pharmacology of depression Flashcards
Which neurotransmitters play a role in: depressed mood, apathy, sleep disturbance, fatigue, guilt, changes in weight/appetite
Depressed mood: NE-5HT-DA projections from brainstem nuclei. Apathy: NE and DA. Sleep disturbances: NE-5HT-DA. Fatigue: NE and DA. Guilt: 5HT. Changes in weight or appetite: 5HT
Monoamine theory of depression
Proposes that depleted brain NE and 5HT induce depression. Depression is due to dysregulation of pre and post synaptic control of NE-5HT neurotransmission.
Monoamine theory of depression limitations
Does not totally explain etiology of depression b/c drugs that enhance NE-5HT-DA availability in synapse work immediately, while mood elevating effect is delayed 2-3 weeks.
Describe acute and chronic changes following antidepressant therapy
acute: inhibit 5HT or NE reuptake/breakdown. Chronic: increased transcription of genes which promote function and survival of cells
neurotrophic hypothesis of antidepressant therapy
stress causes increased glucocorticoids which leads to decreased Brain derived neurotrophic factor (BDNF) gene expression causing neuronal atrophy in the CA3 region of brain (prefrontal cortex and hippocampus). Antidepressive pathways involve monoamines NE and 5-HT acting on G protiein receptors, and BDNF acting on TrkB to turn on genes that promote neurogenesis and protect against apoptosis
Tricyclic antidepressants MOA
Acutely blocks reuptake of NE and/or 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse. Used as 2nd line agents due to poor side effect profile
List Tricyclic antidepressants
amitriptyline, imipramine, desipramine (only blocks NE reuptake)
Tricyclic antidepressants side effects
sedation [Amitriptyline > Desipramine], antimuscarinic such as dry mouth, urinary hesitancy [Amitriptyline > Desipramine-Nortriptyline], cardiovascular such as orthostatic hypertension (a1 blockade) and sudden death in overdose, neurologic such as seizures during overdose
Serotonin selective reuptake inhibitors (SSRIs) MOA
Acutely blocks reuptake of 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse
List Serotonin selective reuptake inhibitors
fluoxetine, paroxetine, sertraline
SSRIs side effects
Acute: Nausea-diarrhea [5HT3] (increased serotonin effects in GI tract), activation-insomnia (commonly), restlessness [5HT2] (akathisia), somnolence (occasionally); dry mouth. Delayed onset: weight gain, sexual dysfunction [5HT3], cognitive blunting. LOW likelihood of fatalities in overdose
SSRIs drug interactions
SSRI + MAOI or SSRI + opioids causes serotonin syndrome (hyperthermia, muscle rigidity, myoclonus, rapid changes in mental status (confusion / agitation) and vital signs (hypertension and tachycardia). Also Inhibition of P450 drug metabolizing enzymes by fluoxetine. St. Johns Wort induces P450 drug metabolizing enzyms
Serotonin and norepinephrine reuptake inhibitors (SNRIs) MOA
Acutely blocks reuptake of NE and 5HT at synapse to prolong their actions, leading to chronic compensatory changes at the synapse
List Serotonin and norepinephrine reuptake inhibitors (SNRIs)
venlafaxine
Venlafaxine side effects
Hypertension, anxiety
Bupropion MOA
Norepinephrine and dopamine reuptake inhibitor
Bupropion side effects
anxiety, seizures at high doses
Trazadone MOA
Mixed postsynaptic antagonist-serotonin reuptake inhibitor
Trazadone side effects
drowsiness. Overdose only leads to minor problems
Mirtazapine MOA
Acute effect is inhibition of presynaptic a2 adrenergic receptor that decreases NE release, such a block results in increased NE release
Mirtazapine side effects
weight gain
MAOIs MOA
Block enzyme of major degradation pathway for NE and 5HT in neuron, presumably allowing more presynaptic accumulation and subsequent release into the synapse and again leading to chronic compensatory changes at the synapse
MAOIs examples
Phenelzine and Selegiline
MAOIs side effects
postural hypotension, seizures, shock, hyperthermia in overdose
MAOIs drug interactions
Hypertensive crisis with certain drugs (meperidine, decongestants) or with foods high in tyramine (beer/wine/cheese) [results from acute increase in norepinephrine displacement].
Electroconvulsive therapy MOA
Increases the amount and activity of the rate-limiting enzymes for synthesis of norepinephrine (tyrosine hydroxylase) and serotonin (tryptophan hydroxylase) resulting in increased levels of these neurotransmitters
MAOIs pharmacokinetics
•Inhibition is irreversible – continues after drug no longer detectable (2 weeks)
SSRIs / Heterocyclic agents / TCADS pharmacokinetics
Wide interpatient variations in Cp for given dose
Describe neurotransmission during a bipolar storm
(1) excessive activity in neuron An(2) widespread input from its dendrites triggers too much axonal flow, mediated by voltage-sensitive sodium channels (VSSC)
(3) this in turn overly activates voltage-sensitive calcium channels (VSCC) linked to glutamate release (4) triggering excessive, chaotic, unpredictable neurotransmission from neuron A to neuron B (5) this “bipolar storm” is then by detected by postsynaptic NMDA receptors on neuron B (6) with subsequent excitation of its own VSSC and so on.
Pharmacotherapy to stabilize mood in bipolar
lithium and valproate
Pharmacotherapy for mania in bipolar
atypical antipsychotics
pharmacotherapy for depression in bipolar
lamotrigine or antidepressants
Pharmacotherapy for acute manic symptoms in bipolar
with BDZs (alprazolam, lorazepam) or atypical antipsychotic agents
MOA of valproate
Blocks voltage sensitive sodium channels
MOA of lamotrigine
block voltage sensitive calcium channels
Lithium MOA
Enhance 5HT action and/or diminish NE and DA effect by interfering with PIP recycling. PIP recycling is required for G protein actions Use dependent
Lithium side effects
interference with Gs and Gi in thyroid leads to hypothyroidism and in kidney leads to polyuria-polydipsia
Lithium pharmacokinetics
competes with Na for reabsorption, so increased Na leads to decreased Lithium plasma levels
lithium drug interactions
Diuretics can decrease renal clearance by as much as 25%. This increase in plasma lithium levels is also seen with NSAID analgesic agents.
