Antidepresivi
4/13/2015
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Antidepresivi /upotreba
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4/13/2015
depresija
anksioznost
Premenstrualni sindrom
Bolni sindromi
Poremećaj sna
Poremećaj ishrane
Odvikavanje od pušenja
autizam
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Diferencijalna dijagnoza
depresije
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4/13/2015
Bolesti tiroideje i paratiroideje
anemija
hipoksija
maligniteti
lijekovi
demencija
Parkinsonova bolest
Obolenja jetre
Cushing’s sindrom/ tretman steroidima
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Lijekovi koji mogu
uzrokovati simptome
depresije
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Antihipertenzivi
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Kardiovaskularni lijekovi
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Corticosteroids, Progestins, (Estrogen)
Analgetici
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Digitalis, Diuretics, Lidocaine, Procaine
Steroidi
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Propanolol, Methyldopa, Reserpine, Clonidine,
Hydralazine, Guanithidine
Narcotics, Indomethacin
Benzodiazepini
antimicrobici, antipsihotici,
hemoterapeutici, alkohol, etc
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Lijekovi za depresiju
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4/13/2015
Generalno, imaju podjednako
djelovanje
Odgovor kod 50 –80% pacijenata
Velike individualne varijacije
Placebo efekt 25-40%
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Monoaminska hipotheza
depresije
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Deficit jednog ili više biogenih amina
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Antidepresivi dovode do povećanja
neurotransmitera u sinaptičkoj pukotini
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4/13/2015
Serotonin (5-HT)
Norepinefrin (NE)
Dopamine (DA)
Aktivacijom hemijskih glasnika (2nd
messenger, interleukina, TNF)
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Kratka istorija
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kasne 1950-te – MAOI i TCA
efikasni
 “prljavi lijekovi” – mnogo NRL
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kasne 1980-te - SSRI
kasne 1990-te
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4/13/2015
atipični antidepresivi
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Podijela antidepresiva
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Triciklični antidepresivi (TCA)
Inhibitori monoamino-oksidaze (MAOI)
Inhibitori ponovnog preuzimanja
serotonina(SSRI)
Inhibitori ponovnog preuzimanja
serotonina i noradrenalina (SNRI)
Antagonisti 5HT2 / inhibitori ponovnog
preuzimanja (SARI)
Noradrenalin i specifični serotonin
antidepresivi (NaSSA)
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Triciklični antidepresivi
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klomipramine (Anafranil) – sličan SSRI’s
nortriptilin (Pamelor) – primarno
adrenergički, najmanje ortost.hipotenz.
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imipramin (Tofranil)
amitriptilin (Elavil)
desipramin (Norpramin) – primarno
adrenergički
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doksepin (Sinequan)
protriptilin (Vivactil)
maprotilin (Ludiomil)/heteroc.
amoksapin (Ascendin) -- blago antipsihotičko
djelovanje, rizik od TD,
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4/13/2015
trimipramine (Surmontil)
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TCA
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Jeftini i “prljavi”
Često smrtni ishod kod predoziranja
Zahtjevaju strogo praćenje pacijenata
Mogu uzrokovati srčane smetnje
(aritmije)
Srčane NRL ograničavaju njihovu
upotrebu
Ekstenzivno se primjenjuju u primarnoj
praksi za:
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4/13/2015
Hronična bol, nesanica, profilaksa
migrene, hronični umor
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Triciklici – 5 lijekova u
jednom
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Povećava nivo 5HT - SRI
Povećava nivo NE - NRI
M1 – antiholinergik, antimuskarinik
 suha usta,opstipacija, poremećaj
vida,pospanost
Alfa 1 – andrenergički antagonist
 vrtoglavica,ortostatska hipotenz.,
pospanost
H 1 – antihistaminik  porast TT,
pospanost
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MAO inhibitori
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Inhibišu enzime (monoamino-oksidaze) koji razlažu
5-HT i NE  povećava se nivo 5HT i NE
Jeftini i djelotvorni
mogu dovesti, ako se uzimaju istovremeno sa
hranom koja sadrži tiramin ili nekim lijekovima do
teških interakcija
fenelzin (Nardil); tranilcipromin (Parnate)
Dobri za atipičnu depresiju
 hiperfagija, hipersomnija,
(pokušati prvo sa SSRI)
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MAOI – mjere opreza
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Interakcije
 OTC dekongestivi, stimulansi CNS,
antidepresivi, narkotici
Dijeta bez tiramina
 sir, zrelo meso, proizvodi od pivskog kvasa,
kiseli kupus, vino,
 Tiramin povećava oslobađanje NE
 Ako se ne pridržava dijete HT kriza
potreban “washout period” poslije tretmana sa
drugim antidepresivima a prije uvođenja MAOI
(npr. 6 ned. nakon fluoksetina)
  izbjegavanje serotoninskog sindroma
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Selektivni inhibitori
preuzimanja serotonina
(SSRI)
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U svijetu, široko propisivani
Lijekovi prvog izbora
Relativno sigurni i kod predoziranja
Niska incidenca NRL
Skupi
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SSRI
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sertralin (Zoloft)
fluoksetin (Prozac)
citalopram (Celexa)
paroksetin (Paxil)
fluvoksamin (Luvox)
Inhibišu CYP4501A2 – povećavaju konc. teofilina,
olanzapina,kofeina
 Doziranje 2x dnevno
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4/13/2015
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SSRI
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Prozak(fluoxetin) – 20-40mg/dan
 Inhibits P4502D6, long t ½, most activating,
appetite suppression
Paxil(paroxetin) – 20-40mg/day
 Inhibits P4502D6, most sedating, more likely
constipation
Zoloft (sertralin)– 50-100mg/day (200mg)
 Less P450 inhibition, well tolerated, diarrhea,
nausea
Celexa(citalopram) – 20-40mg/day
 Minimal to no P450 inhibition, well tolerated in
elderly and those with comorbid medical conditions25
SSRI – najčešće NR
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Seksualna disfunkcija (5HT2)
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Insomnija (5HT2)
nemir/anksioznost (5HT2)
glavobolje
GI neželjeni efekti (5HT3)
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4/13/2015
Veoma često(30-50%+)
Smanjenje apetita, mučnina, dijareja,
suha usta
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Serotoninski sindrom
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Poremećaj termoregulacije
Karakteriše se promjenama mentalnog
statusa (konfuzija/hipomanija), porast
temperature, groznica, agitacija,
hiperrefleksija, drhtanje i tremor
Javlja se rijetko,ali je često fatalan ishod
uzrok – ekscesivna serotonergička
stimulacija ?
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Serotoninski sindrom
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Serotoninski sindrom se javlja ako
se SSRI kombinuju sa
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MAO inhibitorima
 fenelzin,
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tranilcipromin
MAOI (selektivni)
 Selegilin
(MAO-B), moklobemid
(reverzibilni)
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4/13/2015
Triptofan (serotonin prekursor)
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Serotonergički lijekovi
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prekursori serotonina
S–adenyl–L–methionine
 L–tryptophan
 5–hydroxytryptophan
 dopamine
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Serotonergički lijekovi
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Inhibitori preuzimanja serotonina
citalopram, fluoxetine, fluvoxamine,
paroxetine, sertraline, venlafaxine
 clomipramine, imipramine
 nefazodone, trazodone
 chlorpheniramine
 cocaine, dextromethorphan,
pentazocine, pethidine, tramadol
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Serotonergički lijekovi
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Agonisti serotonina
fenfluramine, p–chloramphetamine
 bromocriptine, dihydroergotamine,
gepirone
 sumatriptan
 buspirone, ipsapirone
 eltoprazin, quipazine
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Serotonergički lijekovi
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Inhibitori monoamino oksidaze (MAOIs)
clorgyline, isocarboxazid, nialamide,
pargyline, phenelzine, tranylcypromine
 selegiline
 furazolidone
 procarbazine
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Serotonergički lijekovi
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Reverzibilni inhibitori MAO
brofaramine
 befloxatone, toloxatone
 moclobemide
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Tretman
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Suportivne mjere
Kontrola simptoma
 kontrola temperature
 Adekvatna ventilacija
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5–HT2A antagonisti
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idealni
 sigurni
 efikasni
 dostupni
5–HT2A antagonisti
Cyproheptadine
Chlorpromazine
Chlorprothixene
Haloperidol
Clozapine
Risperidone
Olanzapine
Sertindole
Methysergide
Ketanserin
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Affinity at 5-HT2 = 10-7 x 1/Kd
 Kapur, S et al. (1997). Cyproheptadine: a potent in vivo
serotonin antagonist. American Journal of Psychiatry, 154, 884
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Additional
Antidepressants
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SSRIs, TCAs, and MAOIs easily
classified
Remainder less easily classified
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“atypical antidepressants”
Mechanisms listed for your
understanding
Clinical points more important than
mechanisms
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Venlafaxine (Effexor)
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Increases 5HT & NE - A Serotonin and
NE Reuptake Inhibitor (SNRIs)
Low dose only 5HT reuptake inhibition
Med-High dose both 5HT & NE reuptake
blockade
Very high doses – 3 monoamines
blocked  5HT, NE, DA (minor)
Minimal P450 Inhibition
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Venlafaxine, cont’d
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Dose range 18.75-375mg/day
May work faster than others
SEs like SSRIs
Wierd withdrawal symptoms – reg
release has very short t ½
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Sustained release available – QD
dosing
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Nefazodone (Serzone)
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Increases 5HT & NE  NE & 5HT
reuptake inhibition (therapeutic
effect)
Also 5HT2 receptor blockade
(most powerful effect)
5HT2 blockade  sedation
Alpha 1 blockage  dizzy (NE
reuptake tends to counter this)
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Nefazodone, cont’d
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Less sexual SEs (at low doses)
Less activating (prob 2nd to < 5HT
reuptake activity vs SSRIs)
Good for agitated depression
Potent P4503A4 Inhibitor –
metabolizes alprazolam (xanax)  levels
can double; arrhythmias can occur if
combined with terfenadine, cisapride,
astemizole
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Rare cases of hepatic failure
have occurred—check baseline lft’s
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Nefazodone, cont’d
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Usual dose 300-600mg/day
Side effects
Somnolence  (5HT2 blockade)
 dry mouth  (NE effect)
 Nausea  (serotonergic effect)
 Constipation  (NE effect)
 visual phenomena
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Trazodone
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5HT2 blockade  sedation
Little SSRI action
Very sedating – often used for insomnia
(potent 5HT2 blocker)
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Potent blocker alpha 1 orthostasis
Antihistamine activity -- sedation
No NE reuptake inhibition
Unlikely significant drug-drug interactions
Priapism rare (1/10,000) side effect –
need to mention (mech may be r/t both alpha
– 1 and 5HT2 blockage)
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Blocking 5HT2
Receptors
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Sedation
Enhance slow wave sleep
Decrease anxiety
No sexual dysfunction
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Bupropion (Wellbutrin)
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Increases NE & DA  via NE and
DA reuptake inhibition
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Dose range 150-300mg/day (max
450)
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Can lower seizure threshold –
contraindicated in pts w sz d/o, edo
Less sexual dysfunction (NE effect)
Split doses bid – at least 8 hrs apart
Max 150mg RR/ 200mg SR per dose
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Bupropion (Wellbutrin)
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Exact mechanism unclear
Response may be more r/t
metabolite than parent drug
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Possible higher bld levels if used
w/SSRI w/P450 enzyme inhibition
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Mirtazapine (Remeron)
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Increases NE & 5HT
Blocks some 5HT receptors
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thus called a NE and specific 5HT
antidepressant (NaSSA)
Four principal actions
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Alpha 2 blockade  increases NE 
leads to subsequent increase 5HT
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increase NE takes “brakes” off 5HT
transmission
Less sexual s/e’s  (5HT2 blockade/NE)
Less GI s/e’s  ( 5HT3 blockade)
Weight gain/sedation  antihistamine effect
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Mirtazapine (Remeron)
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Unique mechanism action
Only dual action drug that enhances both
NE and 5HT and does so by blocking
alpha 2 receptors rather than by
blockade of NE reuptake pump
Takes advantage of unique interactions
between NE and 5HT
Promotes sleep pattern that is most like
physiologically normal sleep
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Antidepressant
Management
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Minimal trial 6-8 weeks
Goal = remission
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Response = 50% improvement
Remission = no symptoms
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Less risk relapse w/ remission
Move toward combination drugs to
achieve remission
Continue for 16-20 wks after remission
(preferably longer, i.e. 6-12 mos)
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How Long to Treat?
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Single episode
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Recurrent episode or chronic
depression
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4/13/2015
Treat 6-12 months, best chance
sustained remission if Tx 1 yr
Treatment is usually for years
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Maintenance Treatment
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Importance of maintenance tx:
> 50% will have at least one
lifetime recurrence
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Usually within 2-3 years
If > 2 episodes, risk for another
approaches 90%
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Lack of Response
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Correct diagnosis?
Comorbid conditions?
Optimize dosage
30-40% fail to achieve adequate
response
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Strategies for Failure to
Respond Initial Tx
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Augmentation
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Lithium, Wellbutrin, thyroid,
stimulant, other antidepressant in
combination, Pindolol (questionable
efficacy)
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Switch Medication
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Different class
 30-50%
may respond to alternative
SSRI
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Key Points
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1st Line Tx  SSRI
F/U 4 weeks
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No/Minimal response, mild SEs  Increase
dose
Mod improvement  cont same dose
No/Mild improvement, significant SEs 
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Alternative SSRI
Change class – e.g. Wellbutrin, Effexor,
Atypical (Serzone, Mirtazipine), TCA (if not
contraindicated)
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Discontinuing
Medication
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Taper over several weeks
enables detection of reemergence
of symptoms
 avoids discontinuation syndromes
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Educate about risks and symptoms
of relapse
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SSRI Withdrawal
Syndrome
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More common SSRIs w/shorter t ½
life
Symptoms
Flu-like symptoms
 Peak day 5, can last up 3 weeks
 Can mimic anxiety/depression
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Resolves within 24 hrs restarting
SSRI
Avoid with slow taper of drug
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Common
Misconceptions
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“Antidepressants are addictive”
“Antidepressants are mind-altering
drugs”
“Antidepressants are uppers”
“Once I’m better, I don’t need
medication anymore”
Reference for patients 
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4/13/2015
Prozac and the New Antidepressants, revised ed:
What you need to know about Prozac, Zoloft,
Paxil, etc
 By William Appelton, MD
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Improving Compliance
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Educate when and how to take meds
Delay in response – 2-4 wks
Continue meds even if better
Consult w/ Dr before discontinuing
Educate family
Simplify regimen
Effective communication (Listen!)
Medication assistance if $$ issue
Side effects and complicated dosing
regimen can lead to noncompliance
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Strategies to Manage
S/E’s
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Watch and wait (if no immediate
medical risk)
Alter dosage, frequency, timing of
administration – (SSRI sedation  change
hs dosing)
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Provide specific treatment for SEs
Consider switching medication
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MDD with Psychotic
Features
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Greater risk for suicide (consider
hospitalization)
Treat with both antidepressant and
antipsychotic
ECT can be used as first line
treatment
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MDD with Catatonic
Features
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Clinical features (any of following)
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Motoric immobility (I.e. catalepsy or
stupor)
Extreme agitation
Extreme negativism
Peculiarities of voluntary movement
Echolalia or echopraxia
Benzodiazepines can show immediate
relief
ECT can be used as first-line
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MDD with Atypical
Features
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Clinical features (any of following)
Increased sleep
 Increased appetite and/or wt gain
 Marked mood reactivity
 Sensitivity to emotional rejection
 Severe fatigue (leaden paralysis)
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SSRIs, MAOIs, (possibly bupropion)
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Antidepressants and
Pregnancy
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Carefully consider risk vs benefit
Untreated depression can affect prenatal
care
No known birth defects, but still caution
SSRIs are current drugs of choice
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4/13/2015
most info on Prozac – slight increased
risk minor anomalies; no > risk major
malformations
ECT effective and safe alternative
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Electroconvulsive
Therapy (ECT)
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Most effective and rapid treatment
for depression (70-80% response
rate)
Introduced in Italy in 1938, one of
the oldest medical treatments in
regular use today
Exact mechanism of action
remains unclear
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ECT, cont’d
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Surgical procedure
Electrical stimulus applied to
temporal region (unilateral
associated with less cognitive
impairment) to induce seizure
Brief pulsating current, comparable
to a 20-watt light bulb (pulsation
also decreases cognitive
impairment)
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ECT, cont’d
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Pts usually receive treatments
3/wk
Series usually 6-12 treatments,
mean 9
S/E’s: brief alteration in blood
pressure, pulse, cardiac rhythm;
fx’s in past (now use
succinylcholine); post-ictal
confusion; anterograde amnesia
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Indications for ECT
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Medication refractory depression
Suicidal depression
Depression accompanied by refusal to
eat/take fluids
Depression during pregnancy
H/o positive response to ECT
Catatonic syndromes
Acute forms of schizophrenia
Mania unresponsive to medication
Psychotic or melancholic depression
unresponsive to medication
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Additional Important
Therapies, FYI
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Psychotherapy
Seasonal Affective Disorder
Alternative Therapies
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Medications vs
Psychotherapy
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No illness occurs in a vacuum
Mild-Moderate MDD – one or both
appropriate
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much influenced by pt preference,
Hx, and prior response
Moderate-Severe MDD
Medication indicated
 Psychotherapy adjunct
 Consider ECT
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Features Favoring
Psychotherapy
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Significant psychosocial stressors
Interpersonal difficulties
Comorbid Axis II Disorders
Poor medication compliance
Patient preference
Competent providers
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4/13/2015
Data support efficacy of two types
therapy – cognitive and
interpersonal
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Types of Psychotherapy
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Cognitive-Behavioral
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Interpersonal Therapy
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Focus on interpersonal relationships,
interaction style, social skills, losses, role
transitions
Psychodynamic Psychotherapy
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Challenges irrational beliefs/ behaviors
and distorted thinking that contribute to
depressed mood
Intrapsychic conflict, defense
mechanisms, repression
Less data, usually longer term
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Seasonal Affective
Disorder
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Assess for seasonal component
Symptoms arrive winter, vanish in spring
More common women – 4:1
More common northern climates
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4/13/2015
Sarasota, FL – 8.9%; Nashua, NH – 30%
Decreased daylength  increase in
melatonin  ? Decrease serotonin
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Seasonal Affective
Disorder
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Full spectrum lighting
Intensity is important
 10,000 Lux – 30min – 2 hr in am
 80% improve
 Timing of Tx can phase advance or
delay body’s biological clock
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 affects
sleep patterns, body
temperature, hormone secretion
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4/13/2015
Changes in physiological functions
may be basis of therapeutic effect
81
Herbal Therapies







4/13/2015
Melatonin for sleep disorders
St. John’s Wort for depression
Ginko bilboa for dementia
Omega-3 Fatty Acids for mood disorders
S- adenylmethionine (SAMe) for
depression
Feverfew for migraine prophylaxis
Garlic for cholesterol lowering effects
82
Herbal Therapies

Not FDA regulated




St. John’s Wort most studied



4/13/2015
No guarantee purity or standardization
www.ConsumerLab.com - reputable
testing of products
www.NaturalDatabase.com - great
resource on natural medicines
Beneficial mild-moderate depression
when compared placebo or TCAs
Doses up to 900mg/day x 6 wks rcmd
GI s/e’s, sedation
83
Omega-3 Fatty Acids


Higher blood levels correlate with
significantly lower incidence of
depression in general population and
postpartum depression
Potential mood stabilization properties –
BPAD studies


Studies in Schizophrenic and ADHD
populations
The Omega Connection

4/13/2015
Dr. Andrew Stoll
84
When to Refer to
Psychiatry





4/13/2015
Failure to respond to 1 or more
trials of SSRI
Concerned about safety – suicidal
or homicidal ideation
Psychotic symptoms/ loss of reality
Inability to perform ADLs
Gut instinct – something not right
85
Summary




Depression is highly prevalent,
underdiagnosed and under-treated
Highly treatable
You will prescribe antidepressants
frequently
Keys to Treatment




4/13/2015
Detection
Adequate treatment – minimum 6-12
months
Therapy if indicated
Patient and Family education
86
References

Psychopharmacology of
Antidepressants


Introductory Textbook of
Psychiatry

4/13/2015
Dr. Stephen M. Stahl, MD, PhD
Nancy C. Andreasen, MD, PhD and
Donald W. Black, MD
87