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Antidepressant Drugs
Psych
37
Medical
Graduate
10/26/2011

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Term
monoamine theory of depression
Definition
-deficiency of aminergic transmission in the CNS might be causative of depression (not 100% proven)

-an excess of aminergic transmission could result in mania

NE, ser, dop
Term
amine hypothesis of major depression
Definition
-serotonin and NE are stored in vesicles then released, taken up by transporters
-CREB = cyclic AMP response element binding protein --> affects transcription and plays a role in the blockage of transporters
Term
neurotrophic hypothesis of major depression
Definition
-depresse persons hav fewer dendrites and those dendrites have fewer innervated dendritic sprouts, or spines on them
-leads to a lack of communication
-BDNF: brain derived neurotrophic factor is decreased in depression
-BDNF is transcribed by CREB
Term
noradrenergic terminal
Definition
Tyrosine-->DOPA-->Dopamine(DA)

- DA synthesized in pre-synaptic terminal
-stored in vesicles: DA-->NE
-NE released via vesicles
-NE degraded by monoamine oxidase (MAO)
Term
noradrenergic synapse
Definition
-NE released from vesicle on presynaptic membrane
-reabsorbed pre-synaptically by **NE TRANSPORTER**
**NE transporter also has a site of action for amphetamine
Term
serotonergic terminal
Definition
Tryp-->5-HTP-->5-HT(serotonin)

-same vesicular storage and release as NE
-ser degraded by MAO: main mechanism of metabolism
Term
serotonergic synpase
Definition
**SEROTONIN TRANSPORTER takes up 5-HT from extracellular synapse to be repacked into vesicle
**serotonin transporter also has sites of action for Fluoxetine (prozac) and Fenfluramine (Fen-Phen, acts like an amphetamine)
-post-synaptically: Na ion channel receptor and Gprotein coupled receptor
Term
NE cell bodies
Definition
**located in the LOCUS COERULEUS in the pons**
Term
5-HT cell bodies
Definition
**located in the RAPHE NUCLEI in the pons**
Term
NE and serotonin pathways
Definition
-both have cell bodies originating in the pons
-both pathways go through parallel tracks and innervate the same places

(NE - locus coeruleus
ser - raphe nuclei)
Term
reciprocal innervation of NE and 5-HT neurons
Definition
-NE and 5HT neurons regulate each other's activities
-both cell bodies are in the pons
-direct connection between NE-->5HT
-can affect each other's firing and post-synaptic activity

*affecting one system really affects BOTH systems
Term
drugs used in the treatment of depression
Definition
-SSRIs: citralopram

-atypical antidperessants: bupropion, mirazepine

-SNRIs: venlafaxine

-TCAs

-MAOIs

-ECT
Term
site of action of antidepressants
Definition
-primary action is to BLOCK REUPTAKE

(atypicals are NOT reuptake inhibitors)
Term
SSRIs
selective serotonin reuptake inhibitors
Definition
*CITALOPRAM*
-easy to use
-safety in overdose
-relative tolerability
-cheap
-broad spectrum of uses
Term
SNRIa
selective serotonin and norepinephrine uptake inhibitors
Definition
*VENLAFAXINE*
-best tolerated in extended release form
-has a short half life
Term
atypical antidepressants
Definition
*MIRTAZAPINE*
-potent H1 histamine receptor blocker-->sedating effect
-blocks 5HT-2 and alpha-2-adrenergic receptors too

*BUPROPION*
-weakly blocks dopamine transporter and nicotinic acetylcholine receptors
-NOT sedating
-also used for smoking cessation
Term
TCAs
tricyclic antidepressants
Definition
-among the earliest drugs used but not as much currently
-SE profile that makes them untolerable to some patients
-possible to take a lethal OD
-block reuptake of both NE and serotonin
Term
MAOIs
monoamine oxidase inhibitors
Definition
-increase concentration of DA, NE, ser in synapse
-act by covalently modifying MAO
-very efficacious in depression
-need to does 2-3 times/day
-must have tyramine free diet
-SE profile makes then intolerable to some patients
-lethal overdose is possible
Term
absorption and distribution of antidepressants
Definition
-most are well absorbed

-most are widely distributed
Term
metabolism and elimination of antidepressants
Definition
-most metabolized by P450 then glucuronidation
-many have active metabolites
-most take several days to be eliminated

venlafaxine (SNRI) and bupropion (atyp) have short half-lives
Term
common adverse effects of antidepressants
Definition
-sedation
-hypotension
-antimuscarinic
-GI
-weight gain
-sexual effects
Term
adverse effects of SSRIs
Definition
**nausea and GI symptoms

**sexual effects, decreased libido, sexual dysfunction

-mild restlessness, headaches, insomnia

from activation of serotonin receptors
Term
adverse effects of SNRIs
Definition
serotonin AE:
**GI effects
**sexual side effects

noradrenergic AE:
-agitation
-increase blood pressure
Term
adverse effects of atypical antidepressants
Definition
Mirtazapine:
**sedation
-increased appetite, weight gain
-GI effects

Bupropion:
-dizziness
-agitation
-tremor
-anexoria
-potential for seizures at high doses
Term
adverse effects of TCAs
Definition
tertiary:
**antimuscarinic: dry mouth, dizziness, mental clouding, constipation, blurred vision
**sedation (from histamine block)
**hypotension
-weight gain
-sexual
-extreme CNS depression-->suicide
Term
adverse effects of MAOIs
Definition
-orthostatic hypotension
-weight gain
-sexual effects
Term
MAOI drug interactions
Definition
**DO NOT give with TCAs or SSRIs, may cause serotonin syndrome
-potentiate effect of other CNS depressants
-prolongs cardiovascular effects of indirectly-acting sympathomimetic amines
Term
suicide risk and overdose danger
Definition
-increased risk of suicidal ideation in patients <25y.o.

TCAs: lethal arrhythmias, BP changes, altered mental status

MAOIs: autonomic instability, psychotic symptoms, confusions, seizures

-other antidepressants are safer by comparison
Term
tolerance and physical dependence
Definition
-some tolerance to sedative and automonic TCA effects
-some tolerance to initial nausea of SSRIs

-physical dependence following abrupt withdrawal
Term
withdrawal effects
Definition
-occurs with abrupt discontinuation after taking med for at least 6 weeks
-antidepressant discontinuation symptoms: flu-like, malaise, insomnia, nausea, imbalance, sensory disturbances, hyperarousal
-more likely to occur with a longer duration of treatment and shorter half life of drug
-may get recurrence of morbidity (get depressed again)

TAPER OFF!
Term
drug-drug interactions
Definition
-most metabolism is through CYP450's
-SSRIs esp. compete with metab of other drugs
-TCAs and MAOIs potentiate alcohol and other CNS depressants
-MAOIs should never be combined with SSRIs or SNRIs
Term
safety of antidepressants at different ages
Definition
-safer in pregnancy than untreated depression
-risk:benefit ratio in children uncertain
-risks in geriatric patients higher due to decreased metabolic clearance
Term
drugs to treat bipolar disorder
Definition
mood stabilizers:

-lithium
-anticonvulsive drugs: valproic acid, carbazepine, lamotrigine, ripiprazole
Term
pharmacologic properties of lithium
Definition
-therapeutic doses have NO psychotropic effects in normal individuals
-not a sedative, euphoriant or depressant
-does not negatively effect ionic balance
**alters release and second messenger actions of biologic amines**
Term
therapeutic index of lithium
Definition
**LOW, VERY NARROW**
1: therapeutic effect
2: mild toxicity
3: acute intoxication
4: coma
5: death

1-->5 can happen in a week

need a compliant patient
Term
adverse effects of lithium
(with long-term use)
Definition
Renal
-nephrogenic diabetes insipidus: lose ability to concentrate urine, excessive free water clearance (reversible)

Thyroid
-decreases thyroid function (reversible)
Term
therapeutic uses of lithium
Definition
-bipolar disorder to treat acute mania, often in combo with anticonvulsants/psychotics

-adjunct to antidepressants in severe, recurrent depression or supplement in major depression
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