecific effects of stress
• Homeostatic mechanisms
• Comorbid psychopathology
Dopaminergic system
• Lower CSF levels of homovanillic acid (HVA)
• Not consistent results
• Psychotically depressed individuals
• Lower dopamine b-hydroxylase activity
• Higher plasma dopamine and HVA concentrations
• Mood-elevating properties of dopamine-releasing stimulants
• Not clear if D2 receptor binding and dopamine release after
amphetamine are altered in major depression
Anxiety disorder
• Development of mild forms of anxiety and neurovegetative and/or
cognitive responses to stress à adaptive evolutionary step against
• Environmental / external threats
• Self-triggered / internal threats
• Anxiety disorders = maladaptive conditions à disproportionate
responses to stress / self-evoked responses to stress
• Most frequent psychiatric illnesses à lifetime prevalence = 29%
• Generalized anxiety disorder = 6%
• Social phobia = 12%
• Panic disorder = 5%
• PTSD = 6.8%
Fear & Anxiety
• Animal studies à applicable to humans
• Fear response begins with perception à recognition & cognitive
appraisal of a threat
• Electrical stimulation of amygdala produces fear like behavioural and
physiological responses
• Pharmacological agents can provoke symptoms of anxiety à 2
categories:
• Reduce available oxygen
• Directly manipulate neurotransmitters
• Difficult to define just one symptom
• Hypothesis à patients with anxiety disorders may interpret
physiological changes as more serious à respond with anxiety
• Increased heart rate
• Increased respiration
Noradrenergic systems
• Increased NE activity à increased anxiety
• Vasoconstriction in peripheries à increased heartrate à induces
anxiety and panic
• a2 receptors à stimulants reduces anxiety à used to treat panic
disorder
• Plasticity reduces long term efficacy
Serotonergic system
• Decreased Tryptophan
• Has to look at entire system à can’t make deductions from single
components
• Increased transporter activity à SSRI’s & MAOI’s à desensitization
of autoreceptors responsible for negative feedback
• Less activity in heteroreceptors
• Slow effect
• Interaction with Substance P in pain perception
