ANTIDEPRESSIVI

Classification of Major Affective Disorders

E pisoda lD epress ion

S easona lA ffec tiveD isorder

A typica lD epress ion

M a jor/E ndogenousD epress ion

M ania Bipola rdepress ion

M a jor A ffec tive D isorders

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 complaintsMay 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Core Symptoms: • Feeling of misery, apathy and pessimism.• Withdrawn.• Low self –esteem, feelings of guilt, inadequacy and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.

SindromiSindromidepressivdepressiv

ee

Fattori ambientali

•Fattori pre-nataliFattori pre-natali•PerditePerdite•PrivazioniPrivazioni•DoloreDolore•StressStress•Disastri naturaliDisastri naturali•GuerraGuerra•Sistemi di supporto Sistemi di supporto

socialesociale•AlimentazioneAlimentazione•EsercizioEsercizio•FarmaciFarmaci•MalattieMalattie

Fattori genetici

•Geni di suscettibilità maggiore

•Geni di suscettibilità minore

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).

• 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?.

V. Biogenic Theory of Depression

LE BASI ANATOMICHE LE BASI ANATOMICHE DELLA DEPRESSIONEDELLA DEPRESSIONE

• NEOCORTECCIA e IPPOCAMPO– Cognitività, memoria– Hopelessness, suicidio

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

• IPOTALAMO– Sonno, appetito

• 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 importanti per ottenere un effetto clinicamente rilevante

NA e 5-HT nella NA e 5-HT nella depressionedepressioneNA e 5-HT nella NA e 5-HT nella depressionedepressione

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.

and 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 serotoninergicaTrasmissione serotoninergica

5HT1A

5HT1A

Neurone 5HTNeurone 5HT

5HT5HT

ReuptakeReuptake

5-HT5-HT1A1A

5-HT5-HT1B 1B (solo nei (solo nei

roditori)roditori)

5-HT5-HT1D1D

5-HT5-HT2A2A

5-HT5-HT2C2C

5-HT5-HT33

5-HT5-HT44

5-HT5-HT66

RecettoriRecettoripostsinaptipostsinapti

cici

5HT1D/1A5HT1D/1A

SinapsiSinapsi5HT1D5HT1D

5HT1A5HT1AAutorecettoAutorecettoriri

TCATCA

SSRISSRI

Nature Medicine 7: 541-547 (2001)

Neuroplasticity and cellular resilience in mood disorders

La somministrazione prolungata di farmaci antidepressivi altera la funzionalità e la plasticità

neuronale

Aumento livelli di BDNF

R R

P

Chinasi calcio dipendenti

Normalizzazione funzione

e plasticità neuronale

Rimodellamento sinaptico, neurogenesi,

sopravvivenza neuronale

NA / 5HT

Trattamento con ADsTrattamento con ADs

P

G AC

ATP cAMP

R CCR

CREB

PKA

NA / 5HT

Inibisce il reuptake e il metabolismo di NA e 5HT

P

CREB

CREB

Antidepressants

• TCAs

MAOIs

SS

RIs

TCAs

TCAs

TCAs

TC

As

SSRIs

SSRIs

SS

RIs

SSRIs

MAOIs

MAOIsMAOIs

MAOIs

MAOIs

MAOIs

Venflaxine

Ven

flaxine

Ven

flaxine

MAOIs

MAOIs

maprotiline

Amoxepine

doxepin

isocarboxazide

Nortriptyline

SRI

NRI

SNRISRI

NRI

M1

H1

TCA

1950-601950-601950-601950-60 1970-801970-801970-801970-80 >1990>1990>1990>1990

Evoluzione degli inibitori della Evoluzione degli inibitori della ricaptazione nel trattamento della ricaptazione nel trattamento della

depressionedepressione

Evoluzione degli inibitori della Evoluzione degli inibitori della ricaptazione nel trattamento della ricaptazione nel trattamento della

depressionedepressione

SRI

SSRI

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. 2–AR antagonists.(mirtazapine)

Effetto acuto degli Effetto acuto degli antidepressiviantidepressivi

G proteinaG proteina

EffettoreEffettore

RecettorRecettoree

Catabolismo NTCatabolismo NT

RecettoriRecettoripresinapticipresinaptici

TCA, SSRIs,TCA, SSRIs,SNRIs, NRIs SNRIs, NRIs

MAOI, RIMA MAOI, RIMA

22 antagonisti antagonisti

Aumento dellaAumento dellaconcentrazione sinapticaconcentrazione sinapticadei neurotrasmettitoridei neurotrasmettitori

ReuptakeReuptake

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) = >

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 Antidepressivi triciclicitricicliciAntidepressivi Antidepressivi triciclicitriciclici

VertigineVertigineIpotensione Ipotensione ortostaticaortostaticaProblemi Problemi eiaculatorieiaculatori

Aumento Aumento ponderaleponderaleSonnolenzaSonnolenzaVertiginiVertiginiSedazioneSedazione

Secchezza delle fauci, Secchezza delle fauci, stipsistipsiritenzione urinaria ritenzione urinaria visione offuscata, visione offuscata, tachicardia, disturbitachicardia, disturbicognitivi, deliricognitivi, deliri

Stabilizzazione Stabilizzazione della membranadella membranaDisturbi del ritmo Disturbi del ritmo cardiacocardiaco

Effetti complessi:Effetti complessi:tremore, riduzione soglia tremore, riduzione soglia convulsiva, (mioclono, convulsiva, (mioclono, epilessia) viraggio maniacaleepilessia) viraggio maniacale

EFFETTO EFFETTO ANTIDEPRESSIVANTIDEPRESSIVOO

TCA

NRINRISRISRI

H1H1

MM11

--11

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 => 1-AR and possibly 2-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 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 serotoninergicaTrasmissione serotoninergica

5HT1A

5HT1A

Neurone 5HTNeurone 5HT

5HT5HT

ReuptakeReuptake

5-HT5-HT1A1A

5-HT5-HT1B 1B (solo nei (solo nei

roditori)roditori)

5-HT5-HT1D1D

5-HT5-HT2A2A

5-HT5-HT2C2C

5-HT5-HT33

5-HT5-HT44

5-HT5-HT66

RecettoriRecettoripostsinaptipostsinapti

cici

5HT1D/1A5HT1D/1A

SinapsiSinapsi5HT1D5HT1D

5HT1A5HT1AAutorecettoAutorecettoriri

TCATCA

SSRISSRI

Inibitori selettivi del Inibitori selettivi del reuptake della reuptake della serotoninaserotonina

Inibitori selettivi del Inibitori selettivi del reuptake della reuptake della serotoninaserotonina

• Ampio spettro di attività terapeuticaattività terapeutica (disturbi d’ansia, disturbi di personalità, disturbi psicotici, disturbi dell’alimentazione).

• Efficacia paragonabileEfficacia paragonabile ai TCA nel trattamento della depressione maggiore e nella prevenzione della ricorrenza della depressione.

• Sicurezza.Sicurezza. Minore rischio di tossicità in overdose.

• Tollerabilità.Tollerabilità. Minore incidenza di abbandono a causa degli effetti collaterali.

SRISSRI

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.

5-HT1A5-HT1A Effetto terapeuticoEffetto terapeuticodepressionedepressione corteccia prefrontalecorteccia prefrontaledisturbo di panicodisturbo di panico corteccia limbicacorteccia limbicaOCDOCD gangli della basegangli della basebulimiabulimia ipotalamoipotalamo

Possibili effetti clinici Possibili effetti clinici dell’interazione con i recettori dell’interazione con i recettori

serotoninergiciserotoninergici

Effetti collateraliEffetti collaterali

5-HT25-HT2 Agitazione, ansia, insonnia, Agitazione, ansia, insonnia, disturbi disturbi della sfera sessuale, della sfera sessuale, perditaperdita dell’appetito, tremori dell’appetito, tremori5-HT35-HT3 Nausea, disturbi Nausea, disturbi gastrointestinali, gastrointestinali, cefalea cefalea

Ruolo dei recettori 5HT1ARuolo dei recettori 5HT1Anella trasmissione serotoninergicanella trasmissione serotoninergica

Rispostecellulari

5HT

-25H

T4

Nuclei del raphe Aree di proiezione

5HT5HT

5HT1B/D

5HT

1A

5HT1A

5HT1A

5HT

MAO

CaMKII

Ca2+

*

PKC

PKAcAMP

IP3

+ DAG

Ca2+

PLC

AC

AC

G

G

G

–

+

5HT

Fosfoproteine

SSRISSRI

-

Funzioni cellulari

5HT

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. Heterocyclics2nd 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 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• Maprotiline• Trazodone• Bupropion

Third Generation heterocyclics• Mirtazapine• Venlafaxine• Nefazodone

Similar to TCAs

5-HT antagonists

2-AR antagonist

SSRI-like

NE output

Noradrenergic Control of Serotonergic Release

NE5-HT

NE

2-AR

1-AR

1 2 3

Mianserin

5-HT1

5-HT2

5-HT3

Receptors

SSRIresponders

5-HT 5-HT depletiodepletio

nn

NE NE depletiodepletio

nn

NRIResponders

5-HT 5-HT depletiodepletio

nn

NE NE depletiodepletio

nn

Symptomsreturn

Nosymptoms

return

Nosymptoms

return

Symptomsreturn

5-HT 5-HT depletiondepletion

NE NE depletiodepletio

nn

Nosymptoms

appear

Nosymptoms

appear

Healthy subjects or untreated depressives

Neurotransmitter Depletion Studies:

A Schematic View

Delgado PL, et al. Antidepressant Therapy at the Dawn of the Third Millennium. London: Martin Dunitz Ltd, 1997:141-163.

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

Come superare i limiti dei Come superare i limiti dei SSRISSRICome superare i limiti dei Come superare i limiti dei SSRISSRI

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

Augmentation Therapies Have Augmentation Therapies Have Shown Success in Depression Shown Success in Depression

TreatmentTreatmentNoradrenergic TCAdesipramine (DMI)

SSRI fluoxetine (FLX) +

0 1 2 3 4

HA

MD

Sco

re

0

10

5

25

20

15

30

Weeks

*

* *

*

FLX + DMI

DMI

Weeks

% C

han

ge

in H

AM

D S

core

0

- 40

- 60

- 80

- 20

1 2 3 4

*

**

*

FLX + DMI

DMI

*p<.050 1 2 3 40 1 2 3 40 1 2 3 4

HA

MD

Sco

re

0

10

5

25

20

15

30

Weeks

*

* *

*

FLX + DMI

DMI

Weeks

% C

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ge

in H

AM

D S

core

0

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- 60

- 80

- 20

% C

han

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AM

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core

0

- 40

- 60

- 80

- 20

1 2 3 4

*

**

*

FLX + DMI

DMI

*p<.05 Study in patients with MDD

Support for 5-HT and NE Dual Support for 5-HT and NE Dual Reuptake Inhibitors as More Reuptake Inhibitors as More

Effective AntidepressantsEffective 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 at higher doses, may be more effective than SSRIs.3

1. Nelson et al. Arch Gen Psychiatry. 1992;48:303-307.2. Danish University Antidepressant Group. J Affect Disord.1990;18:289-299; Psychopharmacol. 1986;90:131-138. 3. Thase et al. Br J Psychiatry. 2001;178:234-241.

Level of response MADRS

FLX+DMI FLX DMI

Remission7

(53.8%)*1 (7.1%) 0

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%)

Combination of NE and 5HT uptake inhibitors for the treatment of

depression

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 Inhibitors of 5-HT and NE ReuptakeReuptake

Inhibitors of 5-HT and NE Inhibitors of 5-HT and NE ReuptakeReuptake

VenlafaxineVenlafaxine MilnacipranMilnacipran

SNRISNRI

NRINRI

SRISRI

DuloxetineDuloxetine

Theoretical Representation

SNRI

NE Reuptake Transporter (Blocked)

5-HT

NE

5-HT Reuptake Transporter(Blocked)

Duloxetina:Duloxetina:un SNRI con azione sinaptica un SNRI con azione sinaptica

bilanciatabilanciata

Duloxetina:Duloxetina:un SNRI con azione sinaptica un SNRI con azione sinaptica

bilanciatabilanciata

0

50

100

150

200

250

300

Vehicle 6.25 12.5 25 50 100

DULOXETINE

*

**

Dura

tion

of im

mob

ility

(sec

/5 m

in)

Effect of duloxetine in Effect of duloxetine in the forced swim test in the forced swim test in

micemice

Effect of duloxetine in Effect of duloxetine in the forced swim test in the forced swim test in

micemice

Adapted from Katoh et al., JPET 272:10671075, 1995.

Duloxetine: Greater Affinity and Balance in Reuptake Inhibition of 5-HT and NE in VitroInhibition of binding to human monoamine uptake transporters (Ki*, nM)

Compound NE 5-HT NE/5-HT (1=balance)

Duloxetine 7.5 0.8 9

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 7.5 0.8 9

Duloxetine Has Negligible Affinity for Other Monoamine Receptors

5-HT1A >5000

5-HT1B 3959 ± 810

5-HT1D >3000

5-HT1E 3733 ± 618

5-HT1F 4447 ± 30

5-HT2A 504 ± 87

5-HT2B 2100 ± 206

5-HT2C 916 ± 190

5-HT4 >1000*

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.

5-HT uptake site 0.53±01

NE uptake site 2.1±1.1

Muscarinic cholinergic 3000

Histamine H1 2300

1-adrenergic 8300

2-adrenergic 8600

Dopamine D2 14,000

Receptor DuloxetineKi, (nM)

Receptor DuloxetineKi, (nM)

To analysis

Pump 2 L/min

Microdialysisprobe

Probe stereotaxically implanted in brain region 2-mm probe end contains microdialysis loop Artificial CSF pumped through probe Equilibrium between ACSF and extracellular fluid NTs in dialysate analyzed by sensitive technique Indicates extracellular levels of NT (not synaptic)

2-mm microdialysis loop

Microdialysis Method for DeterminingExtracellular Levels of Neurotransmitters

CaudatoPutamen

NucleoAccumbens

Bulboolfattorio

Cortecciafrontale

Ippocampo Cortecciaoccipitale

A9

A10

LCRapheRaphe

Midollo spinale

Cervelletto

SONDA PER MICRODIALISISONDA PER MICRODIALISI

Duloxetine Increases Dose-Dependently Extracellular Monoamines in Rat Frontal Cortex

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

Serotonin

Time (h)-1 0 1 2 3 4

5-H

T (

% c

ontr

ol)

0

50

100

150

200

250

Duloxetine

300

400

Duloxetine 12.5 mg/kg PO

Vehicle Duloxetine 3.125 mg/kg PODuloxetine 6.25 mg/kg PO

Noradrenaline

Time (h)-1 0 1 2 3 4

NA

(%

con

trol

)

0

50

100

150

200

250

Duloxetine

300

400

Inibizione del reupake di noradrenalina e serotonina

Desensitizzazione degli autorecettori serotoninergici 5HT1a

Desensitizzazione/modulazione degli autorecettori noradrenergici 2

EFFETTI DEL TRATTAMENTO EFFETTI DEL TRATTAMENTO CRONICO CON DULOXETINACRONICO CON DULOXETINAEFFETTI DEL TRATTAMENTO EFFETTI DEL TRATTAMENTO CRONICO CON DULOXETINACRONICO CON DULOXETINA

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.