Final: Antidepressants Flashcards
Diagnosis of depression
5 symptoms for two weeks
main ones: depressed mood, loss of interest/pleasure
Sleeping Difficulties Change in Activity Level Change in Appetite Loss of Energy Negative Self-Concept Difficulty Concentrating Indecisiveness Thoughts of Death Suicidal Ideation
highest heritability mood disorder
bipolar
What explains identical twins not both having same disorder?
Epigenetics: different interpretations of fixed template (genetic code) different read outs dependent upon the variable conditions under which template is interrogated.
Experiment: mama rat and the agouti gene
Makes rat obese and yellow with cancer/diabetes
BUT, diet high in methyl groups silence expression in offspring
Methylation
reduce gene expression
Packs DNA closer together
Acetylation
unravels DNA so increases expression
Chromatin
DNA + Histone proteins that the DNA winds around
Epigenetics
environmental factors that determine if genes expressed
i.e. Diet, drugs, stressors, parental neglect
HPA axis
elevated cortisol
Hypothalamic-Pituitary-Thyroid Axis
Reduced thyroid hormones
Hypothalamic-Pituitary-Gonadal Axis
Reduced estrogen/testosterone
Pineal Gland
Elevated melatonin during daytime
HPA axis in detail
Hypothalamus: CRH
Pituitary: ACTH
Adrenal: Glucocorticoid (Cortisol)
Negative feedback back to hypothalamus, pituitary and adrenal, activates hippocampus, which also inhibits hypothalamus
Corticotropin Releasing Hormone (CRH)
41-Amino Acid Peptide
Hormone Regulating ACTH Release from Anterior Pituitary
Neurotransmitter Released in Anxiety Circuits Within Brain
Baseline cortisol in depression
Cortisol should be high in morning, low at night
But elevated in depression, and levels off (flat rhythm)
Dexamethasone Suppression Test Reveals Impaired Negative Feedback
DEX: synthetic control
MDD/early life stress can’t suppress cortisol, thought that early life stress leads to abnormal axis functioning which brings on elevated cortisol levels and disorder vulnerability.
Depression and REM sleep
rem is active sleep
Depression = REM early. More REM early in the night than later.
REM pattern is intermittent
Depression and sleep patterns
Poor Sleep Difficulty Getting to Sleep Increased Awakening Decreased Sleep Time
Decreased REM Latency Increased Early REM Decreased Late REM
Evidence for the monoamine theory of depression
1) Respirine depletes monoamines/induces depression
2) 5-HIAA levels in CSF reported low in some dpressed patients
3) Failure to suppress cortisol release may be related to deficiency of hypothalamic monoamines (NE)
4) Short alleles for serotonin linked to depression
5) Antidepressants increase synaptic monoamines
Reserpine
depletes monoamines
Inhibits vesiclularization of monoamines
Free monoamines degraded by MAO
Depletes brain of monoamines
precipitates depression
5-HIAA
last metabolite in serotonin degradation
low = more likely to be depressed
serotonin –MAO–> intermediate –aldehyde dehydrogenase–> 5-HIAA
Long and short alleles for SERT genes
Short allele + 3+ life stressors = increase risk of depression
did not hold up in metanalysis
Monoamine oxidase inhibitors
reduce breakdown of monoamines
Tricyclic antidepressants
Reduce reuptake of monoamines
Selective monoamine reuptake inhibitors
reduced selective reuptake of 5-HT, NE
How do antidepressants work?
Treatment –> increase monoamines –> 2-4 weeks later effects start happening (not sure the mechanisms, not sure how, we got theories)
Depression does ____ to BDNF and friends?
Lower BDNF
Raise Glucocorticoid levels
Antidepressants do what to BDNF?
Increase BDNF and 5-HT and NE
What does BDNF do?
Stimulates dendrite growth
How do antidepressants stimulate dendrite growth?
Increase adenylyl cyclase and cAMP
Then increase pKa, pCREB, and BDNF
Results in Dendritic Sprouting, Neurogenesis, Neuronal Remodeling
BDNF binds to
Trk B for proliferation, survival, plasticity, hippocampal function
Antidepressants in the rat hippocampus and BDNF
5-10 mg/kg amitriptyline/venlafaxine for 21 days
They increase BDNF in rat hippocampus
BDNF:
____ acetylation
____ methylation
increase acetylation
decreases methylation
reduces deacetylation
If you inhibit BDNF, get methylation (gene silencing)
Evidence of hippocampal atrophy and loss in MDD patients
Compared to controls, depression patients had smaller hippocampal volumes
Decreased hippocampal volume may be related to depression
PAPA test for depression reveals
Hippocampal Volume Linked to Severity of Depression and Maternal Support
Acute
achievement of REMISSION
6-12 weeks
(symptom free from illness)
Continuations
Prevention of RELAPSE
4-9 months
(no relapse = no return of depressive symptoms once remission occurs)
Maintenance
Prevention of RECURRENCE
> 1 year
(another depressive episode after recovery has been attained)
Response
improvement from the initial onset of your illness
Remission
experience of being symptom free from illness
Recovery
no symptoms for at least 4 months after onset of remission
Relapse
full return of depressive symptoms once remission has occurred
Recurrence
another depressive episode after recovery has been attained
First line of treatment
SSRIs
Treatments for affective disorders
Monoamine Oxidase Inhibitors (MAOI)
Tricyclic Antidepressants (TCA)
Selective Serotonin Reuptake Inhibitors (SSRIs)
Atypical Antidepressants
Ketamine
Psychotherapy
Electroconvulsive Therapy (ECT)
Trans-magnetic Stimulation (TMS)
MAOI
first prescribed antidepressant (50’s)
Effective for atypical forms (overeat, oversleep, upset when criticized)
Inhibit degradation of NE and 5-HT
Risk of hypertensive crisis (food/drug interactions)
*risk reduce with newer MAOI’s selective for DA, but these have less effect
MOIA: hypertensive crisis
Tyramine, an amino acid, found in food.
Acts like amphetamine. MAO breaks it down
MAOI: inhibits degradation of tyramine
Tyramine forces NE from axon terminals
Rapid increase in BP
Stroke or death possible
MAOI-A
inhibit degradation of NE and serotonin
treats atypical depression
MAOI-B
inhibits degradation of dopamine
treat’s Parkinson’s
high dose for treatment of depression
Tricyclic Antidepressants (TCA)
used extensively prior to advent of SSRIs (50’s)
inhibit NE and 5-HT reuptake
side effects, risk of OD (confusion, mania, arrhythmia), some drug interactions with alcohol and MAOI
Example of TCA?
Amitripyline (Elavil)
imipramine (tonfranil)
Know for 3 ring structure
Side effects of TCA
Orthostatic hypotension; Dry mouth; Constipation; Blurred vision; Sedation or activation; Increased heart rate; Fatigue/weakness; Urinary hesitancy; Ataxia/Muscle tremors / twitches; Sexual impairment; Dizziness; Weight gain
If antidepressants block [M] receptors, does it reduce heart rate?
NO
Histamine receptor blocker
sedation
[M] receptor blocker
dry mouth, blurred vision, constipation, increased heart rate, urinary retention
Alpha 1 receptor block
postural hypotension
Serotonin reuptake blocker
reduced libido, impotence, delayed ejaculation
FDA approved use of antidepressants
Depressive disorders
Anxiety
Bulimia
(BAD)
Off-label use of antidepressants
eating disorders, premenstrual dysphoric disorder, ADHD, substance abuse disorder, neuropathic pain
SSRIs
Most popular treatment for depression and anxiety (1980’s)
inhibit reuptake of 5-HT primarily
fewer side-effects than MAOIs or TCAs
Examples of SSRIs (inhibit serotonin reuptake)
Sertraline (Zoloft) Floxetine (Prozac) Citalopram (Celexa) Paroxetine (Paxil) Escitralopram (Lexapro)
SSRIs Side-effects
Nausea, Diarrhea, Insomnia, Somnolence, Dry mouth, Tremor, Anxiety, Sweating, Sexual Dysfunction, Weight gain
Atypical Reuptake Inhibitors
1990’s fewer sexual side effects
Selective Reuptake Inhibitors of NE, 5-HT, DA
Fewer Side-effects than MAOIs or TCAs
What is…
venlafaxine (Effexor)
duloxetine (Cymbalta)
SNRI
serotonin-norepinephrine
atypical reuptake inhibitor
What is…
atomoxetine (Strattera)
NSRI
NE reuptake
atypical reuptake inhibitor
What is…
Bupropion (Wellbutrin, Zyban)
DSRI
dopamine reuptake
atypical reuptake inhibitor
Ketamine
Anesthetic Agent Analgesic agent Psychedelic drug Predatory drug Antidepressant agent (2010's)
What are the antidepressant effects of ketamine?
symptom relief within an hour after intravenous infusion
effect persists for up to a week, sometimes longer
effective in some treatment resistant patients
Limited # of clinical studies to date: long-term effects unknown
off-label at specialty clinics: approved intranasal
Mechanism: increase BDNF
model of animal depression: Porsolt forced swim test
more immobility, more depression
ketamine exerts antidepressant effects, reducing immobility
Ketamine: How does it work?
increases BDNF in mouse hippocampus
Blocks ion channels of NMDA receptors
BDNF translation, synaptic protein synthesis
Rapid acting, can be mere hours
Animal models of depression tested by
swim test, and hung by tail
Why ketamine > SSRIs?
increases BDNF levels faster (30 min)
BDNF down when depression reduced, but traditional SSRIs take a while.
Ketamine and dendrite sprouts
stress = spine loss ketamine = dendrite growth
Ketamine cellular effect
block ion channels NMDA recpetors, sometimes AMPA too
This results in BDNF translation and protein synthesis
Hamilton depression rating scale:
higher # = depression
Just 1 ketamine infusion helps symptoms
Ketamine- dissociative
not connected to body, no hallucinations, more cognitive “like getting drunk w/out eating”
Antidepressant vs. placebo: help patients after 6-8 weeks
20+ patients above placebo
P: 20-40%
AD: 40-60%
Antidepressant vs. placebo: relapse after 1-2 years
prevent relapse in 27 more patients
P: 50%
AD: 23%
Metanalysis: combine and analyze results from individual studies
Placebo for non-severe, saves time and money
Factors in experimental bias
selective reporting, placebo effects, Biased study samples (homeless), failure of subjects to complete study (drop out), short follow up
Davis
merit in concern
but, 33-11% AD>P
Depression so serious, try all we got
Kirsh
It’s all a placebo
Kramer
Antidepressants are they best and cure everything
Drug Over persceiption
Less expensive/time then psychotherapy
money for corporations
reduced risks/side effects
Psychotherapy pros and cons
Pros: often as effective as pharmacotherapy, combinations works well
cons: time consuming, expensive (partial coverage/limited visits)
Amick on antidepressants vs. CBT
no difference between 2nd gen. antidepressants and CBT
Electroconvulsive therapy
Treatment for severest cases of depression
Must induce seizure to be effective
Muscle relaxant, anesthetic, respirator
Administration 3x per week for 3 weeks
Improves 90% of cases with delusional depressants
Anterograde and Retrograde Amnesia (Ach decrease)
Most effective treatment, but for people with very severe depression.
Transcranial Magnetic stimulations (TMS)
40-minute treatment
Two small electromagnetic coils
Aimed at the left prefrontal cortex
Too weak for the patient to feel
Does not trigger seizure
Not a cure
Can’t do if you have facial tattoos with metallic ink
Kirsch
placebo
ioannidis
metaanalysis, only severe
Insel
in the middle on the issue
Kramer
antidepressants for everyone
