What are the six SSRI’s?
fluoxetine (Prozac, Prozac weekly) sertraline (Zoloft) paroxetine (Paxil, Paxil CR, Pexeva) lovoxamine (Luvox, Luvox CR) citalopram (Celexa) escitalopram (Lexapro)
What percent of individuals with major depression, overall, tend to respond to 4 different medications over the course of 1 year?
67% responders
33% non-responders
citralopram
Celexa
What are the rates of responders vs. non-responders in medication trials?
67% responders, 33% non-responders
What are low levels of NE associated with?
Increased negative affect
decreased positive affect
Acute Phase
6-12 Weeks
What are the effects of the 5HT2A receptor?
Decreases DA & NE release (decreases positive affect)
Increases Glu release (increases anxiety)
What symptoms are most likely to be residual?
insomnia fatigue pain concentration loss of interest
Gene activation has been found with use of:
AD’s
lithium
estrogen
exercise
escitalopram
Lexapro
What proportion of major depressive disorders remit after the 4th antidepressant treatment?
6-7%
What are the three main mechanisms of action of AD’s?
Blockade of transporters (re-uptake pumps)
5HT1A partial agonism
Inhibition of monoamine oxidase
What proportion of major depressive disorders remit after the first antidepressant treatment?
33%
What are the two effects of metabolic and gene transcription events initiated by AD’s?
Decrease in various receptors & chemicals associated withs stress, depression, & anxiety
Increase chemicals associated with healthy neurons, resiliency, less depression, & anxiety
What is the mechanism of action, at least initially, of AD’s?
Increased synaptic concentration of monoamines
sertraline
Zoloft
What are the three main monoamines?
5-HT, DA, NE
Low levels of which monoamine is associated with decreased “positive affect” in depression?
DA
Recurrence
A return of symptoms during the maintenance phase.
What are the rates of responders vs. non-responders in placebo trials?
33% responders, 67% non-responders
What are the symptoms linked with negative affect in depression?
dysphoria, rumination, guilt/disgust, worthlessness, loneliness, fear/anxiety, irritability, hostility, suicidality
What symptoms are related to decreased positive affect?
Dysphoria, anhedonia, loss of motivation & enthusiasm, apathy, anergia or psychomotor retardation, impaired attention & cognition, decreased self-confidence
Norephinepherine is considered what type of monoamine?
Catecholamine
What do 5-HT1A receptors on dendrites or soma (somadendritic autoreceptor) do?
Inhibit firing, and thus, 5-HT release
What symptoms tend to be most responsive to treatment?
Depressed mood
suicidal ideation
psychomotor retardation
What terminates NE action?
reuptake via NR transporters (NET)
MAO inside presynaptic neurons & synapse
COMT (catechol-O-methyl transferase)
What defines a response to an antidepressant?
50% or more reduction in symptoms (either in number of symptoms or in severity)
SSRI’s
increased activation of 5HT1A receptors decreases negative affect (dysphoria, rumination, guilt/disgust, worthlessness, loneliness, fear/anxiety, irritability, hostility, suicide
Acute/excessive activation of other 5HT receptors cause what?
Side effects (see slides for details)
What are some of the considerations related to SE’s in regards to 5HT hypothesis of depression?
SE’s tend to appear within the first 1-2 weeks, but will often dissipate in several weeks once the brain has adapted to the increased concentration of 5HT and downregulates
What proportion of major depressive disorders remit after the second antidepressant treatment?
20%
When should antidepressants be discontinued after the first episode of depression?
gradually at the end of the continuation phase
True or False: 5HT1A and 5HT2A receptors have identical effects.
False; they have opposite effects
vilazodone
Vibryd; is an SSRI and 5HT1A partial agonist
When should antidepressants be discontinued after the second episode of depression?
With risk factors: gradually at the end of the continuation phase
With risk factors: never; maintain for life
What defines remission?
A 100% reduction of all symptoms.
You expect a placebo effect of _____% for most treatments.
33%
What are the effects of the 5HT1A receptor?
Increases DA & NE release (improves positive affect)
Decreases Glu release (decreases anxiety)
When should antidepressants be discontinued after the 3rd or more episode?
NEVER; maintain for life.
Maintenance Phase
1 or more years
Continuation Phase
4-9 months
SNRI
serotonin norepinephrine reuptake inhibitors
luvoxamine
Luvox, Luvox CR
How does the serotonin hypothesis of depression help explain the time course of therapeutic effects?
They are delayed due to the time required for 5HT1A autoreceptors to downregulate/desnsitize
What proportion of major depressive disorders remit after the 3rd antidepressant treatment?
6-7%
Relapse
Pt has a return of symptoms in the continuation phase, despite still being on medication; regardless of the degree to which their symptoms of
fluoxetine
Prozac, Prozac weekly (Sarafem for PMDD)
5-HT affects release of which NT’s?
DA, NE, Glu
What phase is remission associated with?
Continuation phase (4-9 months)
paroxetine
Paxil, Paxil CR, Pexeva
What phase is recovery associated with?
Maintenance (>1 year)
Where is 90% of 5-HT located within the body?
Outside of the CNS
Where do NE axons project to?
widely across cortex, cerebellum, spinal cord
How long should antidepressants be continued for after a response or remission to prevent relapse?
4-9 months
Where are the somas of NE neurones primarily located?
locus coeruleus
Low levels of which monoamine is associated with increased “negative affect”?
5-HT
What is the most common mechanism of action for AD’s?
Blockade of transporters/re-uptake pumps
