Antidepressants Flashcards
Monoamine theory of depression
Increase in monoamines–> lower depression, Decrease–> depression (not entirely true (takes long time for it to work) but still works from pharmacological perspective)
MAO depression theory results from functionally deficient monoamine (NE and 5HT) transmission in the CNS
known antidepressants drugs (TCAs and MAOi) facilitate monaminergic transmission
drugs such as reserpine that depletes amines to cause depression
Simple MAO hypothesis no longer tenable as an explanation of depression BUt pharmacological manipulation of MOA transmission remains the most successful approach to treating depression
Neurotransmitter localization in the brains
neurons containing NE are located in the locus coeruleus and innervate the entire brain
Neurons containing serotonin are located in 2 groups of raphe nuclei and project to the entire brain
Neurons containing Dopamine are located in the substantia nigra (project to the striatum) and the VTA of the midbrain
Neurons containing ACh are located in the basal forebrain (septal nuclei and nucleus basilis –> hippocampus and neocortex)
Norepinephrine synapse
Tyrosine is taken up into the axon,
Tyrosine hydroxylase converts tyrosine –> DOPA
DOPA decarboxylase converts DOPA–> dopamine (DA)
DA is taken up into vesicle and converted DA–> NE by Dopamine B hydroxylase
When Ca channels are activated by depolarization, CA allows the vessicles to release the NE into the cleft
NE from synaptic cleft binds a2 and inhibits the vesicles release
NE is taken back up via reuptake (COCAINE BLOCKS)
Metabolized or extra neuronal uptake, diffuse into blood , can be inactivated in the neuron via MAO
TCAs
Acutely reuptake is inhibited and NE increases in the synapse
Chronically, the increased NE, downregulates the post synaptic receptors and NE increases greately in the synapse
SSRIs
SERT is blocked and 5HT remains in the synapse
Down regulation in post synaptic receptors
Mirtazapine
a2 antagonist and increases NE release in the synapse
heteroreceptors on 5HT neurons, and increase 5HT in the synapse
MAO i
Phenelzine, will all downregulate the receptors
Restated Monoamine hypotheisis
Depression is due to a biogenic amine receptor or transmission imbalance, the various drugs act to change the imbalance and restore a more normal affect
The pharmacological treatment of affective disorder in order of usage
- SSRIs
- SNRIs
- Atypical drugs
- TCAS
- MAOi
SSRIs (5HT uptake inhibitors)
FLUOXETINE, FLUVOXAMINE, PAROXETINE, SERTRALINE, CITALOPRAM
Antidepressant actions are similar in efficacy and time- course to those of TCAs
Acute toxicity is less than that of the tricyclic antidepressants and MAOi, therefore overdose risk is reduced
SEs include nausea, insomnia, and sexual dysfunction
No food reactions, but dangerous serotonin reaction (hyperthermia, muscle rigidity, Cardiovascular collapse) can occur if given with MAOis
FDA also now requires warnings about association of SSRIs and SNRIs with the neuroleptic malignant syndrome
ANTIDEPRESSANTS black box warning
in clinical settings, antidepressants increased the risk of suicidal thinking and behavior in children an dadolescents with depression and other psychiatric disorders, anyone considering the use of antidepressants in a child or adolescent must balance the risk with the clinical need, pts who are starting therapy should be observed closely, families and caregivers should discuss any observations of wosening depression, symptoms, suicidal thinking, and behavior, or unusal changes in behavior, can be used with cautio in MDD or obsessive compulsive disorder
symptoms of SSRI withdrawal
dizziness, light headedness, vertigo or feeling faint, shock like sensations, paresthesia, anxiety, diarrhea, fatigue, gait instability , headache, insomnia, irritability, nausea or vomiting, tremor, visual disturbance (neuro and GI symptons)
but fluoxetine rarely gets this because it has a very long t.5 so naturally the body tapers off
SSRI Approved USes
MDD, OCD, Panic disorder, social anxiety, PTSD, GAD, PMS (PDD), hotflashes associated with menopause
commonly perscribed SSRIs
Fluoxetine (prozac)- first SSRI on market, CYP450 2D6 (tamoxifen) and 2C19, long half life active metabolite (7 days), now abailable as a sustained release, PDD use
Sertraline- similar in action to fluoxetine with less effects on metabolism, shorter t.5, OCD, PTSD, Panic, PDD
Paroxetine- hotflashes
Fluvoxamine- OCD
Citalopram and Escitalopram- most specific SSRI, Citalopram can cause prolonged QT interval
SNRIs (Serotonin- norepinephrine reuptake inhibitors)
drugs block both 5ht and NE reuptake, Side effect profile is more like SSRIs
Duloxetine- MDD and anxiety, also approved for neuropathic pain syndromes, fibromyalgia, back pain and osteoarthritis pain, discontinuation syndrome, use with caution in patients with LIVER disease PAIN is a big reason of perscription
Venlafaxine- MDD and anxiety, off label for migraine and cataplexy
Milnacipran- approved for fibromyalgia, MDD
