04/19/23 1

Antidepresivi

04/19/23 2

Antidepresivi /upotreba

depresija anksioznost Premenstrualni sindrom Bolni sindromi Poremećaj sna Poremećaj ishrane Odvikavanje od pušenja autizam

04/19/23 3

Diferencijalna dijagnoza depresije Bolesti tiroideje i paratiroideje anemija hipoksija maligniteti lijekovi demencija Parkinsonova bolest Obolenja jetre Cushing’s sindrom/ tretman steroidima

04/19/23 4

Lijekovi koji mogu uzrokovati simptomedepresije Antihipertenzivi

Propanolol, Methyldopa, Reserpine, Clonidine, Hydralazine, Guanithidine

Kardiovaskularni lijekovi Digitalis, Diuretics, Lidocaine, Procaine

Steroidi Corticosteroids, Progestins, (Estrogen)

Analgetici Narcotics, Indomethacin

Benzodiazepini antimicrobici, antipsihotici,

hemoterapeutici, alkohol, etc

04/19/23 5

Lijekovi za depresiju

Generalno, imaju podjednako djelovanje

Odgovor kod 50 –80% pacijenata Velike individualne varijacije Placebo efekt 25-40%

04/19/23 6

Monoaminska hipotheza depresije Deficit jednog ili više biogenih amina

Serotonin (5-HT) Norepinefrin (NE) Dopamine (DA)

Antidepresivi dovode do povećanja neurotransmitera u sinaptičkoj pukotini Aktivacijom hemijskih glasnika (2nd

messenger, interleukina, TNF)

7

04/19/23 8

04/19/23 9

04/19/23 10

04/19/23 11

04/19/23 12

04/19/23 13

04/19/23 14

04/19/23 15

04/19/23 16

Kratka istorija

kasne 1950-te – MAOI i TCA efikasni “prljavi lijekovi” – mnogo NRL

kasne 1980-te - SSRI kasne 1990-te

atipični antidepresivi

04/19/23 17

Podijela antidepresiva

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)

04/19/23 18

Triciklični antidepresivi klomipramine (Anafranil) – sličan SSRI’s nortriptilin (Pamelor) – primarno

adrenergički, najmanje ortost.hipotenz. imipramin (Tofranil) amitriptilin (Elavil) desipramin (Norpramin) – primarno

adrenergički doksepin (Sinequan) protriptilin (Vivactil) maprotilin (Ludiomil)/heteroc. amoksapin (Ascendin) -- blago antipsihotičko

djelovanje, rizik od TD, trimipramine (Surmontil)

04/19/23 19

TCA 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: Hronična bol, nesanica, profilaksa

migrene, hronični umor

04/19/23 20

Triciklici – 5 lijekova u jednom 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

04/19/23 21

MAO inhibitori

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)

04/19/23 22

MAOI – mjere opreza 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

04/19/23 23

Selektivni inhibitori preuzimanja serotonina (SSRI)

U svijetu, široko propisivani Lijekovi prvog izbora Relativno sigurni i kod predoziranja Niska incidenca NRL Skupi

04/19/23 24

SSRI

sertralin (Zoloft) fluoksetin (Prozac) citalopram (Celexa) paroksetin (Paxil) fluvoksamin (Luvox)

Inhibišu CYP4501A2 – povećavaju konc. teofilina, olanzapina,kofeina

Doziranje 2x dnevno

04/19/23 25

SSRI

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 conditions

04/19/23 26

SSRI – najčešće NR

Seksualna disfunkcija (5HT2) Veoma često(30-50%+)

Insomnija (5HT2) nemir/anksioznost (5HT2) glavobolje GI neželjeni efekti (5HT3)

Smanjenje apetita, mučnina, dijareja, suha usta

04/19/23 27

Serotoninski sindrom

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 ?

04/19/23 30

Serotoninski sindrom

Serotoninski sindrom se javlja ako se SSRI kombinuju sa MAO inhibitorima

fenelzin, tranilcipromin MAOI (selektivni)

Selegilin (MAO-B), moklobemid (reverzibilni)

Triptofan (serotonin prekursor)

Serotonergički lijekovi

prekursori serotonina S–adenyl–L–methionine L–tryptophan 5–hydroxytryptophan dopamine

Serotonergički lijekovi

Inhibitori preuzimanja serotonina citalopram, fluoxetine,

fluvoxamine, paroxetine, sertraline, venlafaxine

clomipramine, imipramine nefazodone, trazodone chlorpheniramine cocaine, dextromethorphan,

pentazocine, pethidine, tramadol

Serotonergički lijekovi

Agonisti serotonina fenfluramine, p–chloramphetamine bromocriptine, dihydroergotamine,

gepirone sumatriptan buspirone, ipsapirone eltoprazin, quipazine

Serotonergički lijekovi Inhibitori monoamino oksidaze (MAOIs)

clorgyline, isocarboxazid, nialamide, pargyline, phenelzine, tranylcypromine

selegiline furazolidone procarbazine

Serotonergički lijekovi Reverzibilni inhibitori MAO

brofaramine befloxatone, toloxatone moclobemide

Tretman

Suportivne mjere Kontrola simptoma kontrola temperature Adekvatna ventilacija

5–HT2A antagonisti idealni

sigurni efikasni dostupni

Kapur, S et al. (1997). Cyproheptadine: a potent in vivo serotonin antagonist. American Journal of Psychiatry, 154, 884

5–HT2A antagonistiCyproheptadine 100Chlorpromazine 71Chlorprothixene 233Haloperidol 2.8Clozapine 62Risperidone 170Olanzapine 25Sertindole 260Methysergide 14Ketanserin 178

Affinity at 5-HT2 = 10-7 x 1/Kd

04/19/23 38

04/19/23 39

04/19/23 40

04/19/23 41

04/19/23 42

04/19/23 43

04/19/23 44

Additional Antidepressants SSRIs, TCAs, and MAOIs easily

classified Remainder less easily classified

“atypical antidepressants” Mechanisms listed for your

understanding Clinical points more important than

mechanisms

04/19/23 45

Venlafaxine (Effexor)

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

04/19/23 46

Venlafaxine, cont’d

Dose range 18.75-375mg/day May work faster than others SEs like SSRIs Wierd withdrawal symptoms – reg

release has very short t ½ Sustained release available – QD

dosing

04/19/23 47

Nefazodone (Serzone)

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)

04/19/23 48

Nefazodone, cont’d 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

Rare cases of hepatic failure have occurred—check baseline lft’s

04/19/23 49

Nefazodone, cont’d

Usual dose 300-600mg/day Side effects

Somnolence (5HT2 blockade) dry mouth (NE effect) Nausea (serotonergic effect) Constipation (NE effect)

visual phenomena

04/19/23 50

Trazodone

5HT2 blockade sedation Little SSRI action Very sedating – often used for insomnia

(potent 5HT2 blocker) 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)

04/19/23 51

Blocking 5HT2 Receptors Sedation Enhance slow wave sleep Decrease anxiety No sexual dysfunction

04/19/23 52

Bupropion (Wellbutrin)

Increases NE & DA via NE and DA reuptake inhibition Can lower seizure threshold –

contraindicated in pts w sz d/o, edo Less sexual dysfunction (NE effect)

Dose range 150-300mg/day (max 450) Split doses bid – at least 8 hrs apart Max 150mg RR/ 200mg SR per dose

04/19/23 53

Bupropion (Wellbutrin)

Exact mechanism unclear Response may be more r/t

metabolite than parent drug Possible higher bld levels if used

w/SSRI w/P450 enzyme inhibition

04/19/23 54

Mirtazapine (Remeron)

Increases NE & 5HT Blocks some 5HT receptors

thus called a NE and specific 5HT antidepressant (NaSSA)

Four principal actions Alpha 2 blockade increases NE

leads to subsequent increase 5HT 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

04/19/23 55

Mirtazapine (Remeron)

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

04/19/23 56

Antidepressant Management Minimal trial 6-8 weeks Goal = remission

Response = 50% improvement Remission = no symptoms

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)

04/19/23 57

How Long to Treat?

Single episode Treat 6-12 months, best chance

sustained remission if Tx 1 yr Recurrent episode or chronic

depression Treatment is usually for years

04/19/23 58

Maintenance Treatment

Importance of maintenance tx: > 50% will have at least one

lifetime recurrence Usually within 2-3 years

If > 2 episodes, risk for another approaches 90%

04/19/23 59

Lack of Response

Correct diagnosis? Comorbid conditions? Optimize dosage 30-40% fail to achieve adequate

response

04/19/23 60

Strategies for Failure to Respond Initial Tx Augmentation

Lithium, Wellbutrin, thyroid, stimulant, other antidepressant in combination, Pindolol (questionable efficacy)

Switch Medication Different class

30-50% may respond to alternative SSRI

04/19/23 61

Key Points

1st Line Tx SSRI F/U 4 weeks

No/Minimal response, mild SEs Increase dose

Mod improvement cont same dose No/Mild improvement, significant SEs

Alternative SSRI Change class – e.g. Wellbutrin, Effexor,

Atypical (Serzone, Mirtazipine), TCA (if not contraindicated)

04/19/23 62

Discontinuing Medication Taper over several weeks

enables detection of reemergence of symptoms

avoids discontinuation syndromes Educate about risks and symptoms

of relapse

04/19/23 63

SSRI Withdrawal Syndrome More common SSRIs w/shorter t ½

life Symptoms

Flu-like symptoms Peak day 5, can last up 3 weeks Can mimic anxiety/depression

Resolves within 24 hrs restarting SSRI

Avoid with slow taper of drug

04/19/23 65

Common Misconceptions “Antidepressants are addictive” “Antidepressants are mind-altering

drugs” “Antidepressants are uppers” “Once I’m better, I don’t need

medication anymore” Reference for patients

Prozac and the New Antidepressants, revised ed: What you need to know about Prozac, Zoloft, Paxil, etc

By William Appelton, MD

04/19/23 66

Improving Compliance

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

04/19/23 67

Strategies to Manage S/E’s Watch and wait (if no immediate

medical risk) Alter dosage, frequency, timing of

administration – (SSRI sedation change hs dosing)

Provide specific treatment for SEs Consider switching medication

04/19/23 68

MDD with Psychotic Features Greater risk for suicide (consider

hospitalization) Treat with both antidepressant and

antipsychotic ECT can be used as first line

treatment

04/19/23 69

MDD with Catatonic Features Clinical features (any of following)

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

04/19/23 70

MDD with Atypical Features Clinical features (any of following)

Increased sleep Increased appetite and/or wt gain Marked mood reactivity Sensitivity to emotional rejection Severe fatigue (leaden paralysis)

SSRIs, MAOIs, (possibly bupropion)

04/19/23 71

Antidepressants and Pregnancy Carefully consider risk vs benefit Untreated depression can affect prenatal

care No known birth defects, but still caution SSRIs are current drugs of choice

most info on Prozac – slight increased risk minor anomalies; no > risk major malformations

ECT effective and safe alternative

04/19/23 72

Electroconvulsive Therapy (ECT) 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

04/19/23 73

ECT, cont’d

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)

04/19/23 74

ECT, cont’d

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

04/19/23 75

Indications for ECT

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

04/19/23 76

Additional Important Therapies, FYI Psychotherapy Seasonal Affective Disorder Alternative Therapies

04/19/23 77

Medications vs Psychotherapy No illness occurs in a vacuum Mild-Moderate MDD – one or both

appropriate much influenced by pt preference,

Hx, and prior response Moderate-Severe MDD

Medication indicated Psychotherapy adjunct Consider ECT

04/19/23 78

Features Favoring Psychotherapy Significant psychosocial stressors Interpersonal difficulties Comorbid Axis II Disorders Poor medication compliance Patient preference Competent providers

Data support efficacy of two types therapy – cognitive and interpersonal

04/19/23 79

Types of Psychotherapy

Cognitive-Behavioral Challenges irrational beliefs/ behaviors

and distorted thinking that contribute to depressed mood

Interpersonal Therapy Focus on interpersonal relationships,

interaction style, social skills, losses, role transitions

Psychodynamic Psychotherapy Intrapsychic conflict, defense

mechanisms, repression Less data, usually longer term

04/19/23 80

Seasonal Affective Disorder Assess for seasonal component Symptoms arrive winter, vanish in spring More common women – 4:1 More common northern climates

Sarasota, FL – 8.9%; Nashua, NH – 30% Decreased daylength increase in

melatonin ? Decrease serotonin

04/19/23 81

Seasonal Affective Disorder 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 affects sleep patterns, body

temperature, hormone secretion Changes in physiological functions

may be basis of therapeutic effect

04/19/23 82

Herbal Therapies

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

04/19/23 83

Herbal Therapies

Not FDA regulated No guarantee purity or standardization www.ConsumerLab.com - reputable

testing of products www.NaturalDatabase.com - great

resource on natural medicines St. John’s Wort most studied

Beneficial mild-moderate depression when compared placebo or TCAs

Doses up to 900mg/day x 6 wks rcmd GI s/e’s, sedation

04/19/23 84

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 Dr. Andrew Stoll

04/19/23 85

When to Refer to Psychiatry 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

04/19/23 86

Summary

Depression is highly prevalent, underdiagnosed and under-treated

Highly treatable You will prescribe antidepressants

frequently Keys to Treatment

Detection Adequate treatment – minimum 6-12

months Therapy if indicated Patient and Family education

04/19/23 87

References

Psychopharmacology of Antidepressants Dr. Stephen M. Stahl, MD, PhD

Introductory Textbook of Psychiatry Nancy C. Andreasen, MD, PhD and

Donald W. Black, MD