ANTIDEPRESSIVI

Classification of Major Affective Disorders

M a jo r A ffe c tiv e
D is o rd e rs

E p is o d a l M a jo r/ M a n ia B ip o la r
D e p re s s io n Endogenous d e p re s s io n
D e p re s s io n

Seasonal
A ffe c tiv e
D is o rd e r

A ty p ic a l
D e p re s s io n
Episodal (reactive) Depression

♦Adverse life events.

♦Physical illness.
♦Hormonal steroids.
♦Drugs.
♦Other psychiatric disorders.
Reactive (episodal) Depression

♦More than 60% of all depressions.

♦Core depressive syndrome: feelings
of misery, apathy, inadequacy,
pessimism, anxiety, tension, guilt.
♦Bodily complaints
♦May respond spontaneously or to a
variety of administrations.
 Major Endogenous Depression

• Recurrent, Cyclic, Seasonal.

• Degree of depression is not adequate
for precipitating event.
• Automaton (unresponsive).
 Major Endogenous Depression
Core Symptoms:
• Feeling of misery, apathy and pessimism.
• Withdrawn.
• Low self –esteem, feelings of guilt, inadequacy and
ugliness.
• Loss of interest in pleasurable activities.
• Indecisiveness, loss of motivation.
• Retardation of thought and action. Sleep
disturbance and significant weight change (without
dieting or changes in appetite).
• Psychomotor agitation or retardation.
 Major Endogenous Depression
Core Symptoms (con’t):
• In severe cases, it is accompanied by
hallucinations and delusions.
• Recurrent suicidal ideation, a suicide attempt or a
specific suicide plan.
 III. Biological Correlates of
Depression
1. Hypersecretion of cortisol.
2. Escape from dexamethasone suppression.
3. Blunted TSH response to TRH.
4. Blunted GH response to hypoglycemia.
5. Altered 24hr rhythm of prolactin secretion.
6. Decreased 5-HT metabolites in plasma.
7. Decreased REM latency.
Fattori genetici Fattori
ambientali
•Fattori pre-natali
•Geni di •Perdite
suscettibilità •Privazioni
maggiore •Dolore
•Stress
•Disastri naturali
•Guerra
•Sistemi di supporto
sociale
•Geni di
•Alimentazione
suscettibilità •Esercizio
minore •Farmaci
•Malattie

Sindromi
depressiv
 IV. Biological Basis for Depression

1. Has a genetic component.

2. Depression can be drug-induced.
3. Depression can be drug-repressed.
4. Depression can be treated with drugs.
5. Depression can be treated with
Electroconvulsive Therapy (ECT).
V. Biogenic Theory of Depression

• The precise cause of affective disorders

remains elusive.
• Evidence implicates alterations in the firing
patterns of a subset of biogenic amines in
the CNS, Norepinephrine (NE) and
Serotonin (5-HT).

↓ Activity of NE and 5 -HT systems?.

LE BASI ANATOMICHE
DELLA DEPRESSIONE
• NEOCORTECCIA e
IPPOCAMPO
– Cognitività, memoria
– Hopelessness,
suicidio

• STRIATO,
AMIGDALA,
ACCUMBENS
– Anedonia, ansia
– Ridotta motivazione

• IPOTALAMO
 NA e 5-HT nella
depressione
• Le ipotesi classiche sulla patogenesi dei
disturbi dell’umore riconoscono una
alterazione funzionale dei sistemi 5-HT e
NA nel cervello

• Il trattamento farmacologico dei disturbi

dell’umore è basato sul potenziamento
della trasmissione serotoninergica e
noradrenergica

• Le strategie di deplezione aminoacidica

indicano che entrambe le amine sono
 VI. NE System
Almost all NE pathways in the brain originate from the cell
bodies of neuronal cells in the locus coereleus in the
midbrain, which send their axons diffusely to the cortex,
cerebellum and limbic areas (hippocampus, amygdala,
hypothalamus, thalamus).
• Mood: -- higher functions performed by the
cortex.
• Cognitive function: -- function of cortex.
• Drive and motivation: -- function of brainstem
• Memory and emotion: -- function of the
hippocampus and amygdala.
• Endocrine response: -- function of hypothalamus.

α and β receptors.
Fig. 3.8. – La figura illustra le
principali vie noradrenergiche.
 VII. Serotonin System
As with the NE system, serotonin neurons located
in the pons and midbrain (in groups known as
raphe nuclei) send their projections diffusely to the
cortex, hippocampus, amygdala, hypothalamus,
thalamus, etc. --same areas implicated in
depression. This system is also involve in:
• Anxiety.
• Sleep.
• Sexual behavior.
• Rhythms (Suprachiasmatic nucleus).
• Temperature regulation.
• CSF production.
Fig. 3.7. – La figura illustra le
principali vie serotoninergiche.
Trasmissione serotoninergica

Recettori
postsinapti
TCA
SSRI
ci
5-HT1A
5-HT1B (solo nei
Reuptake roditori)
A
T1
5H

Neurone 5HT 5-HT1D

5HT
5-HT2A
5HT1
A

5HT1D/1A 5-HT2C
5-HT3
5HT1A
Autorecetto 5-HT4
ri 5HT1D Sinapsi
5-HT6
Neuroplasticity and cellular resilience in mood disorders

Nature Medicine 7: 541-547 (2001)

 La somministrazione prolungata di farmaci
antidepressivi altera la funzionalità e la plasticità
neuronale
Trattamento con ADs

Inibisce il
reuptake e il
metabolismo
NA / 5HT di NA e 5HT NA / 5HT

R R
G AC
Chinasi calcio dipendenti
ATP cAMP

Rimodellamento
R C R C PKA sinaptico, neurogenesi,
sopravvivenza
P CREB neuronale

Aumento
CREB livelli di
P Normalizzazione
BDNF
funzione
P CREB
e plasticità neuronale
 Antidepressants
SSRIs d o
• TCAss T CA MAOIs xep
i
I M s n
O AOIs

TCAs
A TCAse
M SSR
id MAOIs
Is
x a z s
o I
Venflaxine

r b O

V
oc a A TCAs

e
is M

n
maprotiline MAOIs

f la
SSR

MAOIs MAOIsA SSRIs

x i
mo

n
SSRIs

xe

e
Is

Venflaxine pMAOIs
i ne
t yli n e
Nortrip
 Evoluzione degli inibitori della
ricaptazione nel trattamento della
depressione

H1

SRI
TCA SRI SRI
SSRI SNRI
M1
NRI NRI

1950-60 1970-80 >1990

 Antidepressants
1. Tricyclic anti-depressants (TCAs).
Imipramine, desipramine, nortriptyline,
protryptyline, amytriptiline, doxepin.
2. Monoamine oxidase inhibitors (MAOIs).
Isocarboxacid, phenelzine, tranylcypromine.
3. Selective serotonin reuptake inhibitors (SSRIs)
Fluoxetine, sertraline, paroxetine, trazodone.
4. Atypical anti-depressants (Others)
New TCAs, amoxapine, bupropion,
alprazolam, maprotiline, nomifensine, mianserin.
 Mechanism of Action
1. Inhibition of NE and 5-HT reuptake.
(TCAs, SSRIs, Newer TCAs).
2. Inhibition of MAO enzymes.
(MAOIs).
3. 5-HT2A and 5-HT2C antagonists.
(Nefazodone, trazodone, mirtazapine)
4. Alteration of NE output .
(Bupropion)
5. Stimulation of 5-HT1A receptors.
(
6. α2–AR antagonists.
(mirtazapine)
 Effetto acuto degli
antidepressivi
MAOI, RIMA
TCA, SSRIs,
SNRIs, NRIs
Catabolismo NT

α 2 antagonisti
Reuptake Recettori
presinaptici

Aumento della
concentrazione sinaptica
dei neurotrasmettitori
Recettor
e
G proteina

Effettore
Tricyclic Antidepressants (TCAs)

• amytriptiline
• imipramine
• desipramine
• nortriptyline
• protryptyline
• doxepin.
Tricyclic Antidepressants (TCAs)
• Characteristic three ring nucleus.
• Most are incompletely absorbed, all are
metabolized in liver => High first pass effect:
1) Transformation of the tricyclic nucleus
=> hydroxylation => conjugation =>
glucoronides.
2) Alteration of aliphatic side chain =>
demethylation of the nitrogen => active
metabolites.
• High protein binding, high lipid solubility.
Tricyclic Antidepressants (TCAs)

/ CH3 / H
N N
\ CH3 \ CH3

tertiary amine secondary amine

3o => 2o
Tricyclic Antidepressants (TCAs)

3°Amines: Imipramine, Amitriptyline

⇓⇓
2°Amines: Desipramine, Nortriptyline

Selectivity 2o Amines -- NE > 5-HT

3o Amines -- 5-HT > NE
 Tricyclic Antidepressants (TCAs)
Mechanism of Action:
- Inhibition of NT reuptake.
- Immediate action = >↑ NE and 5-HT in synapse.
- After chronic treatment (2 - 4 weeks) = >
↓ β NE-R and ↓5-HT2R.
↓ NE release and turnover.
↓ NE-stimulated cAMP in brain.
↑ Sensitization of 5-HT receptors.
* Adaptive Responses *
- Takes up to 4 weeks for all TCA antidepressants to
have an effect.
 Antidepressivi
triciclici
Secchezza delle fauci,
Vertigine stipsi
Ipotensione ritenzione urinaria
ortostatica visione offuscata,
Problemi tachicardia, disturbi
eiaculatori cognitivi, deliri
α -1
Aumento
M1
ponderale
Sonnolenza H1
Vertigini Stabilizzazione
Sedazione TCA della membrana
Disturbi del ritmo
cardiaco
NRI
SRI
Effetti complessi:
EFFETTO tremore, riduzione soglia
ANTIDEPRESSIV convulsiva, (mioclono,
epilessia) viraggio maniacale
O
 Tricyclic Antidepressants (TCAs)
Side Effects:
• Atropine-like side effects: dry mouth,
paradoxical excessive perspiration,
constipation, blurred vision, mydriasis,
metallic taste, urine retention => muscarinic
blockade.
• Orthostatic hypotension => α1-AR and
possibly α2-AR blockade.
• Drowsiness, sedation and weight gain =>
Histamine-Receptor blockade.
 Tricyclic Antidepressants (TCAs)
Side Effects (con’t):
• Most serious side effect is cardiac toxicity
=> Palpitations, tachycardia, dizziness =>
excessive CNS stimulation => ↑NE in Heart.

• Sexual dysfunction, including loss of libido,

impaired erection and ejaculation and
anorgasmia
. …↓ COMPLIANCE
Tricyclic Antidepressants (TCAs)
Other effects (con’t):
• Metabolism is affected by: Smoking, Barbs,
estrogens, neuroleptics and anticonvulsants.
• Can lower seizure threshold.
• All TCAs can cause: vagal block, postural
hypotension, arrythmias, sinus tachycardia.
• All potentiate CNS depressants (BZDs, Barbs,
ETOH) => coma and death.
• TCA administration in bipolar disorder may
precipitate acute mania or rapid cycling.
• Fatal in overdose (a 2 wk supply can kill anyone).
X. MAO INHIBITORS

• Isocarboxacid
• Phenelzine
• Tranylcypromine.
 X. MAO INHIBITORS
• Developed for the treatment of tuberculosis
(iproniazid derivatives) - 1951.
• These drugs are not widely used today, although
a small number of patients appear to do better in
MAOIs than TCAs or the newer drugs.
• Are readily absorbed from GI tract and widely
distributed throughout the body.
• May have active metabolites, inactivated by
acetylation.
• Effects persist even after these drugs are no
longer detectable in plasma (1-3 weeks).
 X. MAO INHIBITORS
Mechanism of action:
Inhibit MAO enzymes (non-selective):
1) Irreversible MAO inhibitors
Phenelzine and isocarboxazid => hydrazides.
2) Reversible MAO Inhibitors.
Tranylcypromine => non-hydrazide,
prolonged blockade, but reversible within 4hr.

Decrease metabolism of most biogenic amines

(NE, 5HT, DA, tyramine, octopamine).
 X. MAO INHIBITORS
Mechanism of action (con’t):
Acute administration causes:
↑ NE and 5-HT in synaptic terminals in brain but
↓NE in PNS. ↓NE synthesis.
– Acute euphoria
– Suppressed REM sleep.
Chronic administration causes:
↓ NE-stimulated cAMP in brain.
– Down regulation of β receptors.
– Down regulation of 5-HT2 receptors.
 X. MAO INHIBITORS

MAO-A  NE, 5-HT, Tyramine

MAO-B  DA

Selective MAOIs:
Inhibitors MAO-A
Moclobemide, Clorgyline
Inhibitors of MAO-B.
Deprenyl, Selegiline
 X. MAO INHIBITORS

Wine-and-Cheese Reaction
- Fatal interaction with tyramine-
containing foods (fermented foods in
particular, such as wine and cheese).
- ↓ MAO-A => ↑ Tyramine in the body =>
↑NE in circulation => induces
hypertensive crisis => can lead to
intracranial bleeding and other organ
damage.
 X. MAO INHIBITORS
Negative drug interactions with:
Any drug metabolized by MAOs* including
SSRIs, TCAs and meperidine, alcohol, CNS
depressants, sympathomimetics,
phenylephrine (O/C nasal decongestants),
ampetamines, and other indirect-acting
adrenergic drugs.
* Interaction with drugs metabolized by MAOs (e.g.
Meperidine (opioid analgesics) => hyperpyrexia or
“hyperexcitation syndrome” involving high fever,
delirium and hypertension).
 X. MAO INHIBITORS
Other side effects:
• Hypotension
• Hepatotoxicity.
• Sedation.
Trasmissione serotoninergica

Recettori
postsinapti
TCA
SSRI
ci
5-HT1A
5-HT1B (solo nei
Reuptake roditori)
A
T1
5H

Neurone 5HT 5-HT1D

5HT
5-HT2A
5HT1
A

5HT1D/1A 5-HT2C
5-HT3
5HT1A
Autorecetto 5-HT4
ri 5HT1D Sinapsi
5-HT6
Inibitori selettivi del
reuptake della SRI
SSRI
serotonina

• Ampio spettro di attività terapeutica (disturbi

d’ansia, disturbi di personalità, disturbi psicotici,
disturbi dell’alimentazione).
• Efficacia paragonabile ai TCA nel trattamento
della depressione maggiore e nella prevenzione
della ricorrenza della depressione.
• Sicurezza. Minore rischio di tossicità in overdose.
• Tollerabilità. Minore incidenza di abbandono a
causa degli effetti collaterali.
 XI. SSRIs

• Fluoxetine
• Sertraline
• Paroxetine
• Fluvoxamine
(Labeled for obsessive-compulsive disorder)
 XI. SSRIs
• Most widely prescribed drugs for
depression.
• They have few side effects and seem to be
rather safe. More rational prescribing and
better patient compliance.
• Adverse effects include: nausea, decreased
libido, decrease sexual function.
• Low threat for overdose. Suicide may be
considered in severe depression.
 XI. SSRIs
Mechanism of action:
• Specific serotonin uptake inhibitors increase
5-HT by inhibiting reuptake.

Current theory holds that:

• Enhanced stimulation or responsiveness of
postsynaptic 5-HT1A receptors is particularly
important in the action of antidepressants.
 Possibili effetti clinici
dell’interazione con i recettori
serotoninergici
5-HT1A Effetto terapeutico
depressione corteccia prefrontale
disturbo di panico corteccia limbica
OCD gangli della base
bulimia ipotalamo

Effetti collaterali

5-HT2 Agitazione, ansia, insonnia,

disturbi della sfera sessuale,
perdita
dell’appetito, tremori
5-HT3 Nausea, disturbi
gastrointestinali,
cefalea
 Ruolo dei recettori 5HT1A
nella trasmissione serotoninergica
Nuclei del raphe Aree di
proiezione

5HT-2
5HT1B/D PKC
A

G
T1

IP3
5H

MAO
PLC + DAG
Ca2+
Fosfoproteine
5HT 5HT Ca2+

5HT1A
5HT G
*
CaMKII AC –
5HT1 Funzioni
A cAMP PKA Risposte
cellulari
AC +
cellulari

5HT4
G
5HT 5HT
SSRI
-
 XI. SSRIs
Fluoxetine is the prototype.
• Approximately 70% of depressed patients will
respond to an SSRI therapy at the end of 6 weeks
(4 to 6 weeks before effects are evident to patient).
• T1/2 of 16 – 24 hrs. except for fluoxetine’s
metabolite norfluoxetine (T1/2 = 8 days).
• Fluoxetine and paroxetine inhibit liver enzymes,
particularly P450-2D6.
• Paroxetine and Sertraline have PK parameters
similar to TCAs.
 XI. SSRIs
Drug-drug interactions:
dangerous with other antidepressant drugs,
MAOIs in particular.

”Serotonin Syndrome”:
– hyperthermia, muscle rigidity, myoclonus, rapid
changes in mental status and vital signs.
Thus it is important to wait up to 6 weeks after
medication is stopped, before starting with another
drug.
 XII. Heterocyclics
2nd Generation heterocyclics
• amoxapine
• maprotiline
• trazodone
• bupropion
Third Generation heterocyclics
• mirtazapine
• venlafaxine
• nefazodone
 XII. Heterocyclics
• The second and third generation antidepressants
are by no means a homogeneous group.
• As with the TCA's , they all have variable
bioavailability.
• High protein binding.
• Some have active metabolites.
• Trazodone and Venlafaxine have the shortest
plasma half-lives, which mandates divided doses
during the day.
• Nefazodone and fluvoxamine cause inhibition of
CYP3A4.
 XII. Heterocyclics
Mechanism of Action:
1) NT reuptake inhibition.
maprotiline.
2) 5-HT receptor antagonism (for 5-HT2A
or 2C receptors).
nefazodone, mirtazapine, and
trazodone
3) Alteration of NE Output.
bupropion, amoxapine, and trazodone.
 XII. Heterocyclics
Amoxapine. Metabolite of Loxapine (an anti-
psychotic) -- retains some antipsychotic
activity and DA receptor antagonism =>
parkinson's-like symptoms. May be useful
if psychosis is present. NE output.

Maprotiline. A tetracyclic drug, resembles

desipramine with less sedative and
antimuscarinic side effects. Evokes
seizures at high doses. Blocks NT
reuptake.
 XII. Heterocyclics

Trazodone. Antagonist of 5-HT2A or 2C

receptors. Unpredictable efficacy. Highly
sedative (hypnotic), but minimal
antimuscarinic action.

Bupropion. Resembles amphetamine. Blocks

DA reuptake (not important in depression).
Causes CNS stimulation. Inhibits appetite.
Aggravates psychosis. NE output.
 XII. Heterocyclics
Third Generation

Mirtazapine. A derivative of mianserin. Antagonist of

5-HT2A or 5-HT2C receptors. Also antagonizes α 2-
adrenergic receptors, thus increasing NE and 5-HT
release. Very sedating.

Venlafaxine. Short plasma half-live, thus needs to

be given in divided doses. Potent inhibitor of 5-HT
uptake and weaker at NE reuptake (at low
concentrations it acts like an SSRI).

Nefazodone. Antagonist of 5-HT2A or 5-HT2C

receptors. Moderately sedating. Potent inhibitor of
CYP3A4, so cannot be given with cisapride
 XII. Atypical/Heterocyclic
2nd Generation heterocyclics
• Amoxapine Similar to TCAs
• Maprotiline ⇑NE output
α2-AR antagonist
• Trazodone
5-HT antagonists
• Bupropion SSRI-like
Third Generation heterocyclics
• Mirtazapine
• Venlafaxine
• Nefazodone
Noradrenergic Control of Serotonergic Release

Receptors
α 2-AR
NE
5-HT α 1-AR

5-HT1

5-HT2

5-HT3

NE 1 2 3
Mianserin
 Neurotransmitter Depletion
Studies:
A Schematic View
Healthy subjects
SSRI NRI or untreated
responders Responders depressives

5-HT NE 5-HT NE 5-HT NE

depletio depletio depletio depletio depletion depletio
n n n n n

No No No No
Symptoms Symptoms
symptoms symptoms symptoms
return symptoms return
return return appear appear

Delgado PL, et al. Antidepressant Therapy at the Dawn of the Third Millennium. London: Martin
Dunitz Ltd, 1997:141-163.
 Come superare i limiti dei
SSRI
■ Agendo sul singolo neurotrasmettitore (5HT):
➨ Evitando il feedback negativo sul rilascio di 5-HT
indotto dall’attivazione degli autorecettori 5-HT1A
➨ Ripristinando il rilascio di 5-HT nelle aree
cerebrali frontali indotto dai meccanismi locali
(e.g., utilizzando antagonisti auto- ed
eterorecettoriali)

■ Agendo su due neurotrasmettitori (5HT e NA)

➨ Incrementando l’attivazione dei recettori
postsinaptici nelle aree limbiche e corticali
tramite l’aumento della attivazione funzionale di
un secondo neurotrasmettitore
 Augmentation Therapies Have
Shown Success in Depression
SSRI
TreatmentNoradrenergic TCA
fluoxetine (FLX) + desipramine (DMI)
Weeks
1 2 3 4
30 0
FLX + DMI

25 DMI

% Change in HAMD Score

- 20
20
HAMD Score

15 - 40

* *
10
* *
- 60
*
5
FLX + DMI *
* DMI
0 - 80
0 1 2 3 4 *
Weeks *p<.05 Study inpatients withMDD

Nelson JC, et al. Arch Gen Psychiatry. 1991;48:303-307.

 Support for 5-HT and NE Dual
Reuptake Inhibitors as More
Effective Antidepressants
• Agents which selectively increase 5-HT or NE are
effective antidepressants.
• Combined fluoxetine and desipramine had a
greater antidepressant effect than desipramine
alone.1
• Clomipramine, a TCA with effects on both 5-HT
and NE, is more efficacious than paroxetine or
citalopram.2
• Venlafaxine, a compound with dual reuptake
inhibition
1. Nelson et al. Arch Genat higher
Psychiatry. doses, may be more effective
1992;48:303-307.
2. Danish University Antidepressant Group. J Affect Disord.1990;18:289-299; Psychopharmacol.
than SSRIs.3
1986;90:131-138.
Combination of NE and 5HT uptake
inhibitors for the treatment of
depression
Level of
FLX+DMI FLX DMI
response MADRS
7
Remission 1 (7.1%) 0
(53.8%)*

Response 1 (7.7%) 5 (35.7%) 2 (16.7%)

Partial response 0 1 (7.1%) 6 (50%)

Nonresponse 5 (35.7%) 7 (53.8%) 4 (33.3%)

Remission: >75%, Response 50-74%; Partial response: 25-49%; Nonrespnse:
<25%.
Nelson et al. Biological Psychiatry 55: 296-300, 2004
Inhibitors of 5-HT and NE
Reuptake
Duloxetine

SNRI SRI

NR
I

Venlafaxine Milnacipran
 Duloxetina:
un SNRI con azione sinaptica
bilanciata
5-HT Reuptake
Transporter
(Blocked)

5-HT

NE Reuptake
Transporter (Blocked)
SNRI

NE

Theoretical Representation
 Effect of duloxetine in
the forced swim test in
mice
Duration of immobility (sec/5 min)

300

250

200

150
*
100 *
50 *
0
Vehicle 6 1 2 5 10
.25 2.5 5 0 0
DULOXETINE
Adapted from Katoh et al., JPET 272:10671075, 1995.
 Duloxetine: Greater Affinity and Balance
in Reuptake Inhibition of 5-HT and NE in Vitro
Inhibition of binding to human monoamine uptake transporters (Ki*, nM)

Compound NE 5-HT NE/5-HT

(1=balance)

Duloxetine
Duloxetine 7.5
7.5 0.8
0.8 99
Venlafaxine 2480 82 30
Clomipramine 38 0.28 136
Fluoxetine 240 0.81 296
Paroxetine 40 0.13 308
Fluvoxamine 1300 2.2 591
Sertraline 420 0.29 1448
Citalopram 4070 1.2 3,392
*The lower the Ki, the greater the affinity for that receptor.
Wong DTet al. Prog Drug Res. In press.
 Duloxetine Has Negligible Affinity for Other
Monoamine Receptors
Receptor Duloxetine Receptor Duloxetine
Ki, (nM) Ki, (nM)

5-HT1A >5000 5-HT uptake site 0.53±01

5-HT1B 3959 ± 810
NE uptake site 2.1±1.1
5-HT1D >3000
5-HT1E 3733 ± 618 Muscarinic cholinergic 3000
5-HT1F 4447 ± 30
Histamine H1 2300
5-HT2A 504 ± 87
5-HT2B 2100 ± 206 α1-adrenergic 8300
5-HT2C 916 ± 190 α2-adrenergic 8600
5-HT4 >1000* Dopamine D2 14,000
5-HT6 419 ± 89
5-HT7 2261 ± 115
Wong DT. Exp Opin Invest Drugs. 1998;7:1-9. Tatsumi M et al. Eur J Pharmacol. 1997;340:249-258. (+)=+ enantiomer.
 Microdialysis Method for Determining
Extracellular Levels of Neurotransmitters
SONDA PER MICRODIALISI

Pump 2 µL/min
Caudato
Putamen Ippocampo Corteccia
occipitale
Corteccia
To analysis
frontale Cervelletto

A9
Bulbo Raphe LC
Raphe
olfattorio A10

Nucleo
Accumbens Midollo spinale
Microdialysis
probe
 Probe stereotaxically implanted in brain region
 2-mm probe end contains microdialysis loop
 Artificial CSF pumped through probe
2-mm microdialysis loop  Equilibrium between ACSF and extracellular fluid
 NTs in dialysate analyzed by sensitive technique
 Indicates extracellular levels of NT (not synaptic)
 Duloxetine Increases Dose-Dependently
Extracellular Monoamines in Rat Frontal Cortex
Vehicle
Duloxetine 3.125 mg/kg PO
Duloxetine 6.25 mg/kg PO
Duloxetine 12.5 mg/kg PO
400 Serotonin 400 Noradrenaline
300 300
5-HT (% control)

250 250

NA (% control)
200 200
150 150
100 100
50 50
Duloxetine Duloxetine
0 0
-1 0 1 2 3 4 -1 0 1 2 3 4
Time (h) Time (h)

Adapted from Kihara T and Ikeda M. J Pharmacol Exp Ther. 1995;272:177-183.

 EFFETTI DEL TRATTAMENTO
CRONICO CON DULOXETINA
■ Inibizione del reupake di noradrenalina e
serotonina
■ Desensitizzazione degli autorecettori
serotoninergici 5HT1a
■ Desensitizzazione/modulazione degli
autorecettori noradrenergici α2

AUMENTATA ATTIVITA’
SEROTONINERGICA E
NORADRENERGICA
 XIV. Alternative Therapies
No way of a priori knowing which therapy will be
best for a patient.

• Light Therapy
• Psychological Treatment
• ECT
• St. John’s Wort
• Magnetic stimulation of brain
• Electrical stimulation of vagus n.