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Chapter 17: Anxiety and Anxiolytic Drugs - Coggle Diagram
Chapter 17: Anxiety and Anxiolytic Drugs
Characteristics of Anxiety Disorders
10-30% of people in the US will suffer from anxiety disorder at some point
60% of patients with MDD also present signs of an anxiety disorder (comorbidity)
mainfests of feelings of concern or worry
increased muscle tension, restlessness, impaired concentration, sleep disturbances, irritability
sympathetic activation: increased heart rate, sweating, fight or flight response
Types of Anxiety Disorders
Generalized anxiety disorder (GAD) (5% general population between 15-45)
constant worry, anticipation of dreadful events, life is stressful
reduces performance on many tasks and decreases pleasure
Panic disorder
both individual panic attacks and anticipatory anxiety over possibility of having an attack in a place that's not safe (agorabphobia)
dysregulation of NE function
Phobias
fears that individual recognizes as irrational
treated with behavioral desensitization
Social anxiety disorder (SAD)
lifetime prevalence: 12%
extreme fear of being evaluated or criticized by others --> avoid interpersonal situations
Disorders previously categorized but not in DSM-V
PTSD: after severely traumtatic event
fear, sense of helplessness and horror
nightmares and flashbacks
increased physiological reactivity to reminders of the trauma, sleep disturbances, avoidance of stimuli associated with the trauma, numbing of emotional responses for many years
sudden outbursts of irritability
increased probability of attempting suicide
increased substance abuse, marital problems, depression, guilt, anger
OCD: 1.5-3% of people worldwide
Obsessions
recurring persistent, intrustive thoughts of contamination, violence, sex, religion
causes anxiety, guilt, shame
Compulsions
repetitive rituals to relieve the anxiety generated by obsessive thoughts
inappropriate, irrational and consume most of their waking hours, yet they feel forced to do them against their will
some compulsions are unrelated to obessions
Neurobiologly of Anxiety
Amygdala: emotional processing
aids in formation of emotional memories
creates associations between environmental stimulus and aversive stimulus (fear conditioning)
central nucleus within the amygdala
fear response
plays a role in response to sudden, aversive events
events that end abruptly
anxiety is a persistent state
Patients with GAD: increased volume of amygdala
seen in animals exposed to repeated stressors
greater amygdala activity with exposure to negative stimuli in GAD than in healthy individuals
PFC and anterior cingulate cortex
ACC --> inhibitory control over primitive responses of subcortical regions (regions that generate emtion)
anxiety disorders: imbalance between emotion generating centers and higher cortical control
Stress Response: HPA Axis
Anxiety = inappropriate stress response (when stressor is not present or immediately threatening)
HPA Axis: Mediates stress response
In response to stress
HYPOTHALAMUS: secretes CRF (hormone) into bloodstream
PITUITARY: reeleases ACTH
ADRENAL CORTEX (kidney): releases glucocorticoids (stress hormones)
elevated GCs --> negative feedback loop
binds to cortisol receptors and INHIBITS HPA function so cortisol levels return to baseline
Prolonged elevation in GCs in the hippocampus
in hippocampus
INCREASED apoptosis
PREVENTS dendritic outgrowth and elaboration
impacts plasticity
reduction in memory
REDUCES neurogenesis
In amygdala
dendritic growth, increased arborization, spine connectivity
enhanced fear conditioning
CRF as a neurotransmitter: NOT due to HPA Axis
released in amygdala and hippocampus in response to stressors
acts via 2 GPCRs: CRF1 and CRF2
intraventricular infusion of CRF --> behavioral signs of anxiety (a
CRF infusion into the LC is anxiogenic
behavioral effects can be prevented by pretreatment with a CRF antagonist
Prenatal Stress
early exposure to stress/neglect alters the developing brain
produces lifelong tendency for enhanced anxiety
leads to changes in brain structure and synaptic transmission in adulthood
enhanced levels of CRF in amygdala
decreased expression of GC receptors in the hippocampus (reduced negative feedback by the HPA)
early stress makes HPA axis HYPERACTIVE to stress: persists through adulthood
Epigenetic regulation
DECREASED methylation of CRF promoter in amygdala --> ENHANCED protein levels
INCREASED methylation of promotor of GC receptor gene --> DECREASED protein levels
Stress produces opposite effects on hippocampus (atrophy) then on amygdala (enhanced structural properties)
DECREASED length and number of branch points of hippocampal apical dendrites
shrinkage and reduced dendritic complexitiy in hippocampal neurons
increased length and branching in amygdala
Neurotransmitters
NE
Increased firing in LC occurs in animals presented with threatening stimuli
electrical stimulation of LC, administration of yohimbine (a2 autoreceptor antagonist), or CRF receptor activation INDUCES alerting/fear responses
Treatments
Clonidine, a2 autoreceptor agonists
cells in LC are inhibited by GABA and 5HT
benzos: positive allosteric modulators of GABAA receptors
SSRIs
CRF receptor antagonists
GABA
GABAA receptor: Cl- (hyperpolarization)
Anxiolytics: benzos, barbs
cause sedation and reduced anxiety by binding to modulatory sites on receptor complex
benzos binding sites
widely distributed in the brain
high concentration in amygdala and frontal lobe
panic disorder patients
decreased benzo binding --> failure of GABAergic inhibition --> uncontrollable panic attacks
natural differences in anxiety levels correlate with the number of benzo binding sites in several brain areas
5HT
enhance 5HT function (w/SSRI) or stimulating 5HT1A receptors to reduce anxiety
SSRI efficacy is prevented by tryptophan depletion
Anxiolytic drugs (reduce anxietey)
Sedative-hypnotics: CNS depressants
barbs, benzos, alochol (reduce neuronal excitability)
benzos
positive allosteric modulators of GABAA receptors (enhance GABA transmission)
increase number of times channel opens
alters physical state of receptors to increase affinity for GABA
in absense of GABA, benzos have NO EFFECT on channel opening
benzo antagonists prevent enhancement of Cl- conductance
benzos in presence of GABA AND GABA antagonist --> no effect on Cl- conductance
very safe drugs
acutely acting: immediate relief
short-acting benzos are metabolized in 1 step into inactive metabolites
long-acting benzos have active metabolites to prolong drug action
recreational use of BDZs is often combined with alcohol and other CNS depressants --> toxicity
Flumazenil: competitive antagonist for BDZ site --> can be used to reverse effects of BDZ while other depressants are cleared gradually from the body
BDZs relieve worry, fear, and physical symptoms (less mental clouding, loss of judgement, motor incoordination than other sedative-hypnotics)
little-no tolerance to anxiolytic effects
longer-acting: useful hypnotics for sleep, muscle relaxants, anticonvulsants
prevent acute alcohol or barb withdrawal symptoms (cross dependence)
withdrawal to chronic BDZ treatment
Barbiturates: oldest members of drug class, have been replaced by BDZs
increase affinity of GABAA receptor
increase DURATION of channel opening
can open Cl- channel WITHOUT GABA
potentially lethal
Side effects
reducing amount of REM sleep
mental clouding, loss of judgement, slowed reflexes
high doses --> gross intoxication --> coma/death because of respiratory depression
dangerous when combined with alcohol
Repeated use of barbs --> metabolic tolerance/reduced effectiveness
cross-tolerance diminishes effectiveness of other drugs
barbs produce significant physical dependence and abuse (withdrawal is potentially fatal)
BDZs vs. Barbs
BDZs have a high therapeutic index
extremely high doses --> disorientation, cognitive impairment, amnesia
lethal overdose is rare --> little effect on respiratory centers in the medulla
BDZs DO NOT increase number of liver enzymes (no metabolic tolerance)
reduced tolerance to repeated admin and fewer interactions with other drugs
reinforcement value of BDZs is much less than barbs --> low risk of abuse but physical dependence and withdrawal may lead to continued use
produce calm, relaxed state (w/ drowsiness, mental clouding, incoordination)
higher doses --> induce sleep
highest doses --> coma/death
Second-generation anxiolytics: fewer side effects than BDZs
buspirone: 5HT1A receptor partial agonist, less effective in reducing the physical symptoms of anxiety than the cognitive aspects of worry and poor concentrations
Advantages of buspirone
treats depression that often accompanies anxiety
anxiety reduction is NOT accompanied by sedation, confusion, or mental clouding
doesn't enhance CNS-depressant effects of other drugs
little-no potential for recreational use/dependence
no withdrawal syndrome
Disadvantages of buspirone
onset of effectiveness is longer (several wks)
effectiveness in relieving anxiety is less than BDZs (less useful for situational anxiety)
does NOT show cross-dependance with sedative-hypnotics: can't be used as sub for alc/barb withdrawal
no hypnotic effects for insomnia
no muscle-relaxant effects for seizures
Buspirone vs diazepam treated mice: similar reductions in anxiety
buspirone mice --> gradual return of anxiety
diazepam mice --> robust abstinence