Anti-Depressants
Selective Serotonin
Reuptake inhibitors
(SSRIs)
Fluoxetine (Prozac ®), Citalopram, Escitalopram, Paroxetine, Sertraline (Zoloft®)
Mechanism of Action:
Highly selective blockade of serotonine
transporter (SERT)
Little effect on norepinephrine
transporter (NET)
EFFECTS:
Acute increase of serotonergic synaptic
activity
Slower changes in several signaling
pathways and neurotrophic activity
Time to onset of antidepressant effect =
1-2 weeks
Indications:
Psychiatric:
1. Major depression
2. Anxiety disorders
3. Panic disorder
4. Obsessive compulsive
disorder
5. Post-traumatic stress
disorder (PTSD)
6. Bulimia (eating disorders)
Non-psychiatric:
1. Peri-menopausal vasomotor
sysmptoms
**Better tolerated than other clases
**safer in overdose
Notes:
These drugs are safer in terms of
overdose due to no
cardiotoxicity, antimuscarnic
effects or seizure risks
Pharmacokinetics:
Half-lives from 15-75 hrs
Oral activity
In a 5-HT synapse:
1. SRI inhibit 5-HT
reuptake; increased 5HT in synaptic cleft.
Pre and postsynaptic
5-HT receptors are
activated
2. Presynaptic receptors
activated, 5-HT
release is decreased
toward normal
3. 3. Slow response:
presynaptic receptors
desensitize; 5-HT
release increases
4. Other slow responses
inclue down
regulation of beta
receptors a, down
regulation of postsynaptic 5-HT2A
receptors, activation
of transcription
factors, etc.
Adverse Effects
Well tolerated but cause sexual
dysfunction (likely), nausea and
vomiting (with weight loss) and minor
agitation (stimulation, nervousness,
insomnia, anxiety)
Contraindications:
Drug interactions:
MAOIs  serotonin syndrome (alternd
mental status with agitation,
disorientation and hallucination,
sweating, fever, tremor and
myoclonus.)
-must “wash out” if switching
Some CYP inhibition
Tricyclic
Antidepressants (TCAs)
“1st generation”
Imipramine, Amitriptyline, Nortryptiline ( only works on NE and is safer, i.e. less side effects)
Mechanism of Action:
Mixed and variable blockade of NET
and SERT (NE, 5-HT)
EFFECTS:
Acute increase in sertonergic and
adrenergic synaptic activity, plus
significant blockade of autonomic
nervous system histamine receptors
Indictions:
Psychiatric:
1. Major depression NOT
responsive to other drugs
2. Obsessive compulsive
disorder
Non-psychiatric:
1. Chronic pain disorders
2. Incontinence
Notes:
In an NE synapse:
1. TCA inhibits NE reuptake;
increased NE in synaptic
cleft. Post and presynaptic
NE receptors activated
2. Presynaptic receptor
activated, NE release
decreased toward normal
3. Slow response:
Pharmacokinetics:
Adverse Effects:
Long-half-lives
CYP substrates
Active metabolites
Anticholinergic sedation, hypertension,
seizure risk, weight gain, sexual effects
(cardiotoxicity + antimuscarinic effects
can kill)
Contraindications:
Drug interactions:
**histamine receptor blockade results
in sedation
**muscarninc acetylcholine receptor
actions result in antimuscarinic effects
**norepinephrine receptors-mostly 1
result in hypotension and sesual
problems
4.
5.
**nortriptyline is derived from
amitriptyline
** desipramine is derived from
imipramine
Atypical
Antidepressants;
(2nd and 3rd generation)
tetracyclic/unicyclic
Mechanism of Action:
Increased NE and DA activity
(buproprion)
NET >SERT (amoxapine, maprotiline)
Increased release of NE and 5-HT
(mirtazapine,k trazodone)
EFFECTS:
Postsynaptic beta
receptors down regulat (2
are inhibitory and get dwn.
Regulated)
Slow response: presynaptic
2 receptors downregulate; NE release
increases
Other slow responses occur)
Some reported include
changes in GABAB ,
glutamate, muscarinic
receptors,; activation os
some TF, etc.
Bupropion (Wellbutrin®), Trazodone (can cause priapism due to 1 antoganism), atomoxetine, amoxapine,
Maprotiline, Mirtazapine
Indications:
Psychiatric:
1. Major depression
Notes:
Pharmacokinetics:
Extensive metabolism in the liver
Non-psychiatric:
1. Smoking cessation
2. Sedation(mirtazapine)
Adverse Effects:
Lowers seizure threshold significantly
(4+), agitation, and nausea and
vomiting
Contraindications:
Drug Interactions:
1. CYP2D6 inhibitor
Presynaptic release of catecholamines
but no effect on 5-HT
Monoamine oxidase
inhibitors (MAOIs)
Phenelzine (Nardil ®), Tanylcypromine (Parnate ®), selegiline (Ensam ®)
Mechanism of Action:
Blockade of MAO-A and MAO-B
(phenelzine nonselective)
MAO-B irreversible selective MAO-B
inhibition (low dose selegiline)
EFFECTS:
Transdermal osorption of selegiline
achieves levels that ingibit MAO-A
Indications:
Major depression that is
UNRESPONSIVE to other drugs
(TCAs)
Selegiline can be used for PD
Notes:
Slow onset of beneficial effects
Withdrawl reaction when stop using
includes anxiety sweating, and
headaches
Pharmokinetics:
Very slow elimination  essentially
irreversible until new enzyme made
Adverse effects:
Hypotension (postural), insomnia,
headache drowsiness, weight gain,
sexual dysfunction, agitation
Overdose: agitation, seizures, coma
shock, hyperthermia
Contraindications:
Drug Interactions:
1. Hypertensive crisis with
tyramine, other indirect
sympathomimetics
2. Serotonin syndrome with
serotonergic agents,
3.
4.
5.
6.
Antimanics
Lithium Carbonate
(Eskalith ®)
Li+
Mechanism of Action:
Uncertain
Thought to suppress inositol signaling
and inhibits glycogens synthase kinase
-3 (GSK-3), multifunctional protein
kinase
Affects NE and 5-HT neurotransmission
Indications:
1. Bipolar disorder –prophylactic
use can prevent mood swings
between mania and depression
EFFECTS:
Notes:
Mood stabilizing durg, sued for both
acute and mania na dformaintence
to prevent relapse
Narrow therapeutic window
Takes about 2-3 weeks to get
maximum onset of action
No significant antagonistic actions on
autonomic nervous system receptors
or specific CNS receptors
No sedative effects
**Valaproic acid is at least as effective as
lithium with fewer side effects and is
increasingly used as 1st line drug
**carbamazepine and lamotrigine may
also be used
**antipsychotics are good for the manic
phase
Other uses of inhibitors of amine reuptake include
1.
2.
3.
4.
5.
Bipolar disorder
Enuresis
Chronic pain (not just treating reactive depression; SSRI’s less effective
Panic disorder (may not e Rx, alprazolam is better)
SSRIs also used ofr OCD, PTSD, premenstrual dysphoric disorder, and bulimia
These are NOT drugs of abuse; they may increase the risk of souicidal behavior
Pharmacokinetics:
Oral absorption,
Renal elimination- handled like Na+,
renal excretion depends on Na+
intake, therefore a low salt diet can
lead to serious toxicity
Diuretics, diarrhea and dehydration
will increase Lithium levels
Dosing is highly individualized
Clearance is decreased during
pregnancy
Half-life is 20hours
Narrow therapeutic window (must
monitor blood levels)
meperidine
Potentiates many adverse
effects with TCAs
May cause hypertensive
crisis with levadopa
Can cause excitation,
delirium, convlultions,
hyeper pyrexi, rigidity,
severe respiratory
depression with
meperidine and
dextromethorphan
Hypertension with
busipron
Adverse Effects:
Tremor, edema, hypothyroidism
(goiter), renal dysfunction,
dysrrhythmias, GI (nausea, diarrhea,
anorexia), weakness, headache,
confusion, fatigue, memory
impairment
Fine hand tremor, polyurea and
thirst nephrogenic diabetes
insipidus, weight gain, increased
circulating PMN’s,
Toxic consentration ECG changes,
hypotension more intense
symptoms, in coordination, tinnitus,
generalized seizures and death
Contraindications: pregnancy 
category D , lethargy, neonatal goiter,
and hypotonia
Drug Interactions:
1. Clearance decreased by
thiazides and some NSAIDs
Tolerance is most notable to autonimc actions,; no clear tolerance to andepressant actions
Physical dependence is middle and withdarwl can occur