Acute untreated episodes last 6-14 months to >2 years

Secondary depression:
- Hypothyroidism
- Parkinson’s disease
- Inflammatory conditions
DIAGNOSIS:
- Appetite
- Sleep change
- Low energy and low libido
- Poor concentration
- Worthlessness or guilt
- Psychomotor agitation
- Retardation
- Recurrent thoughts of suicide
Start low, go slow
Psychotherapy (CBT) is longer and more expensive
6-8 weeks of treatment for optimal effect
Treat initial episodes for 9-12 months  if relapse, consider lifelong treatment
1) Initial dose success rate – 30-40%  lasts up to 12 weeks
2) Increase dose or add AD from another class
3) Second dose success rate – 70-80%  continue for up to 1 year
4) Long term treatment in more frequent or severe relapses
- WEEK 1 Anxiety, insomnia, appetite
- WEEK 2 Increase in energy and libido, but increased suicide risk
- WEEK 3 Improvement in dysphoria/sadness, pessimism, anhedonia
NEUROTROPHIC HYPOTHESIS

- Depression caused by a drop in BDNF levels in CSF and serum  decrease in tyrosine kinase receptor B activity
- BDNF activates tyrosine kinase receptor B  influence on neuronal survival and growth effects increases neuronal function in hippocampus and other
brain regions
- Increase in CRF  Increase in glucocorticoids  decrease in BDNF  loss of neuronal function
- Stress and glucocorticoids are inhibitory on BDNF activity
MONOAMINE HYPOTHESIS
- Depression caused by deficiency in 5-HT, Norepinephrine or Dopamine
- Antidepressants activate monoamine receptors  increase BDNF transcription
- However: Amine levels increase
o Maximum beneficial effect only seen after WEEKS  possibly time required to synthesize neurotrophic factors
CLASS ACTION METABOLISM INDICATIONS CONTRAINDICATIONS SIDE EFFECTS & TOXICITY

Tricyclic Inhibit serotonin, Metabolised by liver  NOT FIRST LINE 5-6 fold increase in Muscarinic M1 receptor
Antidepressant norepinephrine, dopamine CYP2D6 imipramine dose antagonism:
Used in SSRI or
s transporters  blocks FATAL
SERT and NET - Fluoxetine inhibits SNRI resistant - Anticholinergic effects:
Amitriptyline CYP2D6  increases May cause switching in - Dry mouth
Panic disorder
Slows reuptake of: blood levels of TCA bipolar disorder - Blurred vision
Desipramine
Chronic pain eg. - Constipation
- Serotonin 5% excreted unchanged
Doxepin Neuropathic pain - Urinary retention
- Norepinephrine
Low/inconsistent - Impotence
Imipramine - Dopamine Prophylaxis for
bioavailability - Sinus tachycardia
migraines - Angle closure glaucoma
Nortriptyline Downregulation of post
Narrow therapeutic index aggravation
synaptic receptors NortriptylineSmok
Trimipramin
ing cessation if Histamine H1 receptor
e Clomipramine has little
resistant to antagonism:
affinity for NET; more
bupropion
affinity for SERT
- Sedation
Nortriptyline and - Weight gain
desipramine selective for
Direct membrane effects:
NET
- Reduced seizure threshold
- Reduced cardiac muscle
threshold Arrhythmia
Antiadrenergic effects:
- Orthostatic hypertension
- IMAPRAMINE causes ortho
htn in elderly
- Dizziness
- Reflex tachycardia
 Serotonin 5-HT2 receptor
antagonism:
- Weight gain
- Reduced anxiety

Tetracyclic Inhibits NET >> SERT Hepatic metabolism NOT FIRST LINE Amoxapine  Parkinsonian
Antidepressant syndrome due to D2 antagonism
Amoxapine is D2 receptor Amoxapine 
s
blocker antipsychotic 
Amoxapine – Parkinson
Mirtazapine  antagonist
D2 syndrome
of 2 receptors
Mirtazapine - Sedates patient (H1
- Increases 5-HT and NE
2 blocker) for
release insomnia
Maprotiline - Inhibits 5-HT2 and
HT3 receptors Sedative additive
- Potent H1 blocker  with alcohol and
sedates patient benzos

Selective Inhibits serotonin uptake 2 weeks for improvement Major depression SSRI inhibit CYP450 SEROTONIN SYNDROME 
Serotonin  more effective REDUCE DOSE FOR
Allosterically binds and 3 months  max than benzos HEPATIC DISEASE - Anxiety
Reuptake
inhibits SERT  binds to improvement - Restlessness
Inhibitors
different site than OCD  Paroxetine and fluoxetine - Sleep disturbances
Administer flouexetine in
Fluoxetine serotonin 80% activity CYP2D6 inhibitors - Tachycardia
the morning before - Fluvoxamine,
inhibited at therapeutic - Vomiting and diarrhea 
Paroxetine breakfast to prevent sleep - clomipramine - Eliminate TCA
doses increase serotonergic tone in
disturbance  - Neuroepileptics
Sertraline Panic disorder gut
Small effects on: - Antiarrhythmatics
Fluoxetine is metabolized - Muscle rigidity
Fluvoxamine Generalized anxiety - Beta blockers
- Muscarinic to a more active - Hyperreflexia
Citalopram -  adrenergic
Escitalopram - H1 receptors norfluoxetine metabolite t POST Discontinue Fluoxetine 5-HT3 receptor stimulation:
S-citalopram - Little effect on NET 1/2 ~10 days TRAUMATIC 4-6weeks before
administering MAOI to Nausea and vomiting
STRESS
300-3000 fold greater SSRI inhibit CYP450
DISORDER: mitigate risk of serotonin Sexual dysfunction:
selectivity for serotonin REDUCE DOSE FOR
syndrome  washout
receptor than NE receptor HEPATIC DISEASE - Sertaline - Delayed/impaired orgasm
period
- Paroxetine - Low arousal and libido
Withdrawal symptoms:
Premenstrual
- More likely to occur Repeated treatment 
dysphoric disorder: Drugs causing serotonin
with short t ½ syndrome: 5-HT2c receptor stimulation:
- Downregulation of
PAROXETINE - Fluoxetine
autoreceptor Agitation
WITHDRAWAL - Sertraline - SSRIs
mechanism
- Caused by - Antipsychotics Restlessness
- Desensitization to Bulimia nervosa:
downregulated - Anticonvulsants
mechanism
receptors sudden - Fluoxetine - Antiparkinsonian
- Increase/return of
decrease in available 5- - Analgesics
presynaptic activity General:
HT - Dextromethorphan
- Production and
- ONSET: 24-72hrs - Herbal products Sleep disturbances – Fluoxetine
release of serotonin
- Linezolid
DOA: 7-14 days Insomnia  Fluoxetine and
Sertaline
PAROXETINE and
Hypersomnia Paroxetine and
SERTALINE Withdrawal
fluvoxamine
symptoms start within 24-
72hrs and last 7-14days
”RECEPTOR
REBOUND” Paroxetine specific:
DISCONTINUATION - Cardiac septal defects in first
SYNDROME trimester
- Dizziness - Weight gain
- Nausea - Hypersomnia
- Lethargy
 - Headache
- Parasthesia
-

Selective Bind to SERT and NET Venlafaxine  Depression; if SSRIs DO NOT use in Nausea
Serotonin- transporters Desvenlafaxine (active are NOT effective combination with
Constipation
Norepinephrin metabolite) MAOIs
Venlafaxine: Duloxetine:
e Reuptake Headache
Metabolized by hepatic Use duloxetine with
Inhibitors Low doses <150 - Chronic joint and caution in hepatic
CYP450 Dizziness
serotonin reuptake muscle pain
- Venlafaxine dysfunction
inhibitor – greater affinity Duloxetine extensively - Urinary stress Nervousness
- Desvenlafax
for serotonin metabolized  CAUTION incontinence
ine Somnolence
in hepatic dysfunction - Both 5-HT and
- Levomilnac 150< norepinephrine
NE involved in Dry mouth
ipran reuptake inhibitor Levomilnacipran excreted
pain pathways
- Milnacipra unchanged
Duloxetine inhibits Sexual dysfunction
n
serotonin and Increased seizure risk
norepinephrine at any Milnacipran:
dose Discontinuation syndrome
- Fibromyalgia
Venlafaxine  weak NE Noradrenergic effects:
transporter blocker Desvenlafaxine:
- Increased blood pressure
5-HT and NE involved in - Autism - Increased heart rate
pain pathways - Binge eating - Insomnia
disorders - Anxiety
- Hot flashes - Agitation
Venlafaxine:
- PMS dysphoric NO other receptor side effects
disorder
- PTSD
- Pain syndromes
 -

5-HT2 receptor Inhibits POSTsynaptic 5- NOT FIRST LINE Nefazodone causes H1 blockade  Sedating
inhibitors HT2A receptors severe hepatotoxicity
Trazodone used off label for
Trazodone Inhibit SERT weakly anxiety and insomnia
Nefazodone - adrenergic blockade 
orthostatic hypotension and
dizziness
Nefazodone  severe
hepatotoxicity
CYP3A4 metabolism 
increases trazodone and
simvastatin
Ritonavir and ketoconazole
CYP3A4 inhibitors  increase
trazodone

Monoamine Bind irreversibly to MOA-A – LAST LINE Food-drug interactions: Orthostatic hypotension
oxidase monoamine oxidase treatment for:
inhibitors - Dopamine, NE - Prevents tyramine Weight gain
Prevents inactivation of - Gut and placenta - Anxiety breakdown in gut
Dry mouth
Phenelzine biogenic amines  - Norepinephrine, - Parkinson’s Tyramine pressor
Cortical and limbic epinephrine and 5-HT disease effectsIncreased Sedation
Tranylcypro deficiency of monoamines are substrates BP malignant
mine Sexual dysfunction
HTN, stroke, MI
Blocks destruction of MOA-B – -
Isocarboxazi Low tyramine dietary Sleep disturbance
norepinephrine and
d - Serotonergic, restriction:
serotonin 
Histaminergic - aged cheeses SEROTONIN SYNDROME if
Selegiline neurotransmitters remain
- Platelets - Beer taken with serotonin boosting
for longer
- Soy
- Dried sausage
Moclobemid Increased synaptic levels of - Dopamine and tyramine - Patches bypass MAO drugs stop AD 2 weeks before
e norepinephrine, dopamine are substrates in the gut starting MAO
and serotonin
Stop fluoxetine 4 weeks before
Reduces glutamatergic
transmission associated
Extensively metabolized - Abdominal pain
with elevated glutamate - Diarrhea
First pass effect
levels - Sweats
Amphetamine like CNS - Tachycardia
Phenelzine and stimulating effects: - Hypertension
tranylcypromine - Myoclonus
IRreversible; - Excitement - Irritability
NONselective - Insomnia - Delirium
- Restlessness
Selegiline  IRreversible;  Leads to
MOA-B selective HYPERPYREXIA,
CARDIOVASCULAR
SHOCK, AND DEATH

Norepinephrin More potent in inhibiting Bupropion: Apathetic Insomnia

e Dopamine dopamine than SSRI or depression
75mg-150mg daily Seizure risk
Reuptake SSNRI
Smoking addiction
Inhibitors Well tolerated in elderly (?) Agitation
3-4 nicotinic antagonist
Augmenting agent
Bupropion NO SEXUAL DYSFUNCTION
- If unresponsive LIKE SSRIS AND SSNRIS
- Accelerates
response

5-HT1A Binds to SERT Metabolized by CYP3A4 Drug interaction with Nausea

agonist ketoconazole  inhibitor
Minimal NET binding Excreted unchanged Vomiting
of ketoconoazole
Vilazodone
Vortioxetine Partial 5-HT1A agonist Constipation
Vortioxetine:
Vortioxetine: - Reduce dose with
fluoxetine and
SERT inhibitor
buprion  CYP
5HT1A agonist inhibitors
- Increase dose with
5-HT3 and 5-HT7 rifampin,
antagonist carbamazepine,
phenytoin (inducers)