dep theory – monoamine deficit theory
○ Deficit in monoamine neurotransmitters (NA and 5HT) cause depression
○ Evidence: reserpine (inhibit NA and 5HT) storage ==> depressed mood
Limitations of theory
- Hypothesis formulated for NA but later emphasis shift from NA –> 5HT
- Monoamine markers in depressed pt yield inconsistent and equivocal results
- Inadequate to explain all pharmacological actions in depression
* Monoamines impt but there are complex interactions with other neurotransmitter systems as well
9 classes of antidep
- MAO Ai (reversible)
- TCA
- SSRI
- SNRI
- NDRI (bupropion)
- NaSSA (mirtazapine)
- melatonin receptors (agomelatine)
- Serotonin antagonist and reuptake inhibitor (trazodone)
- multimodal serotonergic antidep (vortioxetine)
MAOi eg
moclobemide (safest, reversible MAOi-A)
phenelzine (MAO-i A > B)
tranylcypromine (MAO-i A,B)
selegiline (MAOi-B)
types of MAO enzymes
- MAO-A
□ 5HT broken down mainly by specific enzyme
□ NA and dopamine - MAO-B
□ NA and dopamine
MAOi/ RIMA MOA
incr biological availability of monoamines
* MAO-A, MAO-B preference
□ affects the conc of neurotransmitters recycled from being degraded by MAO
(A: incr for all 5HT,NA,DA)
(B: more specific for NA,DA)
RIMA indication
- depression (reversible , less SE > older gen)
- social ANX d/o
ADR for MAOi
- Postural hypotension (DA)
- Sympathetic block produced by accumulation of dopamine in cervical ganglia (neck)
- Acts as inhibitory transmitter, not activated quick enough to respond to change in BP
- HYPERTENSIVE CRISIS (NE)
- Restlessness and insomnia, ANX, arrhythmia
- Due to CNS stimulation
- Serotoninergic function
- Not combined with other drugs enhancing serotoninergic function (pethidine)
○ Hyperexcitability, incr muscular tone
○ myoclonus (jerk, involuntary movements)
○ Loss of consciousness
○ seizure
(weight gain, sexual dysfuction)
- Not combined with other drugs enhancing serotoninergic function (pethidine)
DFI for MAOi
- Concomitant intake of too high in tyramine (cheese, cured meats, conc yeast pdt)
○ NA SE: Acute hypertension, severe throbbing headache, intracranial hemorrhage
○ MAOi prevent break down of monoamines (tyramine), excess tyramine = sympathomimetic effect- Tyramine uptake by adrenergic terminals, compete with NA for vesicular compartment - Incr displacement and release of NA into synapse
DDI more likely in___ MAOi
irreversible, non-selective MAOis > reversible, MAO-A selective (moclobemide)
DDI for MAOi
Serotonin syndrome
- DDI with serotonergic drugs = incr serotoninergic activity
- Tremor, hyperthermia, CVS collapse
TCAs MOA
1st gen monoamine reuptake inhibitor antidep
2nd gen has milder SE, improved compliance
(nortriptyline > amitriptyline, imipramine)
types of TCAs + eg
1) non-selective for SERT/ NET – 5HT, NA
(imipramine, amitriptyline, nortriptyline, Clomipramine)
2) selective for NET – NA
(desipramine)
both on presynapse, feedback inhibition pathway
TCA metabolism
amitriptyline (3) –> nortriptyline (2 amine)
imipramine (3) –> desipramine (2)
2*: lower anticholinergic, sedation & cardiotoxic SE
TCA indication
- depression
- Clomipramine (2nd line for OCD)
- amitriptyline (neuropathic pain, migraine prophy)
- nortriptyline (neuropathic pain)
* late preg
ADR of TCAs
- Sedation
- H1
- Tolerance to sedation can develop in 1-2 wks
- Postural hypotension
- a1
- Dry mouth, blurred vision, constipation
- Parasympathetic effect (M1)
- 5HT3 block: GIT & sexual dysfunction
- seizure, QTc prolong (arrhy), weight gain
DDI w/ TCAs
Serotonin syndrome
* DDI with other drugs that incr serotoninergic activity
* Tremor, hyperthermia, CVS collapse
SSRI MOA
- Greater 5HT reuptake selectivity than TCAs
- 50-1000x selectivity for 5HT > NA
* minimal effect/ reuptake of NE, DA
SSRI eg
- Fluoxetine (50x selective for 5HT) —-> norfluoxetine
- Citalopram (1000x 5HT selective)/ escitalopram
- fluvoxamine
- sertraline
- paroxetine
indication of SSRI
- Depression
- eating d/o: fluoxetine,
- OCD: fluoxetine, fluvoxamine, sertraline
- ANX: escitalopram, paroxetine
- Panic: citalopram, sertraline
- Sertraline (BF, post MI depression)
advantage of SSRI compared to TCAs
1) safer in overdose, less SE (better compliance)
a. TCA > MAOi > SSRI (death per px)
2) Better tolerance than TCAs
a. Improved ADR, better compliance
b. lack affinity for (A1: CVS effect)/ (H1: sedation)/ (M1: anticholinergic dry mouth, constipation)
3) Efficacy
ADR of SSRI
- Nausea, Insomnia (trough, b. dose)
* esp fluoxetine - headache, transient nervousness (initiation)
- seizure, bleeding risk, hypoNa (SIADH), EPSE
- GI & Sexual dysfunction (5HT3)
- Sedating effect (H1)
specific eg of SSRI ADR
- Fluoxetine (4-6hr)
* norfluoxetine (4-16d) long t1/2, insomia - Citalopram / escitalopram
* QTc prolongation - paroxetine
* MOST anticholinergic, sedate, weight gain, short t1/2, withdrawl sx
serotonin syndrome
potentiation of action in central and peripheral NS
(serotonergic drug + MAOi/ another serotonergic)
- neuromuscular hyperactivity
(ANX, agitation, confusion, clonus, hyperreflexia, muscle rigidity, unexplained FEVER –> CVS collapse)
