Antidepressants and Mood Stabilizers Flashcards
What are the core symptoms of depression?
- persistent sad, anxious, tense, empty mood
- feelings of hopelessness, pessimism
- feelings of guilt, worthlessness, helplessness
- persistent physical symptoms that don’t respond to treatment such as headaches, digestive disorders, and chronic pain
What are the vital signs of depression?
- difficulty concentrating, remembering, making decisions, loss of interest or pleasure in hobbies and activities, decreased energy, fatigue, being slowed down, insomnia, oversleeping, thoughts of death of suicide, suicide attempts, restlessness
What are the classifications of depression?
- Reactive (secondary) - 60%, mainly core symptoms
- Major depressive disorder (endogenous) - 25%, core and vital symptoms, peak onset 20-40. Responsive to antidepressant drugs and ECT
- Bipolar Disorder (manic) - 15%, alternating episodes of depression and mania. treated w/ mood stabilizers and antidepressants
Biogenic Amine hypothesis
- functional deficit in monoamines thought to cause depression
- NE and 5HT increase immediately but takes weeks = therapeutic lag
- delayed effect b/c of beta receptors, cAMP, and serotonergic neurotransmission, neurogenesis
What receptors can be targeted at presynaptic areas? post synaptic?
- presynaptic : MAOI, NE works at alpha 2 AR, 5HT works at 1D/2A, TCA’s inhibit reuptake as well as SNRI and SSRI
- Postsynaptic : TCAs act at alpha 1 AR
What is the BBW for antidepressants?
risk of suicidal thinking to all everyone, closely monitored especially during initial weeks of treatment
What are some other common problems in antidepressant therapy?
- placebo effect
- St john’s warts for mild to moderate depression - no more effective than placebo and interferes w/ various medications
- Pharmacogenomics or resistance to antidepressant treatment - many of the drugs are substrates for ABCB1 at the BBB liming drug to accumulate in brain and have its effects.
What are the antidepressants that are substrates of MDR1?
citalopram, venlafaxine, paroxetine, amitriptyline
MOA of TCAs
- inhibit reuptake of 5HT and NE into presynaptic terminals
- potentiates and prolongs actions of these neurotransmitters
- also blocks mAch, 5HT, and Histamine receptors
ADE of TCAs
- orthostatic hypotension - alpha AR antagonism
- blurred vision, worsening of narrow-angle glaucoma, dry mouth, constipation, urinary retention, tachycardia, confusion - antagonism of mAchR
- sedation - antagonism of histamine and alpha AR
- metabolic/endocrine - weight gain, sexual disturbances
TCA overdose symptoms
- overall low TI
- CV effets, acidosis, delirium, seizures
PK of TCA
- most incompletely absorbed due to 1st pass
- high lipid solubility and distribution to brain and fat
- highly bound to plasma protein (high Vd)
- tricycling ring subject to oxidation (CYP2D6) and conjugation
drug interactions of TCA
- EtOH and other sedatives, antiparkinson drugs, antipsychotic drugs, biogenic amines, competition for plasma protein binding
- can block effects of clonidine
MOA of trazodone
- mod inhibition of 5HT reuptake but mainly 5HT2a antagonist and 5HT1a partial agonist
- short half life
- inhibits CYP 3A4
MOA of mirtazepine
- enhances release of 5HT and NE by antagonizing presynaptic alpha-2ARs. Also antagnoizes 5HT2 receptors
- potent antihistamic = sedation
- increased weight gain
- less GI and sexual disturbances than SSRIs
MOA of bupropion
- weak blocker of DAT, SERT, and NET
- active metabolite is NE reuptake blocker
- also used in smoking cessation
ADE of bupropion
- agitation, anxiety, restlessness, risk of seizure
MOA of Venlafaxine
- inhibits 5HT and NE reuptake
- devoid of antihistaminergic, anticholinergic, and antiadrenergic properties
- doesn’t have TCA like side effects
ADE of venlafaxine
HTN, sweating dizziness, nausea, anxiety
MOA of duloxetine
SNRI
- most potent available
- highly bound to plasma
- metabolized by CYP2D6 and CYP 1A2
SSRI MOA
selective inhibition of SERT - potentiate and prolongs action of 5HT
Clinical effects of SSRIs
- acute - CNS stimulation, anxiety, agitation
2. Chronic - improvement of most or all clinical symptoms, CNS activation remains
ADE of SSRIs
Nausea, decreased libido, sexual dysfunction
- lower incidence of CV and anticholinergic effects
- high TI (decreased risk of overdose)
- increased risk of birth defects w/ paroxetine
PK of SSRIs
- high protein binding
- long half life
- most metabolized by CYP2d6, 2C19, 3A4 and can exhibit weak to strong inhibition of 2D6 and 2C19
drug interactions for SSRIs
- MAOIs contraindicated (must wait at least 2 weeks)
MAOI examples
Phenelzine: MAOA
Selegiline: MAOB
what is serotonin syndrome?
- onset w/in 24 hours of overdose or concurrent MAOI. due largely to overstimulation of 5HT1A receptors in central grey and medulla
- hyperpyrexia, hyperreflexia, tremor, shivering, myoclonus, agitation, seizures, confusion, delirium, CV collapse, and coma
What are some things that can cause serotonin syndrome?
- increased 5HT release (amphetamines, MDMA)
- 5HT agonists (LSD, buspirone, L-trp)
SSRI examples
Citalopram Fluoxetine Paroxetine Sertraline Fluvoxamine
indications for MAOI
- when pt is unrepsonsive to treatment w/ other antidepressant and for whom ECT is not suitable.
- also used in panic disorder and agoraphobia
MOA of MAOI
blocks oxidative metabolism of monamines by irreversible inhibition of MAO-A and MAO-B in nerve terminals
Clinical effects of MAOI
- acute - CNS stimulation, agitation, possibly euphoria
2. chronic - improvement of most or all symptoms, CNS activation remains
ADE of MAOI
sleep disturbance, orthostatic hypotension, weight gain, some sex dysfunction
PK of MAOI
- inactivated by acetylation
- daily dosing required
- generally well absorbed from GI tract
drug interactions for MAOI
- foods w/ high amounts of tyramine (cheese)
- sympathomimetic drugs –> acute hypertensive reaction
- meperidine, dextromethorpham –> hyperpyrexia, delirium, convulsions, coma, death
- SSRIs
mood stabilizer drugs
- lithium
- valproate
- carbamazepine
Lithium MOA
- poorly understood. 1st line for bipolar disorder
- possibly via inhibition of IP signaling
- also inhibits nt-stimulated AC activity
ADE of Lithium
- very narrow therapeutic window
toxic effects at > 1.5mEq/L - neurologic/ psych - tremor, ataxia, hyperactivity, aphasia, sedation, fatigue
- edema, mild hypothyroidism
- polydipsia, polyuria (nephrogenic DI)
- bradycardia - tachycardia
- acne, folliculitis, exacerbates psoriasis
drug interactions for Li
- diuretics and NSAIDS
anticonvulsants for bipolar disorder
- may be used to treat milder forms of bipolar disorder
- able to increase dose faster, quicker response, better TI than Li
- less experience, efficacy questionable in severe disease
- used usually in combo w/ Li or anti-psychotics
MOA of valproate
- inhibits Na channels by stabilizing inactivated state
- blocks Ca channel
- stimulates GABA synthesis and inhibits GABA degeneration
- at high doses, increases resting K conductances
drugs interactions of valproate
- inhibits its own metabolism and of other 2C drugs
ADE valproate
nausea, ab pain, heartburn
- sedation
- hepatotoxicity
MOA of carbamazepine
- inhibits Na channel
PK of carbamezpine
- 70% bound to plasma protein
- distributes slowly
- metabolized by CYP3A4 to active metabolite
drug interactions of carbamazepine
- enhances metabolism of many drugs via induction of cyp2C and 3A and UGTs
ADE carbamazepine
- diplopia (double vision) and ataxia
- mild GI upset, unsteadiness
- at high doses drowsiness
- rash common idiosyncratic rxn
- aplastic anemia
