Antidepressants Flashcards
Major depressive disorder (MDD)
-depressed mood most of the time in the last 2 weeks
-AKA major depression or unipolar depression
monoamine hypothesis
-idea thar a deficit in function or amount of monoamines is central to the biology of depression
Neurotrophic hypothesis
-evidence that neurotrophic factors play a major role in depression
–nerve growth factors such as brain-derived neurotrophic factor (BDNF)
–BDNF activates tyrosine kinase receptor B in neurons and glia
Neuroendocrine factors
-association with the number of hormonal abnormalities
Evidence to support the monoamine hypothesis
-Reserpine treatment: depression in a subset of patients
-Depressed patients respond to Fluoxetine suffer relapse when given tryptophan free diets
-patients on desipramine less likely to relapse on tryptophan free diets
-all classes of antidepressants enhance availability of 5-HT, NE, DA
Inconsistencies with monoamine hypothesis
-many studies found no alteration in function or levels of monoamines in depressed patients
-Glutamate appears to be important
-antidepressants impact glutamate transmission
-Ketamine shows rapid antidepressant effects
Evidence supporting neurotrophic hypothesis
-decrease in CSF level of BDNF in patients with depression
-major depression decrease size of hippocampus
-All known classes of antidepressants are associated with an increase in BDNF levels in animal models and humans
(chronic, but not acute, administration)
Inconsistencies with the neurotrophic hypothesis
-BDNF knockout mice do not show consistent depressive behavior
-Genetic polymorphisms for BDNF may yield very
different effects
– Mutations in BDNF associated with altered anxiety and
depressive behavior in both animal and human studies
Pathophysiology of depression
-abnormalities in HPA axis
-Thyroid dysregulation
-sex steroid are implicated: post pregnancy, testosterone, hormone replacement therapy
Integration of hypotheses regarding the
pathophysiology of depression
-monoamine, neurotrophic, and neuroendocrine systems are interrellated
–HPA and steroid abnormalities may suppress transcription of BDNF gene
–chronic stress–>cortisol–>decrease BDNF synthesis
-chronic activation of monoamine receptors by antidepressants increases BDNF expression
SSRIs
-inhibit serotonin transporter (SERT)
-indications in GAD, PTSD, OCD, panic disorder, PMDD, and bulimia
-highly lipophilic
mild Serotonin syndrome
fever
-sweating
-agitation
tachycardia
-diarrhea
-tremors
-poor coordination
Moderate serotonin syndrome
-hyperthermia
-hypomania
-hypertension
-hyperflexia
-clonus
-myoclonus
severe serotonin syndrome
-hyperthermia
-seizure
-coma
-death
-rigidity
drugs that block both serotonin and norepinephrine transporters
-SNRIs: newer
-TCAs: older
SNRIs
-serotonin-norepinephrine reuptake inhibitor
-bind serotonin (SERT) and norepinephrine (NET) transporters
Venlafaxine
SNRI
-inhibitor of SERT
-weak inhibitor of NET
desvenlafaxine
SNRI
-Inhibit both SERT and NET
Duloxetine
SNRI
–Inhibit both SERT and NET
Levomilnacipran
SNRI
-more potent inhibitor of NET than SERT
TCAs
-used in depression that is unresponsive to more commonly used SSRIs and SNRIs
-share similar structure
Imipramine
TCA
-more serotonin effects initially but then metabolite had nor NET inhibition
-tryptyline
TCAs
Doxepin
TCA
Desipramine
TCA
-more NET inhibition
-more selective
two 5-HT receptor modulators(antagonists)
-Trazodone
-Vortioxetine
Bupropion
-unicyclic
-resembles amphetamine and has CNS activating properties
-Not commonly associated with sexual side effecs
-modest inhibitors of NET and dopamine reuptake
-no effect on serotonin system
Mirtazapine
-tetracyclic
-not commonly associated with sexual side effects
-antagonist of the presynaptic a2 autoreceptor: enhances release of both NE and 5-HT
-potent H1 antagonist
Amoxapine and Maprotiline
-tetracyclic
-comparable to TCAs
-not commonly perscribed
-potent NET inhibitors and less potent SERT inhibitors
-Amoxapine (unlike TCAs) also moderate inhibitor of postsynaptic D2 receptor – antipsychotic
properties
Vilazodone
-potentially binds to serotonin transporter, but minamally to dopamine and norepi transporters
-partial agonist of the 5-HT1A receptor
MAOIs
-used for unresponsive depression
-some MAOIs resemple amphetamines and selegiline has amphetamine like metabolites
Phenelzime
MAOI
Isocarboxazid
MAOI
Tranylcypromine
MAOI
Selegiline
MAOI
-transdermal and sublingual forms bypass liver and gut
Atypical antipsychotics
-used to treat schizophrenia, bipolar, depression with psychotic features, and MDD without psychotic features
Aripiprazole or quetiapine
-atypical antipsychotic with SSRI and SNRI
Olanzapine with fluoxetine
-treatment resistant major depression
-following inadequate response to at least two antidepressants
Quetiapine
-atypical antipsychotics
-may have antidepressant activity alone
Brexiprazole
-atypical antipsychotic
-FDA approved for major depression
OTC antidepressants
-ST John;s wort: Seratonin syndrome
-S-adenosylmethionine (SAMe)
-Omega-3 fatty acids: mania in BP
-5-hydroxytryptophan (5-HTP)
-Dehydroepiandrosterone (DHEA): mania
Delay in onset of antidepressants
-NTs released at low levels and exert autoinhibitory feedback
-Short term use of antidepressants result in increased release of NT: increased simulation of inhibitory autoreceptors
-chronic used of antidepressants results in downregulation of presynaptic autoreceptors
Serotonin syndrome
-glycoprotein with 12 transmembrane regions
-located in axon terminal and cell body
-Extracellular serotonin binds to transporter, conformational change(serotonin, Na, and Cl moved into cell)
-Binding of intracellular K releases serotonin inside of cell
SSRI effect on SERT
-allosterically inhibit SERT
-not at serotonin site
-80% inhibition at therapeutic doses
-SERT polymorphisms determine activity of transporters
-SSRI habe little effect on other neurotransmitters
SNRIs target
-inhibit serotonin and norepi transporters
-tend to have greater affinity for SERT than NET
Pharmacodynamics of TCAs
-activity is related to inhibition of serotonin and norepi reuptake
-common adverse effects
-tend to be potent histamine H1 receptor antagonists
Trazodone
-inhibits 5-HT2A
-agonists of this receptor are hallucinogenics and anxigenic
-weak, but selective, inhibitor of SERT
-moderate H1 antagonist
Vortioxetine
-multimodal effects on many 5-HT receptors
-allosteric inhibitor of SERT
Why do 5-HT 2 receptor antagonists have
antidepressant effects?
-depressed patients have more 5-HT2A receptors
-over density of receptors suggests involvement of depression
-SSRI downregulate receptors
Pharmacodynamics of MAOIs
-mitigating the actions of MAO in the neuron and increasing
monoamine content
-two types
MAO-A
-present in both DA and NE neurons
-primary substrates are NE and 5-HT
MAO-B
-found primarily in serotonergic and histaminergic neurons
-primary acts on DA
Phenelzine and tranylcypromine
-irreversible
-non selective MAOIs
Selegiline
-irreversible MAO-B specific drug at low doses(Parkinson’s)
- nonselective MAOI at high doses
Shared features of antidepressants
-rapid oral absorption
peak plasma within 2-3 hours
-tightly bound to plasma protein
-undergo hepatic metabolism
-renally cleared
Fluoxetine
-SSRI
-metabolized into active product: norfluoxetine
-longest half life of all SSRIs
-Need to discontinue for 4 weeks before starting MAOI: serotonin sndrome
Selective SNRIs
-Venlafaxine -> desvenlafaxine
-duloxetine
pharmacokinetics of duloxetine
-metabolized by 2D6 and 1A2
hepatic impairment significantly alters levels
pharmacokinetis of TCS
-dose at night: sedating
-substrates of 2D6 systems
-TCA serum levels influenced by concurrent fluoxetine
pharmacokinetics of MAOIs
-extensive first-pass effects that may substantially
decrease bioavailability
