PDA III Exam III - Antidepressants - HM

what is another name for major depressive disorder

unipolar

what are two key components of major depressive disorder

recurring episodes of dysphoria/negative thinking and anhedonia (inability to experience pleasure)

what are signs and symptoms of major depressive disorder

-increase or decrease in appetite

-insomnia or hypersomnia

-increase or decrease in psychomotor activity

-fatigue, loss of energy

-loss of self-esteem

-diminished ability to think, concentrate, make decisions

-suicidal thinking (7-15% depressed individuals commit suicide)

when does untreated depression normally resolve

6-9 months

even though untreated depression resolves with time, what is one of the risks associated with untreated depression

episodes will recur with increasing frequency and intensity

who has more of a lifetime risk, men or women

women (unknown why though)

what does the monoamine hypothesis say

depression is the result of low monoamine levels

what is the shortcoming of the monoamine hypothesis

MAOi's don't work acutely but actually require several weeks of administration (clinical lag)

what is cortisol

hormone that helps all cells of the body deal with stress by using energy through glucose

why is cortisol bad in the long-term

toxicity

what is the usual cortisol pathway in a person without depression

stress stimulates the hippocampus/hypothalamus; the hypothalamus stimulates CRF release into the pituitary which then stimulates the release of ACTH at the adrenal glands; the adrenal glands release glucocorticoids (primarily cortisol in humans); cortisol then uses negative feedback at the hippocampus/hypothalamus to inhibit it's production

what are the levels of cortisol in a depressed patient

higher than normal in response to higher than normal ACTH in response to higher than normal CRF

what does hyper-secretion of cortisol do to the pituitary and adrenal glands

enlargement

what is the primary dysfunction due to in HPA

abnormalities in the hypothalamus (produces too much CRF and has too many CRF producing cells)

what happens to the circadian rhythm in depressed patients

flatter and higher (doesn't really decrease throughout the day after peaking in the morning)

what is the glucocorticoid hypothesis

when glucocorticoid levels are high for prolonged periods of time, hippocampal neurons become damaged and unresponsive

what does the hippocampus normally do to CRF

exerts inhibitory control over CRF release by the hypothalamus

what do the hippocampi look like in depressed patients

smaller

where does neurogenesis occur

hippocampus, not PFC

how do antidepressants affect neurogenesis

increases

what does cortisol do to dendrites and spines

dendritic atrophy of hippocampal neurons

what is the consequence of hippocampal neuron damage

the hippocampus can't inhibit the hypothalamus which leads to even greater glucocorticoid levels which leads to more damage and so on...

where do loss of dendrites and spines occur

in hippocampus and PFC

what is the neurotrophic hypothesis of depression

dendritic atrophy in the hippocampus is related to reductions in brain-derived neurotrophic factor (BDNF) that occurs with stress

what inhibits BDNF

cortisol

what may increase BDNF levels

chronic anti-depressant treatment

stress that occurs while anti-depressants are administered does not what

reduce BDNF levels in the brain

what is asymmetrical desensitization

losing response to an agonist (receptor downregulation)

which synapse does asymmetrical desensitization occur in

only presynaptic autoreceptors, not postsynaptic

what are the first generation antidepressants

TCAs and MAOIs

what are the second generation antidepressants

SSRIs and SNRIs

what is the MOA of TCA's

block reuptake of NE and serotonin

tertiary amines are more potent towards which receptors

serotonergic

secondary amines are more potent towards which receptors

noradrenergic

what are the CNS effects of people taking antidepressants with depression

elevated mood (but not euphoria)

what are the CNS effects of people taking antidepressants without depression

no mood elevation, produce drowsiness

what is the trigger response of TCAs

may see improvement of the physical side effects within the first 10 days (good chance the drug will be effective)

which TCA is most sedating

amitriptyline

what are some side effects of TCAs

orthostatic hypotension (tertiary more likely) and arrhythmias (avoid in cardiac patients)

do TCAs have a short or long half life

long

how much TCA is considered lethal

1500mg taken all at once

what are symptoms of TCA overdose

excessive sedation, confusion, tachycardia, agitation, sweating, anti-sludge, and orthostatic hypotension

what are some other uses of TCAs (rather than antidepressants)

panic attacks, OCD (clomipramine), enuresis (imipramine), and anxiety (doxepin)

what are examples of SSRIs

fluoxetine (Prozac)

sertraline (Zoloft)

paroxetine (Paxil)

citalopram (celexa)

escitalopram (lexapro)

fluvoxamine (luvox)

vortioxetine (brintellix)

what is the MOA of SSRIs

inhibit reuptake of serotonin

what happens to SSRIs at higher doses

lose selectivity and end up blocking norepi too

what are the common side effects SSRIs

sexual dysfunction, GI distress (sertraline and paroxetine), agitation, restlessness (fluoxetine), but overdose is usually non-fatal

what causes serotonin syndrome

2 or more serotonergic drugs at once

what are some symptoms of serotonin syndrome

muscle rigidity, myoclonus, hyperthermia, seizures, HTN, and tachycardia

which SSRIs interact with CYP2D6

fluoxetine and paroxetine are inhibitors

what drugs are CYP2D6 substrates (and therefore will interact with fluoxetine and paroxetine)

TCAs, SSRIs, antipsychotics, beta blockers, and tamoxifen

what can fluoxetine be used to treat

panic disorder, anorexia, bulimia, chronic headache/migraine, and PMDD

what is the efficacy comparison of TCAs and SSRIs

no statistical or clinical differences

when comparing TCAs vs SSRIs, why do side effects matter

SSRIs have less side effects and therefore have a lower drop out rate

when discontinuing SSRIs, what must happen

taper down, especially on those with short half lives

what are examples of SNRIs

venlafaxine (effexor)

desvenlafaxine (pristiq)

duloxetine (cymbalta)

levomilnacipran (fetzima)

what is the MOA of SNRIs

block reuptake of serotonin and norepinephrine

what are the side effects of SNRIs

minimal effects on alpha and muscarinic receptors, prozac-like SE (N/V, sexual dysfunction), increased blood pressure

what is the MOA of trazodone

serotonin antagonist and reuptake inhibitor

what is trazodone mostly used for

not very effective as an anti-depressant, but very sedating so many see it as a sleep aid

what are common side effects of trazodone

headache and GI upset, priapism and orthostatic hypotension often limit use

what is the MOA of mirtazapine

alpha-2 antagonist, 5HT antagonist, and H1 antagonist

what are the side effects of mirtazapine

increase appetite, weight gain, and sedation

how does mirtazapine work

blocks inhibitory autoreceptors and heteroreceptors (elevates norepi and serotonin)

what is the MOA of bupropion

norepinephrine and dopamine reuptake inhibitor (not 5HT)

what other class of drugs are like bupropion

amphetamines (decreases appetite and keeps awake)

what are side effects of bupropion

insomnia, dry mouth, tremor, seizures

what helps to decrease the risk of seizures when taking bupropion

splitting the dose into taking 3-4 times a day instead of just one large dose

what is the MOA of monoamine oxidase inhibitors

prevents degradation of norepi, dopamine, 5HT, and other neurotransmitters stored in vesicles

what are MAOi's better for

atypical depression

what are side effects of MAOi's

hepatotoxicity (not dose related), insomnia, tremors, convulsions, decreased BP, and orthostatic hypotension

MAOi's can cause a hypotensive crisis, why

lack of MAO leads to an overabundance of tyramine (watch for headaches)

how long should someone wait when switching to or from an MAOi

2 weeks

what are examples of MAOi's

phenelzine, tranylcypromine, isocarboxazid

who are MAOi's reserved for

for patients who haven't responded to SSRIs or TCAs

what is the MOA of ketamine

antagonist of the NMDA receptor used for induction and maintenance of anesthesia

what does "NMDA antagonist" mean

restores synaptic dysconnectivity in the prefrontal cortex, and enhances translation of mRNA from BDNF and AMPA

sub-anesthetic doses of ketamine do what for depression

reduce depression symptoms 4 hours after infusion in treatment resistant patients

what is so weird about the timing of when ketamine works

time of onset is after perceptual disturbances have abated and drug is essentially gone from the brain

how long do anti-depressant effects persist after ketamine therapy

3-7 days (40-60% response rate 24 hours after treatment)

what are side effects of ketamine

euphoria, dysphoria, anxiety, nausea, and dizziness

ketamine is a dissociative anesthetic with what

potential for abuse

what is esketamine

S-enantiomer of ketamine

what is so good about esketamine

nasal spray with no clinical lag

what are some limitations to esketamine

requires REMS, so must be given in a clinic

what is brexanolone used for

postpartum depression

brexanolone is a what

analog of allopregnanolone

how does brexanolone work

potentiates effect of GABA at GABAa receptors

what are some non-drug therapies for depression

psychotherapy and electroconvulsive therapy (ECT)

when is electroconvulsive therapy used

for clients who are unresponsive to other treatments, patient refuses, and patient is intensely suicidal