Andrade: Anti-depressants Flashcards
Antidepressant Classes: (3 Main Ones)
Tricyclic Antidepressants (TCAs)
Selective Serotonin (+/- NE) Reuptake Inhibitors (SSRIs and SNRIs)
Monoamine Oxidase Inhibitors (MAOIs)
Other
Tricyclic Antidepressants (TCAs): (3)
Imipramine
Desipramine
Chlorimipramine
Selective Serotonin (+/- NE) Reuptake Inhibitors (SSRIs and SNRIs): (4)
Fluoxetine (SSRI)
Sertraline (SSRI)
Paroxetine (SSRI)
Venlafaxine (SNRI)
Monoamine Oxidase Inhibitors (MAOIs):
Phenelzine
Antidepressant
Other: (4)
- Buproprion
- Nefazodone
- Trazodone
- Mirtazapine
Non-Pharmacological Interventions:
Electroconvulsive therapy
Cognitive therapy and other forms of psychotherapy (appears to be more effective than drugs alone)
- Graph showing patients who remained well after acute treatment (highest percentage= those with prior cognitive therapy)
TCAs/SSRIs/SNRIs/MAOIs
Elicit therapeutic effects on depression by:
MOAs:
TCAs/SSRIs/SNRIs/MAOIs: elicit therapeutic effects on depression by modulating the function of the monoamine systems in the brain
MOA of these Drugs: regulate serotonergic and noradrenergic neurotransmission by inhibiting the reuptake of these monoamines
Function of Monoamine NTs:
Function of Monoamine NTs: neuromodulators that do not transmit fast excitatory or inhibitory signals, but rather regulate how neurons function (ie. how neurons integrate excitatory and inhibitory synaptic transmission)
Can therefore orchestrate the functional state of the brain (ie. appear to help “code” the behavioral state of the organism)
Monoamine NTs
Serotonin:
Serotonin: neurons located mostly in the dorsal raphe nucleus of the brain
- Very active during awake/alert states
Monoamine NTs
NE:
NE: neurons located in the locus ceruleus
- Unlike 5HT, not very much correlation with arousal level
- However, when something happens in the environment that excites the animal (ie. reward or anticipation of reward), activation of these neurons occurs
- Therefore, activity of neurons in this area marks saliency
Imipramine:
Imipramine: inhibits NE and 5HT uptake with comparable potencies
Chlorimipramine:
Chlorimipramine: preferentially inhibits 5HT uptake
Desipramine:
Desipramine: preferentially inhibits NE reuptake
TCAs
Delayed therapeutic onset:
Delayed therapeutic onset: generally takes 2-4 weeks to see effects (although effect of increasing monoamine availability is instantaneous)
Therapeutic delay also reflects the persistence of memory (time for brain to be “rewired”)
TCAs
Delayed therapeutic onset
Suggests the need for:
Examples:
Suggests the need for the development of secondary adaptive responses to treatment
Examples:
- Changes in the beta-adrenergic receptor function
- Changes in the activity of the serotonergic neurons
TCAs
Response varies:
Response varies: not all patients will respond to any given TCA
TCAs
Absorption:
Absorption: generally well absorbed after oral administration
- Lipophilic: bind to plasma proteins (potential for DDIs) and accumulate in tissues
TCAs
Metabolism:
Metabolism: in the liver by CYPs (potential for DDIs) with some production of active metabolites
- Inactivation and elimination of TCAs occurs over days
TCAs
SEs
Anti-muscarinic:
Anti-alpha1 adrenergic:
Anti-muscarinic: dry mouth, constipation, blurred vision etc.
Anti-alpha1 adrenergic: postural hypotension
TCAs
SEs
Other:
Low safety factor:
Other:
o Weight gain, sedation and sexual dysfunction
o Can induce mania in patients with undiagnosed BPD
Low safety factor: ODs potentially life-threatening due to cardiac toxicity (conduction delays and arrhythmias)
Most widely used antidepressants
SSRIs AND SNRIs
SSRIs: (5)
o Fluoxetine* o Citalopram o Paroxetine* o Sertraline* o Fluvoxamine .
SNRIs: (3)
o Venlafaxin*
o Duloxetine
o Milnacipran
.
SSRIs AND SNRIs
Delayed therapeutic onset:
Response varies:
Delayed therapeutic onset: generally at least 2-4 weeks (same as TCAs)
Response varies: not all patients respond to any given SSRI/SNRI (same as TCAs)
SSRIs AND SNRIs
Augment therapeutic effect with 2nd generation APD:
Examples:
Augment therapeutic effect with 2nd generation APD: may be modestly augmented, but also increases adverse effects (ie. weight gain and akathisia)
- Examples: apripazole or olanzapine
SSRIs AND SNRIs
Absorption:
Plasma protein binding:
Half Life:
Absorption: generally well absorbed after oral administration
o Plasma protein binding: variable
o Half Life: variable (less than a day to multiple days)
SSRIs AND SNRIs
Metabolism:
Metabolism: by multiple hepatic enzymes
o In some cases, metabolites are active (ie. norfluoxetine is the active metabolite of fluoxetine)
SSRIs AND SNRIs
Side Effects:
General: MUCH LESS prominent than with TCAs
Some side effects include: o Jitteriness o Insomnia o N/V/D o Headache o Dizziness o Fatigue o Sexual dysfunction
MAOIs
Function of MAO:
Inhibition leads to:
Function of MAO: catalyzes the oxidation of serotonin and NE inside the synaptic terminal
Inhibition leads to increase in intraterminal concentrations of these NTs, thus increasing the concentration packaged into vesicles and a subsequent increase in the release of 5HT and NE
MAOIs
Drugs in the Class: (4)
- Phenelzine*
- Selegiline
- Tranylcypromine
- Moclobemide
MAOIs
MAO Isoforms:
Two Isoforms: show differential expression on 5HT and NE neurons
- MAO-A: found in dorsal raphe (5HT), locus ceruleus (NE) and substantia nigra (DA)
- MAO-B: only found in the dorsal raphe (5HT)
Classic MAOIs (Phenelzine and Tranylcypromine):
Classic MAOIs (Phenelzine and Tranylcypromine): IRREVERSIBLY inhibit MAO-A and MAO-B
Classic MAOIs (Phenelzine and Tranylcypromine) Results:
Loss of ability to metabolize tyramine (indirect acting sympathomimetic) resulting in hypertensive crisis if tyramine levels get too high (“cheese effect”)
Potential DDIs with uptake inhibitors
MAOIs
Moclobemide:
Moclobemide: REVERSIBLE inhibitor of MAO-A only (less likely to trigger cheese effect because if NE begins to rise, will outcompete drug for MAO-A and be broken down–> therefore, never gets too high)
o Not available in US
MAOI
Selegiline:
Selegiline: REVERSIBLE inhibitor of MAO-B only (no cheese effect)
Other Antidepressants: (4)
What can help with insomnia?
General: precise MOAs still unknown; use based upon relief of specific side effects
o Bupropion
o Mirtazapine
o Nefazadone
o Trazodone: sedative properties of trazodone help with insomnia
