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Monoamine/ Biogenic Amine Hypothesis
abnormalities in serotonin (5-HT), norepinephrine (NE), and dopamine (DA) neurotransmission
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Neurotrophic Hypothesis
- changes in nerve growth factors (ie: BDNF) play a role in cell survival and synaptic plasticity
- ex: loss of monoamines or increased glucocorticoids (stress)
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Tricyclic Antidepressants
- Imipramine, Amitriptyline, Desipramine
- block NE and 5-HT reuptake (increased synaptic concentrations)
- largely replaced by SSRIs
- not used for elderly
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Imipramine
- anticholinergic effects (used for enuresis)
- strong 5-HT and NE (to lesser extent) reuptake inhibition
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Desipramine
- less anticholinergic action
- stronger NE reuptake inhibition than 5-HT
- more effective at treating neuropathic pain
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Amitriptyline
- highly anticholinergic
- high alpha blocking properties (causes orthostatic hypotension
- most sedative of TCAs
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TCA side effects
- muscarinic receptor blockers: anticholinergic (dry mouth, constipation, blurred vision)
- CNS toxicity
- cardiotoxicity: Na/Ca channel blockers
- sexual dysfunction
- weight gain
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Specific Serotonin Reuptake Inhibitors (SSRIs)
- Fluoxetine, Paroxetine, Citalopram, Escitalopram, Sertraline
- most widely prescribed
- used for other psychiatric conditions
- block reuptake of 5-HT (increased synaptic concentration)
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SSRI side effects
- safest of all antidepressants
- nervousness, agitation, sweating, fatigue, GI upset
- sexual dysfunction
- serotonin syndrome (when used in combo)
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Serotonin Syndrome
- occurs when SSRI used in combo w/ another SSRI or MAOI
- early: lethargy, restlessness, confusion, diaphoresis, tremor
- untreated: hypertension, hyperthermia, rhabdomyolysis, death
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Discontinuation Syndrome
- sudden discontinuation of short half-life SSRIs
- symptoms: dizziness, paresthesias
- why: clearance of drug occurs faster than re-adaptation to receptor regulation and sensitization
- switch to SSRI with longer half-life (fluoxetine)
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Atypical: Alpha Blocker
- Mirtazapine
- blocks alpha2 receptors (increased synaptic 5-HT and NE)
- blocks 5-HT3 receptors (anti-emetic)
- effects: sedation, weight gain, no sexual
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Atypical: 5-HT2 antagonist
- Trazodone
- weak 5-HT reuptake blockade
- effects: sedative, priapism (peripheral A1 blocker)
- no tolerance or dependence
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Atypical: SNRIs
- Venlafaxine, Duloxetine
- block 5-HT, NE reuptake
- duloxetine- balanced inhibition (used for neuropathic pain)
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Atypical: DA/NE blocker
- Bupropion
- DA/NE reuptake inhibitor
- effects: lowers seizure threshold
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Monoamine Oxidase Inhibitors (MAOIs): irreversible
- Phenelzine, Tranylcypromine
- irreversible binding of MAO-A & B
- MAO-A: liver, brain, GI, sympathetic nerves (5-HT, NE, DA, and Tyramine neurons)
- MAO-B: brain, liver, platelets (DA neurons)
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Monoamine Oxidase Inhibitors (MAOIs): MAO-A competitive
- Moclobemide
- competitive inhibition of MAO-A
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Monoamine Oxidase Inhibitors (MAOIs): MAO-B competitive
- Selegiline
- competitive inhibition of MAO-B
- MAO-B not present in GI, so no tyramine restrictions needed at low doses
- high dose (patch): avoids first pass effect
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MAOI's side effects
- postural hypotension, dry mouth, blurry vision, weight gain, restlessness, anorgasmia
- Phenelzine- irreversible, Moclobemide- transient
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MAO-A inhibitors and Tyramine
- must avoid certain foods (ex: cheese, preserved meats and fish, fava beans, chianti, chocolate)
- tyramine triggers release of catecholamines, which can cause hypertensive crisis (stroke)
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Antidepressant Treatment Notes
- 2-4 weeks to reach max benefit
- SSRIs are safer in overdose
- MAOIs, TCAs, and SSRIs should not be combined
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Lithium
- blocks hydrolysis of IP, inhibits NE release, enhances glutamate reuptake
- mood-stabilizing
- 60-80% success rate for achieving remission from manic phase
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Lithium side effects
- subclinical hypothyroidism
- nephrogenic diabetes insipidus
- weight gain, GI upset, skin reactions, hand tremors
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Lithium drug interactions
- Thiazide and loop diuretics diminish clearance (lead to toxicity)
- diuretics block Na reabsorption: Na and Lithium are reabsorbed from proximal tubule (elevates plasma Li [ ])
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CNS depressant: Barbiturates
- Pentobarbital, Thiopental, Phenobarbital
- anxiolytic by virtue of sedative effects
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