Lecture 18: Antidepressants Flashcards
1
Q
dysthymia
A
relatively mild but prolonged symptoms that persist for at least two years
2
Q
depression is the ___ most disabling disease in the world
A
4th
3
Q
by 2020, depression will be the ___ leading cause of disability
A
2nd
4
Q
WHO estimated that ___ people worldwide have depression
A
300,000,000
5
Q
MDD responsible for __% of psychiatric hospitalizations
A
70
6
Q
MDD responsible for __% of suicides
A
40
7
Q
__ of the US population suffers per year
A
9-10%
8
Q
__% of men and __% of women experience depression
A
10, 25
9
Q
__% of cases are adequately treated per year
A
21
10
Q
MDD is __ more common in 1st degree relatives of someone with depression
A
3x
11
Q
classically, MDD was thought to be caused by ___
A
deficiency in monoamines (5HT, DA, NE)
12
Q
problem with monoamine deficiency hypothesis
A
NT changes occur shortly after taking antidep, but clinical benefits develop slowly
13
Q
now, interest is on long term action, specifically ___
A
2nd messengers and their fx
14
Q
3 possible 2nd messenger effects
A
- protect neurons from damage due to injury or trauma
- promote and maintain health and stability of new neurons
- promote activity-dependent remodeling of existing cells; plasticity
15
Q
neurogenic theory of depression; 2 discoveries
A
- neurons are able to repair/remodel themselves
2. adult brain can make new neurons
16
Q
postnatal neurogenesis
A
brain making new neurons as an adult
17
Q
stressful conditions can damage the ___
A
hippocampus
18
Q
hippocampus shrinks in response to ___
A
corticosteroids
19
Q
depression is now thought of as a ___
A
neurodegenerative disorder
20
Q
stressful conditions reduce neurogenesis in __ (2)
A
hippocampus
frontal cortex
21
Q
network hypothesis of antidepressants
A
recovery from depression is gradual process facilitated by structural guidance and rehab
22
Q
2 possible pathways for antidep MoA starting with 5HT or NE reuptake inhibition
A
- 5HT4,6,7 / beta adrenergic - adenylyl cyclase - cAMP - cAMP dep protein kinase (PKA) - increase creb (cAMP response element binding protein) - BDNF (brain derived neurotrophic factor)
- 5HT2 / alpha1 adrenergic - Ca2+ dep kinases - CREB - BDNF
23
Q
BDNF
A
brain-derived neurotrophic factor
24
Q
CREB
A
cAMP response element-binding protein
25
PKA
cAMP-dependent protein kinase
26
what increases expression of adenylyl cyclase?
stimulation of 5HT4,6,7 or beta adrenergic
27
what increases expression of Ca2+ dependent kinases?
stim of 5HT2 or a1 adrenergic
28
adenylyl cyclase increases __
cAMP
29
cAMP increases ___
PKA
30
PKA increases ___
CREB
31
CREB increases __
BDNF
32
what does BDNF do? (3)
1. trophic actions
2. increased function
3. synaptic remodeling
33
chronic stress decreases the expression of __ in the ___
BDNF, hippocampus
34
stress elevates levels of ___
glucocorticoids
35
what do glucocorticoids do?
reduce expression of BDNF
36
what does reduced expression of BDNF do?
atrophy or death or neurons
37
6 types of AD
1. tricyclic
2. MAOI
3. atypical
4. SSRIs
5. dual action
6. SNRIs
38
1st generation ADs
TCAs, MAOIs
39
1st TCA
imipramine
40
imipramine MoA
blocks presyn transporters for 5HT and NE
41
general TCA action
blocks presyn transporters for 5HT and NE
42
what were TCAs named for?
their structure
43
monoamine hypothesis of mania and depression
depression from deficiency of NE and 5HT; excess leads to mania
44
MAOI mech of action
block enzyme MAO that metabolizes and regulates amount of amine transmitters in nerve terminal
45
difference between MAOI and TCAs
TCAs inhibit reuptake, MAOIs inhibit degradation
46
3 TCA clinical limitations
1. slow onset
2. side effects
3. cardiotoxic/overdose fatality
47
3 second gen compounds
1. trazodone (desyrel)
2. bupropion (wellbutrin)
3. venlafaxine (effexor)
48
4 TCAs
1. imipramine (tofranil)
2. desipramine (norpramin)
3. nortriptyline (pamelor, aventil)
4. clomipramine (anafranil)
49
when were SSRIs invented?
1980s-1990s
50
first SSRI
prozac
51
has availability of SSRIs reduced the number of treatment resistant patients?
no
52
are SSRIs more efficacious?
no, but fewer side effects
53
6 SSRIs
1. fluoxetine (prozac)
2. sertraline (zoloft)
3. paroxetine (paxil)
4. citalopram (celexa)
5. fluvoxamine (luvox)
6. escitalopram (lexapro)
54
when were TCAs and MAOIs introduced?
1950s-1960s
55
prototypic TCA
imipramine (tofranil)
56
pharmacologically active metabolite of imipramine
desipramine (norpramin)
57
2 MoAs of imipramine/desipramine
1. block presyn reuptake transporter for 5HT and NE
| 2. block postsynaptic receptors for histamine, ACh, and NE (alpha adrenergic)
58
blockade of histamine receptors results in ___
drowsiness/sedation
59
blockade of AChRs results in (6)
1. confusion
2. memory and cognitive impairments
3. dry mouth
4. blurred vision
5. increased HR
6. urinary retention
60
blockade of NE receptors results in ___
fx blood pressure, can cause orthostatic hypertension
61
nortriptyline and desipramine have ___ than other TCAs
less sedation and fewer anticholinergic side fx
62
half life of imipramine
10-20h
63
3 TCAs other than imipramine
1. desipramine (norpramin)
2. nortriptyline (pamelor, aventil)
3. clomapramine (anafranil)
64
4 limitations of TCAs
1. slow onset
2. side fx
3. cardiotoxic arrhythmias
4. non universal efficacy
65
surprisingly, TCAs can be effective ___
analgesics
66
MAO effect on GI tract
breaks down tyramine
67
effect of elevated tyramine
increase blood pressure, possible heart attack/stroke
68
trazodone was __ second gen
3rd
69
most common trazodone side effect
drowsiness
70
trazodone MoA
not very potent 5HT and NE reuptake blocker
71
trazodone effect on sex
may improve sex, but has risk of priapism
72
trazodone has ___ half life
short
73
clomipramine (anafranil) is structurally similar to ___, but has greater effect on __
TCAs; more 5HT reuptake effect
74
clomipramine and its active metabolite also inhibit ___
NE
75
clomipramine is classified as a ___
mixed serotonin-NE reuptake inhibitor
76
MoA of SSRIs
block presynaptic transporter for 5HT
77
___ is least selective for 5HT, and ___ is most selective
prozac, celexa
78
which receptor is the basis of therapeutic effect of all SSRIs?
5HT1
79
stimulation of 5HT2 receptors thought to be responsible for (5)
1. insomnia
2. anxiety
3. agitation
4. sexual dysfunction
5. serotonin syndrome
80
2 effects at 5HT1
antidepressant, anxiolytic
81
effect at 5HT3
nausea
82
are SSRIs fatal in OD?
no
83
SSRIs can inhibit ___, causing what dangerous result?
CYP450
| possibly dangerous reactions with other meds
84
5 concerns with SSRIs
1. serotonin syndrome
2. withdrawal
3. sexual dysfunction
4. long term may cause cog impairment
5. fetal effects
85
serotonin syndrome (5)
1. cog disturbance (confusion, hypomania)
2. agitation/restlessness
3. autonomic dysfunction (fever, diarrhea, tachycardia)
4. neuromuscular impairment (ataxia, twitching)
5. visual hallucinations
86
what percent of patients develop SSRI withdrawal?
60%
87
6 core fx of withdrawal from SSRIs
1. flulike symptoms
2. nausea
3. insomnia
4. imbalance
5. sensory disturbances (shocks)
6. hyperarousal
88
___% of depression patients with SSRIs experience sexual dysfunction
80%
89
5 other side fx of SSRIs
1. suicidality
2. sleep disturbance
3. apathy
4. physiological symptoms (nausea, coma, muscle cramps, GI bleeding)
5. pregnancy warning
90
drug most associated with serotonin syndrome, psychosis, temper, delusions, discontinuation
paxil
91
fluvoxamine (luvox) sturctural derivative of ___
prozac
92
large dose of citalopram associated with ___
ECG irregularities, seizures
93
which drug causes problems for liver? which causes least problems?
prozac
| celexa
94
escitalopram is the ___ of celexa
therapeutically active optical isomer of celexa
95
lexapro is __ as potent as celexa
2x
96
first dual-action antidep
TCAs
97
venlafaxine MoA
mixed 5HT-NE reuptake inhibitor
98
duloxetine/cymbalta MoA
blocks reuptake of 5HT and NE
99
mirtazepine (remeron) MoA
increases presyn release of NE and 5HT
1. blocks central alpha2 autoreceptors, increasing NE
2. blocks adrenergic heteroreceptors located on 5HT neuron terminals, which usu inhibit 5HT release (only 5HT1 receptors, because mirtazepine blocks 5HT2 and 5HT3)
100
problem with remeron
causes drowsiness bc of action on histamine; appetite increase/weight gain
101
MoA bupropion
dopamine-norepinephrine reuptake inhibitor
102
are SNRIs better than placebo?
no
103
STAR*D study
sequenced treatment alt to releive depression
104
results of STAR*D
zoloft and escitalopram may have slight advantages, though modest benefits over others
105
combinations of ___ and ___ are being explored.
combo of SSRI and 5HT2 receptor antagonist
106
ketamine MoA
NMDAR antagonist
107
3 benefits of ketamine
1. response in hours
2. promotes synaptogenesis
3. effective in 70% of patients
108
problem with ketamine
best route is IV
109
novel approach to depression
effort to manipulate hypothalamic-pituitary-adrenal (HPA) axis
